User login
Early psychosis: No need for antipsychotics to recover?
Two new studies highlight the importance of early intervention in first-episode psychosis (FEP).
In the first study, Australian investigators conclude that, for some FEP patients, early psychosocial interventions may fend off the need for immediate treatment with antipsychotic medications.
In the second study, UK researchers show that long duration of untreated psychosis (DUP) is linked to a significantly reduced treatment response.
For both studies, the findings highlight the importance of rapid access to a comprehensive range of treatments in the first weeks after FEP onset.
“In a select group of people with first-episode psychosis, we found there was no difference in symptoms and functioning between those who had antipsychotic medication and those who didn’t,” lead author Shona M. Francey, PhD, clinical psychologist at Orygen, the National Center of Excellence in Youth Mental Health, Parkville, Australia, told Medscape Medical News.
“These findings supported our idea that, in the early phases of psychosis, with close monitoring and good psychosocial intervention, antipsychotic medication can be delayed,” Francey said.
The Australian study was published in Schizophrenia Bulletin Open. The British study was published in Lancet Psychiatry.
Adverse effects
Francey and colleagues note that, in comparison with standard treatment, early interventions produce superior outcomes for patients with psychosis. Although there are a variety of treatment options, low-dose second-generation antipsychotics typically play a central role.
However, atypical antipsychotics have rapid metabolic side effects, including weight gain and altered glucose metabolism, that increase the risk for cardiovascular disease and premature mortality. Importantly, such adverse effects are amplified among patients with FEP, who tend to be younger and treatment naive.
On the other hand, a growing body of evidence shows the benefit of nonpharmacologic interventions for patients with FEP, the investigators note. In addition, clinical staging models appear to support the use of less aggressive treatment early in the disease course.
“We have been working in early intervention for psychosis for a number of years and have found it’s possible to intervene early with young people and either prevent the onset of psychosis or ameliorate its impact,” said Francey.
“Since we can see some improvement in people in the prepsychotic phase, we wanted to know if we can also see some benefit without medication after the onset of what we would call full-threshold psychosis,” she added.
Staged Treatment and Acceptability Guidelines in Early Psychosis (STAGES) was a 6-month, triple-blind, randomized controlled noninferiority study that included 90 participants between the ages of 15 and 25 years who had FEP.
To maximize safety, patients were required to have low levels of suicidality and aggression, a DUP of less than 6 months, and to be living in stable accommodation with social support.
Participants were randomly assigned to two groups – one in which patients underwent intensive psychosocial therapy and received low-dose antipsychotic medication (n = 44), and one in which patients underwent intensive psychosocial therapy and were given placebo (n = 46).
Depending on the timing of study enrollment, those in the medication group received risperidone 1 mg or paliperidone 3 mg.
that is strongly focused on therapeutic engagement.
CBCM delivers formulation-driven cognitive-behavioral therapy and psychoeducation within a therapeutic case management framework, Francey said.
The primary outcome was level of functioning at 6, 12, and 24 months, as measured by the Social and Occupational Functioning Scale (SOFAS). The primary prespecified endpoint was outcome at 6 months. A noninferiority margin of 10.5 on the SOFAS was used as the smallest value representing a clinically important effect.
Other assessment tools included the BPRS-4 to test for positive psychotic symptoms, the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety.
At baseline, the two treatment groups were comparable with respect to all measures of functioning and psychopathology.
The study’s discontinuation rate was high. At 6 months, only 16 patients in the psychosocial group had completed therapy, compared with 11 in the antipsychotic group.
At this point, the two groups were comparable in terms of psychopathology and functioning ratings. Both groups had lower symptoms, higher functioning scores, and higher Quality of Life Scale (QLS) scores than at baseline.
SOFAS scores were not significantly different between the groups at this time point. The mean score was 61.7 ± 16.8 in the psychosocial group and 61.5 ± 13.4 in the medication group.
The researchers note that, because the upper limit of the confidence interval (CI) was less than the study’s a priori inferiority margin of 10.5, psychosocial therapy was not inferior to medication at the 6-month assessment point.
Antipsychotics: Use with caution
Although between-group differences in SOFAS scores were not significant at 12 and 24 months, noninferiority of psychosocial therapy alone could not be confirmed because the CIs included the inferiority margin at each time point.
The two groups were statistically comparable at 6 months with respect to all other measures of psychopathology and the QLS. Similar results were found at 12 and 24 months.
The lone exception was with SANS at 12 months, on which patients in the placebo group had significantly higher negative symptom scores than the patients in the medication group.
There were no significant differences between study groups with respect to the number of adverse events.
Francey noted that the findings are important because they suggest that some young people with early-stage FEP and short DUP may be able to achieve symptom remission and function better without antipsychotic medication, provided they receive psychological interventions and comprehensive case management.
This challenges conventional wisdom that antipsychotic medications should be used for all patients who experience psychosis, she added.
However, managing FEP with psychosocial interventions should only be considered when it is safe to do so, Francey noted. In addition, the benefits of psychosocial interventions in these patients are less clear at 12 and 24 months.
Given these caveats, she noted that antipsychotics still play an important role in the treatment of these patients.
“I think there is definitely a place for medications. But I think they should be used cautiously, and you need a good, strong relationship between your treating team and your [patient] to work out what is needed and when it’s needed,” said Francey.
In addition, “when we do use medications, we should use the smallest possible dose that we can and also incorporate psychological support. I think that’s a really important part of it as well,” she said.
Timing matters
In the Lancet Psychiatry study, the researchers note that prolonged DUP is associated with worse outcomes, including increased symptoms, diminished social functioning, and poorer quality of life. The mechanism by which delayed treatment causes more harm remains unclear.
It is possible that symptoms simply accumulate over time, thereby worsening presentation. Another possibility is that continued psychosis after an initial critical period may cause long-term harm, they write.
They hypothesize that untreated psychosis can cause general treatment resistance by exacerbating underlying disease processes and that such damage progresses faster in the early stages of illness and then slows over time.
In addition, socially disruptive symptoms that are evident prior to FEP presentation may have a confounding effect, thereby leading to earlier presentation.
The investigators used data from two longitudinal cohort studies – the National Evaluation of Development of Early Intervention Network (NEDEN) study and the Outlook study.
In the NEDEN trial, 290 of 901 FEP patients (32%) were assessed within 3 weeks of presentation. In Outlook, 69 of 332 patients (21%) were assessed within 3 weeks of presentation.
In both studies, patients were examined at baseline, 6 months, and 12 months using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, the Mania Rating Scale, the Insight Scale, and SOFAS. The latter two measures were used only at baseline and 12-month follow-up. Logistic regression analyses were used to determine the association between DUP and outcomes.
In the NEDEN study, 751 patients were assessed at 6 months, and 719 were assessed at 12 months. In the Outlook study, 238 and 220 were assessed at the same two time points, respectively.
Results showed a curvilinear relationship between DUP and symptom severity. Longer DUP was predictive of reduced treatment response. However, patient response worsened more slowly as DUP lengthened.
For example, increasing DUP by ten times was predictive of less improvement in PANSS total score by 7.34 (95% CI, 5.76 – 8.92; P < .0001) in NEDEN and by 3.85 (95% CI, 1.69 – 600; P =. 0005) in Outlook. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN.
The findings seem to support that the potential harm incurred by delaying treatment among patients with FEP is greatest in the early weeks of psychosis and then levels off, the investigators note.
Given these insights, mental health professionals might consider focusing their efforts on the early detection and treatment of patients for whom DUP is short.
Similarly, because DUP was directly associated with all symptoms, early access to comprehensive treatment “might be preferable to early delivery of particular treatments with particular effects (eg, dopamine antagonists),” they write.
“A pragmatic call”
Commenting on the British study in an accompanying editorial, Lena K. Palaniyappan, MD, University of Western Ontario, London, Canada, and Rajeev Krishnadas, MD, University of Glasgow, Scotland, write that any illness left untreated can become more challenging to treat, including psychosis.
“This should make early intervention in psychosis a pragmatic call with no prima facie argument against it,” they write. A reduction in DUP “underpins the rationale behind early detection and intervention in psychosis.”
The editorialists note that the relationship between DUP and successful treatment in early psychosis “strengthens the argument for more proactive early assessment and intervention to shorten treatment delay.
“As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis,” they write.
Francey also recognizes the value of early intervention in FEP. However, she noted that comprehensive psychosocial therapy might well prove effective enough to stave off antipsychotic therapy in a certain subset of patients.
“For some people, antipsychotics may never need to be introduced,” she said. “Some people recover from their first episode of psychosis and don’t go on to have any more, while others have an episodic illness,” she said.
If another episode develops and the symptoms come back, further psychosocial interventions could then be tried “or you might want to move on” to psychotic medication “because trying to get people better and functioning as well as they can is our primary aim,” Francey said.
The STAGES study was supported by the Australian National Health and Medical Research Council. The British study was funded by the UK Department of Health, the National Institute of Health Research, and the Medical Research Council. Francey and Krishnadas have reported no relevant financial relationships. Palaniyappan has received grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and the Canadian Psychiatric Association.
This article first appeared on Medscape.com.
Two new studies highlight the importance of early intervention in first-episode psychosis (FEP).
In the first study, Australian investigators conclude that, for some FEP patients, early psychosocial interventions may fend off the need for immediate treatment with antipsychotic medications.
In the second study, UK researchers show that long duration of untreated psychosis (DUP) is linked to a significantly reduced treatment response.
For both studies, the findings highlight the importance of rapid access to a comprehensive range of treatments in the first weeks after FEP onset.
“In a select group of people with first-episode psychosis, we found there was no difference in symptoms and functioning between those who had antipsychotic medication and those who didn’t,” lead author Shona M. Francey, PhD, clinical psychologist at Orygen, the National Center of Excellence in Youth Mental Health, Parkville, Australia, told Medscape Medical News.
“These findings supported our idea that, in the early phases of psychosis, with close monitoring and good psychosocial intervention, antipsychotic medication can be delayed,” Francey said.
The Australian study was published in Schizophrenia Bulletin Open. The British study was published in Lancet Psychiatry.
Adverse effects
Francey and colleagues note that, in comparison with standard treatment, early interventions produce superior outcomes for patients with psychosis. Although there are a variety of treatment options, low-dose second-generation antipsychotics typically play a central role.
However, atypical antipsychotics have rapid metabolic side effects, including weight gain and altered glucose metabolism, that increase the risk for cardiovascular disease and premature mortality. Importantly, such adverse effects are amplified among patients with FEP, who tend to be younger and treatment naive.
On the other hand, a growing body of evidence shows the benefit of nonpharmacologic interventions for patients with FEP, the investigators note. In addition, clinical staging models appear to support the use of less aggressive treatment early in the disease course.
“We have been working in early intervention for psychosis for a number of years and have found it’s possible to intervene early with young people and either prevent the onset of psychosis or ameliorate its impact,” said Francey.
“Since we can see some improvement in people in the prepsychotic phase, we wanted to know if we can also see some benefit without medication after the onset of what we would call full-threshold psychosis,” she added.
Staged Treatment and Acceptability Guidelines in Early Psychosis (STAGES) was a 6-month, triple-blind, randomized controlled noninferiority study that included 90 participants between the ages of 15 and 25 years who had FEP.
To maximize safety, patients were required to have low levels of suicidality and aggression, a DUP of less than 6 months, and to be living in stable accommodation with social support.
Participants were randomly assigned to two groups – one in which patients underwent intensive psychosocial therapy and received low-dose antipsychotic medication (n = 44), and one in which patients underwent intensive psychosocial therapy and were given placebo (n = 46).
Depending on the timing of study enrollment, those in the medication group received risperidone 1 mg or paliperidone 3 mg.
that is strongly focused on therapeutic engagement.
CBCM delivers formulation-driven cognitive-behavioral therapy and psychoeducation within a therapeutic case management framework, Francey said.
The primary outcome was level of functioning at 6, 12, and 24 months, as measured by the Social and Occupational Functioning Scale (SOFAS). The primary prespecified endpoint was outcome at 6 months. A noninferiority margin of 10.5 on the SOFAS was used as the smallest value representing a clinically important effect.
Other assessment tools included the BPRS-4 to test for positive psychotic symptoms, the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety.
At baseline, the two treatment groups were comparable with respect to all measures of functioning and psychopathology.
The study’s discontinuation rate was high. At 6 months, only 16 patients in the psychosocial group had completed therapy, compared with 11 in the antipsychotic group.
At this point, the two groups were comparable in terms of psychopathology and functioning ratings. Both groups had lower symptoms, higher functioning scores, and higher Quality of Life Scale (QLS) scores than at baseline.
SOFAS scores were not significantly different between the groups at this time point. The mean score was 61.7 ± 16.8 in the psychosocial group and 61.5 ± 13.4 in the medication group.
The researchers note that, because the upper limit of the confidence interval (CI) was less than the study’s a priori inferiority margin of 10.5, psychosocial therapy was not inferior to medication at the 6-month assessment point.
Antipsychotics: Use with caution
Although between-group differences in SOFAS scores were not significant at 12 and 24 months, noninferiority of psychosocial therapy alone could not be confirmed because the CIs included the inferiority margin at each time point.
The two groups were statistically comparable at 6 months with respect to all other measures of psychopathology and the QLS. Similar results were found at 12 and 24 months.
The lone exception was with SANS at 12 months, on which patients in the placebo group had significantly higher negative symptom scores than the patients in the medication group.
There were no significant differences between study groups with respect to the number of adverse events.
Francey noted that the findings are important because they suggest that some young people with early-stage FEP and short DUP may be able to achieve symptom remission and function better without antipsychotic medication, provided they receive psychological interventions and comprehensive case management.
This challenges conventional wisdom that antipsychotic medications should be used for all patients who experience psychosis, she added.
However, managing FEP with psychosocial interventions should only be considered when it is safe to do so, Francey noted. In addition, the benefits of psychosocial interventions in these patients are less clear at 12 and 24 months.
Given these caveats, she noted that antipsychotics still play an important role in the treatment of these patients.
“I think there is definitely a place for medications. But I think they should be used cautiously, and you need a good, strong relationship between your treating team and your [patient] to work out what is needed and when it’s needed,” said Francey.
In addition, “when we do use medications, we should use the smallest possible dose that we can and also incorporate psychological support. I think that’s a really important part of it as well,” she said.
Timing matters
In the Lancet Psychiatry study, the researchers note that prolonged DUP is associated with worse outcomes, including increased symptoms, diminished social functioning, and poorer quality of life. The mechanism by which delayed treatment causes more harm remains unclear.
It is possible that symptoms simply accumulate over time, thereby worsening presentation. Another possibility is that continued psychosis after an initial critical period may cause long-term harm, they write.
They hypothesize that untreated psychosis can cause general treatment resistance by exacerbating underlying disease processes and that such damage progresses faster in the early stages of illness and then slows over time.
In addition, socially disruptive symptoms that are evident prior to FEP presentation may have a confounding effect, thereby leading to earlier presentation.
The investigators used data from two longitudinal cohort studies – the National Evaluation of Development of Early Intervention Network (NEDEN) study and the Outlook study.
In the NEDEN trial, 290 of 901 FEP patients (32%) were assessed within 3 weeks of presentation. In Outlook, 69 of 332 patients (21%) were assessed within 3 weeks of presentation.
In both studies, patients were examined at baseline, 6 months, and 12 months using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, the Mania Rating Scale, the Insight Scale, and SOFAS. The latter two measures were used only at baseline and 12-month follow-up. Logistic regression analyses were used to determine the association between DUP and outcomes.
In the NEDEN study, 751 patients were assessed at 6 months, and 719 were assessed at 12 months. In the Outlook study, 238 and 220 were assessed at the same two time points, respectively.
Results showed a curvilinear relationship between DUP and symptom severity. Longer DUP was predictive of reduced treatment response. However, patient response worsened more slowly as DUP lengthened.
For example, increasing DUP by ten times was predictive of less improvement in PANSS total score by 7.34 (95% CI, 5.76 – 8.92; P < .0001) in NEDEN and by 3.85 (95% CI, 1.69 – 600; P =. 0005) in Outlook. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN.
The findings seem to support that the potential harm incurred by delaying treatment among patients with FEP is greatest in the early weeks of psychosis and then levels off, the investigators note.
Given these insights, mental health professionals might consider focusing their efforts on the early detection and treatment of patients for whom DUP is short.
Similarly, because DUP was directly associated with all symptoms, early access to comprehensive treatment “might be preferable to early delivery of particular treatments with particular effects (eg, dopamine antagonists),” they write.
“A pragmatic call”
Commenting on the British study in an accompanying editorial, Lena K. Palaniyappan, MD, University of Western Ontario, London, Canada, and Rajeev Krishnadas, MD, University of Glasgow, Scotland, write that any illness left untreated can become more challenging to treat, including psychosis.
“This should make early intervention in psychosis a pragmatic call with no prima facie argument against it,” they write. A reduction in DUP “underpins the rationale behind early detection and intervention in psychosis.”
The editorialists note that the relationship between DUP and successful treatment in early psychosis “strengthens the argument for more proactive early assessment and intervention to shorten treatment delay.
“As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis,” they write.
Francey also recognizes the value of early intervention in FEP. However, she noted that comprehensive psychosocial therapy might well prove effective enough to stave off antipsychotic therapy in a certain subset of patients.
“For some people, antipsychotics may never need to be introduced,” she said. “Some people recover from their first episode of psychosis and don’t go on to have any more, while others have an episodic illness,” she said.
If another episode develops and the symptoms come back, further psychosocial interventions could then be tried “or you might want to move on” to psychotic medication “because trying to get people better and functioning as well as they can is our primary aim,” Francey said.
The STAGES study was supported by the Australian National Health and Medical Research Council. The British study was funded by the UK Department of Health, the National Institute of Health Research, and the Medical Research Council. Francey and Krishnadas have reported no relevant financial relationships. Palaniyappan has received grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and the Canadian Psychiatric Association.
This article first appeared on Medscape.com.
Two new studies highlight the importance of early intervention in first-episode psychosis (FEP).
In the first study, Australian investigators conclude that, for some FEP patients, early psychosocial interventions may fend off the need for immediate treatment with antipsychotic medications.
In the second study, UK researchers show that long duration of untreated psychosis (DUP) is linked to a significantly reduced treatment response.
For both studies, the findings highlight the importance of rapid access to a comprehensive range of treatments in the first weeks after FEP onset.
“In a select group of people with first-episode psychosis, we found there was no difference in symptoms and functioning between those who had antipsychotic medication and those who didn’t,” lead author Shona M. Francey, PhD, clinical psychologist at Orygen, the National Center of Excellence in Youth Mental Health, Parkville, Australia, told Medscape Medical News.
“These findings supported our idea that, in the early phases of psychosis, with close monitoring and good psychosocial intervention, antipsychotic medication can be delayed,” Francey said.
The Australian study was published in Schizophrenia Bulletin Open. The British study was published in Lancet Psychiatry.
Adverse effects
Francey and colleagues note that, in comparison with standard treatment, early interventions produce superior outcomes for patients with psychosis. Although there are a variety of treatment options, low-dose second-generation antipsychotics typically play a central role.
However, atypical antipsychotics have rapid metabolic side effects, including weight gain and altered glucose metabolism, that increase the risk for cardiovascular disease and premature mortality. Importantly, such adverse effects are amplified among patients with FEP, who tend to be younger and treatment naive.
On the other hand, a growing body of evidence shows the benefit of nonpharmacologic interventions for patients with FEP, the investigators note. In addition, clinical staging models appear to support the use of less aggressive treatment early in the disease course.
“We have been working in early intervention for psychosis for a number of years and have found it’s possible to intervene early with young people and either prevent the onset of psychosis or ameliorate its impact,” said Francey.
“Since we can see some improvement in people in the prepsychotic phase, we wanted to know if we can also see some benefit without medication after the onset of what we would call full-threshold psychosis,” she added.
Staged Treatment and Acceptability Guidelines in Early Psychosis (STAGES) was a 6-month, triple-blind, randomized controlled noninferiority study that included 90 participants between the ages of 15 and 25 years who had FEP.
To maximize safety, patients were required to have low levels of suicidality and aggression, a DUP of less than 6 months, and to be living in stable accommodation with social support.
Participants were randomly assigned to two groups – one in which patients underwent intensive psychosocial therapy and received low-dose antipsychotic medication (n = 44), and one in which patients underwent intensive psychosocial therapy and were given placebo (n = 46).
Depending on the timing of study enrollment, those in the medication group received risperidone 1 mg or paliperidone 3 mg.
that is strongly focused on therapeutic engagement.
CBCM delivers formulation-driven cognitive-behavioral therapy and psychoeducation within a therapeutic case management framework, Francey said.
The primary outcome was level of functioning at 6, 12, and 24 months, as measured by the Social and Occupational Functioning Scale (SOFAS). The primary prespecified endpoint was outcome at 6 months. A noninferiority margin of 10.5 on the SOFAS was used as the smallest value representing a clinically important effect.
Other assessment tools included the BPRS-4 to test for positive psychotic symptoms, the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety.
At baseline, the two treatment groups were comparable with respect to all measures of functioning and psychopathology.
The study’s discontinuation rate was high. At 6 months, only 16 patients in the psychosocial group had completed therapy, compared with 11 in the antipsychotic group.
At this point, the two groups were comparable in terms of psychopathology and functioning ratings. Both groups had lower symptoms, higher functioning scores, and higher Quality of Life Scale (QLS) scores than at baseline.
SOFAS scores were not significantly different between the groups at this time point. The mean score was 61.7 ± 16.8 in the psychosocial group and 61.5 ± 13.4 in the medication group.
The researchers note that, because the upper limit of the confidence interval (CI) was less than the study’s a priori inferiority margin of 10.5, psychosocial therapy was not inferior to medication at the 6-month assessment point.
Antipsychotics: Use with caution
Although between-group differences in SOFAS scores were not significant at 12 and 24 months, noninferiority of psychosocial therapy alone could not be confirmed because the CIs included the inferiority margin at each time point.
The two groups were statistically comparable at 6 months with respect to all other measures of psychopathology and the QLS. Similar results were found at 12 and 24 months.
The lone exception was with SANS at 12 months, on which patients in the placebo group had significantly higher negative symptom scores than the patients in the medication group.
There were no significant differences between study groups with respect to the number of adverse events.
Francey noted that the findings are important because they suggest that some young people with early-stage FEP and short DUP may be able to achieve symptom remission and function better without antipsychotic medication, provided they receive psychological interventions and comprehensive case management.
This challenges conventional wisdom that antipsychotic medications should be used for all patients who experience psychosis, she added.
However, managing FEP with psychosocial interventions should only be considered when it is safe to do so, Francey noted. In addition, the benefits of psychosocial interventions in these patients are less clear at 12 and 24 months.
Given these caveats, she noted that antipsychotics still play an important role in the treatment of these patients.
“I think there is definitely a place for medications. But I think they should be used cautiously, and you need a good, strong relationship between your treating team and your [patient] to work out what is needed and when it’s needed,” said Francey.
In addition, “when we do use medications, we should use the smallest possible dose that we can and also incorporate psychological support. I think that’s a really important part of it as well,” she said.
Timing matters
In the Lancet Psychiatry study, the researchers note that prolonged DUP is associated with worse outcomes, including increased symptoms, diminished social functioning, and poorer quality of life. The mechanism by which delayed treatment causes more harm remains unclear.
It is possible that symptoms simply accumulate over time, thereby worsening presentation. Another possibility is that continued psychosis after an initial critical period may cause long-term harm, they write.
They hypothesize that untreated psychosis can cause general treatment resistance by exacerbating underlying disease processes and that such damage progresses faster in the early stages of illness and then slows over time.
In addition, socially disruptive symptoms that are evident prior to FEP presentation may have a confounding effect, thereby leading to earlier presentation.
The investigators used data from two longitudinal cohort studies – the National Evaluation of Development of Early Intervention Network (NEDEN) study and the Outlook study.
In the NEDEN trial, 290 of 901 FEP patients (32%) were assessed within 3 weeks of presentation. In Outlook, 69 of 332 patients (21%) were assessed within 3 weeks of presentation.
In both studies, patients were examined at baseline, 6 months, and 12 months using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, the Mania Rating Scale, the Insight Scale, and SOFAS. The latter two measures were used only at baseline and 12-month follow-up. Logistic regression analyses were used to determine the association between DUP and outcomes.
In the NEDEN study, 751 patients were assessed at 6 months, and 719 were assessed at 12 months. In the Outlook study, 238 and 220 were assessed at the same two time points, respectively.
Results showed a curvilinear relationship between DUP and symptom severity. Longer DUP was predictive of reduced treatment response. However, patient response worsened more slowly as DUP lengthened.
For example, increasing DUP by ten times was predictive of less improvement in PANSS total score by 7.34 (95% CI, 5.76 – 8.92; P < .0001) in NEDEN and by 3.85 (95% CI, 1.69 – 600; P =. 0005) in Outlook. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN.
The findings seem to support that the potential harm incurred by delaying treatment among patients with FEP is greatest in the early weeks of psychosis and then levels off, the investigators note.
Given these insights, mental health professionals might consider focusing their efforts on the early detection and treatment of patients for whom DUP is short.
Similarly, because DUP was directly associated with all symptoms, early access to comprehensive treatment “might be preferable to early delivery of particular treatments with particular effects (eg, dopamine antagonists),” they write.
“A pragmatic call”
Commenting on the British study in an accompanying editorial, Lena K. Palaniyappan, MD, University of Western Ontario, London, Canada, and Rajeev Krishnadas, MD, University of Glasgow, Scotland, write that any illness left untreated can become more challenging to treat, including psychosis.
“This should make early intervention in psychosis a pragmatic call with no prima facie argument against it,” they write. A reduction in DUP “underpins the rationale behind early detection and intervention in psychosis.”
The editorialists note that the relationship between DUP and successful treatment in early psychosis “strengthens the argument for more proactive early assessment and intervention to shorten treatment delay.
“As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis,” they write.
Francey also recognizes the value of early intervention in FEP. However, she noted that comprehensive psychosocial therapy might well prove effective enough to stave off antipsychotic therapy in a certain subset of patients.
“For some people, antipsychotics may never need to be introduced,” she said. “Some people recover from their first episode of psychosis and don’t go on to have any more, while others have an episodic illness,” she said.
If another episode develops and the symptoms come back, further psychosocial interventions could then be tried “or you might want to move on” to psychotic medication “because trying to get people better and functioning as well as they can is our primary aim,” Francey said.
The STAGES study was supported by the Australian National Health and Medical Research Council. The British study was funded by the UK Department of Health, the National Institute of Health Research, and the Medical Research Council. Francey and Krishnadas have reported no relevant financial relationships. Palaniyappan has received grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and the Canadian Psychiatric Association.
This article first appeared on Medscape.com.
Experts call for immediate suspension of ECT, others push back
Experts are calling for the immediate suspension of electroconvulsive therapy (ECT) for major depression.
A new review by investigators led by John Read, PhD, University of East London, conclude there is no evidence to show that ECT is effective in either its target demographic or its target diagnostic group. They say its use should be suspended until more robust research proves it is safe and effective.
However, the review’s conclusions have been met with passionate opposition from expert psychiatrists who say ECT can be a lifesaving treatment for patients, many of whom have exhausted all other treatment options. Other clinicians maintain that the review itself is fraught with methodologic shortcomings that invalidate its conclusions.
“We’ve concluded there is no adequate research on which to base an answer to the question, ‘Does ECT work?,’ ” Read told Medscape Medical News. “We’re not actually saying ECT doesn’t work. We’re saying there’s no way to know whether it works or not on the basis of the current research, which, after 80 years of the treatment being used, is pretty amazing.”
On the other hand, Read said there is substantial evidence to suggest ECT causes significant adverse events. “Depending who you ask, the psychiatrists or the patients, somewhere between 12% and 55% of patients get permanent or persistent memory loss,” he said.
“So there is a very serious cost to its use, and if there’s a serious cost, you ... have to know that there’s a very strong efficacy benefit, and we just don’t know that. That’s why we’re calling for suspension until there is adequate research,” Read added.
The study was published in a recent issue of Ethical Human Psychology and Psychiatry.
Widespread use
ECT remains a popular treatment modality for resistant depression. Global data show that it is used to treat almost a million patients every year. Although ECT continues to be the subject of comparative research, the investigators say that most of these studies do not adhere to the same standards that govern clinical trials of other psychiatric medications and medical interventions.
The investigators also note that to date, only 11 placebo-controlled studies of the efficacy of ECT have been conducted. They write that the last study to compare ECT with sham or simulated ECT (SECT) – in which a general anesthetic was administered but the electricity was not – was performed in 1985. Nevertheless, this relatively small body of evidence has been the basis of many meta-analyses.
In the current review, the authors evaluated the impartiality and robustness of these previous meta-analyses and the quality of the studies that were included.
“The primary goal is not to assess whether or not ECT is effective,” they write. “The intent, instead, is to determine whether the available evidence is robust enough to answer that question.”
For Read, the decision to analyze the current state of ECT research was both personal and professional.
“As a young nursing attendant in a Bronx hospital, I had the job of sitting with people as they came around from ECT. It was my job to try to explain why they didn’t know who they were, where they were, why their head was throbbing, and why people would do something like that to them,” he said.
“On the research side, this is my sixth review, and in each one we’ve reached the same conclusion,” Read added.
Other research stands in direct opposition to the current review’s findings. Many studies have concluded that ECT is safe and effective for patients with depression.
Ongoing debate
A 2018 registry analysis showed no additional risk for cognitive impairment in patients who underwent ECT up to 40 years after therapy. A 2018 study also showed that ECT was efficacious and cost-effective for patients with treatment-resistant depression.
However, the ECT debate continues. As reported early last year, there seems to be little common ground between clinicians who believe in the utility of ECT for depression and those who vehemently do not.
For the current review, Read and colleagues performed a Medline search for meta-analyses of the efficacy of ECT for depression. Meta-analyses were only included if they comprised placebo-controlled trials that compared ECT with SECT.
Once the meta-analyses were identified, investigators assessed their component studies. This assessment was conducted by two independent reviewers who used a 24-point quality scale developed by the authors. This scale, the authors note, combines the “risk of bias” domains of the Cochrane Handbook Risk of Bias Tool with criteria related to quality of study design and reporting, as well as several criteria specific to ECT research.
The two reviewers were blinded to each other’s ratings. Interrater differences were resolved collectively.
The literature search yielded 83 potential articles; after exclusion criteria were applied, 14 remained. Three of these articles were literature reviews, one discussed different types of statistical analyses used in ECT research, one was a meta-analysis in Hungarian, one was a meta-analysis that compared ECT with SECT in a selected population of elderly people, and three focused on transcranial magnetic stimulation.
This left five meta-analyses for the review. These included from 1 to 7 of the 11 studies in question:
- Janicak et al, 1985
- Kho, van Vreewijk, Simpson, & Zwinderman, 2003
- Mutz et al, 2019
- Pagnin, de Queiroz, Pini, & Cassano, 2004
- UK ECT Review Group, 2003
The review revealed shortcomings with both the meta-analyses and the studies they included. The investigators found that the mean quality scores of the 11 studies (10.27 ± 2.45 and 11.91 ± 2.91) were not statistically different between the two raters (P = .17), whose scores were significantly correlated (P = .001).
Among the 264 total ratings, the investigators found 55 inconsistencies, which were all resolved by discussion. The mean final quality score for the 11 studies included in the review was 12.27 ± 3.20/24; eight scored 13 or less.
The results of these studies do little to support the benefits of ECT relative to SECT, the reviewers note. Indeed, only four concluded that ECT is significantly superior to SECT. Five found no significant difference, and the remaining two had mixed results.
What’s more, only two of what the investigators describe as “higher quality” studies reported follow-up data. Of these, one produced an effect size of 0.065 favoring ECT, the other showed a small benefit in favor of SECT (effect size, 0.299).
The investigators describe the five meta-analyses included in the review as “flawed,” stating that the meta-analyses “pay little or no attention to the multiple limitations of the studies they include.”
These limitations include the number of patients included in the studies (which average 37 patients); lack of a description of randomization and blinding processes; lack of patient ratings; selective reporting of findings; and the absence of assessment of patient quality of life. Furthermore, the authors note that none of the 11 studies “convincingly” demonstrate double-blinding.
Given these shortcomings, the investigators say the meta-analyses of ECT fail to prove the following:
- The short- and long-term efficacy benefits of ECT over SECT;
- Whether ECT is effective among patients who have failed other treatments for depression;
- Whether ECT prevents ;
- Whether ECT improves patients’ quality of life;
- Whether ECT is more effective in women than men;
- Whether ECT is effective in children or adolescents.
“Shoddy” research
The authors conclude that the review’s findings demonstrate the weakness of evidence that currently supports the use of ECT for depression.
“I would never have guessed how shoddy some of this research was,” said review coauthor Irving Kirsch, PhD, a lecturer on medicine at Beth Israel Deaconess Medical Center, Boston. Many of these shortcomings, Kirsch said, involve blinding and placebo effects.
“It’s not clear how you could ever run a truly blinded trial of ECT, given how pronounced the immediate side effects are,” he told Medscape Medical News. “And one of the things that’s underappreciated is the pronounced responses to placebo treatment with depression and severe depression. These can last for a very long time.”
Kirsch noted that more invasive placebo treatments, such as SECT, tend to have more pronounced effects.
“Not all placebos are created equal. We know, for example, that placebo injections are more effective than placebo pills and that placebo surgery can be extremely powerful,” he said.
The authors call for an immediate suspension of ECT until new studies address these research shortcomings.
“The doctors who perform ECT aren’t evil or stupid, they’re just ignorant of the research. What they see is very temporary benefit in some of the patients. The research suggests that about a third – half at most – get a very temporary lift in mood, which seems to be the sort of euphoria you get from mild brain injury,” Read explained.
“I have seen people who haven’t spoken or eaten for several weeks start speaking and eating, but we know that 4 weeks later, they’re going to be just as depressed as they were, or worse. And now they’re going to have brain damage as well,” said Read.
He added that physicians often don’t see long-term patient outcomes, just the immediate effect of ECT.
A “lifesaver”
No recent randomized controlled trials regarding ECT have been conducted because “no IRB [institutional review board] on planet earth will allow such a trial because of the overwhelming evidence of efficacy and the risk of anesthesia with no ECT,” noted Mark S. George, MD, the Layton McCurdy Endowed Chair in Psychiatry at the Medical University of South Carolina, Charleston.
It is a “logical fallacy” to conclude that ECT does not work because the trials were flawed, said George, who was not involved with the current review
“This is not supported by anything they have looked at,” he told Medscape Medical News. “It’s not really a scientific study when you make conclusions that aren’t based on your data, or not what you set out to do. That’s what I find egregious here.”
The way he sees it, the utility of ECT is unquestionable. “It is our most effective acute treatment for depression, and it’s our most effective treatment for suicide,” he said.
“The authors of this review don’t see the patients that I see every day, who are catatonic, who can’t eat, who are suicidal. For those people, ECT is a lifesaver,” George added.
FDA’s position
Sameer Jauhar, MBChB, PhD, a consultant psychiatrist at the South London and Maudsley NHS Foundation Trust, London, was equally unimpressed with the quality of the review.
“I try to approach everything with an open mind,” he said. “But as a doctor, if I’m reading about evidence, I expect a well-conducted meta-analysis and/or very clear systematic review with an adequate level of peer review.”
The current review, said Jauhar, doesn’t meet these criteria. He said the article reads more like a narrative review, one in which the authors dictated their own arbitrary criteria of study quality.
Most important, he said, is the fact that ECT has been the focus of a great deal of research. “The best quality synthesis of the evidence I’ve come across is the UK ECT Review Group’s 2003 meta-analysis, published in The Lancet, which asked this very question. None of the studies has changed since then.”
Jauhar also noted that in 2018, the Food and Drug Administration reclassified ECT from class III (higher risk) to class II (moderate risk). Use of ECT was also limited to treatment of “catatonia or a severe major depressive episode associated with major depressive disorder or bipolar disorder in patients age 13 years and older who are treatment-resistant or who require a rapid response treatment due to the severity of their psychiatric or medical condition.”
The FDA also noted that “[t]he safe use of ECT for treatment of these conditions has been well studied and is better understood than other uses. Therefore, sufficient information exists to establish special controls that mitigate known risks and provide a reasonable assurance of safety and effectiveness for these two uses of ECT devices.”
As part of the FDA’s 2018 reclassification, ECT manufacturers were required to file a premarket approval application for all uses that were not reclassified. The full text of the order is available in the Federal Register.
“So the FDA has been through it, The Lancet has been through it, and the findings were clear,” said Jauhar. “It’s very easy to poke holes in studies that were conducted 30 or more years ago. But the fact is, the field has moved on.”
Jauhar acknowledged there are patients who have had bad experiences with ECT, and he accepts that such events occasionally occur. Nevertheless, he said,
Jauhar also noted that the journal in which the review was published has a 2019 CiteScore of 0.3 and ranks in the 15th percentile of the Scopus Clinical Psychology category. He further noted that Kirsch is a member of the journal’s editorial board.
“I would say that the level of peer review here was negligible at best,” Jauhar said. “In addition, the ‘findings’ are driven more by ideology than evidence.”
Asked to respond to Jauhar’s comments, Kirsch noted that although he is on the journal’s advisory board, he has not been actively involved. Kirsch added that he serves on about a dozen academic advisory boards and serves as a reviewer for many top scientific and medical journals, including The Journal of the American Medical Association and the New England Journal of Medicine.
“Our article was peer reviewed,” Kirsch said, “and we revised it following the first round of reviews.” The review process did not differ from those he has gone through with more than 250 published peer-reviewed articles on which he was an author or coauthor, he noted.
A growing movement
Despite such expert opposition, the movement to suspend ECT continues. Recently, Sarah Price Hancock, MS, CRC, CPMC, who is herself a recipient of more than 100 ECT treatments, authored an international petition to standardize, regulate, and audit the modality. Hancock hopes to present the document, which currently has more than 6600 signatures, to the American Psychiatric Association and similar international societies.
A version of the petition was presented to the UK’s National Health Service on July 2, the 59th anniversary of the death by suicide of Ernest Hemingway, who had received some 20 ECT treatments himself.
“Hopefully by his 60th anniversary, America and the world will be taking his death and the thousands living with adverse reactions more seriously by auditing, regulating, and tracking patients with a history of ECT to provide much needed comprehensive brain injury rehabilitation as necessary,” Hancock told Medscape Medical News.
Among the signatories of the petition is Sue Cunliffe, MbChB, who underwent ECT for depression in 2004, with devastating effects. “I was left really badly brain damaged, and so I’ve never been allowed to work again,” she told Medscape Medical News.
Cunliffe said the immediate effects of the treatment were profound. She said her hands shook, her balance and coordination were impaired, and her memories evaporated. However, she found a neuropsychologist who she says was able to help her recover control of her life. “Now at least I’m able to plan my life so that I can live with the brain damage.”
Kirsch acknowledged that sorting through the ECT literature can be daunting. “If you’re a physician, you try to keep up with the literature, but the problem is, the literature is so old and done in ways which would not pass muster right now. The data are really poor, and I guess it’s just that people aren’t aware of it.”
George agreed that the therapy is not without its shortcomings.
“Does ECT have cognitive side effects? Unfortunately, it does. But so do lots of lifesaving therapies in medicine, like cancer chemotherapy,” he said.
“Nobody really gets well with a single ECT session. It’s usually eight to 12 over 3 or 4 weeks. So it’s not particularly durable. That’s why we often combine ECT with other forms of brain stimulation,” George added.
He noted that the recent advent of alternative forms of ECT – including right unilateral ultrabrief pulse ECT and focal electrically administered seizure therapy – are beginning to address some of these shortcomings.
“The holy grail of brain stimulation is to be able to do things less invasively, and we’re moving slowly in that direction,” he said. “But right now, we don’t have anything that is as acutely as effective as ECT. It is our lifesaver at the moment.”
The review authors as well as George, Jauhar, Cunliffe, and Hancock report no relevant financial relationships.
This article first appeared on Medscape.com.
Experts are calling for the immediate suspension of electroconvulsive therapy (ECT) for major depression.
A new review by investigators led by John Read, PhD, University of East London, conclude there is no evidence to show that ECT is effective in either its target demographic or its target diagnostic group. They say its use should be suspended until more robust research proves it is safe and effective.
However, the review’s conclusions have been met with passionate opposition from expert psychiatrists who say ECT can be a lifesaving treatment for patients, many of whom have exhausted all other treatment options. Other clinicians maintain that the review itself is fraught with methodologic shortcomings that invalidate its conclusions.
“We’ve concluded there is no adequate research on which to base an answer to the question, ‘Does ECT work?,’ ” Read told Medscape Medical News. “We’re not actually saying ECT doesn’t work. We’re saying there’s no way to know whether it works or not on the basis of the current research, which, after 80 years of the treatment being used, is pretty amazing.”
On the other hand, Read said there is substantial evidence to suggest ECT causes significant adverse events. “Depending who you ask, the psychiatrists or the patients, somewhere between 12% and 55% of patients get permanent or persistent memory loss,” he said.
“So there is a very serious cost to its use, and if there’s a serious cost, you ... have to know that there’s a very strong efficacy benefit, and we just don’t know that. That’s why we’re calling for suspension until there is adequate research,” Read added.
The study was published in a recent issue of Ethical Human Psychology and Psychiatry.
Widespread use
ECT remains a popular treatment modality for resistant depression. Global data show that it is used to treat almost a million patients every year. Although ECT continues to be the subject of comparative research, the investigators say that most of these studies do not adhere to the same standards that govern clinical trials of other psychiatric medications and medical interventions.
The investigators also note that to date, only 11 placebo-controlled studies of the efficacy of ECT have been conducted. They write that the last study to compare ECT with sham or simulated ECT (SECT) – in which a general anesthetic was administered but the electricity was not – was performed in 1985. Nevertheless, this relatively small body of evidence has been the basis of many meta-analyses.
In the current review, the authors evaluated the impartiality and robustness of these previous meta-analyses and the quality of the studies that were included.
“The primary goal is not to assess whether or not ECT is effective,” they write. “The intent, instead, is to determine whether the available evidence is robust enough to answer that question.”
For Read, the decision to analyze the current state of ECT research was both personal and professional.
“As a young nursing attendant in a Bronx hospital, I had the job of sitting with people as they came around from ECT. It was my job to try to explain why they didn’t know who they were, where they were, why their head was throbbing, and why people would do something like that to them,” he said.
“On the research side, this is my sixth review, and in each one we’ve reached the same conclusion,” Read added.
Other research stands in direct opposition to the current review’s findings. Many studies have concluded that ECT is safe and effective for patients with depression.
Ongoing debate
A 2018 registry analysis showed no additional risk for cognitive impairment in patients who underwent ECT up to 40 years after therapy. A 2018 study also showed that ECT was efficacious and cost-effective for patients with treatment-resistant depression.
However, the ECT debate continues. As reported early last year, there seems to be little common ground between clinicians who believe in the utility of ECT for depression and those who vehemently do not.
For the current review, Read and colleagues performed a Medline search for meta-analyses of the efficacy of ECT for depression. Meta-analyses were only included if they comprised placebo-controlled trials that compared ECT with SECT.
Once the meta-analyses were identified, investigators assessed their component studies. This assessment was conducted by two independent reviewers who used a 24-point quality scale developed by the authors. This scale, the authors note, combines the “risk of bias” domains of the Cochrane Handbook Risk of Bias Tool with criteria related to quality of study design and reporting, as well as several criteria specific to ECT research.
The two reviewers were blinded to each other’s ratings. Interrater differences were resolved collectively.
The literature search yielded 83 potential articles; after exclusion criteria were applied, 14 remained. Three of these articles were literature reviews, one discussed different types of statistical analyses used in ECT research, one was a meta-analysis in Hungarian, one was a meta-analysis that compared ECT with SECT in a selected population of elderly people, and three focused on transcranial magnetic stimulation.
This left five meta-analyses for the review. These included from 1 to 7 of the 11 studies in question:
- Janicak et al, 1985
- Kho, van Vreewijk, Simpson, & Zwinderman, 2003
- Mutz et al, 2019
- Pagnin, de Queiroz, Pini, & Cassano, 2004
- UK ECT Review Group, 2003
The review revealed shortcomings with both the meta-analyses and the studies they included. The investigators found that the mean quality scores of the 11 studies (10.27 ± 2.45 and 11.91 ± 2.91) were not statistically different between the two raters (P = .17), whose scores were significantly correlated (P = .001).
Among the 264 total ratings, the investigators found 55 inconsistencies, which were all resolved by discussion. The mean final quality score for the 11 studies included in the review was 12.27 ± 3.20/24; eight scored 13 or less.
The results of these studies do little to support the benefits of ECT relative to SECT, the reviewers note. Indeed, only four concluded that ECT is significantly superior to SECT. Five found no significant difference, and the remaining two had mixed results.
What’s more, only two of what the investigators describe as “higher quality” studies reported follow-up data. Of these, one produced an effect size of 0.065 favoring ECT, the other showed a small benefit in favor of SECT (effect size, 0.299).
The investigators describe the five meta-analyses included in the review as “flawed,” stating that the meta-analyses “pay little or no attention to the multiple limitations of the studies they include.”
These limitations include the number of patients included in the studies (which average 37 patients); lack of a description of randomization and blinding processes; lack of patient ratings; selective reporting of findings; and the absence of assessment of patient quality of life. Furthermore, the authors note that none of the 11 studies “convincingly” demonstrate double-blinding.
Given these shortcomings, the investigators say the meta-analyses of ECT fail to prove the following:
- The short- and long-term efficacy benefits of ECT over SECT;
- Whether ECT is effective among patients who have failed other treatments for depression;
- Whether ECT prevents ;
- Whether ECT improves patients’ quality of life;
- Whether ECT is more effective in women than men;
- Whether ECT is effective in children or adolescents.
“Shoddy” research
The authors conclude that the review’s findings demonstrate the weakness of evidence that currently supports the use of ECT for depression.
“I would never have guessed how shoddy some of this research was,” said review coauthor Irving Kirsch, PhD, a lecturer on medicine at Beth Israel Deaconess Medical Center, Boston. Many of these shortcomings, Kirsch said, involve blinding and placebo effects.
“It’s not clear how you could ever run a truly blinded trial of ECT, given how pronounced the immediate side effects are,” he told Medscape Medical News. “And one of the things that’s underappreciated is the pronounced responses to placebo treatment with depression and severe depression. These can last for a very long time.”
Kirsch noted that more invasive placebo treatments, such as SECT, tend to have more pronounced effects.
“Not all placebos are created equal. We know, for example, that placebo injections are more effective than placebo pills and that placebo surgery can be extremely powerful,” he said.
The authors call for an immediate suspension of ECT until new studies address these research shortcomings.
“The doctors who perform ECT aren’t evil or stupid, they’re just ignorant of the research. What they see is very temporary benefit in some of the patients. The research suggests that about a third – half at most – get a very temporary lift in mood, which seems to be the sort of euphoria you get from mild brain injury,” Read explained.
“I have seen people who haven’t spoken or eaten for several weeks start speaking and eating, but we know that 4 weeks later, they’re going to be just as depressed as they were, or worse. And now they’re going to have brain damage as well,” said Read.
He added that physicians often don’t see long-term patient outcomes, just the immediate effect of ECT.
A “lifesaver”
No recent randomized controlled trials regarding ECT have been conducted because “no IRB [institutional review board] on planet earth will allow such a trial because of the overwhelming evidence of efficacy and the risk of anesthesia with no ECT,” noted Mark S. George, MD, the Layton McCurdy Endowed Chair in Psychiatry at the Medical University of South Carolina, Charleston.
It is a “logical fallacy” to conclude that ECT does not work because the trials were flawed, said George, who was not involved with the current review
“This is not supported by anything they have looked at,” he told Medscape Medical News. “It’s not really a scientific study when you make conclusions that aren’t based on your data, or not what you set out to do. That’s what I find egregious here.”
The way he sees it, the utility of ECT is unquestionable. “It is our most effective acute treatment for depression, and it’s our most effective treatment for suicide,” he said.
“The authors of this review don’t see the patients that I see every day, who are catatonic, who can’t eat, who are suicidal. For those people, ECT is a lifesaver,” George added.
FDA’s position
Sameer Jauhar, MBChB, PhD, a consultant psychiatrist at the South London and Maudsley NHS Foundation Trust, London, was equally unimpressed with the quality of the review.
“I try to approach everything with an open mind,” he said. “But as a doctor, if I’m reading about evidence, I expect a well-conducted meta-analysis and/or very clear systematic review with an adequate level of peer review.”
The current review, said Jauhar, doesn’t meet these criteria. He said the article reads more like a narrative review, one in which the authors dictated their own arbitrary criteria of study quality.
Most important, he said, is the fact that ECT has been the focus of a great deal of research. “The best quality synthesis of the evidence I’ve come across is the UK ECT Review Group’s 2003 meta-analysis, published in The Lancet, which asked this very question. None of the studies has changed since then.”
Jauhar also noted that in 2018, the Food and Drug Administration reclassified ECT from class III (higher risk) to class II (moderate risk). Use of ECT was also limited to treatment of “catatonia or a severe major depressive episode associated with major depressive disorder or bipolar disorder in patients age 13 years and older who are treatment-resistant or who require a rapid response treatment due to the severity of their psychiatric or medical condition.”
The FDA also noted that “[t]he safe use of ECT for treatment of these conditions has been well studied and is better understood than other uses. Therefore, sufficient information exists to establish special controls that mitigate known risks and provide a reasonable assurance of safety and effectiveness for these two uses of ECT devices.”
As part of the FDA’s 2018 reclassification, ECT manufacturers were required to file a premarket approval application for all uses that were not reclassified. The full text of the order is available in the Federal Register.
“So the FDA has been through it, The Lancet has been through it, and the findings were clear,” said Jauhar. “It’s very easy to poke holes in studies that were conducted 30 or more years ago. But the fact is, the field has moved on.”
Jauhar acknowledged there are patients who have had bad experiences with ECT, and he accepts that such events occasionally occur. Nevertheless, he said,
Jauhar also noted that the journal in which the review was published has a 2019 CiteScore of 0.3 and ranks in the 15th percentile of the Scopus Clinical Psychology category. He further noted that Kirsch is a member of the journal’s editorial board.
“I would say that the level of peer review here was negligible at best,” Jauhar said. “In addition, the ‘findings’ are driven more by ideology than evidence.”
Asked to respond to Jauhar’s comments, Kirsch noted that although he is on the journal’s advisory board, he has not been actively involved. Kirsch added that he serves on about a dozen academic advisory boards and serves as a reviewer for many top scientific and medical journals, including The Journal of the American Medical Association and the New England Journal of Medicine.
“Our article was peer reviewed,” Kirsch said, “and we revised it following the first round of reviews.” The review process did not differ from those he has gone through with more than 250 published peer-reviewed articles on which he was an author or coauthor, he noted.
A growing movement
Despite such expert opposition, the movement to suspend ECT continues. Recently, Sarah Price Hancock, MS, CRC, CPMC, who is herself a recipient of more than 100 ECT treatments, authored an international petition to standardize, regulate, and audit the modality. Hancock hopes to present the document, which currently has more than 6600 signatures, to the American Psychiatric Association and similar international societies.
A version of the petition was presented to the UK’s National Health Service on July 2, the 59th anniversary of the death by suicide of Ernest Hemingway, who had received some 20 ECT treatments himself.
“Hopefully by his 60th anniversary, America and the world will be taking his death and the thousands living with adverse reactions more seriously by auditing, regulating, and tracking patients with a history of ECT to provide much needed comprehensive brain injury rehabilitation as necessary,” Hancock told Medscape Medical News.
Among the signatories of the petition is Sue Cunliffe, MbChB, who underwent ECT for depression in 2004, with devastating effects. “I was left really badly brain damaged, and so I’ve never been allowed to work again,” she told Medscape Medical News.
Cunliffe said the immediate effects of the treatment were profound. She said her hands shook, her balance and coordination were impaired, and her memories evaporated. However, she found a neuropsychologist who she says was able to help her recover control of her life. “Now at least I’m able to plan my life so that I can live with the brain damage.”
Kirsch acknowledged that sorting through the ECT literature can be daunting. “If you’re a physician, you try to keep up with the literature, but the problem is, the literature is so old and done in ways which would not pass muster right now. The data are really poor, and I guess it’s just that people aren’t aware of it.”
George agreed that the therapy is not without its shortcomings.
“Does ECT have cognitive side effects? Unfortunately, it does. But so do lots of lifesaving therapies in medicine, like cancer chemotherapy,” he said.
“Nobody really gets well with a single ECT session. It’s usually eight to 12 over 3 or 4 weeks. So it’s not particularly durable. That’s why we often combine ECT with other forms of brain stimulation,” George added.
He noted that the recent advent of alternative forms of ECT – including right unilateral ultrabrief pulse ECT and focal electrically administered seizure therapy – are beginning to address some of these shortcomings.
“The holy grail of brain stimulation is to be able to do things less invasively, and we’re moving slowly in that direction,” he said. “But right now, we don’t have anything that is as acutely as effective as ECT. It is our lifesaver at the moment.”
The review authors as well as George, Jauhar, Cunliffe, and Hancock report no relevant financial relationships.
This article first appeared on Medscape.com.
Experts are calling for the immediate suspension of electroconvulsive therapy (ECT) for major depression.
A new review by investigators led by John Read, PhD, University of East London, conclude there is no evidence to show that ECT is effective in either its target demographic or its target diagnostic group. They say its use should be suspended until more robust research proves it is safe and effective.
However, the review’s conclusions have been met with passionate opposition from expert psychiatrists who say ECT can be a lifesaving treatment for patients, many of whom have exhausted all other treatment options. Other clinicians maintain that the review itself is fraught with methodologic shortcomings that invalidate its conclusions.
“We’ve concluded there is no adequate research on which to base an answer to the question, ‘Does ECT work?,’ ” Read told Medscape Medical News. “We’re not actually saying ECT doesn’t work. We’re saying there’s no way to know whether it works or not on the basis of the current research, which, after 80 years of the treatment being used, is pretty amazing.”
On the other hand, Read said there is substantial evidence to suggest ECT causes significant adverse events. “Depending who you ask, the psychiatrists or the patients, somewhere between 12% and 55% of patients get permanent or persistent memory loss,” he said.
“So there is a very serious cost to its use, and if there’s a serious cost, you ... have to know that there’s a very strong efficacy benefit, and we just don’t know that. That’s why we’re calling for suspension until there is adequate research,” Read added.
The study was published in a recent issue of Ethical Human Psychology and Psychiatry.
Widespread use
ECT remains a popular treatment modality for resistant depression. Global data show that it is used to treat almost a million patients every year. Although ECT continues to be the subject of comparative research, the investigators say that most of these studies do not adhere to the same standards that govern clinical trials of other psychiatric medications and medical interventions.
The investigators also note that to date, only 11 placebo-controlled studies of the efficacy of ECT have been conducted. They write that the last study to compare ECT with sham or simulated ECT (SECT) – in which a general anesthetic was administered but the electricity was not – was performed in 1985. Nevertheless, this relatively small body of evidence has been the basis of many meta-analyses.
In the current review, the authors evaluated the impartiality and robustness of these previous meta-analyses and the quality of the studies that were included.
“The primary goal is not to assess whether or not ECT is effective,” they write. “The intent, instead, is to determine whether the available evidence is robust enough to answer that question.”
For Read, the decision to analyze the current state of ECT research was both personal and professional.
“As a young nursing attendant in a Bronx hospital, I had the job of sitting with people as they came around from ECT. It was my job to try to explain why they didn’t know who they were, where they were, why their head was throbbing, and why people would do something like that to them,” he said.
“On the research side, this is my sixth review, and in each one we’ve reached the same conclusion,” Read added.
Other research stands in direct opposition to the current review’s findings. Many studies have concluded that ECT is safe and effective for patients with depression.
Ongoing debate
A 2018 registry analysis showed no additional risk for cognitive impairment in patients who underwent ECT up to 40 years after therapy. A 2018 study also showed that ECT was efficacious and cost-effective for patients with treatment-resistant depression.
However, the ECT debate continues. As reported early last year, there seems to be little common ground between clinicians who believe in the utility of ECT for depression and those who vehemently do not.
For the current review, Read and colleagues performed a Medline search for meta-analyses of the efficacy of ECT for depression. Meta-analyses were only included if they comprised placebo-controlled trials that compared ECT with SECT.
Once the meta-analyses were identified, investigators assessed their component studies. This assessment was conducted by two independent reviewers who used a 24-point quality scale developed by the authors. This scale, the authors note, combines the “risk of bias” domains of the Cochrane Handbook Risk of Bias Tool with criteria related to quality of study design and reporting, as well as several criteria specific to ECT research.
The two reviewers were blinded to each other’s ratings. Interrater differences were resolved collectively.
The literature search yielded 83 potential articles; after exclusion criteria were applied, 14 remained. Three of these articles were literature reviews, one discussed different types of statistical analyses used in ECT research, one was a meta-analysis in Hungarian, one was a meta-analysis that compared ECT with SECT in a selected population of elderly people, and three focused on transcranial magnetic stimulation.
This left five meta-analyses for the review. These included from 1 to 7 of the 11 studies in question:
- Janicak et al, 1985
- Kho, van Vreewijk, Simpson, & Zwinderman, 2003
- Mutz et al, 2019
- Pagnin, de Queiroz, Pini, & Cassano, 2004
- UK ECT Review Group, 2003
The review revealed shortcomings with both the meta-analyses and the studies they included. The investigators found that the mean quality scores of the 11 studies (10.27 ± 2.45 and 11.91 ± 2.91) were not statistically different between the two raters (P = .17), whose scores were significantly correlated (P = .001).
Among the 264 total ratings, the investigators found 55 inconsistencies, which were all resolved by discussion. The mean final quality score for the 11 studies included in the review was 12.27 ± 3.20/24; eight scored 13 or less.
The results of these studies do little to support the benefits of ECT relative to SECT, the reviewers note. Indeed, only four concluded that ECT is significantly superior to SECT. Five found no significant difference, and the remaining two had mixed results.
What’s more, only two of what the investigators describe as “higher quality” studies reported follow-up data. Of these, one produced an effect size of 0.065 favoring ECT, the other showed a small benefit in favor of SECT (effect size, 0.299).
The investigators describe the five meta-analyses included in the review as “flawed,” stating that the meta-analyses “pay little or no attention to the multiple limitations of the studies they include.”
These limitations include the number of patients included in the studies (which average 37 patients); lack of a description of randomization and blinding processes; lack of patient ratings; selective reporting of findings; and the absence of assessment of patient quality of life. Furthermore, the authors note that none of the 11 studies “convincingly” demonstrate double-blinding.
Given these shortcomings, the investigators say the meta-analyses of ECT fail to prove the following:
- The short- and long-term efficacy benefits of ECT over SECT;
- Whether ECT is effective among patients who have failed other treatments for depression;
- Whether ECT prevents ;
- Whether ECT improves patients’ quality of life;
- Whether ECT is more effective in women than men;
- Whether ECT is effective in children or adolescents.
“Shoddy” research
The authors conclude that the review’s findings demonstrate the weakness of evidence that currently supports the use of ECT for depression.
“I would never have guessed how shoddy some of this research was,” said review coauthor Irving Kirsch, PhD, a lecturer on medicine at Beth Israel Deaconess Medical Center, Boston. Many of these shortcomings, Kirsch said, involve blinding and placebo effects.
“It’s not clear how you could ever run a truly blinded trial of ECT, given how pronounced the immediate side effects are,” he told Medscape Medical News. “And one of the things that’s underappreciated is the pronounced responses to placebo treatment with depression and severe depression. These can last for a very long time.”
Kirsch noted that more invasive placebo treatments, such as SECT, tend to have more pronounced effects.
“Not all placebos are created equal. We know, for example, that placebo injections are more effective than placebo pills and that placebo surgery can be extremely powerful,” he said.
The authors call for an immediate suspension of ECT until new studies address these research shortcomings.
“The doctors who perform ECT aren’t evil or stupid, they’re just ignorant of the research. What they see is very temporary benefit in some of the patients. The research suggests that about a third – half at most – get a very temporary lift in mood, which seems to be the sort of euphoria you get from mild brain injury,” Read explained.
“I have seen people who haven’t spoken or eaten for several weeks start speaking and eating, but we know that 4 weeks later, they’re going to be just as depressed as they were, or worse. And now they’re going to have brain damage as well,” said Read.
He added that physicians often don’t see long-term patient outcomes, just the immediate effect of ECT.
A “lifesaver”
No recent randomized controlled trials regarding ECT have been conducted because “no IRB [institutional review board] on planet earth will allow such a trial because of the overwhelming evidence of efficacy and the risk of anesthesia with no ECT,” noted Mark S. George, MD, the Layton McCurdy Endowed Chair in Psychiatry at the Medical University of South Carolina, Charleston.
It is a “logical fallacy” to conclude that ECT does not work because the trials were flawed, said George, who was not involved with the current review
“This is not supported by anything they have looked at,” he told Medscape Medical News. “It’s not really a scientific study when you make conclusions that aren’t based on your data, or not what you set out to do. That’s what I find egregious here.”
The way he sees it, the utility of ECT is unquestionable. “It is our most effective acute treatment for depression, and it’s our most effective treatment for suicide,” he said.
“The authors of this review don’t see the patients that I see every day, who are catatonic, who can’t eat, who are suicidal. For those people, ECT is a lifesaver,” George added.
FDA’s position
Sameer Jauhar, MBChB, PhD, a consultant psychiatrist at the South London and Maudsley NHS Foundation Trust, London, was equally unimpressed with the quality of the review.
“I try to approach everything with an open mind,” he said. “But as a doctor, if I’m reading about evidence, I expect a well-conducted meta-analysis and/or very clear systematic review with an adequate level of peer review.”
The current review, said Jauhar, doesn’t meet these criteria. He said the article reads more like a narrative review, one in which the authors dictated their own arbitrary criteria of study quality.
Most important, he said, is the fact that ECT has been the focus of a great deal of research. “The best quality synthesis of the evidence I’ve come across is the UK ECT Review Group’s 2003 meta-analysis, published in The Lancet, which asked this very question. None of the studies has changed since then.”
Jauhar also noted that in 2018, the Food and Drug Administration reclassified ECT from class III (higher risk) to class II (moderate risk). Use of ECT was also limited to treatment of “catatonia or a severe major depressive episode associated with major depressive disorder or bipolar disorder in patients age 13 years and older who are treatment-resistant or who require a rapid response treatment due to the severity of their psychiatric or medical condition.”
The FDA also noted that “[t]he safe use of ECT for treatment of these conditions has been well studied and is better understood than other uses. Therefore, sufficient information exists to establish special controls that mitigate known risks and provide a reasonable assurance of safety and effectiveness for these two uses of ECT devices.”
As part of the FDA’s 2018 reclassification, ECT manufacturers were required to file a premarket approval application for all uses that were not reclassified. The full text of the order is available in the Federal Register.
“So the FDA has been through it, The Lancet has been through it, and the findings were clear,” said Jauhar. “It’s very easy to poke holes in studies that were conducted 30 or more years ago. But the fact is, the field has moved on.”
Jauhar acknowledged there are patients who have had bad experiences with ECT, and he accepts that such events occasionally occur. Nevertheless, he said,
Jauhar also noted that the journal in which the review was published has a 2019 CiteScore of 0.3 and ranks in the 15th percentile of the Scopus Clinical Psychology category. He further noted that Kirsch is a member of the journal’s editorial board.
“I would say that the level of peer review here was negligible at best,” Jauhar said. “In addition, the ‘findings’ are driven more by ideology than evidence.”
Asked to respond to Jauhar’s comments, Kirsch noted that although he is on the journal’s advisory board, he has not been actively involved. Kirsch added that he serves on about a dozen academic advisory boards and serves as a reviewer for many top scientific and medical journals, including The Journal of the American Medical Association and the New England Journal of Medicine.
“Our article was peer reviewed,” Kirsch said, “and we revised it following the first round of reviews.” The review process did not differ from those he has gone through with more than 250 published peer-reviewed articles on which he was an author or coauthor, he noted.
A growing movement
Despite such expert opposition, the movement to suspend ECT continues. Recently, Sarah Price Hancock, MS, CRC, CPMC, who is herself a recipient of more than 100 ECT treatments, authored an international petition to standardize, regulate, and audit the modality. Hancock hopes to present the document, which currently has more than 6600 signatures, to the American Psychiatric Association and similar international societies.
A version of the petition was presented to the UK’s National Health Service on July 2, the 59th anniversary of the death by suicide of Ernest Hemingway, who had received some 20 ECT treatments himself.
“Hopefully by his 60th anniversary, America and the world will be taking his death and the thousands living with adverse reactions more seriously by auditing, regulating, and tracking patients with a history of ECT to provide much needed comprehensive brain injury rehabilitation as necessary,” Hancock told Medscape Medical News.
Among the signatories of the petition is Sue Cunliffe, MbChB, who underwent ECT for depression in 2004, with devastating effects. “I was left really badly brain damaged, and so I’ve never been allowed to work again,” she told Medscape Medical News.
Cunliffe said the immediate effects of the treatment were profound. She said her hands shook, her balance and coordination were impaired, and her memories evaporated. However, she found a neuropsychologist who she says was able to help her recover control of her life. “Now at least I’m able to plan my life so that I can live with the brain damage.”
Kirsch acknowledged that sorting through the ECT literature can be daunting. “If you’re a physician, you try to keep up with the literature, but the problem is, the literature is so old and done in ways which would not pass muster right now. The data are really poor, and I guess it’s just that people aren’t aware of it.”
George agreed that the therapy is not without its shortcomings.
“Does ECT have cognitive side effects? Unfortunately, it does. But so do lots of lifesaving therapies in medicine, like cancer chemotherapy,” he said.
“Nobody really gets well with a single ECT session. It’s usually eight to 12 over 3 or 4 weeks. So it’s not particularly durable. That’s why we often combine ECT with other forms of brain stimulation,” George added.
He noted that the recent advent of alternative forms of ECT – including right unilateral ultrabrief pulse ECT and focal electrically administered seizure therapy – are beginning to address some of these shortcomings.
“The holy grail of brain stimulation is to be able to do things less invasively, and we’re moving slowly in that direction,” he said. “But right now, we don’t have anything that is as acutely as effective as ECT. It is our lifesaver at the moment.”
The review authors as well as George, Jauhar, Cunliffe, and Hancock report no relevant financial relationships.
This article first appeared on Medscape.com.
Still no clear answer on intranasal insulin for MCI and Alzheimer’s disease
The randomized trial of nearly 300 patients showed that, although one insulin administration device produced marked benefit in terms of change in mean score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12) over 12 months, reliability was inconsistent. A second device, used on the majority of patients in the study’s intention-to-treat population, showed no difference in these measures between patients who did and those who did not receive intranasal insulin.
“The primary analysis of the study showed no benefit of intranasal insulin on any measures of cognition or cerebrospinal fluid Alzheimer’s disease biomarkers when using the new device,” said principal investigator Suzanne Craft, PhD.
“But when we looked at our planned secondary analysis with the original device – which has been successful in previous studies – we saw quite a different picture,” added Dr. Craft, director of the Alzheimer’s Disease Research Center at Wake Forest University, Winston-Salem, N.C.
“We found a pronounced benefit with that device, such that after 18 months of administration, participants who had been receiving insulin from the beginning of the study had a large and clinically significant advantage in the primary outcome measure.”
Dr. Craft described the findings as complex. “The primary results were negative,” she added. “But the secondary results replicated those of several earlier studies when we used the same device that was used in those.”
The study was published online June 22 in JAMA Neurology.
Important for brain function
Insulin has been shown to play several important roles in brain function. The hormone is associated with a variety of cognitive functions, including memory. Through its association with vasoreactivity, lipid metabolism, and inflammation, insulin also plays an important role in vascular function.
“In the normal brain in healthy individuals, insulin is very important for synaptic function and viability. Insulin also promotes dendritic growth and facilitates synaptic health. Through this role, it plays an important part in memory,” said Dr. Craft. Given these connections, it is not surprising that reduced insulin levels or activity in brain and cerebrospinal fluid have been documented in some, but not all, studies of Alzheimer’s disease. Markers of insulin resistance also have been detected in both neuronally derived exosomes and brain tissue from adults with Alzheimer’s disease.
In light of the several important roles that insulin plays in the brain – coupled with the evidence connecting dysregulation of brain insulin and AD pathology – restoring brain insulin function may offer therapeutic benefit for adults suffering either Alzheimer’s disease or MCI. “There are a number of ways to do this,” said Dr. Craft. “But one of the approaches that we’ve focused on is providing insulin directly to the brain through intranasal administration. “By doing this, you circumvent potential issues if you administered insulin systemically.”
Previous research has shown that through this mode of administration, insulin can bypass the blood-brain barrier and reach the brain through olfactory and trigeminal perivascular channels, with little effect on peripheral insulin or blood glucose levels.
As previously reported, an earlier pilot study, also conducted by Dr. Craft and her team, showed that 4 months of daily intranasal administration of 20 IU or 40 IU of insulin preserved cognitive performance in individuals with Alzheimer’s disease or MCI.
Deeper dive
In the current investigation, the researchers wanted to broaden these findings in a larger, longer, randomized double-blinded clinical trial. The investigators assessed the efficacy of intranasal insulin on cognition, function, and biomarkers of Alzheimer’s disease, as well as the safety and feasibility of the delivery method. The multicenter trial was conducted from 2014 to 2018 and included 27 sites.
Study participants were between the ages of 55 and 85 years and had been diagnosed with amnestic MCI or Alzheimer’s disease on the basis of National Institute on Aging–Alzheimer Association criteria, a score of 20 or higher on the Mini–Mental State Examination, a clinical dementia rating of 0.5 or 1.0, or a delayed logical memory score within a specified range.
In total, 289 participants were randomly assigned to receive 40 IU of insulin or placebo for 12 months, followed by a 6-month open-label extension phase. The first 49 participants (32 men; mean age, 71.9 years) underwent insulin administration with the same device the investigators used in previous trials.
Of these, 45 completed the blinded phase, and 42 completed the open-label extension. When this device, which uses an electronic nebulizer-like delivery system, proved unreliable, the researchers switched to a second device, which uses a liquid hydrofluoroalkane propellant to deliver a metered dose of insulin through a nose tip without electronic assistance. Device 2 was used for the remaining 240 participants (123 men; mean age, 70.8 years). These patients became the study’s primary intention-to-treat population.
The study’s primary outcome was the mean change in score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12), which was evaluated at 3-month intervals.
Secondary clinical outcomes were assessed at 6-month intervals. These included the mean change in scores for the Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment and the Clinical Dementia Rating Scale Sum of Boxes.
Safety and adherence were also assessed during each study visit. Physical and neurologic examinations were performed at baseline and at months 6, 12, and 18.
Of the primary intention-to-treat population of 240 patients, 121 were randomly assigned to receive intranasal insulin. The remaining 119 received placebo and served as controls. The two groups were demographically comparable.
Better cognitive performance
A total of 215 participants completed the blinded phase; 198 participants completed the open-label extension. Discontinuation rates were comparable in both arms. The researchers found no differences between groups with respect to mean change in ADAS-cog-12 score from baseline to month 12 (0.0258 points; 95% confidence interval, –1.771 to 1.822 points; P = .98). The two groups also proved comparable in terms of performance on all other cognitive tests.
The open-label portion yielded similar results. Participants originally assigned to the insulin arm and their counterparts in the placebo arm did not differ with respect to mean score change on the ADAS-cog-12 test (or any other outcome) at either month 15 or 18.
Cerebrospinal fluid insulin levels were unchanged between groups, as were blood glucose and hemoglobin A1c values. Indeed, levels of A-beta42, A-beta40, total tau protein, and tau p-181 were comparable for the patients who received intranasal insulin and those who received placebo.
The most common adverse events were infections, injuries, respiratory disorders, and nervous system disorders, though these did not differ between groups. In addition, there were no differences between groups with respect to severity of adverse events; most were rated as mild.
In contrast with the intention-to-treat population, the study’s secondary analysis – using data from the original administration device – yielded markedly different results. In the blinded phase, patients who received insulin had better ADAS-cog-12 performance at 12 months (−2.81 points; 95% CI, −6.09 to 0.45 points; P = .09) and nominally significant effects at 6 months (−3.78 points; 95% CI, −6.79 to −0.78 points; P = .01).
Device type critical
These effects persisted in the open-label analyses. Patients who received intranasal insulin had superior ADAS-cog-12 scores at month 15 (−5.70 points; 95% CI, −9.62 to −1.79 points; P = .004) and month 18 (−5.78 points; 95% CI, −10.55 to −1.01 points; P = .02), compared with their counterparts who received insulin via the second device. This part of the study also showed that, although individual biomarkers did not differ significantly between the two arms, the ratios of A-beta42 to A-beta40 (P = .01) and A-beta42 to total tau (P = .03) increased with use of the first device. The number, type, and severity of adverse events were comparable between the insulin and placebo groups in this arm of the study.
The mixed results revealed by the trial demonstrate that the device used for intranasal insulin administration is paramount in determining the therapy’s potential efficacy. “Our take-home message is that the device is a very important factor for these studies and that one needs to validate their ability to effectively deliver insulin to the CNS,” said Dr. Craft.
“We were quite confident that the first device was able to do that. On the other hand, the second device has never been tested in that way, and we still don’t know whether or not that device was able to successfully deliver insulin,” she said.
The investigators recognize the need for more research in the field. Such studies, Dr. Craft noted, will utilize administration devices that have been previously verified to have the ability to deliver insulin to the central nervous system. “We’re currently testing several devices,” she noted. “We’re using a protocol where we administer insulin with the devices and then conduct a lumbar puncture about 30 minutes later to verify that it is actually raising insulin levels in the cerebrospinal fluid.”
Not a failure
Commenting on the findings, Samuel E. Gandy, MD, PhD, who was not involved in the study, said the research illustrates the challenge when a new therapy, a new delivery device, and a cohort of cognitively impaired patients collide. “The result is not quite a slam dunk but is also by no means a failure,” commented Dr. Gandy, Mount Sinai Chair in Alzheimer’s Research at Mount Sinai Medical Center, New York.
“One looks forward to future iterations of the Craft et al. approach, wherein the trialists tweak the ligand and/or the delivery schedule and/or the device and/or the disease and/or the disease stage,” Dr. Gandy added. “Another ligand, VGF, also holds promise for intranasal delivery, based on work from Steve Salton, Michelle Ehrlich, and Eric Schadt, all from Mount Sinai. Perhaps the nose knows!”
For Dr. Craft, the potential upside of intranasal insulin for these patients is significant and warrants further investigation. “I understand why people who are not familiar with prior research in this area might be skeptical of our enthusiasm, given the results in the intention-to-treat population,” she said. “But those of us who have been working along with this for a while now, we feel like we’ve got to do the next study. But we need to have a device that we know works,” Dr. Craft added.
“If this is real, then there may be a very large clinical benefit in symptomatic patients, and there’s nothing so far that has really improved symptomatic disease.”
The study was supported by the National Institute on Aging. Eli Lilly provided diluent placebo for the blinded phase and insulin for the open-label phase of the clinical trial at no cost. Dr. Craft received grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work.
A version of this article originally appeared on Medscape.com.
The randomized trial of nearly 300 patients showed that, although one insulin administration device produced marked benefit in terms of change in mean score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12) over 12 months, reliability was inconsistent. A second device, used on the majority of patients in the study’s intention-to-treat population, showed no difference in these measures between patients who did and those who did not receive intranasal insulin.
“The primary analysis of the study showed no benefit of intranasal insulin on any measures of cognition or cerebrospinal fluid Alzheimer’s disease biomarkers when using the new device,” said principal investigator Suzanne Craft, PhD.
“But when we looked at our planned secondary analysis with the original device – which has been successful in previous studies – we saw quite a different picture,” added Dr. Craft, director of the Alzheimer’s Disease Research Center at Wake Forest University, Winston-Salem, N.C.
“We found a pronounced benefit with that device, such that after 18 months of administration, participants who had been receiving insulin from the beginning of the study had a large and clinically significant advantage in the primary outcome measure.”
Dr. Craft described the findings as complex. “The primary results were negative,” she added. “But the secondary results replicated those of several earlier studies when we used the same device that was used in those.”
The study was published online June 22 in JAMA Neurology.
Important for brain function
Insulin has been shown to play several important roles in brain function. The hormone is associated with a variety of cognitive functions, including memory. Through its association with vasoreactivity, lipid metabolism, and inflammation, insulin also plays an important role in vascular function.
“In the normal brain in healthy individuals, insulin is very important for synaptic function and viability. Insulin also promotes dendritic growth and facilitates synaptic health. Through this role, it plays an important part in memory,” said Dr. Craft. Given these connections, it is not surprising that reduced insulin levels or activity in brain and cerebrospinal fluid have been documented in some, but not all, studies of Alzheimer’s disease. Markers of insulin resistance also have been detected in both neuronally derived exosomes and brain tissue from adults with Alzheimer’s disease.
In light of the several important roles that insulin plays in the brain – coupled with the evidence connecting dysregulation of brain insulin and AD pathology – restoring brain insulin function may offer therapeutic benefit for adults suffering either Alzheimer’s disease or MCI. “There are a number of ways to do this,” said Dr. Craft. “But one of the approaches that we’ve focused on is providing insulin directly to the brain through intranasal administration. “By doing this, you circumvent potential issues if you administered insulin systemically.”
Previous research has shown that through this mode of administration, insulin can bypass the blood-brain barrier and reach the brain through olfactory and trigeminal perivascular channels, with little effect on peripheral insulin or blood glucose levels.
As previously reported, an earlier pilot study, also conducted by Dr. Craft and her team, showed that 4 months of daily intranasal administration of 20 IU or 40 IU of insulin preserved cognitive performance in individuals with Alzheimer’s disease or MCI.
Deeper dive
In the current investigation, the researchers wanted to broaden these findings in a larger, longer, randomized double-blinded clinical trial. The investigators assessed the efficacy of intranasal insulin on cognition, function, and biomarkers of Alzheimer’s disease, as well as the safety and feasibility of the delivery method. The multicenter trial was conducted from 2014 to 2018 and included 27 sites.
Study participants were between the ages of 55 and 85 years and had been diagnosed with amnestic MCI or Alzheimer’s disease on the basis of National Institute on Aging–Alzheimer Association criteria, a score of 20 or higher on the Mini–Mental State Examination, a clinical dementia rating of 0.5 or 1.0, or a delayed logical memory score within a specified range.
In total, 289 participants were randomly assigned to receive 40 IU of insulin or placebo for 12 months, followed by a 6-month open-label extension phase. The first 49 participants (32 men; mean age, 71.9 years) underwent insulin administration with the same device the investigators used in previous trials.
Of these, 45 completed the blinded phase, and 42 completed the open-label extension. When this device, which uses an electronic nebulizer-like delivery system, proved unreliable, the researchers switched to a second device, which uses a liquid hydrofluoroalkane propellant to deliver a metered dose of insulin through a nose tip without electronic assistance. Device 2 was used for the remaining 240 participants (123 men; mean age, 70.8 years). These patients became the study’s primary intention-to-treat population.
The study’s primary outcome was the mean change in score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12), which was evaluated at 3-month intervals.
Secondary clinical outcomes were assessed at 6-month intervals. These included the mean change in scores for the Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment and the Clinical Dementia Rating Scale Sum of Boxes.
Safety and adherence were also assessed during each study visit. Physical and neurologic examinations were performed at baseline and at months 6, 12, and 18.
Of the primary intention-to-treat population of 240 patients, 121 were randomly assigned to receive intranasal insulin. The remaining 119 received placebo and served as controls. The two groups were demographically comparable.
Better cognitive performance
A total of 215 participants completed the blinded phase; 198 participants completed the open-label extension. Discontinuation rates were comparable in both arms. The researchers found no differences between groups with respect to mean change in ADAS-cog-12 score from baseline to month 12 (0.0258 points; 95% confidence interval, –1.771 to 1.822 points; P = .98). The two groups also proved comparable in terms of performance on all other cognitive tests.
The open-label portion yielded similar results. Participants originally assigned to the insulin arm and their counterparts in the placebo arm did not differ with respect to mean score change on the ADAS-cog-12 test (or any other outcome) at either month 15 or 18.
Cerebrospinal fluid insulin levels were unchanged between groups, as were blood glucose and hemoglobin A1c values. Indeed, levels of A-beta42, A-beta40, total tau protein, and tau p-181 were comparable for the patients who received intranasal insulin and those who received placebo.
The most common adverse events were infections, injuries, respiratory disorders, and nervous system disorders, though these did not differ between groups. In addition, there were no differences between groups with respect to severity of adverse events; most were rated as mild.
In contrast with the intention-to-treat population, the study’s secondary analysis – using data from the original administration device – yielded markedly different results. In the blinded phase, patients who received insulin had better ADAS-cog-12 performance at 12 months (−2.81 points; 95% CI, −6.09 to 0.45 points; P = .09) and nominally significant effects at 6 months (−3.78 points; 95% CI, −6.79 to −0.78 points; P = .01).
Device type critical
These effects persisted in the open-label analyses. Patients who received intranasal insulin had superior ADAS-cog-12 scores at month 15 (−5.70 points; 95% CI, −9.62 to −1.79 points; P = .004) and month 18 (−5.78 points; 95% CI, −10.55 to −1.01 points; P = .02), compared with their counterparts who received insulin via the second device. This part of the study also showed that, although individual biomarkers did not differ significantly between the two arms, the ratios of A-beta42 to A-beta40 (P = .01) and A-beta42 to total tau (P = .03) increased with use of the first device. The number, type, and severity of adverse events were comparable between the insulin and placebo groups in this arm of the study.
The mixed results revealed by the trial demonstrate that the device used for intranasal insulin administration is paramount in determining the therapy’s potential efficacy. “Our take-home message is that the device is a very important factor for these studies and that one needs to validate their ability to effectively deliver insulin to the CNS,” said Dr. Craft.
“We were quite confident that the first device was able to do that. On the other hand, the second device has never been tested in that way, and we still don’t know whether or not that device was able to successfully deliver insulin,” she said.
The investigators recognize the need for more research in the field. Such studies, Dr. Craft noted, will utilize administration devices that have been previously verified to have the ability to deliver insulin to the central nervous system. “We’re currently testing several devices,” she noted. “We’re using a protocol where we administer insulin with the devices and then conduct a lumbar puncture about 30 minutes later to verify that it is actually raising insulin levels in the cerebrospinal fluid.”
Not a failure
Commenting on the findings, Samuel E. Gandy, MD, PhD, who was not involved in the study, said the research illustrates the challenge when a new therapy, a new delivery device, and a cohort of cognitively impaired patients collide. “The result is not quite a slam dunk but is also by no means a failure,” commented Dr. Gandy, Mount Sinai Chair in Alzheimer’s Research at Mount Sinai Medical Center, New York.
“One looks forward to future iterations of the Craft et al. approach, wherein the trialists tweak the ligand and/or the delivery schedule and/or the device and/or the disease and/or the disease stage,” Dr. Gandy added. “Another ligand, VGF, also holds promise for intranasal delivery, based on work from Steve Salton, Michelle Ehrlich, and Eric Schadt, all from Mount Sinai. Perhaps the nose knows!”
For Dr. Craft, the potential upside of intranasal insulin for these patients is significant and warrants further investigation. “I understand why people who are not familiar with prior research in this area might be skeptical of our enthusiasm, given the results in the intention-to-treat population,” she said. “But those of us who have been working along with this for a while now, we feel like we’ve got to do the next study. But we need to have a device that we know works,” Dr. Craft added.
“If this is real, then there may be a very large clinical benefit in symptomatic patients, and there’s nothing so far that has really improved symptomatic disease.”
The study was supported by the National Institute on Aging. Eli Lilly provided diluent placebo for the blinded phase and insulin for the open-label phase of the clinical trial at no cost. Dr. Craft received grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work.
A version of this article originally appeared on Medscape.com.
The randomized trial of nearly 300 patients showed that, although one insulin administration device produced marked benefit in terms of change in mean score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12) over 12 months, reliability was inconsistent. A second device, used on the majority of patients in the study’s intention-to-treat population, showed no difference in these measures between patients who did and those who did not receive intranasal insulin.
“The primary analysis of the study showed no benefit of intranasal insulin on any measures of cognition or cerebrospinal fluid Alzheimer’s disease biomarkers when using the new device,” said principal investigator Suzanne Craft, PhD.
“But when we looked at our planned secondary analysis with the original device – which has been successful in previous studies – we saw quite a different picture,” added Dr. Craft, director of the Alzheimer’s Disease Research Center at Wake Forest University, Winston-Salem, N.C.
“We found a pronounced benefit with that device, such that after 18 months of administration, participants who had been receiving insulin from the beginning of the study had a large and clinically significant advantage in the primary outcome measure.”
Dr. Craft described the findings as complex. “The primary results were negative,” she added. “But the secondary results replicated those of several earlier studies when we used the same device that was used in those.”
The study was published online June 22 in JAMA Neurology.
Important for brain function
Insulin has been shown to play several important roles in brain function. The hormone is associated with a variety of cognitive functions, including memory. Through its association with vasoreactivity, lipid metabolism, and inflammation, insulin also plays an important role in vascular function.
“In the normal brain in healthy individuals, insulin is very important for synaptic function and viability. Insulin also promotes dendritic growth and facilitates synaptic health. Through this role, it plays an important part in memory,” said Dr. Craft. Given these connections, it is not surprising that reduced insulin levels or activity in brain and cerebrospinal fluid have been documented in some, but not all, studies of Alzheimer’s disease. Markers of insulin resistance also have been detected in both neuronally derived exosomes and brain tissue from adults with Alzheimer’s disease.
In light of the several important roles that insulin plays in the brain – coupled with the evidence connecting dysregulation of brain insulin and AD pathology – restoring brain insulin function may offer therapeutic benefit for adults suffering either Alzheimer’s disease or MCI. “There are a number of ways to do this,” said Dr. Craft. “But one of the approaches that we’ve focused on is providing insulin directly to the brain through intranasal administration. “By doing this, you circumvent potential issues if you administered insulin systemically.”
Previous research has shown that through this mode of administration, insulin can bypass the blood-brain barrier and reach the brain through olfactory and trigeminal perivascular channels, with little effect on peripheral insulin or blood glucose levels.
As previously reported, an earlier pilot study, also conducted by Dr. Craft and her team, showed that 4 months of daily intranasal administration of 20 IU or 40 IU of insulin preserved cognitive performance in individuals with Alzheimer’s disease or MCI.
Deeper dive
In the current investigation, the researchers wanted to broaden these findings in a larger, longer, randomized double-blinded clinical trial. The investigators assessed the efficacy of intranasal insulin on cognition, function, and biomarkers of Alzheimer’s disease, as well as the safety and feasibility of the delivery method. The multicenter trial was conducted from 2014 to 2018 and included 27 sites.
Study participants were between the ages of 55 and 85 years and had been diagnosed with amnestic MCI or Alzheimer’s disease on the basis of National Institute on Aging–Alzheimer Association criteria, a score of 20 or higher on the Mini–Mental State Examination, a clinical dementia rating of 0.5 or 1.0, or a delayed logical memory score within a specified range.
In total, 289 participants were randomly assigned to receive 40 IU of insulin or placebo for 12 months, followed by a 6-month open-label extension phase. The first 49 participants (32 men; mean age, 71.9 years) underwent insulin administration with the same device the investigators used in previous trials.
Of these, 45 completed the blinded phase, and 42 completed the open-label extension. When this device, which uses an electronic nebulizer-like delivery system, proved unreliable, the researchers switched to a second device, which uses a liquid hydrofluoroalkane propellant to deliver a metered dose of insulin through a nose tip without electronic assistance. Device 2 was used for the remaining 240 participants (123 men; mean age, 70.8 years). These patients became the study’s primary intention-to-treat population.
The study’s primary outcome was the mean change in score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12), which was evaluated at 3-month intervals.
Secondary clinical outcomes were assessed at 6-month intervals. These included the mean change in scores for the Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment and the Clinical Dementia Rating Scale Sum of Boxes.
Safety and adherence were also assessed during each study visit. Physical and neurologic examinations were performed at baseline and at months 6, 12, and 18.
Of the primary intention-to-treat population of 240 patients, 121 were randomly assigned to receive intranasal insulin. The remaining 119 received placebo and served as controls. The two groups were demographically comparable.
Better cognitive performance
A total of 215 participants completed the blinded phase; 198 participants completed the open-label extension. Discontinuation rates were comparable in both arms. The researchers found no differences between groups with respect to mean change in ADAS-cog-12 score from baseline to month 12 (0.0258 points; 95% confidence interval, –1.771 to 1.822 points; P = .98). The two groups also proved comparable in terms of performance on all other cognitive tests.
The open-label portion yielded similar results. Participants originally assigned to the insulin arm and their counterparts in the placebo arm did not differ with respect to mean score change on the ADAS-cog-12 test (or any other outcome) at either month 15 or 18.
Cerebrospinal fluid insulin levels were unchanged between groups, as were blood glucose and hemoglobin A1c values. Indeed, levels of A-beta42, A-beta40, total tau protein, and tau p-181 were comparable for the patients who received intranasal insulin and those who received placebo.
The most common adverse events were infections, injuries, respiratory disorders, and nervous system disorders, though these did not differ between groups. In addition, there were no differences between groups with respect to severity of adverse events; most were rated as mild.
In contrast with the intention-to-treat population, the study’s secondary analysis – using data from the original administration device – yielded markedly different results. In the blinded phase, patients who received insulin had better ADAS-cog-12 performance at 12 months (−2.81 points; 95% CI, −6.09 to 0.45 points; P = .09) and nominally significant effects at 6 months (−3.78 points; 95% CI, −6.79 to −0.78 points; P = .01).
Device type critical
These effects persisted in the open-label analyses. Patients who received intranasal insulin had superior ADAS-cog-12 scores at month 15 (−5.70 points; 95% CI, −9.62 to −1.79 points; P = .004) and month 18 (−5.78 points; 95% CI, −10.55 to −1.01 points; P = .02), compared with their counterparts who received insulin via the second device. This part of the study also showed that, although individual biomarkers did not differ significantly between the two arms, the ratios of A-beta42 to A-beta40 (P = .01) and A-beta42 to total tau (P = .03) increased with use of the first device. The number, type, and severity of adverse events were comparable between the insulin and placebo groups in this arm of the study.
The mixed results revealed by the trial demonstrate that the device used for intranasal insulin administration is paramount in determining the therapy’s potential efficacy. “Our take-home message is that the device is a very important factor for these studies and that one needs to validate their ability to effectively deliver insulin to the CNS,” said Dr. Craft.
“We were quite confident that the first device was able to do that. On the other hand, the second device has never been tested in that way, and we still don’t know whether or not that device was able to successfully deliver insulin,” she said.
The investigators recognize the need for more research in the field. Such studies, Dr. Craft noted, will utilize administration devices that have been previously verified to have the ability to deliver insulin to the central nervous system. “We’re currently testing several devices,” she noted. “We’re using a protocol where we administer insulin with the devices and then conduct a lumbar puncture about 30 minutes later to verify that it is actually raising insulin levels in the cerebrospinal fluid.”
Not a failure
Commenting on the findings, Samuel E. Gandy, MD, PhD, who was not involved in the study, said the research illustrates the challenge when a new therapy, a new delivery device, and a cohort of cognitively impaired patients collide. “The result is not quite a slam dunk but is also by no means a failure,” commented Dr. Gandy, Mount Sinai Chair in Alzheimer’s Research at Mount Sinai Medical Center, New York.
“One looks forward to future iterations of the Craft et al. approach, wherein the trialists tweak the ligand and/or the delivery schedule and/or the device and/or the disease and/or the disease stage,” Dr. Gandy added. “Another ligand, VGF, also holds promise for intranasal delivery, based on work from Steve Salton, Michelle Ehrlich, and Eric Schadt, all from Mount Sinai. Perhaps the nose knows!”
For Dr. Craft, the potential upside of intranasal insulin for these patients is significant and warrants further investigation. “I understand why people who are not familiar with prior research in this area might be skeptical of our enthusiasm, given the results in the intention-to-treat population,” she said. “But those of us who have been working along with this for a while now, we feel like we’ve got to do the next study. But we need to have a device that we know works,” Dr. Craft added.
“If this is real, then there may be a very large clinical benefit in symptomatic patients, and there’s nothing so far that has really improved symptomatic disease.”
The study was supported by the National Institute on Aging. Eli Lilly provided diluent placebo for the blinded phase and insulin for the open-label phase of the clinical trial at no cost. Dr. Craft received grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work.
A version of this article originally appeared on Medscape.com.
FROM JAMA NEUROLOGY
New insight into neurobehavioral effects of legalized cannabis
Researchers have published one of the first studies to characterize the association between the consumption of legal cannabis and subsequent pharmacologic and neurobehavioral outcomes, with somewhat surprising results.
The study showed that, although cannabis consumption did not affect most short-term neurobehavioral measures, it delayed recall memory and impaired balance.
The investigation also showed that users of much more potent cannabis concentrates actually demonstrated similar or lower levels of subjective drug intoxication and short-term impairment than did their counterparts who used lower-potency forms of the cannabis flower.
“It does not appear that the potency being used matters that much,” senior investigator Kent E. Hutchison, PhD, said in an interview. “People seem to be titrating to a certain level of intoxication or a certain level of feeling high. And for some people that requires a lot of drug, and for other people not as much.”
added Dr. Hutchison, a professor of psychology and neuroscience at the University of Colorado Boulder.
The study was published online June 10 in JAMA Psychiatry.
Widespread availability, little research
Recreational cannabis is now legal in 11 states and the District of Columbia, while medical cannabis is legal in 33. However, despite growing popularity of cannabis, there is little research on its potential health and biobehavioral risks, largely because of federal restrictions on cannabis research.
Cannabis users typically consume various forms of the cannabis flower, which can boast concentrations of the psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) of up to 30%. However, use of concentrated forms of cannabis – which are made by extracting plant cannabinoids into a different form – is increasing.
Such formulations can boast THC concentrations as high as 90%. Nevertheless, data regarding the relative risks of these higher-strength products are limited.
Previous research has shown a variety of negative short-term and long-term neurobehavioral effects associated with cannabis use, including harmful cognitive and motor effects. Extended exposure to THC may also negatively affect brain regions that are associated with the control of coordinated movement, and create brain-activation deficits in motor control regions that persist well beyond the effects of short-term intoxication.
Despite such findings, Dr. Hutchison said the existing literature on the subject does not yield a real-world view of current cannabis use because it tends to focus on low-THC products that are increasingly less common in today’s legal market.
Given such shortcomings, the investigators wanted to address persistent questions surrounding the neurobehavioral effects of legal cannabis flower products (16% or 24% THC) and cannabis concentrate products (70% or 90% THC). In doing so, they examined three primary topics:
- The association between short-term use of these products and THC plasma levels; subjective intoxication; and mood, cognitive performance, and balance
- Differences in such associations between users of cannabis flower and concentrate products
- Potential variations in these associations by THC potency
High- versus low-potency varieties
The study included 133 individuals (aged 21-70 years), who were designated as either cannabis flower users or cannabis concentrate users. Participants had all used cannabis at least four times in the previous month with no adverse reaction and were not receiving treatment for a psychotic disorder or bipolar disorder.
Participants were randomly assigned to consume either higher-potency or lower-potency products that had been purchased from a local dispensary. Flower users were randomized to purchase 3 g of either a 16% THC or 24% THC product, while concentrate users were randomized to purchase 1g of either 70% THC or 90% THC.
Participants completed a series of four assessments, one at baseline and three others at a mobile laboratory. The mobile laboratory assessments occurred before, immediately after, and one hour after participants had all consumed their cannabis ad libitum.
Of the original cohort of 133 participants, 55 flower cannabis users (mean age, 28.8 years; 46% women) and 66 concentrate cannabis users (mean age, 28.3 years; 45% women) complied with the study’s instructions and had complete data.
The study’s primary outcome measures included plasma cannabinoids, subjective drug intoxication and mood, and neurobehavioral outcomes such as attention, memory, inhibitory control, and balance.
Mixed results
With respect to cannabis concentrations, results showed that users of concentrate exhibited higher levels of both plasma THC and the active metabolite of THC (11-hydroxy-delta9-THC) across all points than did their counterparts who used cannabis flower products.
Specifically, mean plasma THC levels were 1,016 ± 1,380 mcg/ml in concentrate users and 455±503 mcg/mL in flower users after ad libitum cannabis consumption. Nevertheless, self-reported levels of intoxication were no different between users of cannabis flower or concentrate products.
Although results also showed that most neurobehavioral measures were not altered by short-term cannabis consumption, there were some notable exceptions. There was a negative linear effect with delayed verbal recall errors, suggesting poorer performance after cannabis use (F1, 203 = 32.31; P < .001).
On the other hand, investigators found a positive linear effect with inhibitory control and working memory, which actually suggests better performance after cannabis use. This finding, the researchers note, may be the result of a practice effect. Cannabis flower users performed better across all inhibitory control assessments.
The researchers also tested participants’ balance with their eyes open and closed. In the eyes-open condition, they found a trend toward impaired balance after cannabis use, though this normalized within an hour. When subjects closed their eyes, however, researchers observed a significant short-term increase in sway after cannabis use, which fell back to pre-use levels one hour after use (F1, 203 = 18.88; P < .001).
Of note, outcomes did not differ between groups according to the type of cannabis product consumed or its relative potency.
The study yielded several surprising findings, beginning with self-reported intoxication levels, which were not statistically significant between different cannabis flower and concentrate users, despite significantly different plasma THC levels between the two groups.
Dr. Hutchison explained that this may be the result of greater THC tolerance among concentrate users, THC saturation of cannabinoid receptors, or interindividual differences among users with respect to cannabis metabolism or sensitivity.
“I thought for sure that high-potency users would be much more compromised,” he said. “I guess it just goes to show we have a lot to learn about how these things work.”
Additionally, there were virtually no significant changes in acute performance after cannabis use, with the exception of delayed verbal recall. In fact, the most marked change observed in the study was the effect of cannabis on balance immediately after drug use, though these changes seemed to abate within an hour.
Nevertheless, the study highlights several potential public health implications of cannabis consumption, Dr. Hutchison added. “What happens when people with high blood concentrations decide to quit?” he asked. “Do they have trouble quitting? Do they have withdrawal symptoms?”
The long-term effects of cannabis use is another important question that still needs to be answered, he added.
Finally, Dr. Hutchison noted that, although the study showed little difference between users of cannabis flower and concentrates, study participants were all experienced users.
“There is certainly the potential for harm when a naive person uses cannabis concentrate,” he said. “Suddenly they have way more THC than they thought they were going to get, and that’s where a lot of people get into trouble with cannabis.”
Pitfalls and hurdles
In an accompanying editorial, Margaret Haney, PhD, of Columbia University Irving Medical Center, New York, explained that cannabis’ awkward position as simultaneously legal and illegal, medical and recreational, has hampered researchers’ ability to study its effects as comprehensively as they would otherwise like.
“With a federally illegal drug legalized in individual states, scientists constrained, and federal agencies somewhat silent, clinicians have none of the data that guide their decisions for other medications (eg, which indication, product, cannabinoid ratio, dose, or route of administration; what risks for individual patients [eg, pregnant, adolescent, psychiatric?]),” Dr. Haney wrote.
These pitfalls are compounded by the significant regulatory hurdles.
“The FDA is appropriately cautious about what it allows scientists to test in patients, and none of the products available in dispensaries or online have undergone the safety and manufacturing procedures needed for FDA approval,” she continued. “How then to conduct the studies so needed?”
Yet as Haney noted, giving cannabinoid researchers a Schedule I exemption may help address many of the barriers facing these scientists. Such a move, she said, would increase the number of randomized controlled trials being performed, “and thereby begin to breach the divide between the use of these products and empirical evidence.”
Dr. Hutchison has disclosed no relevant financial relationships. Dr. Haney disclosed funding from the US National Institute on Drug Abuse and from the Thompson Family Foundation Initiative. The study was funded by the NIH and Colorado Department of Public Health and Environment.
A version of this article originally appeared on Medscape.com.
Researchers have published one of the first studies to characterize the association between the consumption of legal cannabis and subsequent pharmacologic and neurobehavioral outcomes, with somewhat surprising results.
The study showed that, although cannabis consumption did not affect most short-term neurobehavioral measures, it delayed recall memory and impaired balance.
The investigation also showed that users of much more potent cannabis concentrates actually demonstrated similar or lower levels of subjective drug intoxication and short-term impairment than did their counterparts who used lower-potency forms of the cannabis flower.
“It does not appear that the potency being used matters that much,” senior investigator Kent E. Hutchison, PhD, said in an interview. “People seem to be titrating to a certain level of intoxication or a certain level of feeling high. And for some people that requires a lot of drug, and for other people not as much.”
added Dr. Hutchison, a professor of psychology and neuroscience at the University of Colorado Boulder.
The study was published online June 10 in JAMA Psychiatry.
Widespread availability, little research
Recreational cannabis is now legal in 11 states and the District of Columbia, while medical cannabis is legal in 33. However, despite growing popularity of cannabis, there is little research on its potential health and biobehavioral risks, largely because of federal restrictions on cannabis research.
Cannabis users typically consume various forms of the cannabis flower, which can boast concentrations of the psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) of up to 30%. However, use of concentrated forms of cannabis – which are made by extracting plant cannabinoids into a different form – is increasing.
Such formulations can boast THC concentrations as high as 90%. Nevertheless, data regarding the relative risks of these higher-strength products are limited.
Previous research has shown a variety of negative short-term and long-term neurobehavioral effects associated with cannabis use, including harmful cognitive and motor effects. Extended exposure to THC may also negatively affect brain regions that are associated with the control of coordinated movement, and create brain-activation deficits in motor control regions that persist well beyond the effects of short-term intoxication.
Despite such findings, Dr. Hutchison said the existing literature on the subject does not yield a real-world view of current cannabis use because it tends to focus on low-THC products that are increasingly less common in today’s legal market.
Given such shortcomings, the investigators wanted to address persistent questions surrounding the neurobehavioral effects of legal cannabis flower products (16% or 24% THC) and cannabis concentrate products (70% or 90% THC). In doing so, they examined three primary topics:
- The association between short-term use of these products and THC plasma levels; subjective intoxication; and mood, cognitive performance, and balance
- Differences in such associations between users of cannabis flower and concentrate products
- Potential variations in these associations by THC potency
High- versus low-potency varieties
The study included 133 individuals (aged 21-70 years), who were designated as either cannabis flower users or cannabis concentrate users. Participants had all used cannabis at least four times in the previous month with no adverse reaction and were not receiving treatment for a psychotic disorder or bipolar disorder.
Participants were randomly assigned to consume either higher-potency or lower-potency products that had been purchased from a local dispensary. Flower users were randomized to purchase 3 g of either a 16% THC or 24% THC product, while concentrate users were randomized to purchase 1g of either 70% THC or 90% THC.
Participants completed a series of four assessments, one at baseline and three others at a mobile laboratory. The mobile laboratory assessments occurred before, immediately after, and one hour after participants had all consumed their cannabis ad libitum.
Of the original cohort of 133 participants, 55 flower cannabis users (mean age, 28.8 years; 46% women) and 66 concentrate cannabis users (mean age, 28.3 years; 45% women) complied with the study’s instructions and had complete data.
The study’s primary outcome measures included plasma cannabinoids, subjective drug intoxication and mood, and neurobehavioral outcomes such as attention, memory, inhibitory control, and balance.
Mixed results
With respect to cannabis concentrations, results showed that users of concentrate exhibited higher levels of both plasma THC and the active metabolite of THC (11-hydroxy-delta9-THC) across all points than did their counterparts who used cannabis flower products.
Specifically, mean plasma THC levels were 1,016 ± 1,380 mcg/ml in concentrate users and 455±503 mcg/mL in flower users after ad libitum cannabis consumption. Nevertheless, self-reported levels of intoxication were no different between users of cannabis flower or concentrate products.
Although results also showed that most neurobehavioral measures were not altered by short-term cannabis consumption, there were some notable exceptions. There was a negative linear effect with delayed verbal recall errors, suggesting poorer performance after cannabis use (F1, 203 = 32.31; P < .001).
On the other hand, investigators found a positive linear effect with inhibitory control and working memory, which actually suggests better performance after cannabis use. This finding, the researchers note, may be the result of a practice effect. Cannabis flower users performed better across all inhibitory control assessments.
The researchers also tested participants’ balance with their eyes open and closed. In the eyes-open condition, they found a trend toward impaired balance after cannabis use, though this normalized within an hour. When subjects closed their eyes, however, researchers observed a significant short-term increase in sway after cannabis use, which fell back to pre-use levels one hour after use (F1, 203 = 18.88; P < .001).
Of note, outcomes did not differ between groups according to the type of cannabis product consumed or its relative potency.
The study yielded several surprising findings, beginning with self-reported intoxication levels, which were not statistically significant between different cannabis flower and concentrate users, despite significantly different plasma THC levels between the two groups.
Dr. Hutchison explained that this may be the result of greater THC tolerance among concentrate users, THC saturation of cannabinoid receptors, or interindividual differences among users with respect to cannabis metabolism or sensitivity.
“I thought for sure that high-potency users would be much more compromised,” he said. “I guess it just goes to show we have a lot to learn about how these things work.”
Additionally, there were virtually no significant changes in acute performance after cannabis use, with the exception of delayed verbal recall. In fact, the most marked change observed in the study was the effect of cannabis on balance immediately after drug use, though these changes seemed to abate within an hour.
Nevertheless, the study highlights several potential public health implications of cannabis consumption, Dr. Hutchison added. “What happens when people with high blood concentrations decide to quit?” he asked. “Do they have trouble quitting? Do they have withdrawal symptoms?”
The long-term effects of cannabis use is another important question that still needs to be answered, he added.
Finally, Dr. Hutchison noted that, although the study showed little difference between users of cannabis flower and concentrates, study participants were all experienced users.
“There is certainly the potential for harm when a naive person uses cannabis concentrate,” he said. “Suddenly they have way more THC than they thought they were going to get, and that’s where a lot of people get into trouble with cannabis.”
Pitfalls and hurdles
In an accompanying editorial, Margaret Haney, PhD, of Columbia University Irving Medical Center, New York, explained that cannabis’ awkward position as simultaneously legal and illegal, medical and recreational, has hampered researchers’ ability to study its effects as comprehensively as they would otherwise like.
“With a federally illegal drug legalized in individual states, scientists constrained, and federal agencies somewhat silent, clinicians have none of the data that guide their decisions for other medications (eg, which indication, product, cannabinoid ratio, dose, or route of administration; what risks for individual patients [eg, pregnant, adolescent, psychiatric?]),” Dr. Haney wrote.
These pitfalls are compounded by the significant regulatory hurdles.
“The FDA is appropriately cautious about what it allows scientists to test in patients, and none of the products available in dispensaries or online have undergone the safety and manufacturing procedures needed for FDA approval,” she continued. “How then to conduct the studies so needed?”
Yet as Haney noted, giving cannabinoid researchers a Schedule I exemption may help address many of the barriers facing these scientists. Such a move, she said, would increase the number of randomized controlled trials being performed, “and thereby begin to breach the divide between the use of these products and empirical evidence.”
Dr. Hutchison has disclosed no relevant financial relationships. Dr. Haney disclosed funding from the US National Institute on Drug Abuse and from the Thompson Family Foundation Initiative. The study was funded by the NIH and Colorado Department of Public Health and Environment.
A version of this article originally appeared on Medscape.com.
Researchers have published one of the first studies to characterize the association between the consumption of legal cannabis and subsequent pharmacologic and neurobehavioral outcomes, with somewhat surprising results.
The study showed that, although cannabis consumption did not affect most short-term neurobehavioral measures, it delayed recall memory and impaired balance.
The investigation also showed that users of much more potent cannabis concentrates actually demonstrated similar or lower levels of subjective drug intoxication and short-term impairment than did their counterparts who used lower-potency forms of the cannabis flower.
“It does not appear that the potency being used matters that much,” senior investigator Kent E. Hutchison, PhD, said in an interview. “People seem to be titrating to a certain level of intoxication or a certain level of feeling high. And for some people that requires a lot of drug, and for other people not as much.”
added Dr. Hutchison, a professor of psychology and neuroscience at the University of Colorado Boulder.
The study was published online June 10 in JAMA Psychiatry.
Widespread availability, little research
Recreational cannabis is now legal in 11 states and the District of Columbia, while medical cannabis is legal in 33. However, despite growing popularity of cannabis, there is little research on its potential health and biobehavioral risks, largely because of federal restrictions on cannabis research.
Cannabis users typically consume various forms of the cannabis flower, which can boast concentrations of the psychoactive cannabinoid delta-9-tetrahydrocannabinol (THC) of up to 30%. However, use of concentrated forms of cannabis – which are made by extracting plant cannabinoids into a different form – is increasing.
Such formulations can boast THC concentrations as high as 90%. Nevertheless, data regarding the relative risks of these higher-strength products are limited.
Previous research has shown a variety of negative short-term and long-term neurobehavioral effects associated with cannabis use, including harmful cognitive and motor effects. Extended exposure to THC may also negatively affect brain regions that are associated with the control of coordinated movement, and create brain-activation deficits in motor control regions that persist well beyond the effects of short-term intoxication.
Despite such findings, Dr. Hutchison said the existing literature on the subject does not yield a real-world view of current cannabis use because it tends to focus on low-THC products that are increasingly less common in today’s legal market.
Given such shortcomings, the investigators wanted to address persistent questions surrounding the neurobehavioral effects of legal cannabis flower products (16% or 24% THC) and cannabis concentrate products (70% or 90% THC). In doing so, they examined three primary topics:
- The association between short-term use of these products and THC plasma levels; subjective intoxication; and mood, cognitive performance, and balance
- Differences in such associations between users of cannabis flower and concentrate products
- Potential variations in these associations by THC potency
High- versus low-potency varieties
The study included 133 individuals (aged 21-70 years), who were designated as either cannabis flower users or cannabis concentrate users. Participants had all used cannabis at least four times in the previous month with no adverse reaction and were not receiving treatment for a psychotic disorder or bipolar disorder.
Participants were randomly assigned to consume either higher-potency or lower-potency products that had been purchased from a local dispensary. Flower users were randomized to purchase 3 g of either a 16% THC or 24% THC product, while concentrate users were randomized to purchase 1g of either 70% THC or 90% THC.
Participants completed a series of four assessments, one at baseline and three others at a mobile laboratory. The mobile laboratory assessments occurred before, immediately after, and one hour after participants had all consumed their cannabis ad libitum.
Of the original cohort of 133 participants, 55 flower cannabis users (mean age, 28.8 years; 46% women) and 66 concentrate cannabis users (mean age, 28.3 years; 45% women) complied with the study’s instructions and had complete data.
The study’s primary outcome measures included plasma cannabinoids, subjective drug intoxication and mood, and neurobehavioral outcomes such as attention, memory, inhibitory control, and balance.
Mixed results
With respect to cannabis concentrations, results showed that users of concentrate exhibited higher levels of both plasma THC and the active metabolite of THC (11-hydroxy-delta9-THC) across all points than did their counterparts who used cannabis flower products.
Specifically, mean plasma THC levels were 1,016 ± 1,380 mcg/ml in concentrate users and 455±503 mcg/mL in flower users after ad libitum cannabis consumption. Nevertheless, self-reported levels of intoxication were no different between users of cannabis flower or concentrate products.
Although results also showed that most neurobehavioral measures were not altered by short-term cannabis consumption, there were some notable exceptions. There was a negative linear effect with delayed verbal recall errors, suggesting poorer performance after cannabis use (F1, 203 = 32.31; P < .001).
On the other hand, investigators found a positive linear effect with inhibitory control and working memory, which actually suggests better performance after cannabis use. This finding, the researchers note, may be the result of a practice effect. Cannabis flower users performed better across all inhibitory control assessments.
The researchers also tested participants’ balance with their eyes open and closed. In the eyes-open condition, they found a trend toward impaired balance after cannabis use, though this normalized within an hour. When subjects closed their eyes, however, researchers observed a significant short-term increase in sway after cannabis use, which fell back to pre-use levels one hour after use (F1, 203 = 18.88; P < .001).
Of note, outcomes did not differ between groups according to the type of cannabis product consumed or its relative potency.
The study yielded several surprising findings, beginning with self-reported intoxication levels, which were not statistically significant between different cannabis flower and concentrate users, despite significantly different plasma THC levels between the two groups.
Dr. Hutchison explained that this may be the result of greater THC tolerance among concentrate users, THC saturation of cannabinoid receptors, or interindividual differences among users with respect to cannabis metabolism or sensitivity.
“I thought for sure that high-potency users would be much more compromised,” he said. “I guess it just goes to show we have a lot to learn about how these things work.”
Additionally, there were virtually no significant changes in acute performance after cannabis use, with the exception of delayed verbal recall. In fact, the most marked change observed in the study was the effect of cannabis on balance immediately after drug use, though these changes seemed to abate within an hour.
Nevertheless, the study highlights several potential public health implications of cannabis consumption, Dr. Hutchison added. “What happens when people with high blood concentrations decide to quit?” he asked. “Do they have trouble quitting? Do they have withdrawal symptoms?”
The long-term effects of cannabis use is another important question that still needs to be answered, he added.
Finally, Dr. Hutchison noted that, although the study showed little difference between users of cannabis flower and concentrates, study participants were all experienced users.
“There is certainly the potential for harm when a naive person uses cannabis concentrate,” he said. “Suddenly they have way more THC than they thought they were going to get, and that’s where a lot of people get into trouble with cannabis.”
Pitfalls and hurdles
In an accompanying editorial, Margaret Haney, PhD, of Columbia University Irving Medical Center, New York, explained that cannabis’ awkward position as simultaneously legal and illegal, medical and recreational, has hampered researchers’ ability to study its effects as comprehensively as they would otherwise like.
“With a federally illegal drug legalized in individual states, scientists constrained, and federal agencies somewhat silent, clinicians have none of the data that guide their decisions for other medications (eg, which indication, product, cannabinoid ratio, dose, or route of administration; what risks for individual patients [eg, pregnant, adolescent, psychiatric?]),” Dr. Haney wrote.
These pitfalls are compounded by the significant regulatory hurdles.
“The FDA is appropriately cautious about what it allows scientists to test in patients, and none of the products available in dispensaries or online have undergone the safety and manufacturing procedures needed for FDA approval,” she continued. “How then to conduct the studies so needed?”
Yet as Haney noted, giving cannabinoid researchers a Schedule I exemption may help address many of the barriers facing these scientists. Such a move, she said, would increase the number of randomized controlled trials being performed, “and thereby begin to breach the divide between the use of these products and empirical evidence.”
Dr. Hutchison has disclosed no relevant financial relationships. Dr. Haney disclosed funding from the US National Institute on Drug Abuse and from the Thompson Family Foundation Initiative. The study was funded by the NIH and Colorado Department of Public Health and Environment.
A version of this article originally appeared on Medscape.com.
‘Nietzsche was wrong’: Past stressors do not create psychological resilience.
The famous quote from the German philosopher Friedrich Nietzsche, “That which does not kill us makes us stronger,” may not be true after all – at least when it comes to mental health.
Results of a new study show that individuals who have a history of a stressful life events are more likely to develop posttraumatic stress disorder (PTSD) and/or major depressive disorder (MDD) following a major natural disaster than their counterparts who do not have such a history.
The investigation of more than a thousand Chilean residents – all of whom experienced one of the most powerful earthquakes in the country’s history – showed that the odds of developing postdisaster PTSD or MDD increased according to the number of predisaster stressors participants had experienced.
“We’ve learned that Nietzsche was wrong in this case and that the people who have had prior stressful and traumatic histories were more likely to develop PTSD and depression than those with fewer, study investigator Stephen L. Buka, PhD, professor of epidemiology at Brown University, Providence, Rhode Island, said in an interview.
The study was published online June 11 in the British Journal of Psychiatry.
Stress inoculation hypothesis
The so-called stress inoculation hypothesis proposes that individuals who experience manageable stressors may be able to better cope with subsequent stressors, inasmuch as such experience affords them opportunities to practice effective coping skills and develop a sense of mastery over stressors.
, particularly with respect to such common mental health disorders as MDD and PTSD. Although less severe day-to-day stressors may be easier to cope with, major trauma can overwhelm an individual’s coping mechanisms.
Findings from previous research have been mixed. Some studiessuggest that prior stressors can increase the risk of developing later psychiatric disorders. On the other hand, previous research has also shown that exposure to prior trauma alone does not predict subsequent PTSD.
Given these contradictions, the investigators wanted to determine whether a history of prior stressors was associated with psychiatric resilience among individuals who had no psychiatric history of MDD or PTSD.
“Only a small minority of people who have experienced a traumatic event go on to develop PTSD or MDD,” said lead author Cristina Fernandez, PhD, a psychiatric epidemiologist at the PAHO/WHO Collaborating Center for Research on Psychiatric Epidemiology and Mental Health, Brown University, Providence, R.I.
“So most people are resilient and move on without developing these disorders. But what is unique about this minority of individuals that makes them more susceptible to developing these disorders?” she continued. “It’s one of the most significant questions in the PTSD literature,” she added.
The analysis included data from 10 sites in the Chilean cities of Concepción and Talcahuano that had participated in the PREDICT investigation, a prospective cohort study that sought to predict mental health outcomes among primary care patients.
While the PREDICT study was being conducted, in February 2010, a major earthquake struck the coast of central Chile, killing more than 500 people and displacing 800,000. Concepción and Talcahuano experienced the most damage from the earthquake and its subsequent effects, including a tsunami that ravaged Talcahuano.
Dose-dependent effect
At baseline and 1 year after the disaster, all participants completed the Composite International Diagnostic Interview, which assesses for the presence of PTSD and/or MDD. Participants also completed the List of Threatening Experiences, a 12-item questionnaire that measures major stressful life events.
Of 3,000 participants who initially agreed to take part in the trial, 1708 completed both the predisaster assessment in 2003 and the postdisaster assessment in 2011, 1 year after the earthquake and tsunami occurred. After excluding for a variety other criteria, 1,160 individuals were included in the final analysis.
“As it turns out, it was a very natural experiment,” said Dr. Buka. “We had a group of people whose past traumatic experiences we knew about, and then they were all subjected to this terrible earthquake, and then we were able to look forward into time and see who did and didn’t develop PTSD and MDD.”
When the study began in 2003, none of the 1,160 participants had a history of PTSD or MDD. After the 2010 earthquake, 9.1% of the survivors (n = 106) were diagnosed with PTSD, and 14.4% were diagnosed with MDD (n = 167).
Further analyses showed that prior disaster exposure was not a significant predictor of postdisaster PTSD. Nevertheless, for every unit increase in prior nondisaster stressors, the odds of developing postdisaster PTSD increased (odds ratio, 1.21; 95% confidence interval, 1.08-1.37; P = .001).
When categorizing predisaster stressors, the investigators found that individuals who had four or more predisaster stressors had a significantly greater chance of developing postdisaster PTSD than those with no predisaster stressors (OR, 2.77; 95% CI, 1.52 – 5.04).
Similar logistic regression analyses were performed for MDD, with comparable results. Although prior disaster exposure was not a significant predictor of postdisaster MDD, each one-unit increase in prior nondisaster stressors increased the odds of developing postdisaster MDD by 16% (OR, 1.16; 95% CI, 1.06-1.27; P = .001).
Categorization of these stressors revealed that experiencing any number of stressors significantly increased the odds of developing postdisaster MDD in a dose-response fashion.
In other words, every predisaster stressor – even a single one – increased an individual’s risk of developing postdisaster MDD, and each additional stressor further increased the risk.
Predisaster stressors
Interestingly, the study also showed that the risk of developing both PTSD and MDD was particularly high among those who had experienced multiple predisaster stressors, such as serious illness or injury, death of a loved one, divorce, unemployment, financial struggles, legal troubles, or the loss of a valuable possession.
These findings, the researchers note, demonstrate that a history of stressors increases what they called “stress sensitization,” which may make individuals more vulnerable to the negative effects of subsequent stressors rather than more resilient.
As such, individuals who have experienced several stressors over the course of a lifetime are at higher risk of developing a psychiatric disorder.
This was the case with PTSD, in which exposure to at least four previous manageable stressors was associated with greater odds of developing postdisaster PTSD. For MDD, on the other hand, there was a distinct dose-response relationship between the number of manageable predisaster stressors and the risk for postdisaster MDD.
The investigators explain that these findings are particularly relevant in light of the COVID-19 pandemic and the current focus on racial and economic inequality in the United States. “The findings highlight the sectors of the population that are at greatest risk,” Dr. Buka said. “And those are the ones who’ve had more challenging and traumatic lives and more hardship.
“So it certainly calls for greater concentration of psychiatric services in traditionally underserved areas, because those are also areas that have greater histories of trauma.”
“Fascinating” research
Commenting on the findings fin an interview, Patricia A. Resick, PhD, who was not involved in the study, said she found the research fascinating.
“The fact that they had preexisting data and then had the wherewithal to go back after the earthquake is quite amazing,” she said.
The findings came as little surprise to Dr. Resick, professor of psychiatry and behavioral sciences at Duke University Medical Center in Durham, N.C.
“I think most people are in agreement that the more stress you have, the more likely you are to get PTSD when you experience a traumatic stressor,” she said.
Treating these individuals remains a challenge, Dr. Resick noted, though knowing their history of stressors and traumas is an important starting point.
“We have to get a good history and figure out where to start treating them, because we always want to start with the event that causes the most PTSD symptoms,” she explained.
She also characterized the issue as being as much a public health concern as one for psychiatrists. “These are people you will want to have surveillance on and encourage them to get help,” Dr. Resick added.
Dr. Fernandez agreed.
“In the face of a disaster,” she said, “there needs to be more attention paid to vulnerable populations, because they likely don’t have the support they need.
“At the clinical level, these findings help the clinician know which patients are more likely to need more intensive services,” Dr. Buka added. “And the more trauma and hardship they’ve experienced, the more attention they need and the less likely they’re going to be able to cope and manage on their own.”
The study was funded by the U.S. National Institute of Mental Health and FONDEF Chile. Dr. Fernandez, Dr. Buka, and Dr. Resick have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The famous quote from the German philosopher Friedrich Nietzsche, “That which does not kill us makes us stronger,” may not be true after all – at least when it comes to mental health.
Results of a new study show that individuals who have a history of a stressful life events are more likely to develop posttraumatic stress disorder (PTSD) and/or major depressive disorder (MDD) following a major natural disaster than their counterparts who do not have such a history.
The investigation of more than a thousand Chilean residents – all of whom experienced one of the most powerful earthquakes in the country’s history – showed that the odds of developing postdisaster PTSD or MDD increased according to the number of predisaster stressors participants had experienced.
“We’ve learned that Nietzsche was wrong in this case and that the people who have had prior stressful and traumatic histories were more likely to develop PTSD and depression than those with fewer, study investigator Stephen L. Buka, PhD, professor of epidemiology at Brown University, Providence, Rhode Island, said in an interview.
The study was published online June 11 in the British Journal of Psychiatry.
Stress inoculation hypothesis
The so-called stress inoculation hypothesis proposes that individuals who experience manageable stressors may be able to better cope with subsequent stressors, inasmuch as such experience affords them opportunities to practice effective coping skills and develop a sense of mastery over stressors.
, particularly with respect to such common mental health disorders as MDD and PTSD. Although less severe day-to-day stressors may be easier to cope with, major trauma can overwhelm an individual’s coping mechanisms.
Findings from previous research have been mixed. Some studiessuggest that prior stressors can increase the risk of developing later psychiatric disorders. On the other hand, previous research has also shown that exposure to prior trauma alone does not predict subsequent PTSD.
Given these contradictions, the investigators wanted to determine whether a history of prior stressors was associated with psychiatric resilience among individuals who had no psychiatric history of MDD or PTSD.
“Only a small minority of people who have experienced a traumatic event go on to develop PTSD or MDD,” said lead author Cristina Fernandez, PhD, a psychiatric epidemiologist at the PAHO/WHO Collaborating Center for Research on Psychiatric Epidemiology and Mental Health, Brown University, Providence, R.I.
“So most people are resilient and move on without developing these disorders. But what is unique about this minority of individuals that makes them more susceptible to developing these disorders?” she continued. “It’s one of the most significant questions in the PTSD literature,” she added.
The analysis included data from 10 sites in the Chilean cities of Concepción and Talcahuano that had participated in the PREDICT investigation, a prospective cohort study that sought to predict mental health outcomes among primary care patients.
While the PREDICT study was being conducted, in February 2010, a major earthquake struck the coast of central Chile, killing more than 500 people and displacing 800,000. Concepción and Talcahuano experienced the most damage from the earthquake and its subsequent effects, including a tsunami that ravaged Talcahuano.
Dose-dependent effect
At baseline and 1 year after the disaster, all participants completed the Composite International Diagnostic Interview, which assesses for the presence of PTSD and/or MDD. Participants also completed the List of Threatening Experiences, a 12-item questionnaire that measures major stressful life events.
Of 3,000 participants who initially agreed to take part in the trial, 1708 completed both the predisaster assessment in 2003 and the postdisaster assessment in 2011, 1 year after the earthquake and tsunami occurred. After excluding for a variety other criteria, 1,160 individuals were included in the final analysis.
“As it turns out, it was a very natural experiment,” said Dr. Buka. “We had a group of people whose past traumatic experiences we knew about, and then they were all subjected to this terrible earthquake, and then we were able to look forward into time and see who did and didn’t develop PTSD and MDD.”
When the study began in 2003, none of the 1,160 participants had a history of PTSD or MDD. After the 2010 earthquake, 9.1% of the survivors (n = 106) were diagnosed with PTSD, and 14.4% were diagnosed with MDD (n = 167).
Further analyses showed that prior disaster exposure was not a significant predictor of postdisaster PTSD. Nevertheless, for every unit increase in prior nondisaster stressors, the odds of developing postdisaster PTSD increased (odds ratio, 1.21; 95% confidence interval, 1.08-1.37; P = .001).
When categorizing predisaster stressors, the investigators found that individuals who had four or more predisaster stressors had a significantly greater chance of developing postdisaster PTSD than those with no predisaster stressors (OR, 2.77; 95% CI, 1.52 – 5.04).
Similar logistic regression analyses were performed for MDD, with comparable results. Although prior disaster exposure was not a significant predictor of postdisaster MDD, each one-unit increase in prior nondisaster stressors increased the odds of developing postdisaster MDD by 16% (OR, 1.16; 95% CI, 1.06-1.27; P = .001).
Categorization of these stressors revealed that experiencing any number of stressors significantly increased the odds of developing postdisaster MDD in a dose-response fashion.
In other words, every predisaster stressor – even a single one – increased an individual’s risk of developing postdisaster MDD, and each additional stressor further increased the risk.
Predisaster stressors
Interestingly, the study also showed that the risk of developing both PTSD and MDD was particularly high among those who had experienced multiple predisaster stressors, such as serious illness or injury, death of a loved one, divorce, unemployment, financial struggles, legal troubles, or the loss of a valuable possession.
These findings, the researchers note, demonstrate that a history of stressors increases what they called “stress sensitization,” which may make individuals more vulnerable to the negative effects of subsequent stressors rather than more resilient.
As such, individuals who have experienced several stressors over the course of a lifetime are at higher risk of developing a psychiatric disorder.
This was the case with PTSD, in which exposure to at least four previous manageable stressors was associated with greater odds of developing postdisaster PTSD. For MDD, on the other hand, there was a distinct dose-response relationship between the number of manageable predisaster stressors and the risk for postdisaster MDD.
The investigators explain that these findings are particularly relevant in light of the COVID-19 pandemic and the current focus on racial and economic inequality in the United States. “The findings highlight the sectors of the population that are at greatest risk,” Dr. Buka said. “And those are the ones who’ve had more challenging and traumatic lives and more hardship.
“So it certainly calls for greater concentration of psychiatric services in traditionally underserved areas, because those are also areas that have greater histories of trauma.”
“Fascinating” research
Commenting on the findings fin an interview, Patricia A. Resick, PhD, who was not involved in the study, said she found the research fascinating.
“The fact that they had preexisting data and then had the wherewithal to go back after the earthquake is quite amazing,” she said.
The findings came as little surprise to Dr. Resick, professor of psychiatry and behavioral sciences at Duke University Medical Center in Durham, N.C.
“I think most people are in agreement that the more stress you have, the more likely you are to get PTSD when you experience a traumatic stressor,” she said.
Treating these individuals remains a challenge, Dr. Resick noted, though knowing their history of stressors and traumas is an important starting point.
“We have to get a good history and figure out where to start treating them, because we always want to start with the event that causes the most PTSD symptoms,” she explained.
She also characterized the issue as being as much a public health concern as one for psychiatrists. “These are people you will want to have surveillance on and encourage them to get help,” Dr. Resick added.
Dr. Fernandez agreed.
“In the face of a disaster,” she said, “there needs to be more attention paid to vulnerable populations, because they likely don’t have the support they need.
“At the clinical level, these findings help the clinician know which patients are more likely to need more intensive services,” Dr. Buka added. “And the more trauma and hardship they’ve experienced, the more attention they need and the less likely they’re going to be able to cope and manage on their own.”
The study was funded by the U.S. National Institute of Mental Health and FONDEF Chile. Dr. Fernandez, Dr. Buka, and Dr. Resick have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The famous quote from the German philosopher Friedrich Nietzsche, “That which does not kill us makes us stronger,” may not be true after all – at least when it comes to mental health.
Results of a new study show that individuals who have a history of a stressful life events are more likely to develop posttraumatic stress disorder (PTSD) and/or major depressive disorder (MDD) following a major natural disaster than their counterparts who do not have such a history.
The investigation of more than a thousand Chilean residents – all of whom experienced one of the most powerful earthquakes in the country’s history – showed that the odds of developing postdisaster PTSD or MDD increased according to the number of predisaster stressors participants had experienced.
“We’ve learned that Nietzsche was wrong in this case and that the people who have had prior stressful and traumatic histories were more likely to develop PTSD and depression than those with fewer, study investigator Stephen L. Buka, PhD, professor of epidemiology at Brown University, Providence, Rhode Island, said in an interview.
The study was published online June 11 in the British Journal of Psychiatry.
Stress inoculation hypothesis
The so-called stress inoculation hypothesis proposes that individuals who experience manageable stressors may be able to better cope with subsequent stressors, inasmuch as such experience affords them opportunities to practice effective coping skills and develop a sense of mastery over stressors.
, particularly with respect to such common mental health disorders as MDD and PTSD. Although less severe day-to-day stressors may be easier to cope with, major trauma can overwhelm an individual’s coping mechanisms.
Findings from previous research have been mixed. Some studiessuggest that prior stressors can increase the risk of developing later psychiatric disorders. On the other hand, previous research has also shown that exposure to prior trauma alone does not predict subsequent PTSD.
Given these contradictions, the investigators wanted to determine whether a history of prior stressors was associated with psychiatric resilience among individuals who had no psychiatric history of MDD or PTSD.
“Only a small minority of people who have experienced a traumatic event go on to develop PTSD or MDD,” said lead author Cristina Fernandez, PhD, a psychiatric epidemiologist at the PAHO/WHO Collaborating Center for Research on Psychiatric Epidemiology and Mental Health, Brown University, Providence, R.I.
“So most people are resilient and move on without developing these disorders. But what is unique about this minority of individuals that makes them more susceptible to developing these disorders?” she continued. “It’s one of the most significant questions in the PTSD literature,” she added.
The analysis included data from 10 sites in the Chilean cities of Concepción and Talcahuano that had participated in the PREDICT investigation, a prospective cohort study that sought to predict mental health outcomes among primary care patients.
While the PREDICT study was being conducted, in February 2010, a major earthquake struck the coast of central Chile, killing more than 500 people and displacing 800,000. Concepción and Talcahuano experienced the most damage from the earthquake and its subsequent effects, including a tsunami that ravaged Talcahuano.
Dose-dependent effect
At baseline and 1 year after the disaster, all participants completed the Composite International Diagnostic Interview, which assesses for the presence of PTSD and/or MDD. Participants also completed the List of Threatening Experiences, a 12-item questionnaire that measures major stressful life events.
Of 3,000 participants who initially agreed to take part in the trial, 1708 completed both the predisaster assessment in 2003 and the postdisaster assessment in 2011, 1 year after the earthquake and tsunami occurred. After excluding for a variety other criteria, 1,160 individuals were included in the final analysis.
“As it turns out, it was a very natural experiment,” said Dr. Buka. “We had a group of people whose past traumatic experiences we knew about, and then they were all subjected to this terrible earthquake, and then we were able to look forward into time and see who did and didn’t develop PTSD and MDD.”
When the study began in 2003, none of the 1,160 participants had a history of PTSD or MDD. After the 2010 earthquake, 9.1% of the survivors (n = 106) were diagnosed with PTSD, and 14.4% were diagnosed with MDD (n = 167).
Further analyses showed that prior disaster exposure was not a significant predictor of postdisaster PTSD. Nevertheless, for every unit increase in prior nondisaster stressors, the odds of developing postdisaster PTSD increased (odds ratio, 1.21; 95% confidence interval, 1.08-1.37; P = .001).
When categorizing predisaster stressors, the investigators found that individuals who had four or more predisaster stressors had a significantly greater chance of developing postdisaster PTSD than those with no predisaster stressors (OR, 2.77; 95% CI, 1.52 – 5.04).
Similar logistic regression analyses were performed for MDD, with comparable results. Although prior disaster exposure was not a significant predictor of postdisaster MDD, each one-unit increase in prior nondisaster stressors increased the odds of developing postdisaster MDD by 16% (OR, 1.16; 95% CI, 1.06-1.27; P = .001).
Categorization of these stressors revealed that experiencing any number of stressors significantly increased the odds of developing postdisaster MDD in a dose-response fashion.
In other words, every predisaster stressor – even a single one – increased an individual’s risk of developing postdisaster MDD, and each additional stressor further increased the risk.
Predisaster stressors
Interestingly, the study also showed that the risk of developing both PTSD and MDD was particularly high among those who had experienced multiple predisaster stressors, such as serious illness or injury, death of a loved one, divorce, unemployment, financial struggles, legal troubles, or the loss of a valuable possession.
These findings, the researchers note, demonstrate that a history of stressors increases what they called “stress sensitization,” which may make individuals more vulnerable to the negative effects of subsequent stressors rather than more resilient.
As such, individuals who have experienced several stressors over the course of a lifetime are at higher risk of developing a psychiatric disorder.
This was the case with PTSD, in which exposure to at least four previous manageable stressors was associated with greater odds of developing postdisaster PTSD. For MDD, on the other hand, there was a distinct dose-response relationship between the number of manageable predisaster stressors and the risk for postdisaster MDD.
The investigators explain that these findings are particularly relevant in light of the COVID-19 pandemic and the current focus on racial and economic inequality in the United States. “The findings highlight the sectors of the population that are at greatest risk,” Dr. Buka said. “And those are the ones who’ve had more challenging and traumatic lives and more hardship.
“So it certainly calls for greater concentration of psychiatric services in traditionally underserved areas, because those are also areas that have greater histories of trauma.”
“Fascinating” research
Commenting on the findings fin an interview, Patricia A. Resick, PhD, who was not involved in the study, said she found the research fascinating.
“The fact that they had preexisting data and then had the wherewithal to go back after the earthquake is quite amazing,” she said.
The findings came as little surprise to Dr. Resick, professor of psychiatry and behavioral sciences at Duke University Medical Center in Durham, N.C.
“I think most people are in agreement that the more stress you have, the more likely you are to get PTSD when you experience a traumatic stressor,” she said.
Treating these individuals remains a challenge, Dr. Resick noted, though knowing their history of stressors and traumas is an important starting point.
“We have to get a good history and figure out where to start treating them, because we always want to start with the event that causes the most PTSD symptoms,” she explained.
She also characterized the issue as being as much a public health concern as one for psychiatrists. “These are people you will want to have surveillance on and encourage them to get help,” Dr. Resick added.
Dr. Fernandez agreed.
“In the face of a disaster,” she said, “there needs to be more attention paid to vulnerable populations, because they likely don’t have the support they need.
“At the clinical level, these findings help the clinician know which patients are more likely to need more intensive services,” Dr. Buka added. “And the more trauma and hardship they’ve experienced, the more attention they need and the less likely they’re going to be able to cope and manage on their own.”
The study was funded by the U.S. National Institute of Mental Health and FONDEF Chile. Dr. Fernandez, Dr. Buka, and Dr. Resick have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Cognitive-behavioral therapy a standout for better immune function
Psychosocial interventions, particularly cognitive-behavioral therapy (CBT), are associated with enhanced immune system function, new research suggests.
Results of a systematic review and meta-analysis that included 56 randomized controlled trials and more than 4,000 participants showed that over time, psychosocial interventions appeared to augment beneficial immune system function while concurrently decreasing harmful immune system function in comparison with control conditions.
“These associations were most reliable for cognitive-behavioral therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers, which are key indicators of inflammation in the body,” study investigator George M. Slavich, PhD, said in an interview.
“The analysis helps address the question of which types of psychosocial interventions are most consistently associated with changes in immune system function, under what conditions, and for whom. This knowledge could, in turn, be used to inform research efforts and public policy aimed at using psychosocial interventions to improve immune-related health outcomes,” added Dr. Slavich, director of the Laboratory for Stress Assessment and Research, University of California, Los Angeles.
The study was published online June 3 in JAMA Psychiatry.
Link to serious physical, mental illnesses
There is substantial evidence that the immune system plays a role in a variety of mental and physical health problems. Such problems include anxiety disorders, depression, suicide, schizophrenia, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases. It has been recently suggested that more than half of all deaths worldwide are attributable to inflammation-related conditions.
Although pharmacologic interventions can play a role in addressing inflammation, they are not without drawbacks, most notably, cost and adverse side effects.
The World Health Organization, the National Academy of Medicine, the National Institutes of Health, and other groups have emphasized the importance of addressing global disease burden through psychosocial interventions when possible.
Such recommendations are supported by scientific evidence. Previous research has shown that immune system processes are influenced by a variety of social, neurocognitive, and behavioral factors.
Given such findings, researchers have examined the effects of interventions that reduce stress or bolster psychological resources on immune system function.
However, such research has yielded conflicting findings. Some studies show that psychosocial interventions clearly enhance immunity, whereas others do not.
In addition, questions remain regarding which types of interventions reliably improve immune system function, under what conditions, and for whom.
“Research has shown that psychological factors – such as life stress, negative emotions, and social support – are associated with changes in immune system function,” Dr. Slavich noted.
“In addition, there is growing appreciation that immune system processes involved in inflammation may contribute to peoples’ risk for several major mental and physical health problems, including anxiety disorders, depression, heart disease, and autoimmune and neurodegenerative disorders.”
First study of its kind
To shed light on these potential links, the researchers conducted what they believe is the first systematic review and meta-analysis of randomized clinical trials of the effects of psychosocial interventions on immune system outcomes.
As part of the review, Dr. Slavich and colleagues estimated the associations between eight psychosocial interventions and seven markers of immune system function.
The eight psychosocial interventions were behavior therapy, cognitive therapy, CBT, CBT plus additive treatment or mode of delivery, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation.
The seven immune outcomes that might be influenced by these interventions are proinflammatory cytokines and markers, anti-inflammatory cytokines, antibodies, immune cell counts, natural killer cell activity, viral load, and other immune outcomes.
The researchers also examined nine potential factors that might moderate the associations between psychosocial interventions and immune system function.
They searched a variety of databases for all relevant randomized controlled trials published through Dec. 31, 2018. Studies were eligible for inclusion if they included a psychosocial intervention and immune outcome, as well as preintervention and postintervention immunologic assessments.
The researchers identified 4,621 studies. Of these studies, 62 were eligible for inclusion; 56, which included 4,060 patients, were included in the final meta-analysis.
Results showed that psychosocial interventions were associated with enhanced immune system function (P < .001). There was relatively low heterogeneity between studies in these effect sizes, which, the investigators said, indicates that the association was relatively consistent across studies and conditions.
The meta-analysis showed that individuals who were assigned to a psychosocial intervention condition demonstrated a 14.7% improvement (95% confidence interval [CI], 5.7%–23.8%) in beneficial immune system function compared with their counterparts who were assigned to a control condition.
Similarly, participants who received psychosocial interventions demonstrated an 18.0% decrease (95% CI, 7.2%–28.8%) in harmful immune system function over time.
A standout
Regarding the effect of the type of intervention on the association, only CBT (31 studies; P < .001) and multiple or combined interventions (seven studies; P = .01) were significantly associated with changes in immune system outcomes.
The analysis also found that interventions that included a group component were more consistently associated with enhanced immune function than were those that did not include a group component. Nevertheless, this difference did not reach statistical significance (P = .06).
Contrary to the researchers’ expectations, the analysis also revealed that intervention length did not moderate the association between psychosocial interventions and immune system function (P = .93).
With respect to the type of immune marker studied, the meta-analysis found that psychosocial interventions had significantly different associations with the various immune markers studied. Of the seven immune outcomes investigated, only proinflammatory cytokine or marker levels (33 studies; P < .001) and immune cell counts (27 studies; P < .001) were significantly associated with the psychosocial interventions examined.
and were robust across age, sex, and intervention duration.
These results suggest that psychosocial interventions – particularly CBT and multiple or combined psychotherapeutic modalities – may play an important role in improving immune-related health outcomes.
Such interventions may not only be effective, they may also prove to be affordable alternatives to current therapeutic options. The mean length of a CBT intervention in the meta-analysis was 10.4 weeks, which the investigators equated with a total cost of $1,560 per patient.
“By comparison, the cost of using infliximab to reduce inflammation in persons with an autoimmune disorder is approximately $25,000 per patient per year,” they wrote.
“The results suggest the possibility that psychotherapy may be helpful for reducing inflammation and improving immune-related health in certain circumstances,” Dr. Slavich concluded. “However, the studies that we examined differed in terms of their quality, and we did not examine health outcomes in the present investigation.
“Therefore, more research needs to be done to determine how the present findings might be translated into treatment options or public policy.”
A path to better health
In an accompanying editorial, Veronika Engert, PhD, Joshua A. Grant, PhD, and Bernhard Strauss, PhD, noted that although infectious disease was once the primary cause of death in society, it has been supplanted by other complex and chronic illnesses, which often do not follow simple cause-and-effect associations.
“Rather,” they wrote, “these illnesses develop from a complex milieu of biological, psychological, and social factors that may also influence the disease progress and its prognosis. Against this backdrop, the meta-analysis by Shields and colleagues is an important confirmation of the biopsychosocial model.”
The editorialists explained that recent psychophysiological, neurobiological, and epigenetic research offers a glimpse into the relationship between psychological and social factors in pathogenesis. Nevertheless, the authors noted that a comprehensive examination of the potential effects of psychosocial interventions on immune parameters in various physical health conditions has been lacking.
“The evidence provided by Shields et al. is exactly what is needed to more fully shift treatment from an illness-centered to a patient-centered approach,” they wrote. “To that end, this meta-analysis may serve as a guide for policy makers aiming to improve immune-associated health.”
The research was supported by a Society in Science–Branco Weiss Fellowship, Brain and Behavior Research, and the National Institutes of Health. Dr. Slavich, Dr. Engert, Dr. Grant, and Dr. Strauss have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Psychosocial interventions, particularly cognitive-behavioral therapy (CBT), are associated with enhanced immune system function, new research suggests.
Results of a systematic review and meta-analysis that included 56 randomized controlled trials and more than 4,000 participants showed that over time, psychosocial interventions appeared to augment beneficial immune system function while concurrently decreasing harmful immune system function in comparison with control conditions.
“These associations were most reliable for cognitive-behavioral therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers, which are key indicators of inflammation in the body,” study investigator George M. Slavich, PhD, said in an interview.
“The analysis helps address the question of which types of psychosocial interventions are most consistently associated with changes in immune system function, under what conditions, and for whom. This knowledge could, in turn, be used to inform research efforts and public policy aimed at using psychosocial interventions to improve immune-related health outcomes,” added Dr. Slavich, director of the Laboratory for Stress Assessment and Research, University of California, Los Angeles.
The study was published online June 3 in JAMA Psychiatry.
Link to serious physical, mental illnesses
There is substantial evidence that the immune system plays a role in a variety of mental and physical health problems. Such problems include anxiety disorders, depression, suicide, schizophrenia, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases. It has been recently suggested that more than half of all deaths worldwide are attributable to inflammation-related conditions.
Although pharmacologic interventions can play a role in addressing inflammation, they are not without drawbacks, most notably, cost and adverse side effects.
The World Health Organization, the National Academy of Medicine, the National Institutes of Health, and other groups have emphasized the importance of addressing global disease burden through psychosocial interventions when possible.
Such recommendations are supported by scientific evidence. Previous research has shown that immune system processes are influenced by a variety of social, neurocognitive, and behavioral factors.
Given such findings, researchers have examined the effects of interventions that reduce stress or bolster psychological resources on immune system function.
However, such research has yielded conflicting findings. Some studies show that psychosocial interventions clearly enhance immunity, whereas others do not.
In addition, questions remain regarding which types of interventions reliably improve immune system function, under what conditions, and for whom.
“Research has shown that psychological factors – such as life stress, negative emotions, and social support – are associated with changes in immune system function,” Dr. Slavich noted.
“In addition, there is growing appreciation that immune system processes involved in inflammation may contribute to peoples’ risk for several major mental and physical health problems, including anxiety disorders, depression, heart disease, and autoimmune and neurodegenerative disorders.”
First study of its kind
To shed light on these potential links, the researchers conducted what they believe is the first systematic review and meta-analysis of randomized clinical trials of the effects of psychosocial interventions on immune system outcomes.
As part of the review, Dr. Slavich and colleagues estimated the associations between eight psychosocial interventions and seven markers of immune system function.
The eight psychosocial interventions were behavior therapy, cognitive therapy, CBT, CBT plus additive treatment or mode of delivery, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation.
The seven immune outcomes that might be influenced by these interventions are proinflammatory cytokines and markers, anti-inflammatory cytokines, antibodies, immune cell counts, natural killer cell activity, viral load, and other immune outcomes.
The researchers also examined nine potential factors that might moderate the associations between psychosocial interventions and immune system function.
They searched a variety of databases for all relevant randomized controlled trials published through Dec. 31, 2018. Studies were eligible for inclusion if they included a psychosocial intervention and immune outcome, as well as preintervention and postintervention immunologic assessments.
The researchers identified 4,621 studies. Of these studies, 62 were eligible for inclusion; 56, which included 4,060 patients, were included in the final meta-analysis.
Results showed that psychosocial interventions were associated with enhanced immune system function (P < .001). There was relatively low heterogeneity between studies in these effect sizes, which, the investigators said, indicates that the association was relatively consistent across studies and conditions.
The meta-analysis showed that individuals who were assigned to a psychosocial intervention condition demonstrated a 14.7% improvement (95% confidence interval [CI], 5.7%–23.8%) in beneficial immune system function compared with their counterparts who were assigned to a control condition.
Similarly, participants who received psychosocial interventions demonstrated an 18.0% decrease (95% CI, 7.2%–28.8%) in harmful immune system function over time.
A standout
Regarding the effect of the type of intervention on the association, only CBT (31 studies; P < .001) and multiple or combined interventions (seven studies; P = .01) were significantly associated with changes in immune system outcomes.
The analysis also found that interventions that included a group component were more consistently associated with enhanced immune function than were those that did not include a group component. Nevertheless, this difference did not reach statistical significance (P = .06).
Contrary to the researchers’ expectations, the analysis also revealed that intervention length did not moderate the association between psychosocial interventions and immune system function (P = .93).
With respect to the type of immune marker studied, the meta-analysis found that psychosocial interventions had significantly different associations with the various immune markers studied. Of the seven immune outcomes investigated, only proinflammatory cytokine or marker levels (33 studies; P < .001) and immune cell counts (27 studies; P < .001) were significantly associated with the psychosocial interventions examined.
and were robust across age, sex, and intervention duration.
These results suggest that psychosocial interventions – particularly CBT and multiple or combined psychotherapeutic modalities – may play an important role in improving immune-related health outcomes.
Such interventions may not only be effective, they may also prove to be affordable alternatives to current therapeutic options. The mean length of a CBT intervention in the meta-analysis was 10.4 weeks, which the investigators equated with a total cost of $1,560 per patient.
“By comparison, the cost of using infliximab to reduce inflammation in persons with an autoimmune disorder is approximately $25,000 per patient per year,” they wrote.
“The results suggest the possibility that psychotherapy may be helpful for reducing inflammation and improving immune-related health in certain circumstances,” Dr. Slavich concluded. “However, the studies that we examined differed in terms of their quality, and we did not examine health outcomes in the present investigation.
“Therefore, more research needs to be done to determine how the present findings might be translated into treatment options or public policy.”
A path to better health
In an accompanying editorial, Veronika Engert, PhD, Joshua A. Grant, PhD, and Bernhard Strauss, PhD, noted that although infectious disease was once the primary cause of death in society, it has been supplanted by other complex and chronic illnesses, which often do not follow simple cause-and-effect associations.
“Rather,” they wrote, “these illnesses develop from a complex milieu of biological, psychological, and social factors that may also influence the disease progress and its prognosis. Against this backdrop, the meta-analysis by Shields and colleagues is an important confirmation of the biopsychosocial model.”
The editorialists explained that recent psychophysiological, neurobiological, and epigenetic research offers a glimpse into the relationship between psychological and social factors in pathogenesis. Nevertheless, the authors noted that a comprehensive examination of the potential effects of psychosocial interventions on immune parameters in various physical health conditions has been lacking.
“The evidence provided by Shields et al. is exactly what is needed to more fully shift treatment from an illness-centered to a patient-centered approach,” they wrote. “To that end, this meta-analysis may serve as a guide for policy makers aiming to improve immune-associated health.”
The research was supported by a Society in Science–Branco Weiss Fellowship, Brain and Behavior Research, and the National Institutes of Health. Dr. Slavich, Dr. Engert, Dr. Grant, and Dr. Strauss have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Psychosocial interventions, particularly cognitive-behavioral therapy (CBT), are associated with enhanced immune system function, new research suggests.
Results of a systematic review and meta-analysis that included 56 randomized controlled trials and more than 4,000 participants showed that over time, psychosocial interventions appeared to augment beneficial immune system function while concurrently decreasing harmful immune system function in comparison with control conditions.
“These associations were most reliable for cognitive-behavioral therapy and multiple or combined interventions and for studies that assessed proinflammatory cytokines or markers, which are key indicators of inflammation in the body,” study investigator George M. Slavich, PhD, said in an interview.
“The analysis helps address the question of which types of psychosocial interventions are most consistently associated with changes in immune system function, under what conditions, and for whom. This knowledge could, in turn, be used to inform research efforts and public policy aimed at using psychosocial interventions to improve immune-related health outcomes,” added Dr. Slavich, director of the Laboratory for Stress Assessment and Research, University of California, Los Angeles.
The study was published online June 3 in JAMA Psychiatry.
Link to serious physical, mental illnesses
There is substantial evidence that the immune system plays a role in a variety of mental and physical health problems. Such problems include anxiety disorders, depression, suicide, schizophrenia, cardiovascular disease, autoimmune disorders, and neurodegenerative diseases. It has been recently suggested that more than half of all deaths worldwide are attributable to inflammation-related conditions.
Although pharmacologic interventions can play a role in addressing inflammation, they are not without drawbacks, most notably, cost and adverse side effects.
The World Health Organization, the National Academy of Medicine, the National Institutes of Health, and other groups have emphasized the importance of addressing global disease burden through psychosocial interventions when possible.
Such recommendations are supported by scientific evidence. Previous research has shown that immune system processes are influenced by a variety of social, neurocognitive, and behavioral factors.
Given such findings, researchers have examined the effects of interventions that reduce stress or bolster psychological resources on immune system function.
However, such research has yielded conflicting findings. Some studies show that psychosocial interventions clearly enhance immunity, whereas others do not.
In addition, questions remain regarding which types of interventions reliably improve immune system function, under what conditions, and for whom.
“Research has shown that psychological factors – such as life stress, negative emotions, and social support – are associated with changes in immune system function,” Dr. Slavich noted.
“In addition, there is growing appreciation that immune system processes involved in inflammation may contribute to peoples’ risk for several major mental and physical health problems, including anxiety disorders, depression, heart disease, and autoimmune and neurodegenerative disorders.”
First study of its kind
To shed light on these potential links, the researchers conducted what they believe is the first systematic review and meta-analysis of randomized clinical trials of the effects of psychosocial interventions on immune system outcomes.
As part of the review, Dr. Slavich and colleagues estimated the associations between eight psychosocial interventions and seven markers of immune system function.
The eight psychosocial interventions were behavior therapy, cognitive therapy, CBT, CBT plus additive treatment or mode of delivery, bereavement or supportive therapy, multiple or combined interventions, other psychotherapy, and psychoeducation.
The seven immune outcomes that might be influenced by these interventions are proinflammatory cytokines and markers, anti-inflammatory cytokines, antibodies, immune cell counts, natural killer cell activity, viral load, and other immune outcomes.
The researchers also examined nine potential factors that might moderate the associations between psychosocial interventions and immune system function.
They searched a variety of databases for all relevant randomized controlled trials published through Dec. 31, 2018. Studies were eligible for inclusion if they included a psychosocial intervention and immune outcome, as well as preintervention and postintervention immunologic assessments.
The researchers identified 4,621 studies. Of these studies, 62 were eligible for inclusion; 56, which included 4,060 patients, were included in the final meta-analysis.
Results showed that psychosocial interventions were associated with enhanced immune system function (P < .001). There was relatively low heterogeneity between studies in these effect sizes, which, the investigators said, indicates that the association was relatively consistent across studies and conditions.
The meta-analysis showed that individuals who were assigned to a psychosocial intervention condition demonstrated a 14.7% improvement (95% confidence interval [CI], 5.7%–23.8%) in beneficial immune system function compared with their counterparts who were assigned to a control condition.
Similarly, participants who received psychosocial interventions demonstrated an 18.0% decrease (95% CI, 7.2%–28.8%) in harmful immune system function over time.
A standout
Regarding the effect of the type of intervention on the association, only CBT (31 studies; P < .001) and multiple or combined interventions (seven studies; P = .01) were significantly associated with changes in immune system outcomes.
The analysis also found that interventions that included a group component were more consistently associated with enhanced immune function than were those that did not include a group component. Nevertheless, this difference did not reach statistical significance (P = .06).
Contrary to the researchers’ expectations, the analysis also revealed that intervention length did not moderate the association between psychosocial interventions and immune system function (P = .93).
With respect to the type of immune marker studied, the meta-analysis found that psychosocial interventions had significantly different associations with the various immune markers studied. Of the seven immune outcomes investigated, only proinflammatory cytokine or marker levels (33 studies; P < .001) and immune cell counts (27 studies; P < .001) were significantly associated with the psychosocial interventions examined.
and were robust across age, sex, and intervention duration.
These results suggest that psychosocial interventions – particularly CBT and multiple or combined psychotherapeutic modalities – may play an important role in improving immune-related health outcomes.
Such interventions may not only be effective, they may also prove to be affordable alternatives to current therapeutic options. The mean length of a CBT intervention in the meta-analysis was 10.4 weeks, which the investigators equated with a total cost of $1,560 per patient.
“By comparison, the cost of using infliximab to reduce inflammation in persons with an autoimmune disorder is approximately $25,000 per patient per year,” they wrote.
“The results suggest the possibility that psychotherapy may be helpful for reducing inflammation and improving immune-related health in certain circumstances,” Dr. Slavich concluded. “However, the studies that we examined differed in terms of their quality, and we did not examine health outcomes in the present investigation.
“Therefore, more research needs to be done to determine how the present findings might be translated into treatment options or public policy.”
A path to better health
In an accompanying editorial, Veronika Engert, PhD, Joshua A. Grant, PhD, and Bernhard Strauss, PhD, noted that although infectious disease was once the primary cause of death in society, it has been supplanted by other complex and chronic illnesses, which often do not follow simple cause-and-effect associations.
“Rather,” they wrote, “these illnesses develop from a complex milieu of biological, psychological, and social factors that may also influence the disease progress and its prognosis. Against this backdrop, the meta-analysis by Shields and colleagues is an important confirmation of the biopsychosocial model.”
The editorialists explained that recent psychophysiological, neurobiological, and epigenetic research offers a glimpse into the relationship between psychological and social factors in pathogenesis. Nevertheless, the authors noted that a comprehensive examination of the potential effects of psychosocial interventions on immune parameters in various physical health conditions has been lacking.
“The evidence provided by Shields et al. is exactly what is needed to more fully shift treatment from an illness-centered to a patient-centered approach,” they wrote. “To that end, this meta-analysis may serve as a guide for policy makers aiming to improve immune-associated health.”
The research was supported by a Society in Science–Branco Weiss Fellowship, Brain and Behavior Research, and the National Institutes of Health. Dr. Slavich, Dr. Engert, Dr. Grant, and Dr. Strauss have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Movement-based yoga ‘viable’ for depression in many mental disorders
Movement-based yoga appears to ease depressive symptoms in a wide range of mental health disorders, a new systematic review and meta-analysis suggest.
Results of the research, which included 19 studies and more than 1,000 patients with a variety of mental health diagnoses, showed that those who practiced yoga experienced greater reductions in depressive symptoms versus those undergoing no treatment, usual treatment, or attention-control exercises. In addition, there was a dose-dependent effect such that more weekly yoga sessions were associated with the greatest reduction in depressive symptoms.
“Once we reviewed all the existing science about the mental health benefits of movement-based yoga, we found that movement-based yoga – which is the same thing as postural yoga or asana – helped reduce symptoms of depression,” study investigator Jacinta Brinsley, BClinExPhys, of the University of South Australia, Adelaide, said in an interview.
“We also found those who practiced more frequently had bigger reductions. However, it didn’t matter how long the individual sessions were; what mattered was how many times per week people practiced,” she added.
The researchers noted that the study is the first to focus specifically on movement-based yoga.
“We excluded meditative forms of yoga, which have often been included in previous reviews, yielding mixed findings. The other thing we’ve done a bit differently is pool all the different diagnoses together and then look at depressive symptoms across them,” said Ms. Brinsley.
The study was published online May 18 in the British Journal of Sports Medicine.
Getting clarity
Depressive disorders are currently the world’s leading cause of disability, affecting more than 340 million people.
Most individuals who suffer from depressive disorders also experience a host of physical comorbidities including obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease.
Perhaps not surprisingly, physical inactivity is also associated with higher levels of depressive symptoms, which may be the reason some international organizations now recommend that physical activity be included as part of routine psychiatric care.
One potential form of exercise is yoga, which has become popular in Western culture, including among psychiatric patients. Although previous systematic reviews and meta-analyses have examined the effects of various yoga interventions on mental health, none has investigated the benefits of yoga across a range of psychiatric diagnoses.
What’s more, the authors of these reviews all urge caution when interpreting their results because of potential heterogeneity of the various yoga interventions, as well as poor methodological reporting.
“As an exercise physiologist, I prescribe evidence-based treatment,” said Ms. Brinsley. “I was interested in seeing if there’s evidence to support movement-based yoga in people who were struggling with mental health or who had a diagnosed mental illness.
“The [previous] findings are quite contradictory and there’s not a clear outcome in terms of intervention results, so we pooled the data and ran the meta-analysis, thinking it would be a great way to add some important evidence to the science,” she added.
To allow for a more comprehensive assessment of yoga’s potential mental health benefits, the investigators included a range of mental health diagnoses.
Dose-dependent effect
Studies were only included in the analysis if they were randomized, controlled trials with a yoga intervention that had a minimum of 50% physical activity during each session in adults with a recognized diagnosed mental disorder. Control conditions were defined as treatment as usual, wait list, or attention controls.
Two investigators independently scanned article titles and abstracts, and a final list of articles for the study was decided by consensus. Study quality was reported using the PEDro checklist; a random-effects meta-analysis was conducted using Comprehensive Meta-Analysis software.
A total of 3,880 records were identified and screened. The investigators assessed full-text versions of 80 articles, 19 of which (1,080 patients) were eligible for inclusion in the review.
Of these, nine studies included patients with a depressive disorder; five trials were in patients with a diagnosis of schizophrenia, three studies included patients with a diagnosis of PTSD, one study included patients diagnosed with alcohol dependence, and one study included patients with a range of psychiatric disorders.
Of the 1,080 patients included in the review, 578 were assigned to yoga and 502 to control conditions. Yoga practice involved a mixture of movement, breathing exercises, and/or mindfulness, but the movement component took up more than half of each session.
The yoga interventions lasted an average of 2.4 months (range, 1.5-2.5 months), with an average of 1.6 sessions per week (range, 1-3 sessions) that lasted an average of 60 minutes (range, 20-90 minutes).
Of the 19 studies (632 patients), 13 reported changes in depressive symptoms and were therefore included in the meta-analysis. The six studies excluded from the quantitative analysis did not report depression symptom scores.
With respect to primary outcomes, individuals who performed yoga showed a greater reduction in depressive symptoms, compared with the three control groups (standardized mean difference, –0.41; 95% CI, –0.65 to –0.17; P < .001).
Specific subgroup analyses showed a moderate effect of yoga on depressive symptoms, compared with wait-list controls (SMD, –0.58; P < .05), treatment as usual (SMD, –0.39; P = .31), and attention controls (SMD, –0.21; P = .22).
Subgroup analyses were also performed with respect to diagnostic category. These data showed a moderate effect of yoga on depressive symptoms in depressive disorders (SMD, –0.40; P < .01), no effect in PTSD (SMD, –0.01; P = .95), a nominal effect in alcohol use disorders (SMD, –0.24; P = .69), and a marked effect in schizophrenia (SMD, –0.90; P < .01).
Movement may be key
Researchers also performed a series of meta-regression analyses, which showed that the number of yoga sessions performed each week had a significant effect on depressive symptoms. Indeed, individuals with higher session frequencies demonstrated a greater improvement in symptoms (beta, –0.44; P < .001).
These findings, said Ms. Brinsley, suggest yoga may be a viable intervention for managing depressive symptoms in patients with a variety of mental disorders.
Based on these findings, along with other conventional forms of exercise.
Equally important was the finding that the number of weekly yoga sessions moderated the effect of depressive symptoms, as it may inform the future design of yoga interventions in patients with mental disorders.
With this in mind, the researchers recommended that such interventions should aim to increase the frequency or weekly sessions rather than the duration of each individual session or the overall duration of the intervention.
However, said Ms. Brinsley, these findings suggest it is the physical aspect of the yoga practice that may be key.
“Yoga comprises several different components, including the movement postures, the breathing component, and the mindfulness or meditative component, but in this meta-analysis we looked specifically at yoga that was at least 50% movement based. So it might have also included mindfulness and breathing, but it had to have the movement,” she said.
Don’t discount meditation
Commenting on the findings, Holger Cramer, MSc, PhD, DSc, who was not involved in the study, noted that the systematic review and meta-analysis builds on a number of previous reviews regarding the benefits of yoga for mental disorders.
“Surprisingly, the largest effect in this analysis was found in schizophrenia, even higher than in patients with depressive disorders,” said Dr. Cramer of the University of Duisburg-Essen (Germany). “This is in strong contradiction to what would otherwise be expected. As the authors point out, only about a quarter of all schizophrenia patients suffer from depression, so there should not be so much room for improvement.”
Dr. Cramer also advised against reducing yoga to simply a physical undertaking. “We have shown in our meta-analysis that those interventions focusing on meditation and/or breathing techniques are the most effective ones,” he added.
As such, he urged that breathing techniques be a part of yoga for treating depression in psychiatric disorders, though care should be taken in patients with PTSD, “since breath control might be perceived as unpleasant.”
For Ms. Brinsley, the findings help solidify yoga’s potential as a genuine treatment option for a variety of mental health patients suffering depressive symptoms.
“It’s about acknowledging that yoga can be a helpful part of treatment and can have a significant effect on mental health,” she noted.
At the same time, practitioners also need to acknowledge that patients suffering from mental health disorders may struggle with motivation when it comes to activities such as yoga.
“Engaging in a new activity can be particularly challenging if you’re struggling with mental health. Nevertheless, it’s important for people to have a choice and do something they enjoy. And yoga can be another tool in their toolbox for managing their mental health,” she said.
The study was funded by the U.K. National Institute for Health Research and Health Education England. Ms. Brinsley and Dr. Cramer have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Movement-based yoga appears to ease depressive symptoms in a wide range of mental health disorders, a new systematic review and meta-analysis suggest.
Results of the research, which included 19 studies and more than 1,000 patients with a variety of mental health diagnoses, showed that those who practiced yoga experienced greater reductions in depressive symptoms versus those undergoing no treatment, usual treatment, or attention-control exercises. In addition, there was a dose-dependent effect such that more weekly yoga sessions were associated with the greatest reduction in depressive symptoms.
“Once we reviewed all the existing science about the mental health benefits of movement-based yoga, we found that movement-based yoga – which is the same thing as postural yoga or asana – helped reduce symptoms of depression,” study investigator Jacinta Brinsley, BClinExPhys, of the University of South Australia, Adelaide, said in an interview.
“We also found those who practiced more frequently had bigger reductions. However, it didn’t matter how long the individual sessions were; what mattered was how many times per week people practiced,” she added.
The researchers noted that the study is the first to focus specifically on movement-based yoga.
“We excluded meditative forms of yoga, which have often been included in previous reviews, yielding mixed findings. The other thing we’ve done a bit differently is pool all the different diagnoses together and then look at depressive symptoms across them,” said Ms. Brinsley.
The study was published online May 18 in the British Journal of Sports Medicine.
Getting clarity
Depressive disorders are currently the world’s leading cause of disability, affecting more than 340 million people.
Most individuals who suffer from depressive disorders also experience a host of physical comorbidities including obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease.
Perhaps not surprisingly, physical inactivity is also associated with higher levels of depressive symptoms, which may be the reason some international organizations now recommend that physical activity be included as part of routine psychiatric care.
One potential form of exercise is yoga, which has become popular in Western culture, including among psychiatric patients. Although previous systematic reviews and meta-analyses have examined the effects of various yoga interventions on mental health, none has investigated the benefits of yoga across a range of psychiatric diagnoses.
What’s more, the authors of these reviews all urge caution when interpreting their results because of potential heterogeneity of the various yoga interventions, as well as poor methodological reporting.
“As an exercise physiologist, I prescribe evidence-based treatment,” said Ms. Brinsley. “I was interested in seeing if there’s evidence to support movement-based yoga in people who were struggling with mental health or who had a diagnosed mental illness.
“The [previous] findings are quite contradictory and there’s not a clear outcome in terms of intervention results, so we pooled the data and ran the meta-analysis, thinking it would be a great way to add some important evidence to the science,” she added.
To allow for a more comprehensive assessment of yoga’s potential mental health benefits, the investigators included a range of mental health diagnoses.
Dose-dependent effect
Studies were only included in the analysis if they were randomized, controlled trials with a yoga intervention that had a minimum of 50% physical activity during each session in adults with a recognized diagnosed mental disorder. Control conditions were defined as treatment as usual, wait list, or attention controls.
Two investigators independently scanned article titles and abstracts, and a final list of articles for the study was decided by consensus. Study quality was reported using the PEDro checklist; a random-effects meta-analysis was conducted using Comprehensive Meta-Analysis software.
A total of 3,880 records were identified and screened. The investigators assessed full-text versions of 80 articles, 19 of which (1,080 patients) were eligible for inclusion in the review.
Of these, nine studies included patients with a depressive disorder; five trials were in patients with a diagnosis of schizophrenia, three studies included patients with a diagnosis of PTSD, one study included patients diagnosed with alcohol dependence, and one study included patients with a range of psychiatric disorders.
Of the 1,080 patients included in the review, 578 were assigned to yoga and 502 to control conditions. Yoga practice involved a mixture of movement, breathing exercises, and/or mindfulness, but the movement component took up more than half of each session.
The yoga interventions lasted an average of 2.4 months (range, 1.5-2.5 months), with an average of 1.6 sessions per week (range, 1-3 sessions) that lasted an average of 60 minutes (range, 20-90 minutes).
Of the 19 studies (632 patients), 13 reported changes in depressive symptoms and were therefore included in the meta-analysis. The six studies excluded from the quantitative analysis did not report depression symptom scores.
With respect to primary outcomes, individuals who performed yoga showed a greater reduction in depressive symptoms, compared with the three control groups (standardized mean difference, –0.41; 95% CI, –0.65 to –0.17; P < .001).
Specific subgroup analyses showed a moderate effect of yoga on depressive symptoms, compared with wait-list controls (SMD, –0.58; P < .05), treatment as usual (SMD, –0.39; P = .31), and attention controls (SMD, –0.21; P = .22).
Subgroup analyses were also performed with respect to diagnostic category. These data showed a moderate effect of yoga on depressive symptoms in depressive disorders (SMD, –0.40; P < .01), no effect in PTSD (SMD, –0.01; P = .95), a nominal effect in alcohol use disorders (SMD, –0.24; P = .69), and a marked effect in schizophrenia (SMD, –0.90; P < .01).
Movement may be key
Researchers also performed a series of meta-regression analyses, which showed that the number of yoga sessions performed each week had a significant effect on depressive symptoms. Indeed, individuals with higher session frequencies demonstrated a greater improvement in symptoms (beta, –0.44; P < .001).
These findings, said Ms. Brinsley, suggest yoga may be a viable intervention for managing depressive symptoms in patients with a variety of mental disorders.
Based on these findings, along with other conventional forms of exercise.
Equally important was the finding that the number of weekly yoga sessions moderated the effect of depressive symptoms, as it may inform the future design of yoga interventions in patients with mental disorders.
With this in mind, the researchers recommended that such interventions should aim to increase the frequency or weekly sessions rather than the duration of each individual session or the overall duration of the intervention.
However, said Ms. Brinsley, these findings suggest it is the physical aspect of the yoga practice that may be key.
“Yoga comprises several different components, including the movement postures, the breathing component, and the mindfulness or meditative component, but in this meta-analysis we looked specifically at yoga that was at least 50% movement based. So it might have also included mindfulness and breathing, but it had to have the movement,” she said.
Don’t discount meditation
Commenting on the findings, Holger Cramer, MSc, PhD, DSc, who was not involved in the study, noted that the systematic review and meta-analysis builds on a number of previous reviews regarding the benefits of yoga for mental disorders.
“Surprisingly, the largest effect in this analysis was found in schizophrenia, even higher than in patients with depressive disorders,” said Dr. Cramer of the University of Duisburg-Essen (Germany). “This is in strong contradiction to what would otherwise be expected. As the authors point out, only about a quarter of all schizophrenia patients suffer from depression, so there should not be so much room for improvement.”
Dr. Cramer also advised against reducing yoga to simply a physical undertaking. “We have shown in our meta-analysis that those interventions focusing on meditation and/or breathing techniques are the most effective ones,” he added.
As such, he urged that breathing techniques be a part of yoga for treating depression in psychiatric disorders, though care should be taken in patients with PTSD, “since breath control might be perceived as unpleasant.”
For Ms. Brinsley, the findings help solidify yoga’s potential as a genuine treatment option for a variety of mental health patients suffering depressive symptoms.
“It’s about acknowledging that yoga can be a helpful part of treatment and can have a significant effect on mental health,” she noted.
At the same time, practitioners also need to acknowledge that patients suffering from mental health disorders may struggle with motivation when it comes to activities such as yoga.
“Engaging in a new activity can be particularly challenging if you’re struggling with mental health. Nevertheless, it’s important for people to have a choice and do something they enjoy. And yoga can be another tool in their toolbox for managing their mental health,” she said.
The study was funded by the U.K. National Institute for Health Research and Health Education England. Ms. Brinsley and Dr. Cramer have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Movement-based yoga appears to ease depressive symptoms in a wide range of mental health disorders, a new systematic review and meta-analysis suggest.
Results of the research, which included 19 studies and more than 1,000 patients with a variety of mental health diagnoses, showed that those who practiced yoga experienced greater reductions in depressive symptoms versus those undergoing no treatment, usual treatment, or attention-control exercises. In addition, there was a dose-dependent effect such that more weekly yoga sessions were associated with the greatest reduction in depressive symptoms.
“Once we reviewed all the existing science about the mental health benefits of movement-based yoga, we found that movement-based yoga – which is the same thing as postural yoga or asana – helped reduce symptoms of depression,” study investigator Jacinta Brinsley, BClinExPhys, of the University of South Australia, Adelaide, said in an interview.
“We also found those who practiced more frequently had bigger reductions. However, it didn’t matter how long the individual sessions were; what mattered was how many times per week people practiced,” she added.
The researchers noted that the study is the first to focus specifically on movement-based yoga.
“We excluded meditative forms of yoga, which have often been included in previous reviews, yielding mixed findings. The other thing we’ve done a bit differently is pool all the different diagnoses together and then look at depressive symptoms across them,” said Ms. Brinsley.
The study was published online May 18 in the British Journal of Sports Medicine.
Getting clarity
Depressive disorders are currently the world’s leading cause of disability, affecting more than 340 million people.
Most individuals who suffer from depressive disorders also experience a host of physical comorbidities including obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease.
Perhaps not surprisingly, physical inactivity is also associated with higher levels of depressive symptoms, which may be the reason some international organizations now recommend that physical activity be included as part of routine psychiatric care.
One potential form of exercise is yoga, which has become popular in Western culture, including among psychiatric patients. Although previous systematic reviews and meta-analyses have examined the effects of various yoga interventions on mental health, none has investigated the benefits of yoga across a range of psychiatric diagnoses.
What’s more, the authors of these reviews all urge caution when interpreting their results because of potential heterogeneity of the various yoga interventions, as well as poor methodological reporting.
“As an exercise physiologist, I prescribe evidence-based treatment,” said Ms. Brinsley. “I was interested in seeing if there’s evidence to support movement-based yoga in people who were struggling with mental health or who had a diagnosed mental illness.
“The [previous] findings are quite contradictory and there’s not a clear outcome in terms of intervention results, so we pooled the data and ran the meta-analysis, thinking it would be a great way to add some important evidence to the science,” she added.
To allow for a more comprehensive assessment of yoga’s potential mental health benefits, the investigators included a range of mental health diagnoses.
Dose-dependent effect
Studies were only included in the analysis if they were randomized, controlled trials with a yoga intervention that had a minimum of 50% physical activity during each session in adults with a recognized diagnosed mental disorder. Control conditions were defined as treatment as usual, wait list, or attention controls.
Two investigators independently scanned article titles and abstracts, and a final list of articles for the study was decided by consensus. Study quality was reported using the PEDro checklist; a random-effects meta-analysis was conducted using Comprehensive Meta-Analysis software.
A total of 3,880 records were identified and screened. The investigators assessed full-text versions of 80 articles, 19 of which (1,080 patients) were eligible for inclusion in the review.
Of these, nine studies included patients with a depressive disorder; five trials were in patients with a diagnosis of schizophrenia, three studies included patients with a diagnosis of PTSD, one study included patients diagnosed with alcohol dependence, and one study included patients with a range of psychiatric disorders.
Of the 1,080 patients included in the review, 578 were assigned to yoga and 502 to control conditions. Yoga practice involved a mixture of movement, breathing exercises, and/or mindfulness, but the movement component took up more than half of each session.
The yoga interventions lasted an average of 2.4 months (range, 1.5-2.5 months), with an average of 1.6 sessions per week (range, 1-3 sessions) that lasted an average of 60 minutes (range, 20-90 minutes).
Of the 19 studies (632 patients), 13 reported changes in depressive symptoms and were therefore included in the meta-analysis. The six studies excluded from the quantitative analysis did not report depression symptom scores.
With respect to primary outcomes, individuals who performed yoga showed a greater reduction in depressive symptoms, compared with the three control groups (standardized mean difference, –0.41; 95% CI, –0.65 to –0.17; P < .001).
Specific subgroup analyses showed a moderate effect of yoga on depressive symptoms, compared with wait-list controls (SMD, –0.58; P < .05), treatment as usual (SMD, –0.39; P = .31), and attention controls (SMD, –0.21; P = .22).
Subgroup analyses were also performed with respect to diagnostic category. These data showed a moderate effect of yoga on depressive symptoms in depressive disorders (SMD, –0.40; P < .01), no effect in PTSD (SMD, –0.01; P = .95), a nominal effect in alcohol use disorders (SMD, –0.24; P = .69), and a marked effect in schizophrenia (SMD, –0.90; P < .01).
Movement may be key
Researchers also performed a series of meta-regression analyses, which showed that the number of yoga sessions performed each week had a significant effect on depressive symptoms. Indeed, individuals with higher session frequencies demonstrated a greater improvement in symptoms (beta, –0.44; P < .001).
These findings, said Ms. Brinsley, suggest yoga may be a viable intervention for managing depressive symptoms in patients with a variety of mental disorders.
Based on these findings, along with other conventional forms of exercise.
Equally important was the finding that the number of weekly yoga sessions moderated the effect of depressive symptoms, as it may inform the future design of yoga interventions in patients with mental disorders.
With this in mind, the researchers recommended that such interventions should aim to increase the frequency or weekly sessions rather than the duration of each individual session or the overall duration of the intervention.
However, said Ms. Brinsley, these findings suggest it is the physical aspect of the yoga practice that may be key.
“Yoga comprises several different components, including the movement postures, the breathing component, and the mindfulness or meditative component, but in this meta-analysis we looked specifically at yoga that was at least 50% movement based. So it might have also included mindfulness and breathing, but it had to have the movement,” she said.
Don’t discount meditation
Commenting on the findings, Holger Cramer, MSc, PhD, DSc, who was not involved in the study, noted that the systematic review and meta-analysis builds on a number of previous reviews regarding the benefits of yoga for mental disorders.
“Surprisingly, the largest effect in this analysis was found in schizophrenia, even higher than in patients with depressive disorders,” said Dr. Cramer of the University of Duisburg-Essen (Germany). “This is in strong contradiction to what would otherwise be expected. As the authors point out, only about a quarter of all schizophrenia patients suffer from depression, so there should not be so much room for improvement.”
Dr. Cramer also advised against reducing yoga to simply a physical undertaking. “We have shown in our meta-analysis that those interventions focusing on meditation and/or breathing techniques are the most effective ones,” he added.
As such, he urged that breathing techniques be a part of yoga for treating depression in psychiatric disorders, though care should be taken in patients with PTSD, “since breath control might be perceived as unpleasant.”
For Ms. Brinsley, the findings help solidify yoga’s potential as a genuine treatment option for a variety of mental health patients suffering depressive symptoms.
“It’s about acknowledging that yoga can be a helpful part of treatment and can have a significant effect on mental health,” she noted.
At the same time, practitioners also need to acknowledge that patients suffering from mental health disorders may struggle with motivation when it comes to activities such as yoga.
“Engaging in a new activity can be particularly challenging if you’re struggling with mental health. Nevertheless, it’s important for people to have a choice and do something they enjoy. And yoga can be another tool in their toolbox for managing their mental health,” she said.
The study was funded by the U.K. National Institute for Health Research and Health Education England. Ms. Brinsley and Dr. Cramer have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Cautionary tale spurs ‘world’s first’ COVID-19 psychiatric ward
There was no hand sanitizer on the hospital’s psychiatric ward for fear patients would drink it; they slept together on futons in communal rooms and the windows were sealed shut to prevent suicide attempts — all conditions that created the perfect environment for the rapid spread of a potentially deadly virus.
This scenario may sound like a something out of a horror film, but as reported last month by the UK newspaper The Independent, it was the reality in the psychiatric ward of South Korea’s Daenam Hospital after COVID-19 struck. Eventually health officials put the ward on lockdown, but it wasn’t long before all but two of the unit’s 103 patients were positive for the virus.
To avoid a similar catastrophe, staff at an Israeli hospital have created what they describe as the “world’s first” dedicated COVID-19 unit for psychiatric inpatients.
Clinicians at Israel’s national hospital, Sheba Medical Center Tel HaShomer in Tel Aviv, believe the 16-bed unit, which officially opened on March 26, will stop psychiatric inpatients with the virus — who may have trouble with social distancing — from spreading it to others on the ward.
“Psychiatric patients are going to get sick from coronavirus just like anybody else,” Mark Weiser, MD, head of the psychiatric division at the institution told Medscape Medical News. “But we’re concerned that, on a psychiatric ward, a patient who is COVID-19 positive can also be psychotic, manic, cognitively impaired, or have poor judgment … making it difficult for that patient to keep social distancing, and very quickly you’ll have an entire ward of patients infected.
“So the basic public health issue is how to prevent a single psychiatric patient who is hospitalized and COVID-19-positive from making everybody else sick,” he added.
Unique Challenges, Rapid Response
Adapting an existing psychiatric ward to one exclusively used by inpatients with COVID-19 required significant planning, coordination, and modifications to ensure the well-being of patients and staff.
A dedicated entrance for the exclusive use of infected psychiatric inpatients was also created.
In addition, two-way television cameras in patients’ rooms were installed to facilitate a constant flow of communication and enable therapeutic sessions and family visits. All of these modifications were completed in under a week.
“Under normal circumstances, we have cameras in the public areas of our wards, but in order to respect people’s privacy, we do not have cameras in their rooms.
“In this specific ward, on the other hand, we did put cameras in the rooms, so if a patient needs to be watched more closely, it could be done remotely without exposing staff to the virus. We have a person who’s watching the screens at all times, just to see what’s going on and see what patients are doing,” said Weiser.
Protective personal equipment (PPE) and clothing for staff was tailored to the unique challenges posed by the ward’s patient population.
“Of course, you need to wear clothes that are protective against the virus,” said Weiser. “But sometimes our patients can get agitated or even violent, so you’ve got protect against that as well.”
With this in mind, all personnel working on the ward must put on an extra layer of PPE as well as a tear-proof robe. The institution has also implemented a strict protocol that dictates the order in which PPE is donned and doffed.
“It’s got to be done in a very careful and very specific way,” said Weiser. “We have all of it organized with a poster that explains what should be taken off or put on, and in what order.”
For institutions considering setting up a similar unit, Weiser said close proximity to an active care hospital with the capacity to provide urgent care is key.
“We’re psychiatrists; we’re not great at treating acute respiratory problems. So patients with significant respiratory problems need a place to get appropriate care quickly,” he said.
In setting up the unit, there were still a few obstacles, Weiser noted. For instance, despite the many protective and safety measures undertaken by the institution, some of the hospital staff were concerned about their risk of contracting the virus.
To address these concerns, the hospital’s leadership brought in infectious disease experts to educate hospital personnel about the virus and transmission risk.
“They told our staff that given all the precautions we had taken, there was very little risk anyone else could become infected,” Weiser said.
Despite the many challenges, Weiser said he and his colleagues are thrilled with the dedicated ward and the positive reception it has received.
“My colleagues and the directors of psychiatric hospitals all around the country are very happy with this because now they’re not hospitalizing infected patients. They’re very happy for us to take care of this,” he said.
“No Easy Solutions”
Commenting on the initiative for Medscape Medical News, John M. Oldham, MD, chief of staff at Baylor College of Medicine’s Menninger Clinic in Houston, Texas, raised some questions.
“Is it really going to be the treatment unit or a quarantine unit? Because if you don’t have a comparable level of established, effective treatment for these patients, then you’re simply herding them off to a different place where they’re going to suffer both illnesses,” he cautioned.
Nevertheless, Oldham recognized that the issue of how to treat psychiatric patients who test positive for COVID-19 is complex.
“We’re still wrestling with that question here at Menninger. We have created an enclosed section of the inpatient area reserved for this possibility.
“If we have a patient who tests positive, we will immediately put that patient in one of these rooms in the quarantine section. Then we will use protective equipment for our staff to go and provide care for the patient,” he said.
However, he acknowledged that a psychiatric hospital is in no position to treat patients who develop severe illness from COVID-19.
“We’re certainly worried about it,” he said, “because how many inpatient general medical units are going to want to take a significantly symptomatic COVID-19 patient who was in the hospital for being acutely suicidal? There are no easy solutions.”
This article first appeared on Medscape.com.
There was no hand sanitizer on the hospital’s psychiatric ward for fear patients would drink it; they slept together on futons in communal rooms and the windows were sealed shut to prevent suicide attempts — all conditions that created the perfect environment for the rapid spread of a potentially deadly virus.
This scenario may sound like a something out of a horror film, but as reported last month by the UK newspaper The Independent, it was the reality in the psychiatric ward of South Korea’s Daenam Hospital after COVID-19 struck. Eventually health officials put the ward on lockdown, but it wasn’t long before all but two of the unit’s 103 patients were positive for the virus.
To avoid a similar catastrophe, staff at an Israeli hospital have created what they describe as the “world’s first” dedicated COVID-19 unit for psychiatric inpatients.
Clinicians at Israel’s national hospital, Sheba Medical Center Tel HaShomer in Tel Aviv, believe the 16-bed unit, which officially opened on March 26, will stop psychiatric inpatients with the virus — who may have trouble with social distancing — from spreading it to others on the ward.
“Psychiatric patients are going to get sick from coronavirus just like anybody else,” Mark Weiser, MD, head of the psychiatric division at the institution told Medscape Medical News. “But we’re concerned that, on a psychiatric ward, a patient who is COVID-19 positive can also be psychotic, manic, cognitively impaired, or have poor judgment … making it difficult for that patient to keep social distancing, and very quickly you’ll have an entire ward of patients infected.
“So the basic public health issue is how to prevent a single psychiatric patient who is hospitalized and COVID-19-positive from making everybody else sick,” he added.
Unique Challenges, Rapid Response
Adapting an existing psychiatric ward to one exclusively used by inpatients with COVID-19 required significant planning, coordination, and modifications to ensure the well-being of patients and staff.
A dedicated entrance for the exclusive use of infected psychiatric inpatients was also created.
In addition, two-way television cameras in patients’ rooms were installed to facilitate a constant flow of communication and enable therapeutic sessions and family visits. All of these modifications were completed in under a week.
“Under normal circumstances, we have cameras in the public areas of our wards, but in order to respect people’s privacy, we do not have cameras in their rooms.
“In this specific ward, on the other hand, we did put cameras in the rooms, so if a patient needs to be watched more closely, it could be done remotely without exposing staff to the virus. We have a person who’s watching the screens at all times, just to see what’s going on and see what patients are doing,” said Weiser.
Protective personal equipment (PPE) and clothing for staff was tailored to the unique challenges posed by the ward’s patient population.
“Of course, you need to wear clothes that are protective against the virus,” said Weiser. “But sometimes our patients can get agitated or even violent, so you’ve got protect against that as well.”
With this in mind, all personnel working on the ward must put on an extra layer of PPE as well as a tear-proof robe. The institution has also implemented a strict protocol that dictates the order in which PPE is donned and doffed.
“It’s got to be done in a very careful and very specific way,” said Weiser. “We have all of it organized with a poster that explains what should be taken off or put on, and in what order.”
For institutions considering setting up a similar unit, Weiser said close proximity to an active care hospital with the capacity to provide urgent care is key.
“We’re psychiatrists; we’re not great at treating acute respiratory problems. So patients with significant respiratory problems need a place to get appropriate care quickly,” he said.
In setting up the unit, there were still a few obstacles, Weiser noted. For instance, despite the many protective and safety measures undertaken by the institution, some of the hospital staff were concerned about their risk of contracting the virus.
To address these concerns, the hospital’s leadership brought in infectious disease experts to educate hospital personnel about the virus and transmission risk.
“They told our staff that given all the precautions we had taken, there was very little risk anyone else could become infected,” Weiser said.
Despite the many challenges, Weiser said he and his colleagues are thrilled with the dedicated ward and the positive reception it has received.
“My colleagues and the directors of psychiatric hospitals all around the country are very happy with this because now they’re not hospitalizing infected patients. They’re very happy for us to take care of this,” he said.
“No Easy Solutions”
Commenting on the initiative for Medscape Medical News, John M. Oldham, MD, chief of staff at Baylor College of Medicine’s Menninger Clinic in Houston, Texas, raised some questions.
“Is it really going to be the treatment unit or a quarantine unit? Because if you don’t have a comparable level of established, effective treatment for these patients, then you’re simply herding them off to a different place where they’re going to suffer both illnesses,” he cautioned.
Nevertheless, Oldham recognized that the issue of how to treat psychiatric patients who test positive for COVID-19 is complex.
“We’re still wrestling with that question here at Menninger. We have created an enclosed section of the inpatient area reserved for this possibility.
“If we have a patient who tests positive, we will immediately put that patient in one of these rooms in the quarantine section. Then we will use protective equipment for our staff to go and provide care for the patient,” he said.
However, he acknowledged that a psychiatric hospital is in no position to treat patients who develop severe illness from COVID-19.
“We’re certainly worried about it,” he said, “because how many inpatient general medical units are going to want to take a significantly symptomatic COVID-19 patient who was in the hospital for being acutely suicidal? There are no easy solutions.”
This article first appeared on Medscape.com.
There was no hand sanitizer on the hospital’s psychiatric ward for fear patients would drink it; they slept together on futons in communal rooms and the windows were sealed shut to prevent suicide attempts — all conditions that created the perfect environment for the rapid spread of a potentially deadly virus.
This scenario may sound like a something out of a horror film, but as reported last month by the UK newspaper The Independent, it was the reality in the psychiatric ward of South Korea’s Daenam Hospital after COVID-19 struck. Eventually health officials put the ward on lockdown, but it wasn’t long before all but two of the unit’s 103 patients were positive for the virus.
To avoid a similar catastrophe, staff at an Israeli hospital have created what they describe as the “world’s first” dedicated COVID-19 unit for psychiatric inpatients.
Clinicians at Israel’s national hospital, Sheba Medical Center Tel HaShomer in Tel Aviv, believe the 16-bed unit, which officially opened on March 26, will stop psychiatric inpatients with the virus — who may have trouble with social distancing — from spreading it to others on the ward.
“Psychiatric patients are going to get sick from coronavirus just like anybody else,” Mark Weiser, MD, head of the psychiatric division at the institution told Medscape Medical News. “But we’re concerned that, on a psychiatric ward, a patient who is COVID-19 positive can also be psychotic, manic, cognitively impaired, or have poor judgment … making it difficult for that patient to keep social distancing, and very quickly you’ll have an entire ward of patients infected.
“So the basic public health issue is how to prevent a single psychiatric patient who is hospitalized and COVID-19-positive from making everybody else sick,” he added.
Unique Challenges, Rapid Response
Adapting an existing psychiatric ward to one exclusively used by inpatients with COVID-19 required significant planning, coordination, and modifications to ensure the well-being of patients and staff.
A dedicated entrance for the exclusive use of infected psychiatric inpatients was also created.
In addition, two-way television cameras in patients’ rooms were installed to facilitate a constant flow of communication and enable therapeutic sessions and family visits. All of these modifications were completed in under a week.
“Under normal circumstances, we have cameras in the public areas of our wards, but in order to respect people’s privacy, we do not have cameras in their rooms.
“In this specific ward, on the other hand, we did put cameras in the rooms, so if a patient needs to be watched more closely, it could be done remotely without exposing staff to the virus. We have a person who’s watching the screens at all times, just to see what’s going on and see what patients are doing,” said Weiser.
Protective personal equipment (PPE) and clothing for staff was tailored to the unique challenges posed by the ward’s patient population.
“Of course, you need to wear clothes that are protective against the virus,” said Weiser. “But sometimes our patients can get agitated or even violent, so you’ve got protect against that as well.”
With this in mind, all personnel working on the ward must put on an extra layer of PPE as well as a tear-proof robe. The institution has also implemented a strict protocol that dictates the order in which PPE is donned and doffed.
“It’s got to be done in a very careful and very specific way,” said Weiser. “We have all of it organized with a poster that explains what should be taken off or put on, and in what order.”
For institutions considering setting up a similar unit, Weiser said close proximity to an active care hospital with the capacity to provide urgent care is key.
“We’re psychiatrists; we’re not great at treating acute respiratory problems. So patients with significant respiratory problems need a place to get appropriate care quickly,” he said.
In setting up the unit, there were still a few obstacles, Weiser noted. For instance, despite the many protective and safety measures undertaken by the institution, some of the hospital staff were concerned about their risk of contracting the virus.
To address these concerns, the hospital’s leadership brought in infectious disease experts to educate hospital personnel about the virus and transmission risk.
“They told our staff that given all the precautions we had taken, there was very little risk anyone else could become infected,” Weiser said.
Despite the many challenges, Weiser said he and his colleagues are thrilled with the dedicated ward and the positive reception it has received.
“My colleagues and the directors of psychiatric hospitals all around the country are very happy with this because now they’re not hospitalizing infected patients. They’re very happy for us to take care of this,” he said.
“No Easy Solutions”
Commenting on the initiative for Medscape Medical News, John M. Oldham, MD, chief of staff at Baylor College of Medicine’s Menninger Clinic in Houston, Texas, raised some questions.
“Is it really going to be the treatment unit or a quarantine unit? Because if you don’t have a comparable level of established, effective treatment for these patients, then you’re simply herding them off to a different place where they’re going to suffer both illnesses,” he cautioned.
Nevertheless, Oldham recognized that the issue of how to treat psychiatric patients who test positive for COVID-19 is complex.
“We’re still wrestling with that question here at Menninger. We have created an enclosed section of the inpatient area reserved for this possibility.
“If we have a patient who tests positive, we will immediately put that patient in one of these rooms in the quarantine section. Then we will use protective equipment for our staff to go and provide care for the patient,” he said.
However, he acknowledged that a psychiatric hospital is in no position to treat patients who develop severe illness from COVID-19.
“We’re certainly worried about it,” he said, “because how many inpatient general medical units are going to want to take a significantly symptomatic COVID-19 patient who was in the hospital for being acutely suicidal? There are no easy solutions.”
This article first appeared on Medscape.com.
COVID-19: Mental health pros come to the aid of frontline comrades
Frontline COVID-19 healthcare workers across North America are dealing with unprecedented stress, but mental health therapists in both Canada and the US are doing their part to ensure the psychological well-being of their colleagues on the frontlines of the pandemic.
Over the past few weeks, thousands of licensed psychologists, psychotherapists, and social workers have signed up to offer free therapy sessions to healthcare professionals who find themselves psychologically overwhelmed by the pandemic’s economic, social, and financial fallout.
In Canada, the movement was started by Toronto psychotherapist Karen Dougherty, MA, who saw a social media post from someone in New York asking mental health workers to volunteer their time.
Inspired by this, Dougherty reached out to some of her close colleagues with a social media post of her own. A few days later, 450 people had signed up to volunteer and Ontario COVID-19 Therapists was born.
The sessions are provided by licensed Canadian psychotherapists and are free of charge to healthcare workers providing frontline COVID-19 care. After signing up online, users can choose from one of three therapists who will provide up to five free phone sessions.
In New York state, a similar initiative — which is not limited to healthcare workers — has gained incredible momentum. On March 21, Gov. Andrew Cuomo announced the creation of a statewide hotline [844-863-9314] to provide free mental health services to individuals sheltering at home who may be experiencing stress and anxiety as a result of COVID-19.
The governor called on mental-health professionals to volunteer their time and provide telephone and/or telehealth counseling. The New York State Psychiatric Association quickly got on board and encouraged its members to participate.
Just four days later, more than 6,000 mental health workers had volunteered their services, making New York the first state to address the mental health consequences of the pandemic in this way.
Self-care is vital for healthcare workers during the COVID-19 pandemic, particularly as stress mounts and workdays become longer and grimmer. Dougherty recommended that frontline workers manage overwhelming thoughts by limiting their intake of information about the virus.
Self-Care a “Selfless Act”
Clinicians need to balance the need to stay informed with the potential for information overload, which can contribute to anxiety, she said.
She also recommended that individuals continue to connect with loved ones while practicing social distancing. Equally important is talking to someone about the struggles people may be facing at work.
For Amin Azzam MD, MA, the benefits of these initiatives are obvious.
“There is always value in providing additional mental health services and tending to psychological well-being,” Azzam, adjunct professor of psychiatry, University of California, San Francisco and UC Berkeley, told Medscape Medical News.
“If there ever were a time when we can use all the emotional support possible, then it would be during a global pandemic,” added Azzam, who is also director of Open Learning Initiatives at Osmosis, a nonprofit health education company.
Azzam urged healthcare professionals to avail themselves of such resources as often as necessary.
“Taking care of ourselves is not a selfish act. When the oxygen masks come down on airplanes we are always instructed to put our own masks on first before helping those in need. It’s a sign of strength, not weakness, to seek emotional support,” he said.
However, it isn’t always easy. The longstanding stigma associated with seeking help for mental health issues has not stopped for COVID-19. Even workers who are in close daily contact with people infected with the virus are finding they’re not immune to the stigma associated with seeking mental health treatment, Azzam added.
“Nevertheless, the burden these frontline workers are facing is real…and often crushing. Some Ontario doctors have reported pretraumatic stress disorder, which they attribute to having watched the virus wreak havoc in other countries, and knowing that similar difficulties are headed their way,” he said.
A Growing Movement
Doris Grinspun, PhD, MSN, the CEO of Registered Nurses’ Association of Ontario (RNAO), said the province’s nurses are under intense pressure at work, then fear infecting family members once they come home. Some are even staying at hotels to ensure they don’t infect others, as reported by CBC News.
However, she added, most recognize the important role that psychotherapy can play, especially since many frontline healthcare workers find it difficult to speak with their families about the issues they face at work, for fear of adding stress to their family life as well.
“None of us are superhuman and immune to stress. When healthcare workers are facing workplace challenges never before seen in their lifetimes, they need opportunities to decompress to maintain their own health and well-being. This will help them pace themselves for the marathon — not sprint — to continue doing the important work of helping others,” said Azzam.
Given the attention it has garnered in such a short time, Azzam is hopeful that the free therapy movement will spread.
In Canada, mental health professionals in other provinces have already reached out to Dougherty, lending credence to the notion of a pan-Canadian network of therapists offering free services to healthcare workers during the outbreak.
In the US, other local initiatives are already underway.
“The one that I’m personally aware of is at my home institution at the University of California, San Francisco,” Azzam said. “We have a Care for the Caregiver program that is being greatly expanded at this time. As part of that initiative, the institution’s psychiatry department has solicited licensed mental health care providers to volunteer their time to provide those additional services.”
Azzam has also worked with colleagues developing a series of mental health tools that Osmosis has made available free of charge.
These include a central site with educational material about COVID-19, a video about supporting educators’ mental health during high-stress periods; a video about managing students’ mental health during public health emergencies; a summary of recommended resources for psychological health in distressing times; and a YouTube Live event he held regarding tips for maximizing psychological health during stressful times.
This article first appeared on Medscape.com.
Frontline COVID-19 healthcare workers across North America are dealing with unprecedented stress, but mental health therapists in both Canada and the US are doing their part to ensure the psychological well-being of their colleagues on the frontlines of the pandemic.
Over the past few weeks, thousands of licensed psychologists, psychotherapists, and social workers have signed up to offer free therapy sessions to healthcare professionals who find themselves psychologically overwhelmed by the pandemic’s economic, social, and financial fallout.
In Canada, the movement was started by Toronto psychotherapist Karen Dougherty, MA, who saw a social media post from someone in New York asking mental health workers to volunteer their time.
Inspired by this, Dougherty reached out to some of her close colleagues with a social media post of her own. A few days later, 450 people had signed up to volunteer and Ontario COVID-19 Therapists was born.
The sessions are provided by licensed Canadian psychotherapists and are free of charge to healthcare workers providing frontline COVID-19 care. After signing up online, users can choose from one of three therapists who will provide up to five free phone sessions.
In New York state, a similar initiative — which is not limited to healthcare workers — has gained incredible momentum. On March 21, Gov. Andrew Cuomo announced the creation of a statewide hotline [844-863-9314] to provide free mental health services to individuals sheltering at home who may be experiencing stress and anxiety as a result of COVID-19.
The governor called on mental-health professionals to volunteer their time and provide telephone and/or telehealth counseling. The New York State Psychiatric Association quickly got on board and encouraged its members to participate.
Just four days later, more than 6,000 mental health workers had volunteered their services, making New York the first state to address the mental health consequences of the pandemic in this way.
Self-care is vital for healthcare workers during the COVID-19 pandemic, particularly as stress mounts and workdays become longer and grimmer. Dougherty recommended that frontline workers manage overwhelming thoughts by limiting their intake of information about the virus.
Self-Care a “Selfless Act”
Clinicians need to balance the need to stay informed with the potential for information overload, which can contribute to anxiety, she said.
She also recommended that individuals continue to connect with loved ones while practicing social distancing. Equally important is talking to someone about the struggles people may be facing at work.
For Amin Azzam MD, MA, the benefits of these initiatives are obvious.
“There is always value in providing additional mental health services and tending to psychological well-being,” Azzam, adjunct professor of psychiatry, University of California, San Francisco and UC Berkeley, told Medscape Medical News.
“If there ever were a time when we can use all the emotional support possible, then it would be during a global pandemic,” added Azzam, who is also director of Open Learning Initiatives at Osmosis, a nonprofit health education company.
Azzam urged healthcare professionals to avail themselves of such resources as often as necessary.
“Taking care of ourselves is not a selfish act. When the oxygen masks come down on airplanes we are always instructed to put our own masks on first before helping those in need. It’s a sign of strength, not weakness, to seek emotional support,” he said.
However, it isn’t always easy. The longstanding stigma associated with seeking help for mental health issues has not stopped for COVID-19. Even workers who are in close daily contact with people infected with the virus are finding they’re not immune to the stigma associated with seeking mental health treatment, Azzam added.
“Nevertheless, the burden these frontline workers are facing is real…and often crushing. Some Ontario doctors have reported pretraumatic stress disorder, which they attribute to having watched the virus wreak havoc in other countries, and knowing that similar difficulties are headed their way,” he said.
A Growing Movement
Doris Grinspun, PhD, MSN, the CEO of Registered Nurses’ Association of Ontario (RNAO), said the province’s nurses are under intense pressure at work, then fear infecting family members once they come home. Some are even staying at hotels to ensure they don’t infect others, as reported by CBC News.
However, she added, most recognize the important role that psychotherapy can play, especially since many frontline healthcare workers find it difficult to speak with their families about the issues they face at work, for fear of adding stress to their family life as well.
“None of us are superhuman and immune to stress. When healthcare workers are facing workplace challenges never before seen in their lifetimes, they need opportunities to decompress to maintain their own health and well-being. This will help them pace themselves for the marathon — not sprint — to continue doing the important work of helping others,” said Azzam.
Given the attention it has garnered in such a short time, Azzam is hopeful that the free therapy movement will spread.
In Canada, mental health professionals in other provinces have already reached out to Dougherty, lending credence to the notion of a pan-Canadian network of therapists offering free services to healthcare workers during the outbreak.
In the US, other local initiatives are already underway.
“The one that I’m personally aware of is at my home institution at the University of California, San Francisco,” Azzam said. “We have a Care for the Caregiver program that is being greatly expanded at this time. As part of that initiative, the institution’s psychiatry department has solicited licensed mental health care providers to volunteer their time to provide those additional services.”
Azzam has also worked with colleagues developing a series of mental health tools that Osmosis has made available free of charge.
These include a central site with educational material about COVID-19, a video about supporting educators’ mental health during high-stress periods; a video about managing students’ mental health during public health emergencies; a summary of recommended resources for psychological health in distressing times; and a YouTube Live event he held regarding tips for maximizing psychological health during stressful times.
This article first appeared on Medscape.com.
Frontline COVID-19 healthcare workers across North America are dealing with unprecedented stress, but mental health therapists in both Canada and the US are doing their part to ensure the psychological well-being of their colleagues on the frontlines of the pandemic.
Over the past few weeks, thousands of licensed psychologists, psychotherapists, and social workers have signed up to offer free therapy sessions to healthcare professionals who find themselves psychologically overwhelmed by the pandemic’s economic, social, and financial fallout.
In Canada, the movement was started by Toronto psychotherapist Karen Dougherty, MA, who saw a social media post from someone in New York asking mental health workers to volunteer their time.
Inspired by this, Dougherty reached out to some of her close colleagues with a social media post of her own. A few days later, 450 people had signed up to volunteer and Ontario COVID-19 Therapists was born.
The sessions are provided by licensed Canadian psychotherapists and are free of charge to healthcare workers providing frontline COVID-19 care. After signing up online, users can choose from one of three therapists who will provide up to five free phone sessions.
In New York state, a similar initiative — which is not limited to healthcare workers — has gained incredible momentum. On March 21, Gov. Andrew Cuomo announced the creation of a statewide hotline [844-863-9314] to provide free mental health services to individuals sheltering at home who may be experiencing stress and anxiety as a result of COVID-19.
The governor called on mental-health professionals to volunteer their time and provide telephone and/or telehealth counseling. The New York State Psychiatric Association quickly got on board and encouraged its members to participate.
Just four days later, more than 6,000 mental health workers had volunteered their services, making New York the first state to address the mental health consequences of the pandemic in this way.
Self-care is vital for healthcare workers during the COVID-19 pandemic, particularly as stress mounts and workdays become longer and grimmer. Dougherty recommended that frontline workers manage overwhelming thoughts by limiting their intake of information about the virus.
Self-Care a “Selfless Act”
Clinicians need to balance the need to stay informed with the potential for information overload, which can contribute to anxiety, she said.
She also recommended that individuals continue to connect with loved ones while practicing social distancing. Equally important is talking to someone about the struggles people may be facing at work.
For Amin Azzam MD, MA, the benefits of these initiatives are obvious.
“There is always value in providing additional mental health services and tending to psychological well-being,” Azzam, adjunct professor of psychiatry, University of California, San Francisco and UC Berkeley, told Medscape Medical News.
“If there ever were a time when we can use all the emotional support possible, then it would be during a global pandemic,” added Azzam, who is also director of Open Learning Initiatives at Osmosis, a nonprofit health education company.
Azzam urged healthcare professionals to avail themselves of such resources as often as necessary.
“Taking care of ourselves is not a selfish act. When the oxygen masks come down on airplanes we are always instructed to put our own masks on first before helping those in need. It’s a sign of strength, not weakness, to seek emotional support,” he said.
However, it isn’t always easy. The longstanding stigma associated with seeking help for mental health issues has not stopped for COVID-19. Even workers who are in close daily contact with people infected with the virus are finding they’re not immune to the stigma associated with seeking mental health treatment, Azzam added.
“Nevertheless, the burden these frontline workers are facing is real…and often crushing. Some Ontario doctors have reported pretraumatic stress disorder, which they attribute to having watched the virus wreak havoc in other countries, and knowing that similar difficulties are headed their way,” he said.
A Growing Movement
Doris Grinspun, PhD, MSN, the CEO of Registered Nurses’ Association of Ontario (RNAO), said the province’s nurses are under intense pressure at work, then fear infecting family members once they come home. Some are even staying at hotels to ensure they don’t infect others, as reported by CBC News.
However, she added, most recognize the important role that psychotherapy can play, especially since many frontline healthcare workers find it difficult to speak with their families about the issues they face at work, for fear of adding stress to their family life as well.
“None of us are superhuman and immune to stress. When healthcare workers are facing workplace challenges never before seen in their lifetimes, they need opportunities to decompress to maintain their own health and well-being. This will help them pace themselves for the marathon — not sprint — to continue doing the important work of helping others,” said Azzam.
Given the attention it has garnered in such a short time, Azzam is hopeful that the free therapy movement will spread.
In Canada, mental health professionals in other provinces have already reached out to Dougherty, lending credence to the notion of a pan-Canadian network of therapists offering free services to healthcare workers during the outbreak.
In the US, other local initiatives are already underway.
“The one that I’m personally aware of is at my home institution at the University of California, San Francisco,” Azzam said. “We have a Care for the Caregiver program that is being greatly expanded at this time. As part of that initiative, the institution’s psychiatry department has solicited licensed mental health care providers to volunteer their time to provide those additional services.”
Azzam has also worked with colleagues developing a series of mental health tools that Osmosis has made available free of charge.
These include a central site with educational material about COVID-19, a video about supporting educators’ mental health during high-stress periods; a video about managing students’ mental health during public health emergencies; a summary of recommended resources for psychological health in distressing times; and a YouTube Live event he held regarding tips for maximizing psychological health during stressful times.
This article first appeared on Medscape.com.
EEG signature predicts antidepressant response
Personalized treatment for depression may soon become a reality, thanks to an artificial intelligence (AI) algorithm that accurately predicts antidepressant efficacy in specific patients.
A landmark study of more than 300 patients with major depressive disorder (MDD) showed that a latent-space machine-learning algorithm tailored for resting-state EEG robustly predicted patient response to sertraline. The findings were generalizable across different study sites and EEG equipment.
“We found that the use of the artificial intelligence algorithm can identify the EEG signature for patients who do well on sertraline,” study investigator Madhukar H. Trivedi, MD, professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas, said in an interview.
“Interestingly, when we looked further, it became clear that patients with that same EEG signature do not do well on placebo,” he added.
The study was published online Feb. 10 in Nature Biotechnology (doi: 10.1038/s41587-019-0397-3).
Pivotal study
Currently, major depression is defined using a range of clinical criteria. As such, it encompasses a heterogeneous mix of neurobiological phenotypes. Such heterogeneity may account for the modest superiority of antidepressant medication relative to placebo.
While recent research suggests that resting-state EEG may help identify treatment-predictive heterogeneity in depression, these studies have also been hindered by a lack of cross-validation and small sample sizes.
What’s more, these studies have either identified nonspecific predictors or failed to yield generalizable neural signatures that are predictive at the individual patient level (Am J Psychiatry. 2019 Jan 1;176[1]:44-56).
For these reasons, there is currently no robust neurobiological signature for an antidepressant-responsive phenotype that may help identify which patients would benefit from antidepressant medication. Nevertheless, said Dr. Trivedi, detailing such a signature would promote a neurobiological understanding of treatment response, with the potential for notable clinical implications.
“The idea behind this [National Institutes of Health]–funded study was to develop biomarkers that can distinguish treatment outcomes between drug and placebo,” he said. “To do so, we needed a randomized, placebo-controlled trial that has significant breadth in terms of biomarker evaluation and validation, and this study was designed specifically with this end in mind.
“There has not been a drug-placebo study that has looked at this in patients with depression,” Dr. Trivedi said. “So in that sense, this was really a pivotal study.”
To help address these challenges, the investigators developed a machine-learning algorithm they called SELSER (Sparse EEG Latent Space Regression).
Using data from four separate studies, they first established the resting-state EEG predictive signature by training SELSER on data from 309 patients from the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care) study, a neuroimaging-coupled, placebo-controlled, randomized clinical study of antidepressant efficacy.
The generalizability of the antidepressant-predictive signature was then tested in a second independent sample of 72 depressed patients.
In a third independent sample of 24 depressed patients, the researchers assessed the convergent validity and neurobiological significance of the treatment-predictive, resting-state EEG signature.
Finally, a fourth sample of 152 depressed patients was used to test the generalizability of the results.
‘Fantastic’ result but validation needed
These combined efforts were aimed at revealing a treatment responsive phenotype in depression, dissociate between medication and placebo response, establish its mechanistic significance, and provide initial evidence regarding the potential for treatment selection on the basis of a resting-state EEG signature.
The study showed that improvement in patients’ symptoms was robustly predicted by the algorithm. These predictions were specific for sertraline relative to placebo.
When generalized to two depression samples, the researchers also found that the algorithm reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation (TMS) treatment outcome.
“Although we only looked at sertraline,” Dr. Trivedi said, “we also applied the signature to a sample of patients who had been treated with transcranial magnetic stimulation. And we found that the signature for TMS [response] is different than the signature for sertraline.”
Interestingly, the antidepressant-predictive signature identified by SELSER was also superior to that of conventional machine-learning models or latent modeling methods, such as independent-component analysis or principal-component analysis. This SELSER signature was also superior to a model trained on clinical data alone and was able to predict outcome using resting-state EEG data acquired at a study site not included in the model training set.
The study also revealed evidence of multimodal convergent validity for the antidepressant-response signature by virtue of its correlation with expression of a task-based functional MRI signature in one of the four datasets.
The strength of the resting-state signature was also found to correlate with prefrontal neural responsivity, as indexed by direct stimulation with single-pulse TMS and EEG.
Given the ability of the algorithm to both predict outcome with sertraline and distinguish response between sertraline and placebo at the individual patient level, the investigators believe SELSER may one day support machine learning–driven personalized approaches to depression treatment.
“Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression,” the authors wrote.
Yet, their work is far from over.
“Identifying this signature was fantastic, but you’ve got to be able to validate it as well,” Dr. Trivedi noted. “And luckily, we were able to validate it in the three additional studies.
“The next question is whether it can be broadened to other illnesses.”
Promising research
Commenting on the findings in an interview, Michele Ferrante, PhD, said he believes there may soon be a time during which algorithms such as this are used to personalize depression treatment.
“It’s well known that there are no good biological tests in psychiatry, but promising computational tools, biomarkers, and behavioral signatures for segregating patients according to treatment response are starting to emerge for depression,” said Dr. Ferrante, program chief of the Theoretical and Computational Neuroscience Program at the National Institute of Mental Health (NIMH).
“Precision in the ability to predict what patient will respond to each treatment will improve over time, I have no doubt,” added Dr. Ferrante, who was not involved with the current study.
However, he noted, such approaches are not without their potential drawbacks.
“The greatest challenge is to continuously validate these computational tools as they keep on learning from more heterogeneous groups. Another challenge will be to make sure that these computational tools become well-established, widely adopted, safe, and regulated by the [Food and Drug Administration] as Software as a Medical Device,” he said.
The current algorithm will also need to undergo further testing, said Dr. Ferrante.
“It has been validated on an external dataset,” he said, “but now we need to do rigorous prospective clinical trials where patients are selectively assigned by the AI to a treatment according to their biosignature, to see if these results hold true.
“Down the road, it would be important to implement computational models [that are] able to assign patients across the multiple treatments available for depression, including pharmaceuticals, psychosocial interventions, and neural devices.”
The study was funded directly and indirectly by the NIMH of the National Institutes of Health, the Stanford Neurosciences Institute, the Hersh Foundation, the National Key Research and Development Plan of China, and the National Natural Science Foundation of China.
Dr. Trivedi disclosed numerous financial relationships with pharmaceutical companies and device manufacturers. He has received grants/research support from the Agency for Healthcare Research and Quality, Cyberonic, the National Alliance for Research in Schizophrenia and Depression, the NIMH, and the National Institute on Drug Abuse.
A version of this article first appeared on Medscape.com.
Personalized treatment for depression may soon become a reality, thanks to an artificial intelligence (AI) algorithm that accurately predicts antidepressant efficacy in specific patients.
A landmark study of more than 300 patients with major depressive disorder (MDD) showed that a latent-space machine-learning algorithm tailored for resting-state EEG robustly predicted patient response to sertraline. The findings were generalizable across different study sites and EEG equipment.
“We found that the use of the artificial intelligence algorithm can identify the EEG signature for patients who do well on sertraline,” study investigator Madhukar H. Trivedi, MD, professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas, said in an interview.
“Interestingly, when we looked further, it became clear that patients with that same EEG signature do not do well on placebo,” he added.
The study was published online Feb. 10 in Nature Biotechnology (doi: 10.1038/s41587-019-0397-3).
Pivotal study
Currently, major depression is defined using a range of clinical criteria. As such, it encompasses a heterogeneous mix of neurobiological phenotypes. Such heterogeneity may account for the modest superiority of antidepressant medication relative to placebo.
While recent research suggests that resting-state EEG may help identify treatment-predictive heterogeneity in depression, these studies have also been hindered by a lack of cross-validation and small sample sizes.
What’s more, these studies have either identified nonspecific predictors or failed to yield generalizable neural signatures that are predictive at the individual patient level (Am J Psychiatry. 2019 Jan 1;176[1]:44-56).
For these reasons, there is currently no robust neurobiological signature for an antidepressant-responsive phenotype that may help identify which patients would benefit from antidepressant medication. Nevertheless, said Dr. Trivedi, detailing such a signature would promote a neurobiological understanding of treatment response, with the potential for notable clinical implications.
“The idea behind this [National Institutes of Health]–funded study was to develop biomarkers that can distinguish treatment outcomes between drug and placebo,” he said. “To do so, we needed a randomized, placebo-controlled trial that has significant breadth in terms of biomarker evaluation and validation, and this study was designed specifically with this end in mind.
“There has not been a drug-placebo study that has looked at this in patients with depression,” Dr. Trivedi said. “So in that sense, this was really a pivotal study.”
To help address these challenges, the investigators developed a machine-learning algorithm they called SELSER (Sparse EEG Latent Space Regression).
Using data from four separate studies, they first established the resting-state EEG predictive signature by training SELSER on data from 309 patients from the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care) study, a neuroimaging-coupled, placebo-controlled, randomized clinical study of antidepressant efficacy.
The generalizability of the antidepressant-predictive signature was then tested in a second independent sample of 72 depressed patients.
In a third independent sample of 24 depressed patients, the researchers assessed the convergent validity and neurobiological significance of the treatment-predictive, resting-state EEG signature.
Finally, a fourth sample of 152 depressed patients was used to test the generalizability of the results.
‘Fantastic’ result but validation needed
These combined efforts were aimed at revealing a treatment responsive phenotype in depression, dissociate between medication and placebo response, establish its mechanistic significance, and provide initial evidence regarding the potential for treatment selection on the basis of a resting-state EEG signature.
The study showed that improvement in patients’ symptoms was robustly predicted by the algorithm. These predictions were specific for sertraline relative to placebo.
When generalized to two depression samples, the researchers also found that the algorithm reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation (TMS) treatment outcome.
“Although we only looked at sertraline,” Dr. Trivedi said, “we also applied the signature to a sample of patients who had been treated with transcranial magnetic stimulation. And we found that the signature for TMS [response] is different than the signature for sertraline.”
Interestingly, the antidepressant-predictive signature identified by SELSER was also superior to that of conventional machine-learning models or latent modeling methods, such as independent-component analysis or principal-component analysis. This SELSER signature was also superior to a model trained on clinical data alone and was able to predict outcome using resting-state EEG data acquired at a study site not included in the model training set.
The study also revealed evidence of multimodal convergent validity for the antidepressant-response signature by virtue of its correlation with expression of a task-based functional MRI signature in one of the four datasets.
The strength of the resting-state signature was also found to correlate with prefrontal neural responsivity, as indexed by direct stimulation with single-pulse TMS and EEG.
Given the ability of the algorithm to both predict outcome with sertraline and distinguish response between sertraline and placebo at the individual patient level, the investigators believe SELSER may one day support machine learning–driven personalized approaches to depression treatment.
“Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression,” the authors wrote.
Yet, their work is far from over.
“Identifying this signature was fantastic, but you’ve got to be able to validate it as well,” Dr. Trivedi noted. “And luckily, we were able to validate it in the three additional studies.
“The next question is whether it can be broadened to other illnesses.”
Promising research
Commenting on the findings in an interview, Michele Ferrante, PhD, said he believes there may soon be a time during which algorithms such as this are used to personalize depression treatment.
“It’s well known that there are no good biological tests in psychiatry, but promising computational tools, biomarkers, and behavioral signatures for segregating patients according to treatment response are starting to emerge for depression,” said Dr. Ferrante, program chief of the Theoretical and Computational Neuroscience Program at the National Institute of Mental Health (NIMH).
“Precision in the ability to predict what patient will respond to each treatment will improve over time, I have no doubt,” added Dr. Ferrante, who was not involved with the current study.
However, he noted, such approaches are not without their potential drawbacks.
“The greatest challenge is to continuously validate these computational tools as they keep on learning from more heterogeneous groups. Another challenge will be to make sure that these computational tools become well-established, widely adopted, safe, and regulated by the [Food and Drug Administration] as Software as a Medical Device,” he said.
The current algorithm will also need to undergo further testing, said Dr. Ferrante.
“It has been validated on an external dataset,” he said, “but now we need to do rigorous prospective clinical trials where patients are selectively assigned by the AI to a treatment according to their biosignature, to see if these results hold true.
“Down the road, it would be important to implement computational models [that are] able to assign patients across the multiple treatments available for depression, including pharmaceuticals, psychosocial interventions, and neural devices.”
The study was funded directly and indirectly by the NIMH of the National Institutes of Health, the Stanford Neurosciences Institute, the Hersh Foundation, the National Key Research and Development Plan of China, and the National Natural Science Foundation of China.
Dr. Trivedi disclosed numerous financial relationships with pharmaceutical companies and device manufacturers. He has received grants/research support from the Agency for Healthcare Research and Quality, Cyberonic, the National Alliance for Research in Schizophrenia and Depression, the NIMH, and the National Institute on Drug Abuse.
A version of this article first appeared on Medscape.com.
Personalized treatment for depression may soon become a reality, thanks to an artificial intelligence (AI) algorithm that accurately predicts antidepressant efficacy in specific patients.
A landmark study of more than 300 patients with major depressive disorder (MDD) showed that a latent-space machine-learning algorithm tailored for resting-state EEG robustly predicted patient response to sertraline. The findings were generalizable across different study sites and EEG equipment.
“We found that the use of the artificial intelligence algorithm can identify the EEG signature for patients who do well on sertraline,” study investigator Madhukar H. Trivedi, MD, professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas, said in an interview.
“Interestingly, when we looked further, it became clear that patients with that same EEG signature do not do well on placebo,” he added.
The study was published online Feb. 10 in Nature Biotechnology (doi: 10.1038/s41587-019-0397-3).
Pivotal study
Currently, major depression is defined using a range of clinical criteria. As such, it encompasses a heterogeneous mix of neurobiological phenotypes. Such heterogeneity may account for the modest superiority of antidepressant medication relative to placebo.
While recent research suggests that resting-state EEG may help identify treatment-predictive heterogeneity in depression, these studies have also been hindered by a lack of cross-validation and small sample sizes.
What’s more, these studies have either identified nonspecific predictors or failed to yield generalizable neural signatures that are predictive at the individual patient level (Am J Psychiatry. 2019 Jan 1;176[1]:44-56).
For these reasons, there is currently no robust neurobiological signature for an antidepressant-responsive phenotype that may help identify which patients would benefit from antidepressant medication. Nevertheless, said Dr. Trivedi, detailing such a signature would promote a neurobiological understanding of treatment response, with the potential for notable clinical implications.
“The idea behind this [National Institutes of Health]–funded study was to develop biomarkers that can distinguish treatment outcomes between drug and placebo,” he said. “To do so, we needed a randomized, placebo-controlled trial that has significant breadth in terms of biomarker evaluation and validation, and this study was designed specifically with this end in mind.
“There has not been a drug-placebo study that has looked at this in patients with depression,” Dr. Trivedi said. “So in that sense, this was really a pivotal study.”
To help address these challenges, the investigators developed a machine-learning algorithm they called SELSER (Sparse EEG Latent Space Regression).
Using data from four separate studies, they first established the resting-state EEG predictive signature by training SELSER on data from 309 patients from the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care) study, a neuroimaging-coupled, placebo-controlled, randomized clinical study of antidepressant efficacy.
The generalizability of the antidepressant-predictive signature was then tested in a second independent sample of 72 depressed patients.
In a third independent sample of 24 depressed patients, the researchers assessed the convergent validity and neurobiological significance of the treatment-predictive, resting-state EEG signature.
Finally, a fourth sample of 152 depressed patients was used to test the generalizability of the results.
‘Fantastic’ result but validation needed
These combined efforts were aimed at revealing a treatment responsive phenotype in depression, dissociate between medication and placebo response, establish its mechanistic significance, and provide initial evidence regarding the potential for treatment selection on the basis of a resting-state EEG signature.
The study showed that improvement in patients’ symptoms was robustly predicted by the algorithm. These predictions were specific for sertraline relative to placebo.
When generalized to two depression samples, the researchers also found that the algorithm reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation (TMS) treatment outcome.
“Although we only looked at sertraline,” Dr. Trivedi said, “we also applied the signature to a sample of patients who had been treated with transcranial magnetic stimulation. And we found that the signature for TMS [response] is different than the signature for sertraline.”
Interestingly, the antidepressant-predictive signature identified by SELSER was also superior to that of conventional machine-learning models or latent modeling methods, such as independent-component analysis or principal-component analysis. This SELSER signature was also superior to a model trained on clinical data alone and was able to predict outcome using resting-state EEG data acquired at a study site not included in the model training set.
The study also revealed evidence of multimodal convergent validity for the antidepressant-response signature by virtue of its correlation with expression of a task-based functional MRI signature in one of the four datasets.
The strength of the resting-state signature was also found to correlate with prefrontal neural responsivity, as indexed by direct stimulation with single-pulse TMS and EEG.
Given the ability of the algorithm to both predict outcome with sertraline and distinguish response between sertraline and placebo at the individual patient level, the investigators believe SELSER may one day support machine learning–driven personalized approaches to depression treatment.
“Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression,” the authors wrote.
Yet, their work is far from over.
“Identifying this signature was fantastic, but you’ve got to be able to validate it as well,” Dr. Trivedi noted. “And luckily, we were able to validate it in the three additional studies.
“The next question is whether it can be broadened to other illnesses.”
Promising research
Commenting on the findings in an interview, Michele Ferrante, PhD, said he believes there may soon be a time during which algorithms such as this are used to personalize depression treatment.
“It’s well known that there are no good biological tests in psychiatry, but promising computational tools, biomarkers, and behavioral signatures for segregating patients according to treatment response are starting to emerge for depression,” said Dr. Ferrante, program chief of the Theoretical and Computational Neuroscience Program at the National Institute of Mental Health (NIMH).
“Precision in the ability to predict what patient will respond to each treatment will improve over time, I have no doubt,” added Dr. Ferrante, who was not involved with the current study.
However, he noted, such approaches are not without their potential drawbacks.
“The greatest challenge is to continuously validate these computational tools as they keep on learning from more heterogeneous groups. Another challenge will be to make sure that these computational tools become well-established, widely adopted, safe, and regulated by the [Food and Drug Administration] as Software as a Medical Device,” he said.
The current algorithm will also need to undergo further testing, said Dr. Ferrante.
“It has been validated on an external dataset,” he said, “but now we need to do rigorous prospective clinical trials where patients are selectively assigned by the AI to a treatment according to their biosignature, to see if these results hold true.
“Down the road, it would be important to implement computational models [that are] able to assign patients across the multiple treatments available for depression, including pharmaceuticals, psychosocial interventions, and neural devices.”
The study was funded directly and indirectly by the NIMH of the National Institutes of Health, the Stanford Neurosciences Institute, the Hersh Foundation, the National Key Research and Development Plan of China, and the National Natural Science Foundation of China.
Dr. Trivedi disclosed numerous financial relationships with pharmaceutical companies and device manufacturers. He has received grants/research support from the Agency for Healthcare Research and Quality, Cyberonic, the National Alliance for Research in Schizophrenia and Depression, the NIMH, and the National Institute on Drug Abuse.
A version of this article first appeared on Medscape.com.
FROM NATURE BIOTECHNOLOGY