Schizophrenia & Other Psychotic Disorders

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

Antipsychotics are not responsible for the increased COVID-related death rate among patients with serious mental illness (SMI), new research shows.

The significant increase in COVID-19 mortality that continues to be reported among those with schizophrenia and schizoaffective disorder “underscores the importance of protective interventions for this group, including priority vaccination,” study investigator Katlyn Nemani, MD, research assistant professor, department of psychiatry, New York University, told this news organization.

The study was published online September 22 in JAMA Psychiatry.
 

Threefold increase in death

Previous research has linked a diagnosis of a schizophrenia spectrum disorder, which includes schizophrenia and schizoaffective disorder, to an almost threefold increase in mortality among patients with COVID-19.

Some population-based research has also reported a link between antipsychotic medication use and increased risk for COVID-related mortality, but these studies did not take psychiatric diagnoses into account.

“This raised the question of whether the increased risk observed in this population is related to underlying psychiatric illness or its treatment,” said Dr. Nemani.

The retrospective cohort study included 464 adults (mean age, 53 years) who were diagnosed with COVID-19 between March 3, 2020, and Feb. 17, 2021, and who had previously been diagnosed with schizophrenia spectrum disorder or bipolar disorder. Of these, 42.2% were treated with an antipsychotic medication.

The primary endpoint was death within 60 days of COVID-19 diagnosis. Covariates included sociodemographic characteristics, such as patient-reported race and ethnicity, age, and insurance type, a psychiatric diagnosis, medical comorbidities, and smoking status.

Of the total, 41 patients (8.8%) died. The 60-day fatality rate was 13.7% among patients with a schizophrenia spectrum disorder (n = 182) and 5.7% among patients with bipolar disorder (n = 282).

Antipsychotic treatment was not significantly associated with mortality (odds ratio, 1.00; 95% confidence interval, 0.48-2.08; P = .99).

“This suggests that antipsychotic medication is unlikely to be responsible for the increased risk we’ve observed in this population, although this finding needs to be replicated,” said Dr. Nemani.
 

Surprise finding

A diagnosis of a schizophrenia spectrum disorder was associated with an almost threefold increased risk for mortality compared with bipolar disorder (OR, 2.88; 95% CI, 1.36-6.11; P = .006).

“This was a surprising finding,” said Dr. Nemani. “A possible explanation is differences in immune function associated with schizophrenia spectrum illness.”

She noted that there is evidence suggesting the immune system may play a role in the pathogenesis of schizophrenia, and research has shown that pneumonia and infection are among the leading causes of premature mortality in this population.

As well, several potential risk factors disproportionately affect people with serious mental illness, including an increase in the prevalence of medical comorbidities such as cardiovascular disease and diabetes, socioeconomic disadvantages, and barriers to accessing timely care. Prior studies have also found that people with SMI are less likely to receive preventive care interventions, including vaccination, said Dr. Nemani.

However, these factors are unlikely to fully account for the increased risk found in the study, she said.

“Our study population was limited to people who had received treatment within the NYU Langone Health System. We took a comprehensive list of sociodemographic and medical risk factors into account, and our research was conducted prior to the availability of COVID-19 vaccines,” she said.

Further research is necessary to understand what underlies the increase in susceptibility to severe infection among patients with schizophrenia and to identify interventions that may mitigate risk, said Dr. Nemani.

“This includes evaluating systems-level factors, such as access to preventive interventions and treatment, as well as investigating underlying immune mechanisms that may contribute to severe and fatal infection,” she said.

The researchers could not validate psychiatric diagnoses or capture deaths not documented in the electronic health record. In addition, the limited sample size precluded analysis of the use of individual antipsychotic medications, which may differ in their associated effects.

“It’s possible individual antipsychotic medications may be associated with harmful or protective effects,” said Dr. Nemani.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Antipsychotics are not responsible for the increased COVID-related death rate among patients with serious mental illness (SMI), new research shows.

The significant increase in COVID-19 mortality that continues to be reported among those with schizophrenia and schizoaffective disorder “underscores the importance of protective interventions for this group, including priority vaccination,” study investigator Katlyn Nemani, MD, research assistant professor, department of psychiatry, New York University, told this news organization.

The study was published online September 22 in JAMA Psychiatry.
 

Threefold increase in death

Previous research has linked a diagnosis of a schizophrenia spectrum disorder, which includes schizophrenia and schizoaffective disorder, to an almost threefold increase in mortality among patients with COVID-19.

Some population-based research has also reported a link between antipsychotic medication use and increased risk for COVID-related mortality, but these studies did not take psychiatric diagnoses into account.

“This raised the question of whether the increased risk observed in this population is related to underlying psychiatric illness or its treatment,” said Dr. Nemani.

The retrospective cohort study included 464 adults (mean age, 53 years) who were diagnosed with COVID-19 between March 3, 2020, and Feb. 17, 2021, and who had previously been diagnosed with schizophrenia spectrum disorder or bipolar disorder. Of these, 42.2% were treated with an antipsychotic medication.

The primary endpoint was death within 60 days of COVID-19 diagnosis. Covariates included sociodemographic characteristics, such as patient-reported race and ethnicity, age, and insurance type, a psychiatric diagnosis, medical comorbidities, and smoking status.

Of the total, 41 patients (8.8%) died. The 60-day fatality rate was 13.7% among patients with a schizophrenia spectrum disorder (n = 182) and 5.7% among patients with bipolar disorder (n = 282).

Antipsychotic treatment was not significantly associated with mortality (odds ratio, 1.00; 95% confidence interval, 0.48-2.08; P = .99).

“This suggests that antipsychotic medication is unlikely to be responsible for the increased risk we’ve observed in this population, although this finding needs to be replicated,” said Dr. Nemani.
 

Surprise finding

A diagnosis of a schizophrenia spectrum disorder was associated with an almost threefold increased risk for mortality compared with bipolar disorder (OR, 2.88; 95% CI, 1.36-6.11; P = .006).

“This was a surprising finding,” said Dr. Nemani. “A possible explanation is differences in immune function associated with schizophrenia spectrum illness.”

She noted that there is evidence suggesting the immune system may play a role in the pathogenesis of schizophrenia, and research has shown that pneumonia and infection are among the leading causes of premature mortality in this population.

As well, several potential risk factors disproportionately affect people with serious mental illness, including an increase in the prevalence of medical comorbidities such as cardiovascular disease and diabetes, socioeconomic disadvantages, and barriers to accessing timely care. Prior studies have also found that people with SMI are less likely to receive preventive care interventions, including vaccination, said Dr. Nemani.

However, these factors are unlikely to fully account for the increased risk found in the study, she said.

“Our study population was limited to people who had received treatment within the NYU Langone Health System. We took a comprehensive list of sociodemographic and medical risk factors into account, and our research was conducted prior to the availability of COVID-19 vaccines,” she said.

Further research is necessary to understand what underlies the increase in susceptibility to severe infection among patients with schizophrenia and to identify interventions that may mitigate risk, said Dr. Nemani.

“This includes evaluating systems-level factors, such as access to preventive interventions and treatment, as well as investigating underlying immune mechanisms that may contribute to severe and fatal infection,” she said.

The researchers could not validate psychiatric diagnoses or capture deaths not documented in the electronic health record. In addition, the limited sample size precluded analysis of the use of individual antipsychotic medications, which may differ in their associated effects.

“It’s possible individual antipsychotic medications may be associated with harmful or protective effects,” said Dr. Nemani.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Antipsychotics are not responsible for the increased COVID-related death rate among patients with serious mental illness (SMI), new research shows.

The significant increase in COVID-19 mortality that continues to be reported among those with schizophrenia and schizoaffective disorder “underscores the importance of protective interventions for this group, including priority vaccination,” study investigator Katlyn Nemani, MD, research assistant professor, department of psychiatry, New York University, told this news organization.

The study was published online September 22 in JAMA Psychiatry.
 

Threefold increase in death

Previous research has linked a diagnosis of a schizophrenia spectrum disorder, which includes schizophrenia and schizoaffective disorder, to an almost threefold increase in mortality among patients with COVID-19.

Some population-based research has also reported a link between antipsychotic medication use and increased risk for COVID-related mortality, but these studies did not take psychiatric diagnoses into account.

“This raised the question of whether the increased risk observed in this population is related to underlying psychiatric illness or its treatment,” said Dr. Nemani.

The retrospective cohort study included 464 adults (mean age, 53 years) who were diagnosed with COVID-19 between March 3, 2020, and Feb. 17, 2021, and who had previously been diagnosed with schizophrenia spectrum disorder or bipolar disorder. Of these, 42.2% were treated with an antipsychotic medication.

The primary endpoint was death within 60 days of COVID-19 diagnosis. Covariates included sociodemographic characteristics, such as patient-reported race and ethnicity, age, and insurance type, a psychiatric diagnosis, medical comorbidities, and smoking status.

Of the total, 41 patients (8.8%) died. The 60-day fatality rate was 13.7% among patients with a schizophrenia spectrum disorder (n = 182) and 5.7% among patients with bipolar disorder (n = 282).

Antipsychotic treatment was not significantly associated with mortality (odds ratio, 1.00; 95% confidence interval, 0.48-2.08; P = .99).

“This suggests that antipsychotic medication is unlikely to be responsible for the increased risk we’ve observed in this population, although this finding needs to be replicated,” said Dr. Nemani.
 

Surprise finding

A diagnosis of a schizophrenia spectrum disorder was associated with an almost threefold increased risk for mortality compared with bipolar disorder (OR, 2.88; 95% CI, 1.36-6.11; P = .006).

“This was a surprising finding,” said Dr. Nemani. “A possible explanation is differences in immune function associated with schizophrenia spectrum illness.”

She noted that there is evidence suggesting the immune system may play a role in the pathogenesis of schizophrenia, and research has shown that pneumonia and infection are among the leading causes of premature mortality in this population.

As well, several potential risk factors disproportionately affect people with serious mental illness, including an increase in the prevalence of medical comorbidities such as cardiovascular disease and diabetes, socioeconomic disadvantages, and barriers to accessing timely care. Prior studies have also found that people with SMI are less likely to receive preventive care interventions, including vaccination, said Dr. Nemani.

However, these factors are unlikely to fully account for the increased risk found in the study, she said.

“Our study population was limited to people who had received treatment within the NYU Langone Health System. We took a comprehensive list of sociodemographic and medical risk factors into account, and our research was conducted prior to the availability of COVID-19 vaccines,” she said.

Further research is necessary to understand what underlies the increase in susceptibility to severe infection among patients with schizophrenia and to identify interventions that may mitigate risk, said Dr. Nemani.

“This includes evaluating systems-level factors, such as access to preventive interventions and treatment, as well as investigating underlying immune mechanisms that may contribute to severe and fatal infection,” she said.

The researchers could not validate psychiatric diagnoses or capture deaths not documented in the electronic health record. In addition, the limited sample size precluded analysis of the use of individual antipsychotic medications, which may differ in their associated effects.

“It’s possible individual antipsychotic medications may be associated with harmful or protective effects,” said Dr. Nemani.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Results of a phase 3 study show that treatment with lumateperone (Caplyta) significantly improved depressive symptoms for patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

“Bipolar depression represents the most prevalent and debilitating presentation of bipolar disorder. There is a critical need for more treatments that are effective and have favorable safety profiles,” study investigator Gary S. Sachs, MD, associate clinical professor in psychiatry, Harvard Medical School, Boston, said in a company news release.

“The strong efficacy and impressive safety results reported in this trial for a broad patient population position lumateperone as a potentially important advancement in the treatment of this disorder,” said Dr. Sachs, who is also founding director of the Bipolar Clinic and Research Program at Massachusetts General Hospital, Boston.

The findings were published online September 23 in the American Journal of Psychiatry.
 

First-in-class antipsychotic

Lumateperone is a first-in-class antipsychotic that acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

It was approved by the U.S. Food and Drug Administration in late 2019 for the treatment of adults with schizophrenia, as reported at the time by this news organization.

The current study included 377 patients who had received a clinical diagnosis of bipolar I or bipolar II disorder and were subject to major depressive episodes. All were randomly allocated in a 1:1 ratio to receive 6 weeks of lumateperone monotherapy at 42 mg/d or matching placebo.

At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score in comparison with placebo (drug-placebo difference, -4.6 points; P < .0001; effect size = -0.56), which met the study’s primary endpoint.

The study drug led to significant improvement in MADRS total score as early as the first week, which was the first time point measured. Improvement continued throughout the study.

Treatment with lumateperone also led to significantly greater improvement in the key secondary endpoints of total score on the severity scale of the Clinical Global Impressions Scale–Bipolar Version (CGI-BP-S) (P < .0001; effect size = -0.46) and the CGI-BP-S depression score (P < .001; effect size = -50).

In addition, it was superior to placebo both for patients with bipolar I disorder and those with bipolar II disorder.

Somnolence and nausea were the most commonly reported adverse events associated with lumateperone. Minimal changes were observed in weight and vital signs and in results of metabolic or endocrine assessments. These findings are in line with previous studies involving patients with schizophrenia.

The incidence of extrapyramidal symptom–related events was low and was similar to those with placebo.

The company has submitted a supplemental new drug application for lumateperone for the treatment of bipolar depression, which is currently under review with the FDA. The target action date is December 17.

A version of this article first appeared on Medscape.com.

Results of a phase 3 study show that treatment with lumateperone (Caplyta) significantly improved depressive symptoms for patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

“Bipolar depression represents the most prevalent and debilitating presentation of bipolar disorder. There is a critical need for more treatments that are effective and have favorable safety profiles,” study investigator Gary S. Sachs, MD, associate clinical professor in psychiatry, Harvard Medical School, Boston, said in a company news release.

“The strong efficacy and impressive safety results reported in this trial for a broad patient population position lumateperone as a potentially important advancement in the treatment of this disorder,” said Dr. Sachs, who is also founding director of the Bipolar Clinic and Research Program at Massachusetts General Hospital, Boston.

The findings were published online September 23 in the American Journal of Psychiatry.
 

First-in-class antipsychotic

Lumateperone is a first-in-class antipsychotic that acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

It was approved by the U.S. Food and Drug Administration in late 2019 for the treatment of adults with schizophrenia, as reported at the time by this news organization.

The current study included 377 patients who had received a clinical diagnosis of bipolar I or bipolar II disorder and were subject to major depressive episodes. All were randomly allocated in a 1:1 ratio to receive 6 weeks of lumateperone monotherapy at 42 mg/d or matching placebo.

At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score in comparison with placebo (drug-placebo difference, -4.6 points; P < .0001; effect size = -0.56), which met the study’s primary endpoint.

The study drug led to significant improvement in MADRS total score as early as the first week, which was the first time point measured. Improvement continued throughout the study.

Treatment with lumateperone also led to significantly greater improvement in the key secondary endpoints of total score on the severity scale of the Clinical Global Impressions Scale–Bipolar Version (CGI-BP-S) (P < .0001; effect size = -0.46) and the CGI-BP-S depression score (P < .001; effect size = -50).

In addition, it was superior to placebo both for patients with bipolar I disorder and those with bipolar II disorder.

Somnolence and nausea were the most commonly reported adverse events associated with lumateperone. Minimal changes were observed in weight and vital signs and in results of metabolic or endocrine assessments. These findings are in line with previous studies involving patients with schizophrenia.

The incidence of extrapyramidal symptom–related events was low and was similar to those with placebo.

The company has submitted a supplemental new drug application for lumateperone for the treatment of bipolar depression, which is currently under review with the FDA. The target action date is December 17.

A version of this article first appeared on Medscape.com.

Results of a phase 3 study show that treatment with lumateperone (Caplyta) significantly improved depressive symptoms for patients with major depressive episodes associated with both bipolar I and bipolar II disorders.

“Bipolar depression represents the most prevalent and debilitating presentation of bipolar disorder. There is a critical need for more treatments that are effective and have favorable safety profiles,” study investigator Gary S. Sachs, MD, associate clinical professor in psychiatry, Harvard Medical School, Boston, said in a company news release.

“The strong efficacy and impressive safety results reported in this trial for a broad patient population position lumateperone as a potentially important advancement in the treatment of this disorder,” said Dr. Sachs, who is also founding director of the Bipolar Clinic and Research Program at Massachusetts General Hospital, Boston.

The findings were published online September 23 in the American Journal of Psychiatry.
 

First-in-class antipsychotic

Lumateperone is a first-in-class antipsychotic that acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems.

It was approved by the U.S. Food and Drug Administration in late 2019 for the treatment of adults with schizophrenia, as reported at the time by this news organization.

The current study included 377 patients who had received a clinical diagnosis of bipolar I or bipolar II disorder and were subject to major depressive episodes. All were randomly allocated in a 1:1 ratio to receive 6 weeks of lumateperone monotherapy at 42 mg/d or matching placebo.

At day 43, lumateperone treatment was associated with significantly greater improvement from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score in comparison with placebo (drug-placebo difference, -4.6 points; P < .0001; effect size = -0.56), which met the study’s primary endpoint.

The study drug led to significant improvement in MADRS total score as early as the first week, which was the first time point measured. Improvement continued throughout the study.

Treatment with lumateperone also led to significantly greater improvement in the key secondary endpoints of total score on the severity scale of the Clinical Global Impressions Scale–Bipolar Version (CGI-BP-S) (P < .0001; effect size = -0.46) and the CGI-BP-S depression score (P < .001; effect size = -50).

In addition, it was superior to placebo both for patients with bipolar I disorder and those with bipolar II disorder.

Somnolence and nausea were the most commonly reported adverse events associated with lumateperone. Minimal changes were observed in weight and vital signs and in results of metabolic or endocrine assessments. These findings are in line with previous studies involving patients with schizophrenia.

The incidence of extrapyramidal symptom–related events was low and was similar to those with placebo.

The company has submitted a supplemental new drug application for lumateperone for the treatment of bipolar depression, which is currently under review with the FDA. The target action date is December 17.

A version of this article first appeared on Medscape.com.

Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.

ChrisChrisW/iStock/Getty Images Plus

A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.

In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.

“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.

“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.

The study was published online Sept. 15, 2021, in JAMA Psychiatry.
 

Reliable biomarkers

“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.

However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.

Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.

“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.

The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”

They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).

These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.

Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”

The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”

Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”

Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”

Control samples consisted of participants without the relevant condition.
 

Biological overlap?

The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.

MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.

“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.

However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.

When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”

In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”

“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.

“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”

The authors highlighted potential confounders, including study region and medication use.

Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.

Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.

In light of these confounders, the findings should be considered “preliminary,” the investigators noted.

Greater standardization needed

Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”

In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.

Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.

Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.

A version of this article first appeared on Medscape.com .

Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.

ChrisChrisW/iStock/Getty Images Plus

A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.

In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.

“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.

“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.

The study was published online Sept. 15, 2021, in JAMA Psychiatry.
 

Reliable biomarkers

“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.

However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.

Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.

“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.

The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”

They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).

These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.

Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”

The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”

Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”

Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”

Control samples consisted of participants without the relevant condition.
 

Biological overlap?

The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.

MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.

“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.

However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.

When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”

In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”

“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.

“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”

The authors highlighted potential confounders, including study region and medication use.

Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.

Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.

In light of these confounders, the findings should be considered “preliminary,” the investigators noted.

Greater standardization needed

Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”

In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.

Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.

Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.

A version of this article first appeared on Medscape.com .

Disturbances in gut microbiota are associated with depletion of anti-inflammatory bacteria and proliferation of proinflammatory bacteria, a pattern tied to several major psychiatric disorders including depression, bipolar disorder (BD), schizophrenia, and anxiety, new research shows.

ChrisChrisW/iStock/Getty Images Plus

A meta-analysis of 59 studies, encompassing roughly 2,600 patients with psychiatric conditions, showed a decrease in microbial richness in patients with psychiatric conditions versus controls.

In addition, those with depression, anxiety, BD, and psychosis had a similar set of abnormalities in the microbiota, particularly lower levels of Faecalibacterium and Coprococcus – two types of bacteria that have an anti-inflammatory effect in gut – and higher levels of Eggerthella, a bacterium with proinflammatory effects.

“The wealth of evidence we have summarized clearly demonstrates that the gut microbiota is vitally important to the wider mental health of individuals,” lead author Viktoriya Nikolova, MRes, Centre for Affective Disorders, King’s College London, said in an interview.

“While it is still too early to recommend specific interventions, it’s clear that clinicians need to place a greater awareness of gut health when considering the treatment of certain psychiatric disorders,” she said.

The study was published online Sept. 15, 2021, in JAMA Psychiatry.
 

Reliable biomarkers

“Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers,” the authors wrote.

However, “while there is a wealth of evidence to suggest that abnormalities within the composition of the gut microbiota are connected to a number of psychiatric disorders, there haven’t been any attempts to evaluate the specificity of this evidence – that is, if these changes are unique to specific disorders or shared across many,” Ms. Nikolova said.

Previous research in individual disorders has identified “patterns that may be promising biomarker targets,” with the potential to “improve diagnostic accuracy, guide treatment, and assist the monitoring of treatment response,” the authors noted.

“We wanted to see if we could reliably establish biomarkers for individual conditions in an effort to further our understanding of the relationship between mental illness and gut microbiota,” said Ms. Nikolova.

The researchers wanted to “evaluate the specificity and reproducibility of gut microbiota alterations and delineate those with potential to become biomarkers.”

They identified 59 studies (64 case-control comparisons; n = 2,643 patients, 2,336 controls). Most (54.2%) were conducted in East Asia, followed by Westernized populations (40.7%) and Africa (1.7%).

These studies evaluated diversity or abundance of gut microbes in adult populations encompassing an array of psychiatric disorders: major depressive disorder (MDD), BD, psychosis and schizophrenia, eating disorders (anorexia nervosa and bulimia nervosa), anxiety, obsessive-compulsive disorder (OCD), PTSD, and ADHD.

Although studies were similar in exclusion criteria, few attempted to minimize dietary changes or control dietary intake. In addition, use of psychiatric medication also “varied substantially.”

The researchers conducted several analyses, with primary outcomes consisting of “community-level measures of gut microbiota composition (alpha and beta diversity) as well as taxonomic findings at the phylum, family, and genus levels (relative abundance).”

Alpha diversity provides a “summary of the microbial community in individual samples,” which “can be compared across groups to evaluate the role of a particular factor (in this case psychiatric diagnosis) on the richness (number of species) and evenness (how well each species is represented) in the sample.”

Beta diversity, on the other hand, “measures interindividual (between samples) diversity that assesses similarity of communities, compared with the other samples analyzed.”

Control samples consisted of participants without the relevant condition.
 

Biological overlap?

The alpha-diversity meta-analysis encompassed 34 studies (n = 1,519 patients, 1,429 controls). The researchers found significant decreases in microbial richness in patients, compared with controls (observed species standardized mean difference, −0.26; 95% CI, −0.47 to −0.06; Chao1 SMD, −0.5; 95% CI, −0.79 to −0.21). On the other hand, when they examined each diagnosis separately, they found consistent decreases only in bipolar disorder. There was a small, nonsignificant decrease in phylogenetic diversity between groups.

MDD, psychosis, and schizophrenia were the only conditions in which differences in beta diversity were consistently observed.

“These findings suggest there is reliable evidence for differences in the shared phylogenetic structure in MDD and psychosis and schizophrenia compared with controls,” the authors write.

However, “method of measurement and method of patient classification (symptom vs. diagnosis based) may affect findings,” they added.

When they focused on relative abundance, they found “little evidence” of disorder specificity, but rather a “transdiagnostic pattern of microbiota signatures.”

In particular, depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were “consistently shared” between MDD, BD, psychosis and schizophrenia, and anxiety, “suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while proinflammatory genera are enriched.”

“The finding that these perturbations do not appear to be disorder-specific suggests that the microbiota is affected in a similar manner by conditions such as depression, anxiety, bipolar disorder, and psychosis,” said Ms. Nikolova.

“We have seen similar findings from previous meta-analyses of inflammatory marker studies and genetic studies, for example, suggesting that there is a biological overlap between these conditions, which we have now also seen in the microbiota.”

The authors highlighted potential confounders, including study region and medication use.

Conditions such as MDD, psychosis, and schizophrenia were “largely investigated in the East,” while anorexia nervosa and OCD were primarily investigated in the West.

Moreover, comparing results from medication-free studies with those in which 80% or more of patients were taking psychiatric medication showed increases in bacterial families Lactobacillaceae, Klebsiella, Streptococcus, and Megasphaera only in medicated groups, and decreases in Dialister.

In light of these confounders, the findings should be considered “preliminary,” the investigators noted.

Greater standardization needed

Commenting on the study, Emeran Mayer, MD, director of the Oppenheimer Center for Neurobiology of Stress and Resilience at the University of California, Los Angeles, said it is “intriguing to speculate that low-grade immune activation due to reduced production of butyrate may be such a generalized factor affecting microbial composition shared similarly in several brain disorders. However, such a mechanism has not been confirmed in mechanistic studies to date.”

In addition, the study “lumps together a large number of studies and heterogeneous patient populations, with and without centrally acting medication, without adequate dietary history, studied in different ethnic populations, studied with highly variable collection and analysis methods, including highly variable sample and study sizes for different diseases, and using only measures of microbial composition but not function,” cautioned Dr. Mayer, who was not involved in the research.

Future studies “with much greater standardization of subject populations and clinical and biological analyses techniques should be performed to reevaluate the results of the current study and confirm or reject the main hypotheses,” asserted Dr. Mayer, who is also the founding director of the UCLA Brain Gut Microbiome Center.

Ms. Nikolova is funded by a Medical Research Council PhD Studentship. Other sources of funding include the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Ms. Nikolova has disclosed no relevant financial relationships. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.

A version of this article first appeared on Medscape.com .

In 1950, at Staten Island’s Sea View Hospital, a group of patients with terminal tuberculosis were given a new antibiotic called isoniazid, which caused some unexpected side effects. The patients reported euphoria, mental stimulation, and improved sleep, and even began socializing with more vigor. The press was all over the case, writing about the sick “dancing in the halls tho’ they had holes in their lungs.” Soon doctors started prescribing isoniazid as the first-ever antidepressant.

ChrisChrisW/iStock/Getty Images

The Sea View Hospital experiment was an early hint that changing the composition of the gut microbiome – in this case, via antibiotics – might affect our mental health. Yet only in the last 2 decades has research into connections between what we ingest and psychiatric disorders really taken off. In 2004, a landmark study showed that germ-free mice (born in such sterile conditions that they lacked a microbiome) had an exaggerated stress response. The effects were reversed, however, if the mice were fed a bacterial strain, Bifidobacterium infantis, a probiotic. This sparked academic interest, and thousands of research papers followed.

According to Stephen Ilardi, PhD, a clinical psychologist at the University of Kansas, Lawrence, focusing on the etiology and treatment of depression, now is the “time of exciting discovery” in the field of probiotics and psychiatric disorders, although, admittedly, a lot still remains unknown.
 

Gut microbiome profiles in mental health disorders

We humans have about 100 trillion microbes residing in our guts. Some of these are archaea, some fungi, some protozoans and even viruses, but most are bacteria. Things like diet, sleep, and stress can all impact the composition of our gut microbiome. When the microbiome differs considerably from the typical, doctors and researchers describe it as dysbiosis, or imbalance. Studies have uncovered dysbiosis in patients with depression, anxiety, schizophrenia, and bipolar disorder.

“I think there is now pretty good evidence that the gut microbiome is actually an important factor in a number of psychiatric disorders,” says Allan Young, MBChB, clinical psychiatrist at King’s College London. The gut microbiome composition does seem to differ between psychiatric patients and the healthy. In depression, for example, a recent review of nine studies found an increase on the genus level in Streptococcus and Oscillibacter and low abundance of Lactobacillus and Coprococcus, among others. In generalized anxiety disorder, meanwhile, there appears to be an increase in Fusobacteria and Escherichia/Shigella .

For Dr. Ilardi, the next important question is whether there are plausible mechanisms that could explain how gut microbiota may influence brain function. And, it appears there are.

“The microbes in the gut can release neurotransmitters into blood that cross into the brain and influence brain function. They can release hormones into the blood that again cross into the brain. They’ve got a lot of tricks up their sleeve,” he says.

One particularly important pathway runs through the vagus nerve – the longest nerve that emerges directly from the brain, connecting it to the gut. Another is the immune pathway. Gut bacteria can interact with immune cells and reduce cytokine production, which in turn can reduce systemic inflammation. Inflammatory processes have been implicated in both depression and bipolar disorder. What’s more, gut microbes can upregulate the expression of a protein called BDNF – brain-derived neurotrophic factor – which helps the development and survival of nerve cells in the brain.
 

Probiotics’ promise varies for different conditions

As the pathways by which gut dysbiosis may influence psychiatric disorders become clearer, the next logical step is to try to influence the composition of the microbiome to prevent and treat depression, anxiety, or schizophrenia. That’s where probiotics come in.

The evidence for the effects of probiotics – live microorganisms which, when ingested in adequate amounts, confer a health benefit – so far is the strongest for depression, says Viktoriya Nikolova, MRes, MSc, a PhD student and researcher at King’s College London. In their 2021 meta-analysis of seven trials, Mr. Nikolova and colleagues revealed that probiotics can significantly reduce depressive symptoms after just 8 weeks. There was a caveat, however – the probiotics only worked when used in addition to an approved antidepressant. Another meta-analysis, published in 2018, also showed that probiotics, when compared with placebo, improve mood in people with depressive symptoms (here, no antidepressant treatment was necessary).

Roumen Milev, MD, PhD, a neuroscientist at Queen’s University, Kingston, Ont., and coauthor of a review on probiotics and depression published in the Annals of General Psychiatry, warns, however, that the research is still in its infancy. “Currently, the probiotics should be used concomitant with antidepressant treatment,” he says.

When it comes to using probiotics to relieve anxiety, “the evidence in the animal literature is really compelling,” says Dr. Ilardi. Human studies are less convincing, however, which Dr. Dr. Ilardi showed in his 2018 review and meta-analysis involving 743 animals and 1,527 humans. “Studies are small for the most part, and some of them aren’t terribly well conducted, and they often use very low doses of probiotics,” he says. One of the larger double-blind and placebo-controlled trials showed that supplementation with Lactobacillus plantarum helps reduce stress and anxiety, while the levels of proinflammatory cytokines go down. Another meta-analysis, published in June, revealed that, when it comes to reducing stress and anxiety in youth, the results are mixed.

Evidence of probiotics’ efficiency in schizophrenia is emerging, yet also limited. A 2019 review concluded that currently available results only “hint” at a possibility that probiotics could make a difference in schizophrenia. Similarly, a 2020 review summed up that the role of probiotics in bipolar disorder “remains unclear and underexplored.”
 

Better studies, remaining questions

Apart from small samples, one issue with research on probiotics is that they generally tend to use varied doses of different strains of bacteria, or even multistrain mixtures, making it tough to compare results. Although there are hundreds of species of bacteria in the human gut, only a few have been evaluated for their antidepressant or antianxiety effects.

“To make it even worse, it’s almost certainly the case that depending on a person’s actual genetics or maybe their epigenetics, a strain that is helpful for one person may not be helpful for another. There is almost certainly no one-size-fits-all probiotic formulation,” says Dr. Ilardi.

Another critical question that remains to be answered is that of potential side effects.

“Probiotics are often seen as food supplements, so they don’t follow under the same regulations as drugs would,” says Mr. Nikolova. “They don’t necessarily have to follow the pattern of drug trials in many countries, which means that the monitoring of side effects is not the requirement.”

That’s something that worries King’s College psychiatrist Young too. “If you are giving it to modulate how the brain works, you could potentially induce psychiatric symptoms or a psychiatric disorder. There could be allergic reactions. There could be lots of different things,” he says.

When you search the web for “probiotics,” chances are you will come across sites boasting amazing effects that such products can have on cardiovascular heath, the immune system, and yes, mental well-being. Many also sell various probiotic supplements “formulated” for your gut health or improved moods. However, many such commercially available strains have never been actually tested in clinical trials. What’s more, according to Kathrin Cohen Kadosh, PhD, a neuroscientist at University of Surrey (England), “it is not always clear whether the different strains actually reach the gut intact.”

For now, considering the limited research evidence, a safer bet is to try to improve gut health through consumption of fermented foods that naturally contain probiotics, such as miso, kefir, or sauerkraut. Alternatively, you could reach for prebiotics, such as foods containing fiber (prebiotics enhance the growth of beneficial gut microbes). This, Dr. Kadosh says, could be “a gentler way of improving gut health” than popping a pill. Whether an improved mental well-being might follow still remains to be seen.

A version of this article first appeared on Medscape.com.

In 1950, at Staten Island’s Sea View Hospital, a group of patients with terminal tuberculosis were given a new antibiotic called isoniazid, which caused some unexpected side effects. The patients reported euphoria, mental stimulation, and improved sleep, and even began socializing with more vigor. The press was all over the case, writing about the sick “dancing in the halls tho’ they had holes in their lungs.” Soon doctors started prescribing isoniazid as the first-ever antidepressant.

ChrisChrisW/iStock/Getty Images

The Sea View Hospital experiment was an early hint that changing the composition of the gut microbiome – in this case, via antibiotics – might affect our mental health. Yet only in the last 2 decades has research into connections between what we ingest and psychiatric disorders really taken off. In 2004, a landmark study showed that germ-free mice (born in such sterile conditions that they lacked a microbiome) had an exaggerated stress response. The effects were reversed, however, if the mice were fed a bacterial strain, Bifidobacterium infantis, a probiotic. This sparked academic interest, and thousands of research papers followed.

According to Stephen Ilardi, PhD, a clinical psychologist at the University of Kansas, Lawrence, focusing on the etiology and treatment of depression, now is the “time of exciting discovery” in the field of probiotics and psychiatric disorders, although, admittedly, a lot still remains unknown.
 

Gut microbiome profiles in mental health disorders

We humans have about 100 trillion microbes residing in our guts. Some of these are archaea, some fungi, some protozoans and even viruses, but most are bacteria. Things like diet, sleep, and stress can all impact the composition of our gut microbiome. When the microbiome differs considerably from the typical, doctors and researchers describe it as dysbiosis, or imbalance. Studies have uncovered dysbiosis in patients with depression, anxiety, schizophrenia, and bipolar disorder.

“I think there is now pretty good evidence that the gut microbiome is actually an important factor in a number of psychiatric disorders,” says Allan Young, MBChB, clinical psychiatrist at King’s College London. The gut microbiome composition does seem to differ between psychiatric patients and the healthy. In depression, for example, a recent review of nine studies found an increase on the genus level in Streptococcus and Oscillibacter and low abundance of Lactobacillus and Coprococcus, among others. In generalized anxiety disorder, meanwhile, there appears to be an increase in Fusobacteria and Escherichia/Shigella .

For Dr. Ilardi, the next important question is whether there are plausible mechanisms that could explain how gut microbiota may influence brain function. And, it appears there are.

“The microbes in the gut can release neurotransmitters into blood that cross into the brain and influence brain function. They can release hormones into the blood that again cross into the brain. They’ve got a lot of tricks up their sleeve,” he says.

One particularly important pathway runs through the vagus nerve – the longest nerve that emerges directly from the brain, connecting it to the gut. Another is the immune pathway. Gut bacteria can interact with immune cells and reduce cytokine production, which in turn can reduce systemic inflammation. Inflammatory processes have been implicated in both depression and bipolar disorder. What’s more, gut microbes can upregulate the expression of a protein called BDNF – brain-derived neurotrophic factor – which helps the development and survival of nerve cells in the brain.
 

Probiotics’ promise varies for different conditions

As the pathways by which gut dysbiosis may influence psychiatric disorders become clearer, the next logical step is to try to influence the composition of the microbiome to prevent and treat depression, anxiety, or schizophrenia. That’s where probiotics come in.

The evidence for the effects of probiotics – live microorganisms which, when ingested in adequate amounts, confer a health benefit – so far is the strongest for depression, says Viktoriya Nikolova, MRes, MSc, a PhD student and researcher at King’s College London. In their 2021 meta-analysis of seven trials, Mr. Nikolova and colleagues revealed that probiotics can significantly reduce depressive symptoms after just 8 weeks. There was a caveat, however – the probiotics only worked when used in addition to an approved antidepressant. Another meta-analysis, published in 2018, also showed that probiotics, when compared with placebo, improve mood in people with depressive symptoms (here, no antidepressant treatment was necessary).

Roumen Milev, MD, PhD, a neuroscientist at Queen’s University, Kingston, Ont., and coauthor of a review on probiotics and depression published in the Annals of General Psychiatry, warns, however, that the research is still in its infancy. “Currently, the probiotics should be used concomitant with antidepressant treatment,” he says.

When it comes to using probiotics to relieve anxiety, “the evidence in the animal literature is really compelling,” says Dr. Ilardi. Human studies are less convincing, however, which Dr. Dr. Ilardi showed in his 2018 review and meta-analysis involving 743 animals and 1,527 humans. “Studies are small for the most part, and some of them aren’t terribly well conducted, and they often use very low doses of probiotics,” he says. One of the larger double-blind and placebo-controlled trials showed that supplementation with Lactobacillus plantarum helps reduce stress and anxiety, while the levels of proinflammatory cytokines go down. Another meta-analysis, published in June, revealed that, when it comes to reducing stress and anxiety in youth, the results are mixed.

Evidence of probiotics’ efficiency in schizophrenia is emerging, yet also limited. A 2019 review concluded that currently available results only “hint” at a possibility that probiotics could make a difference in schizophrenia. Similarly, a 2020 review summed up that the role of probiotics in bipolar disorder “remains unclear and underexplored.”
 

Better studies, remaining questions

Apart from small samples, one issue with research on probiotics is that they generally tend to use varied doses of different strains of bacteria, or even multistrain mixtures, making it tough to compare results. Although there are hundreds of species of bacteria in the human gut, only a few have been evaluated for their antidepressant or antianxiety effects.

“To make it even worse, it’s almost certainly the case that depending on a person’s actual genetics or maybe their epigenetics, a strain that is helpful for one person may not be helpful for another. There is almost certainly no one-size-fits-all probiotic formulation,” says Dr. Ilardi.

Another critical question that remains to be answered is that of potential side effects.

“Probiotics are often seen as food supplements, so they don’t follow under the same regulations as drugs would,” says Mr. Nikolova. “They don’t necessarily have to follow the pattern of drug trials in many countries, which means that the monitoring of side effects is not the requirement.”

That’s something that worries King’s College psychiatrist Young too. “If you are giving it to modulate how the brain works, you could potentially induce psychiatric symptoms or a psychiatric disorder. There could be allergic reactions. There could be lots of different things,” he says.

When you search the web for “probiotics,” chances are you will come across sites boasting amazing effects that such products can have on cardiovascular heath, the immune system, and yes, mental well-being. Many also sell various probiotic supplements “formulated” for your gut health or improved moods. However, many such commercially available strains have never been actually tested in clinical trials. What’s more, according to Kathrin Cohen Kadosh, PhD, a neuroscientist at University of Surrey (England), “it is not always clear whether the different strains actually reach the gut intact.”

For now, considering the limited research evidence, a safer bet is to try to improve gut health through consumption of fermented foods that naturally contain probiotics, such as miso, kefir, or sauerkraut. Alternatively, you could reach for prebiotics, such as foods containing fiber (prebiotics enhance the growth of beneficial gut microbes). This, Dr. Kadosh says, could be “a gentler way of improving gut health” than popping a pill. Whether an improved mental well-being might follow still remains to be seen.

A version of this article first appeared on Medscape.com.

In 1950, at Staten Island’s Sea View Hospital, a group of patients with terminal tuberculosis were given a new antibiotic called isoniazid, which caused some unexpected side effects. The patients reported euphoria, mental stimulation, and improved sleep, and even began socializing with more vigor. The press was all over the case, writing about the sick “dancing in the halls tho’ they had holes in their lungs.” Soon doctors started prescribing isoniazid as the first-ever antidepressant.

ChrisChrisW/iStock/Getty Images

The Sea View Hospital experiment was an early hint that changing the composition of the gut microbiome – in this case, via antibiotics – might affect our mental health. Yet only in the last 2 decades has research into connections between what we ingest and psychiatric disorders really taken off. In 2004, a landmark study showed that germ-free mice (born in such sterile conditions that they lacked a microbiome) had an exaggerated stress response. The effects were reversed, however, if the mice were fed a bacterial strain, Bifidobacterium infantis, a probiotic. This sparked academic interest, and thousands of research papers followed.

According to Stephen Ilardi, PhD, a clinical psychologist at the University of Kansas, Lawrence, focusing on the etiology and treatment of depression, now is the “time of exciting discovery” in the field of probiotics and psychiatric disorders, although, admittedly, a lot still remains unknown.
 

Gut microbiome profiles in mental health disorders

We humans have about 100 trillion microbes residing in our guts. Some of these are archaea, some fungi, some protozoans and even viruses, but most are bacteria. Things like diet, sleep, and stress can all impact the composition of our gut microbiome. When the microbiome differs considerably from the typical, doctors and researchers describe it as dysbiosis, or imbalance. Studies have uncovered dysbiosis in patients with depression, anxiety, schizophrenia, and bipolar disorder.

“I think there is now pretty good evidence that the gut microbiome is actually an important factor in a number of psychiatric disorders,” says Allan Young, MBChB, clinical psychiatrist at King’s College London. The gut microbiome composition does seem to differ between psychiatric patients and the healthy. In depression, for example, a recent review of nine studies found an increase on the genus level in Streptococcus and Oscillibacter and low abundance of Lactobacillus and Coprococcus, among others. In generalized anxiety disorder, meanwhile, there appears to be an increase in Fusobacteria and Escherichia/Shigella .

For Dr. Ilardi, the next important question is whether there are plausible mechanisms that could explain how gut microbiota may influence brain function. And, it appears there are.

“The microbes in the gut can release neurotransmitters into blood that cross into the brain and influence brain function. They can release hormones into the blood that again cross into the brain. They’ve got a lot of tricks up their sleeve,” he says.

One particularly important pathway runs through the vagus nerve – the longest nerve that emerges directly from the brain, connecting it to the gut. Another is the immune pathway. Gut bacteria can interact with immune cells and reduce cytokine production, which in turn can reduce systemic inflammation. Inflammatory processes have been implicated in both depression and bipolar disorder. What’s more, gut microbes can upregulate the expression of a protein called BDNF – brain-derived neurotrophic factor – which helps the development and survival of nerve cells in the brain.
 

Probiotics’ promise varies for different conditions

As the pathways by which gut dysbiosis may influence psychiatric disorders become clearer, the next logical step is to try to influence the composition of the microbiome to prevent and treat depression, anxiety, or schizophrenia. That’s where probiotics come in.

The evidence for the effects of probiotics – live microorganisms which, when ingested in adequate amounts, confer a health benefit – so far is the strongest for depression, says Viktoriya Nikolova, MRes, MSc, a PhD student and researcher at King’s College London. In their 2021 meta-analysis of seven trials, Mr. Nikolova and colleagues revealed that probiotics can significantly reduce depressive symptoms after just 8 weeks. There was a caveat, however – the probiotics only worked when used in addition to an approved antidepressant. Another meta-analysis, published in 2018, also showed that probiotics, when compared with placebo, improve mood in people with depressive symptoms (here, no antidepressant treatment was necessary).

Roumen Milev, MD, PhD, a neuroscientist at Queen’s University, Kingston, Ont., and coauthor of a review on probiotics and depression published in the Annals of General Psychiatry, warns, however, that the research is still in its infancy. “Currently, the probiotics should be used concomitant with antidepressant treatment,” he says.

When it comes to using probiotics to relieve anxiety, “the evidence in the animal literature is really compelling,” says Dr. Ilardi. Human studies are less convincing, however, which Dr. Dr. Ilardi showed in his 2018 review and meta-analysis involving 743 animals and 1,527 humans. “Studies are small for the most part, and some of them aren’t terribly well conducted, and they often use very low doses of probiotics,” he says. One of the larger double-blind and placebo-controlled trials showed that supplementation with Lactobacillus plantarum helps reduce stress and anxiety, while the levels of proinflammatory cytokines go down. Another meta-analysis, published in June, revealed that, when it comes to reducing stress and anxiety in youth, the results are mixed.

Evidence of probiotics’ efficiency in schizophrenia is emerging, yet also limited. A 2019 review concluded that currently available results only “hint” at a possibility that probiotics could make a difference in schizophrenia. Similarly, a 2020 review summed up that the role of probiotics in bipolar disorder “remains unclear and underexplored.”
 

Better studies, remaining questions

Apart from small samples, one issue with research on probiotics is that they generally tend to use varied doses of different strains of bacteria, or even multistrain mixtures, making it tough to compare results. Although there are hundreds of species of bacteria in the human gut, only a few have been evaluated for their antidepressant or antianxiety effects.

“To make it even worse, it’s almost certainly the case that depending on a person’s actual genetics or maybe their epigenetics, a strain that is helpful for one person may not be helpful for another. There is almost certainly no one-size-fits-all probiotic formulation,” says Dr. Ilardi.

Another critical question that remains to be answered is that of potential side effects.

“Probiotics are often seen as food supplements, so they don’t follow under the same regulations as drugs would,” says Mr. Nikolova. “They don’t necessarily have to follow the pattern of drug trials in many countries, which means that the monitoring of side effects is not the requirement.”

That’s something that worries King’s College psychiatrist Young too. “If you are giving it to modulate how the brain works, you could potentially induce psychiatric symptoms or a psychiatric disorder. There could be allergic reactions. There could be lots of different things,” he says.

When you search the web for “probiotics,” chances are you will come across sites boasting amazing effects that such products can have on cardiovascular heath, the immune system, and yes, mental well-being. Many also sell various probiotic supplements “formulated” for your gut health or improved moods. However, many such commercially available strains have never been actually tested in clinical trials. What’s more, according to Kathrin Cohen Kadosh, PhD, a neuroscientist at University of Surrey (England), “it is not always clear whether the different strains actually reach the gut intact.”

For now, considering the limited research evidence, a safer bet is to try to improve gut health through consumption of fermented foods that naturally contain probiotics, such as miso, kefir, or sauerkraut. Alternatively, you could reach for prebiotics, such as foods containing fiber (prebiotics enhance the growth of beneficial gut microbes). This, Dr. Kadosh says, could be “a gentler way of improving gut health” than popping a pill. Whether an improved mental well-being might follow still remains to be seen.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, department of psychiatry and psychotherapy, Technical University of Munich School of Medicine, Germany, told this news organization.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.
 

Unique meta-analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events, including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics – haloperidol or fluphenazine – or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4,776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Dr. Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Dr. Leucht.
 

Go slow to go low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply but then flattened at about 5-mg/day risperidone equivalent (odds ratio, 0.20; 95% confidence interval, 0.13-0.31; relative risk, 0.43; 95% CI, 0.31-0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Dr. Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Dr. Leucht also pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Dr. Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Dr. Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87-2.25) and the RR was 1.38 (95% CI, 0.87-2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52-5.45) and the RR was 2.68 (95% CI, 1.49-4.62).
 

Patient preference key

The data were insufficient to assess differences between men and women or between older and younger patients, Dr. Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Dr. Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects, and they want to go on a lower dose,” said Dr. Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.
 

Reflects real-world experience

Commenting on the findings, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Dr. Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Dr. Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Dr. Sedlak.

He also noted that severely ill patients are often underrepresented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Dr. Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Dr. Sedlak has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, department of psychiatry and psychotherapy, Technical University of Munich School of Medicine, Germany, told this news organization.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.
 

Unique meta-analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events, including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics – haloperidol or fluphenazine – or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4,776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Dr. Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Dr. Leucht.
 

Go slow to go low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply but then flattened at about 5-mg/day risperidone equivalent (odds ratio, 0.20; 95% confidence interval, 0.13-0.31; relative risk, 0.43; 95% CI, 0.31-0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Dr. Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Dr. Leucht also pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Dr. Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Dr. Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87-2.25) and the RR was 1.38 (95% CI, 0.87-2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52-5.45) and the RR was 2.68 (95% CI, 1.49-4.62).
 

Patient preference key

The data were insufficient to assess differences between men and women or between older and younger patients, Dr. Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Dr. Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects, and they want to go on a lower dose,” said Dr. Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.
 

Reflects real-world experience

Commenting on the findings, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Dr. Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Dr. Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Dr. Sedlak.

He also noted that severely ill patients are often underrepresented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Dr. Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Dr. Sedlak has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, department of psychiatry and psychotherapy, Technical University of Munich School of Medicine, Germany, told this news organization.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.
 

Unique meta-analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events, including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics – haloperidol or fluphenazine – or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4,776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Dr. Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Dr. Leucht.
 

Go slow to go low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply but then flattened at about 5-mg/day risperidone equivalent (odds ratio, 0.20; 95% confidence interval, 0.13-0.31; relative risk, 0.43; 95% CI, 0.31-0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Dr. Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Dr. Leucht also pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Dr. Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Dr. Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87-2.25) and the RR was 1.38 (95% CI, 0.87-2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52-5.45) and the RR was 2.68 (95% CI, 1.49-4.62).
 

Patient preference key

The data were insufficient to assess differences between men and women or between older and younger patients, Dr. Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Dr. Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects, and they want to go on a lower dose,” said Dr. Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.
 

Reflects real-world experience

Commenting on the findings, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Dr. Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Dr. Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Dr. Sedlak.

He also noted that severely ill patients are often underrepresented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Dr. Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Dr. Sedlak has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a 6-month injection form of the long-acting atypical antipsychotic paliperidone palmitate (Invega Hafyera, Janssen Pharmaceuticals) for the treatment of schizophrenia in adults, the company has announced.

This marks the “first-and-only twice-yearly injectable” approved for treating schizophrenia, the company added in a press release.
 

Before transitioning to the 6-month form, patients must be adequately treated for a minimum of 4 months with the company’s 1-month formulation of paliperidone (Invega Sustenna), or with the 3-month version (Invega Trinza) for at least one 3-month injection cycle.

The FDA approved the twice-yearly formulation on the basis of results from a 12-month, randomized, double-blind, phase 3 study that enrolled 702 adults with schizophrenia from 20 countries.

“The phase 3 trial results provide compelling evidence that 6-month paliperidone palmitate offers longer-term symptom control with the fewest doses per year, which may support greater patient adherence,” Gustavo Alva, MD, medical director at ATP Clinical Research, Costa Mesa, Calif., and 6-month paliperidone palmitate clinical trial investigator, said in the release.

Noninferiority results

In the phase 3 trial, the twice-yearly version of the drug proved noninferior to the 3-month version on the primary endpoint of time to first relapse at the end of 12 months, with 92.5% and 95% of patients, respectively, relapse-free at 12 months.

Relapse was defined as psychiatric hospitalization, increase in Positive and Negative Syndrome Scale (PANSS) total score, increase in individual PANSS item scores, self-injury, violent behavior, or suicidal/homicidal ideation.

The safety profile observed in the trial was in line with prior studies of the 1-month and 3-month versions, with no new safety signals, the researchers note.

The most common adverse reactions affecting at least 5% of participants in the clinical trial receiving twice-year paliperidone were upper respiratory tract infection (12%), injection site reaction (11%), weight gain (9%), headache (7%), and parkinsonism (5%).

Relapse is common in adults with schizophrenia, often because of missed doses of medication, the company said in the news release.

“For too long, we’ve accepted relapse as a normal part of living with schizophrenia, while research continues to demonstrate that stronger medication adherence means better patient outcomes,” Dr. Alva said.

Recently updated evidence-based guidelines from the American Psychiatric Association recommend consideration of long-acting injectables for appropriate adults living with schizophrenia.

 “Long-acting injectable treatments offer a number of advantages, compared to oral medication for schizophrenia, including relief from needing to remember to take medication daily, lower discontinuation rates, and sustained treatment over longer periods,” Bill Martin, PhD, with Janssen Research & Development, said in the release.

“Today’s approval enables us to rethink how we manage this chronic disease by offering patients and caregivers the potential for a life less defined by schizophrenia medication,” Dr. Martin added.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a 6-month injection form of the long-acting atypical antipsychotic paliperidone palmitate (Invega Hafyera, Janssen Pharmaceuticals) for the treatment of schizophrenia in adults, the company has announced.

This marks the “first-and-only twice-yearly injectable” approved for treating schizophrenia, the company added in a press release.
 

Before transitioning to the 6-month form, patients must be adequately treated for a minimum of 4 months with the company’s 1-month formulation of paliperidone (Invega Sustenna), or with the 3-month version (Invega Trinza) for at least one 3-month injection cycle.

The FDA approved the twice-yearly formulation on the basis of results from a 12-month, randomized, double-blind, phase 3 study that enrolled 702 adults with schizophrenia from 20 countries.

“The phase 3 trial results provide compelling evidence that 6-month paliperidone palmitate offers longer-term symptom control with the fewest doses per year, which may support greater patient adherence,” Gustavo Alva, MD, medical director at ATP Clinical Research, Costa Mesa, Calif., and 6-month paliperidone palmitate clinical trial investigator, said in the release.

Noninferiority results

In the phase 3 trial, the twice-yearly version of the drug proved noninferior to the 3-month version on the primary endpoint of time to first relapse at the end of 12 months, with 92.5% and 95% of patients, respectively, relapse-free at 12 months.

Relapse was defined as psychiatric hospitalization, increase in Positive and Negative Syndrome Scale (PANSS) total score, increase in individual PANSS item scores, self-injury, violent behavior, or suicidal/homicidal ideation.

The safety profile observed in the trial was in line with prior studies of the 1-month and 3-month versions, with no new safety signals, the researchers note.

The most common adverse reactions affecting at least 5% of participants in the clinical trial receiving twice-year paliperidone were upper respiratory tract infection (12%), injection site reaction (11%), weight gain (9%), headache (7%), and parkinsonism (5%).

Relapse is common in adults with schizophrenia, often because of missed doses of medication, the company said in the news release.

“For too long, we’ve accepted relapse as a normal part of living with schizophrenia, while research continues to demonstrate that stronger medication adherence means better patient outcomes,” Dr. Alva said.

Recently updated evidence-based guidelines from the American Psychiatric Association recommend consideration of long-acting injectables for appropriate adults living with schizophrenia.

 “Long-acting injectable treatments offer a number of advantages, compared to oral medication for schizophrenia, including relief from needing to remember to take medication daily, lower discontinuation rates, and sustained treatment over longer periods,” Bill Martin, PhD, with Janssen Research & Development, said in the release.

“Today’s approval enables us to rethink how we manage this chronic disease by offering patients and caregivers the potential for a life less defined by schizophrenia medication,” Dr. Martin added.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a 6-month injection form of the long-acting atypical antipsychotic paliperidone palmitate (Invega Hafyera, Janssen Pharmaceuticals) for the treatment of schizophrenia in adults, the company has announced.

This marks the “first-and-only twice-yearly injectable” approved for treating schizophrenia, the company added in a press release.
 

Before transitioning to the 6-month form, patients must be adequately treated for a minimum of 4 months with the company’s 1-month formulation of paliperidone (Invega Sustenna), or with the 3-month version (Invega Trinza) for at least one 3-month injection cycle.

The FDA approved the twice-yearly formulation on the basis of results from a 12-month, randomized, double-blind, phase 3 study that enrolled 702 adults with schizophrenia from 20 countries.

“The phase 3 trial results provide compelling evidence that 6-month paliperidone palmitate offers longer-term symptom control with the fewest doses per year, which may support greater patient adherence,” Gustavo Alva, MD, medical director at ATP Clinical Research, Costa Mesa, Calif., and 6-month paliperidone palmitate clinical trial investigator, said in the release.

Noninferiority results

In the phase 3 trial, the twice-yearly version of the drug proved noninferior to the 3-month version on the primary endpoint of time to first relapse at the end of 12 months, with 92.5% and 95% of patients, respectively, relapse-free at 12 months.

Relapse was defined as psychiatric hospitalization, increase in Positive and Negative Syndrome Scale (PANSS) total score, increase in individual PANSS item scores, self-injury, violent behavior, or suicidal/homicidal ideation.

The safety profile observed in the trial was in line with prior studies of the 1-month and 3-month versions, with no new safety signals, the researchers note.

The most common adverse reactions affecting at least 5% of participants in the clinical trial receiving twice-year paliperidone were upper respiratory tract infection (12%), injection site reaction (11%), weight gain (9%), headache (7%), and parkinsonism (5%).

Relapse is common in adults with schizophrenia, often because of missed doses of medication, the company said in the news release.

“For too long, we’ve accepted relapse as a normal part of living with schizophrenia, while research continues to demonstrate that stronger medication adherence means better patient outcomes,” Dr. Alva said.

Recently updated evidence-based guidelines from the American Psychiatric Association recommend consideration of long-acting injectables for appropriate adults living with schizophrenia.

 “Long-acting injectable treatments offer a number of advantages, compared to oral medication for schizophrenia, including relief from needing to remember to take medication daily, lower discontinuation rates, and sustained treatment over longer periods,” Bill Martin, PhD, with Janssen Research & Development, said in the release.

“Today’s approval enables us to rethink how we manage this chronic disease by offering patients and caregivers the potential for a life less defined by schizophrenia medication,” Dr. Martin added.

A version of this article first appeared on Medscape.com.

Many psychiatrists conceptualize mental illnesses, including psychotic disorders, across a continuum where their borders can be ambiguous.¹ The same can be said of individual symptoms such as delusions, where the line separating clear-cut pathology from nonpathological or subclinical “delusion-like beliefs” is often blurred.^2,3 However, the categorical distinction between mental illness and normality is fundamental to diagnostic reliability and crucial to clinical decisions about whether and how to intervene.

Conspiracy theory beliefs are delusion-like beliefs that are commonly encountered within today’s political landscape. Surveys have consistently revealed that approximately one-half of the population believes in at least 1 conspiracy theory, highlighting the normality of such beliefs despite their potential outlandishness.⁴ Here are 3 questions you can ask to help differentiate conspiracy theory beliefs from delusions.

1. What is the evidence for the belief?

Drawing from Karl Jaspers’ conceptualization of delusions as “impossible” and “unshareable,” the DSM-5 distinguishes delusions from culturally-sanctioned shared beliefs such as religious creeds.³ Whereas delusions often arise out of anomalous subjective experiences, individuals who come to believe in conspiracytheories have typically sought explanations and found them from secondary sources, often on the internet.⁵ Despite the familiar term “conspiracy theorist,” most who believe in conspiracy theories aren’t so much theorizing as they are adopting counter-narratives based on assimilated information. Unlike delusions, conspiracy theory beliefs are learned, with the “evidence” to support them easily located online.

2. Is the belief self-referential?

The stereotypical unshareability of delusions often hinges upon their self-referential content. For example, while it is easy to find others who believe in the Second Coming, it would be much harder to convince others that you are the Second Coming. Unlike delusions, conspiracy theories are beliefs about the world and explanations of real-life events; their content is rarely, if ever, directly related to the believer.

Conspiracy theory beliefs involve a negation of authoritative accounts that is rooted in “epistemic mistrust” of authoritative sources of information.⁵ While conspiratorial mistrust has been compared with paranoia, with paranoia found to be associated with belief in conspiracy theories,⁶ epistemic mistrust encompasses a range of justified cultural mistrust, unwarranted mistrust based on racial prejudice, and subclinical paranoia typical of schizotypy. The more self-referential the underlying paranoia, the more likely an associated belief is to cross the boundary from conspiracy theory to delusion.⁷

3. Is there overlap?

Conspiracy theory beliefs and delusions are not mutually exclusive. “Gang stalking” offers a vexing example of paranoia that is part shared conspiracy theory, part idiosyncratic delusion.⁸ Reliably disentangling these components requires identifying the conspiracy theory component as a widely-shared belief about government surveillance, while carefully analyzing the self-referential component to determine credibility and potential delusionality.

Many psychiatrists conceptualize mental illnesses, including psychotic disorders, across a continuum where their borders can be ambiguous.¹ The same can be said of individual symptoms such as delusions, where the line separating clear-cut pathology from nonpathological or subclinical “delusion-like beliefs” is often blurred.^2,3 However, the categorical distinction between mental illness and normality is fundamental to diagnostic reliability and crucial to clinical decisions about whether and how to intervene.

Conspiracy theory beliefs are delusion-like beliefs that are commonly encountered within today’s political landscape. Surveys have consistently revealed that approximately one-half of the population believes in at least 1 conspiracy theory, highlighting the normality of such beliefs despite their potential outlandishness.⁴ Here are 3 questions you can ask to help differentiate conspiracy theory beliefs from delusions.

1. What is the evidence for the belief?

Drawing from Karl Jaspers’ conceptualization of delusions as “impossible” and “unshareable,” the DSM-5 distinguishes delusions from culturally-sanctioned shared beliefs such as religious creeds.³ Whereas delusions often arise out of anomalous subjective experiences, individuals who come to believe in conspiracytheories have typically sought explanations and found them from secondary sources, often on the internet.⁵ Despite the familiar term “conspiracy theorist,” most who believe in conspiracy theories aren’t so much theorizing as they are adopting counter-narratives based on assimilated information. Unlike delusions, conspiracy theory beliefs are learned, with the “evidence” to support them easily located online.

2. Is the belief self-referential?

The stereotypical unshareability of delusions often hinges upon their self-referential content. For example, while it is easy to find others who believe in the Second Coming, it would be much harder to convince others that you are the Second Coming. Unlike delusions, conspiracy theories are beliefs about the world and explanations of real-life events; their content is rarely, if ever, directly related to the believer.

Conspiracy theory beliefs involve a negation of authoritative accounts that is rooted in “epistemic mistrust” of authoritative sources of information.⁵ While conspiratorial mistrust has been compared with paranoia, with paranoia found to be associated with belief in conspiracy theories,⁶ epistemic mistrust encompasses a range of justified cultural mistrust, unwarranted mistrust based on racial prejudice, and subclinical paranoia typical of schizotypy. The more self-referential the underlying paranoia, the more likely an associated belief is to cross the boundary from conspiracy theory to delusion.⁷

3. Is there overlap?

Conspiracy theory beliefs and delusions are not mutually exclusive. “Gang stalking” offers a vexing example of paranoia that is part shared conspiracy theory, part idiosyncratic delusion.⁸ Reliably disentangling these components requires identifying the conspiracy theory component as a widely-shared belief about government surveillance, while carefully analyzing the self-referential component to determine credibility and potential delusionality.

Many psychiatrists conceptualize mental illnesses, including psychotic disorders, across a continuum where their borders can be ambiguous.¹ The same can be said of individual symptoms such as delusions, where the line separating clear-cut pathology from nonpathological or subclinical “delusion-like beliefs” is often blurred.^2,3 However, the categorical distinction between mental illness and normality is fundamental to diagnostic reliability and crucial to clinical decisions about whether and how to intervene.

Conspiracy theory beliefs are delusion-like beliefs that are commonly encountered within today’s political landscape. Surveys have consistently revealed that approximately one-half of the population believes in at least 1 conspiracy theory, highlighting the normality of such beliefs despite their potential outlandishness.⁴ Here are 3 questions you can ask to help differentiate conspiracy theory beliefs from delusions.

1. What is the evidence for the belief?

Drawing from Karl Jaspers’ conceptualization of delusions as “impossible” and “unshareable,” the DSM-5 distinguishes delusions from culturally-sanctioned shared beliefs such as religious creeds.³ Whereas delusions often arise out of anomalous subjective experiences, individuals who come to believe in conspiracytheories have typically sought explanations and found them from secondary sources, often on the internet.⁵ Despite the familiar term “conspiracy theorist,” most who believe in conspiracy theories aren’t so much theorizing as they are adopting counter-narratives based on assimilated information. Unlike delusions, conspiracy theory beliefs are learned, with the “evidence” to support them easily located online.

2. Is the belief self-referential?

The stereotypical unshareability of delusions often hinges upon their self-referential content. For example, while it is easy to find others who believe in the Second Coming, it would be much harder to convince others that you are the Second Coming. Unlike delusions, conspiracy theories are beliefs about the world and explanations of real-life events; their content is rarely, if ever, directly related to the believer.

Conspiracy theory beliefs involve a negation of authoritative accounts that is rooted in “epistemic mistrust” of authoritative sources of information.⁵ While conspiratorial mistrust has been compared with paranoia, with paranoia found to be associated with belief in conspiracy theories,⁶ epistemic mistrust encompasses a range of justified cultural mistrust, unwarranted mistrust based on racial prejudice, and subclinical paranoia typical of schizotypy. The more self-referential the underlying paranoia, the more likely an associated belief is to cross the boundary from conspiracy theory to delusion.⁷

3. Is there overlap?

Conspiracy theory beliefs and delusions are not mutually exclusive. “Gang stalking” offers a vexing example of paranoia that is part shared conspiracy theory, part idiosyncratic delusion.⁸ Reliably disentangling these components requires identifying the conspiracy theory component as a widely-shared belief about government surveillance, while carefully analyzing the self-referential component to determine credibility and potential delusionality.

CASE Unresponsive after a presumed seizure

Mr. F, age 44, has schizophrenia. He is brought to the hospital by ambulance after he is found on the ground outside of his mother’s house following a presumed seizure and fall. On arrival to the emergency department, he is unresponsive. His laboratory values are significant for a sodium level of 110 mEq/L (reference range: 135 to 145 mEq/L), indicating hyponatremia.

HISTORY Fixated on purity

Mr. F’s mother reports that Mr. F had an unremarkable childhood. He was raised in a household with both parents and a younger sister. Mr. F did well academically and studied engineering and physics in college. There was no reported history of trauma or substance use.

During his senior year of college, Mr. F began experiencing paranoia, auditory hallucinations, and religious delusions. He required hospitalization and was diagnosed with schizophrenia. Following multiple hospitalizations over 5 years, he moved in with his mother, who was granted guardianship.

His mother said Mr. F’s religious delusions were of purity and cleansing the soul. He spent hours memorizing the Bible and would go for days without eating but would drink large amounts of water. She said she thought this was due to his desire to flush out imperfections.

In the past 3 years, Mr. F has been hospitalized several times for severe hyponatremia. At home, his mother attempted to restrict his water intake. However, Mr. F would still drink out of sinks and hoses. Mr. F’s mother reports that over the past month he had become more isolated. He would spend entire days reading the Bible, and his water intake had further increased.

Prior medication trials for Mr. F included haloperidol, up to 10 mg twice per day; aripiprazole, up to 20 mg/d; and risperidone, up to 6 mg nightly. These had been effective, but Mr. F had difficulty with adherence. He did not receive a long-acting injectable (LAI) antipsychotic initially due to lack of access at the rural clinic where he was treated, and later due to his mother’s preference for her son to receive oral medications. Prior to his current presentation, Mr. F’s medication regimen was olanzapine, 10 mg twice a day; perphenazine, 8 mg twice a day; and long-acting propranolol, 60 mg/d. Mr. F had no other chronic medical problems.

EVALUATION Hyponatremia, but why?

Mr. F is intubated and admitted to the surgical service for stabilization due to injuries from his fall. He has fractures of his right sinus and bilateral nasal bones, which are managed nonoperatively. He is delirious, with waxing and waning attention, memory disturbances, and disorientation. His psychotropic medications are held.

Continue to: Imaging of his head...

Imaging of his head does not reveal acute abnormalities suggesting a malignant or paraneoplastic process, and there are no concerns for ongoing seizures. An infection workup is negative. His urine toxicology is negative and blood alcohol level is 0. His sodium normalizes after 3 days of IV fluids and fluid restriction. Therefore, further tests to differentiate the causes of hyponatremia, such as urine electrolytes and urine osmolality, are not pursued.

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The authors’ observations

The differential diagnosis for hyponatremia is broad in the setting of psychiatric illness. Low sodium levels could be due to psychotropic medications, psychiatrically-driven behaviors, or an underlying medical problem. Our differential diagnosis for Mr. F included iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH), diabetes insipidus, or psychogenic polydipsia, a form of primary polydipsia. Other causes of primary polydipsia are related to substances, such as heavy beer intakeor use of 3,4-methylenedioxymethamphetamine (MDMA, also known as “ecstasy”), or brain lesions,¹ but these causes were less likely given Mr. F’s negative urine toxicology and head imaging.

While psychogenic polydipsia is due to increased water consumption, both SIADH and diabetes insipidus are due to alterations in fluid homeostasis.^2,3 Table 1^2-4 outlines distinguishing characteristics of SIADH, diabetes insipidus, and psychogenic polydipsia. Urine studies were not pursued because Mr. F’s sodium resolved and acute concerns, such as malignancy or infection, were ruled out. Mr. F’s hyponatremia was presumed to be due to psychogenic polydipsia because of his increased fluid intake and normalization of sodium with hypertonic fluids and subsequent fluid restriction. During this time, he was managed on the surgical service; the plan was to pursue urine studies and possibly a fluid challenge if his hyponatremia persisted.

EVALUATION Delirium resolves, delusions persist

While Mr. F is on the surgical service, the treatment team focuses on stabilizing his sodium level and assessing for causes of altered mental status that led to his fall. Psychiatry is consulted for management of his agitation. Following the gradual correction of his sodium level and extubation, his sensorium improves. By hospital Day 5, Mr. F’s delirium resolves.

During this time, Mr. F’s disorganization and religious delusions become apparent. He spends much of his time reading his Bible. He has poor hygiene and limited engagement in activities of daily living. Due to his psychosis and inability to care for himself, Mr. F is transferred to the psychiatric unit with consent from his mother.

Continue to: TREATMENT Olanzapine and fluid restriction

In the psychiatric unit, Mr. F is restarted on olanzapine, but not on perphenazine due to anticholinergic effects and not on propranolol due to continued orthostatic hypotension. Five days later, he is at his baseline level of functioning with residual psychosis. His fluid intake is restricted to <1.5 L per day and he is easily compliant.

Mr. F’s mother is comfortable with his discharge home on a regimen of olanzapine, 25 mg/d, and the team discusses the fluid restrictions with her. The treatment team suggests initiating an LAI before Mr. F is discharged, but this is not pursued because his mother thinks he is doing well with the oral medication. She wants to monitor him with the medication changes in the clinic before pursuing an LAI; however, she is open to it in the future.

The authors’ observations

Approximately 20% of patients with schizophrenia may experience psychogenic polydipsia.^4,5 The cause of psychogenic polydipsia in patients with serious mental illness is multifactorial. It may stem from malfunction of the hypothalamic-pituitary axis, which leads to alterations in antidiuretic hormone secretion and function.^4-6

Mr. F’s case highlights several challenges associated with treating psychogenic polydipsia in patients with serious mental illness. Antipsychotics with high dopamine affinity, such as risperidone and haloperidol, may increase the risk of psychogenic polydipsia, while antipsychotics with lower dopamine affinity, such as clozapine, may decrease the occurrence.⁵ Antipsychotics block postsynaptic dopamine receptors, which can induce supersensitivity by increasing presynaptic dopamine release in the hypothalamic areas, where thirst regulation occurs. This increase in dopamine leads to increased thirst drive and fluid intake.³

Quetiapine or clozapine may have been a better antipsychotic choice because these agents have lower D2 receptor affinity, whereas olanzapine has intermediate binding to D2 receptors.^6,7 However, quetiapine and clozapine are more strongly associated with orthostasis, which was a concern during Mr. F’s hospitalization. The weekly laboratory testing required with clozapine use would have been an unfeasible burden for Mr. F because he lived in a rural environment. Perphenazine was not continued due to higher D2 affinity and anticholinergic effects, which can increase thirst.⁶

Continue to: In addition to switching...

In addition to switching to an antipsychotic with looser D2 binding, other medications for treating polydipsia have been studied. It is hypothesized that the alpha-2 adrenergic system may play a role in thirst regulation. For example, mianserin, an alpha-2 antagonist, may decrease water intake. However, studies have been small and inconsistent.^8,9 Propranolol,¹⁰ a beta adrenergic receptor blocker; irbesartan,¹¹ an angiotensin-II receptor blocker; demeclocycline,¹² a tetracycline that inhibits antidiuretic hormone action; and naltrexone,⁹ a mu opioid antagonist, have been studied with inconclusive results and a variety of adverse effects^5,7,13 (Table 2^8-13).

Behavioral interventions for patients with psychogenic polydipsia include fluid restriction, twice-daily weight checks, cognitive-behavioral therapy, and reinforcement schedules, which may be useful but less realistic due to need for increased supervision.^11,12 Patient and family education on the signs of hyponatremia are important to prevent serious complications, such as those Mr. F experienced.

OUTCOME Repeated hospitalizations

Mr. F is discharged with follow-up in our psychiatry clinic and attends 1 appointment. At that time, his mother reports that Mr. F is compliant with his medication and has limited fluid intake. However, over the next 2 months, he is admitted to our psychiatric unit twice with similar presentations. Each time, the treatment team has extensive discussions with Mr. F’s mother about strategies to limit his water intake and the possibility of residential placement due to his need for a higher level of care. Although she acknowledges that nursing home placement may be needed in the future, she is not ready to take this step.

Three months later, Mr. F returns to our hospital with severe abdominal pain and is found to have a perforated bowel obstruction. His sodium is within normal limits on presentation, and the psychiatry team is not involved during this hospitalization. Mr. F is treated for sepsis and undergoes 3 exploratory laparotomies with continued decline in his health. He dies during this hospitalization. The cause of Mr. F’s perforated bowel obstruction is not determined, and his family does not pursue an autopsy.

The authors’ observations

At Mr. F’s final hospital presentation, his sodium was normal. It is possible Mr. F and his mother had found an acceptable fluid restriction routine, and he may have been doing better from a psychiatric perspective, but this will remain unknown.

Continue to: This case highlights...

This case highlights the clinical and ethical complexity of treating patients with psychogenic polydipsia. Because Mr. F no longer had autonomy, we had to determine if his mother was acting in his best interest as his guardian. Guardianship requirements and expectations vary by state. In our state of Missouri, a guardian is appointed by the court to act in the best interest of the ward, and may be a family member (preferred) or state-appointed. The guardian is responsible for providing the ward’s care and is in charge of financial and medical decisions. In Missouri, the guardian must assure the ward resides in the “least restrictive setting reasonably available,” which is the minimum necessary to provide the ward safe care and housing.¹⁴ Full guardianship, as in Mr. F’s case, is different from limited guardianship, which is an option in states such as Missouri. In limited guardianship, the court decides the extent of the guardian’s role in decisions for the ward.^14,15

Mr. F’s mother believed she was acting in her son’s best interest by having him home with his family. She believed by living at home, he would derive more enjoyment from life than living in a nursing home. By the time Mr. F presented to our hospital, he had been living with decompensated schizophrenia for years, so some level of psychosis was likely to persist, even with treatment. Given his increasingly frequent hospitalizations for hyponatremia due to increased water intake, more intense supervision may have been needed to maintain his safety, in line with nonmaleficence. The treatment team considered Mr. F’s best interest when discussing placement and worked to understand his mother’s preferences.

His mother continued to acknowledge the need for changes and adjustments at home. She was receptive to the need for fluid restriction and increased structure at home. Therefore, we felt she continued to be acting in his best interest, and his home would be the least restrictive setting for his care. If Mr. F had continued to require repeated hospitalizations and had not passed away, we would have pursued an ethics consult to discuss the need for nursing home placement and how to best approach this with Mr. F’s mother.

Bottom Line

Patients with serious mental illness who present with hyponatremia should be evaluated for psychogenic polydipsia by assessing their dietary and fluid intakes, along with collateral from family. The use of antipsychotics with high dopamine affinity may increase the risk of psychogenic polydipsia. Behavioral interventions include fluid restriction, weight checks, cognitive-behavioral therapy, and reinforcement schedules.

Related Resources

• Sharp CS, Wilson MP. Hyponatremia. In: Nordstrom KD, Wilson MP, eds. Quick guide to psychiatric emergencies. Springer International Publishing; 2018:115-119. doi:10.1007/ 978-3-319-58260-3_21
• Sailer C, Winzeler B, Christ-Crain M. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. Swiss Med Wkly. 2017;147:w14514. doi:10.4414/ smw.2017.14514

Drug Brand Names

Amiloride • Midamor
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Demeclocycline • Declomycin
Desmopressin • DDAVP
Haloperidol • Haldol
Irbesartan • Avapro
Lithium • Eskalith, Lithobid
Losartan • Cozaar
Mianserin • Tolvon
Naloxone • Narcan
Naltrexone • Revia
Olanzapine • Zyprexa
Perphenazine • Trilafon
Propranolol • Inderal LA
Quetiapine • Seroquel
Risperidone • Risperda

CASE Unresponsive after a presumed seizure

Mr. F, age 44, has schizophrenia. He is brought to the hospital by ambulance after he is found on the ground outside of his mother’s house following a presumed seizure and fall. On arrival to the emergency department, he is unresponsive. His laboratory values are significant for a sodium level of 110 mEq/L (reference range: 135 to 145 mEq/L), indicating hyponatremia.

HISTORY Fixated on purity

Mr. F’s mother reports that Mr. F had an unremarkable childhood. He was raised in a household with both parents and a younger sister. Mr. F did well academically and studied engineering and physics in college. There was no reported history of trauma or substance use.

During his senior year of college, Mr. F began experiencing paranoia, auditory hallucinations, and religious delusions. He required hospitalization and was diagnosed with schizophrenia. Following multiple hospitalizations over 5 years, he moved in with his mother, who was granted guardianship.

His mother said Mr. F’s religious delusions were of purity and cleansing the soul. He spent hours memorizing the Bible and would go for days without eating but would drink large amounts of water. She said she thought this was due to his desire to flush out imperfections.

In the past 3 years, Mr. F has been hospitalized several times for severe hyponatremia. At home, his mother attempted to restrict his water intake. However, Mr. F would still drink out of sinks and hoses. Mr. F’s mother reports that over the past month he had become more isolated. He would spend entire days reading the Bible, and his water intake had further increased.

Prior medication trials for Mr. F included haloperidol, up to 10 mg twice per day; aripiprazole, up to 20 mg/d; and risperidone, up to 6 mg nightly. These had been effective, but Mr. F had difficulty with adherence. He did not receive a long-acting injectable (LAI) antipsychotic initially due to lack of access at the rural clinic where he was treated, and later due to his mother’s preference for her son to receive oral medications. Prior to his current presentation, Mr. F’s medication regimen was olanzapine, 10 mg twice a day; perphenazine, 8 mg twice a day; and long-acting propranolol, 60 mg/d. Mr. F had no other chronic medical problems.

EVALUATION Hyponatremia, but why?

Mr. F is intubated and admitted to the surgical service for stabilization due to injuries from his fall. He has fractures of his right sinus and bilateral nasal bones, which are managed nonoperatively. He is delirious, with waxing and waning attention, memory disturbances, and disorientation. His psychotropic medications are held.

Continue to: Imaging of his head...

Imaging of his head does not reveal acute abnormalities suggesting a malignant or paraneoplastic process, and there are no concerns for ongoing seizures. An infection workup is negative. His urine toxicology is negative and blood alcohol level is 0. His sodium normalizes after 3 days of IV fluids and fluid restriction. Therefore, further tests to differentiate the causes of hyponatremia, such as urine electrolytes and urine osmolality, are not pursued.

[polldaddy:10910406]

The authors’ observations

The differential diagnosis for hyponatremia is broad in the setting of psychiatric illness. Low sodium levels could be due to psychotropic medications, psychiatrically-driven behaviors, or an underlying medical problem. Our differential diagnosis for Mr. F included iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH), diabetes insipidus, or psychogenic polydipsia, a form of primary polydipsia. Other causes of primary polydipsia are related to substances, such as heavy beer intakeor use of 3,4-methylenedioxymethamphetamine (MDMA, also known as “ecstasy”), or brain lesions,¹ but these causes were less likely given Mr. F’s negative urine toxicology and head imaging.

While psychogenic polydipsia is due to increased water consumption, both SIADH and diabetes insipidus are due to alterations in fluid homeostasis.^2,3 Table 1^2-4 outlines distinguishing characteristics of SIADH, diabetes insipidus, and psychogenic polydipsia. Urine studies were not pursued because Mr. F’s sodium resolved and acute concerns, such as malignancy or infection, were ruled out. Mr. F’s hyponatremia was presumed to be due to psychogenic polydipsia because of his increased fluid intake and normalization of sodium with hypertonic fluids and subsequent fluid restriction. During this time, he was managed on the surgical service; the plan was to pursue urine studies and possibly a fluid challenge if his hyponatremia persisted.

EVALUATION Delirium resolves, delusions persist

While Mr. F is on the surgical service, the treatment team focuses on stabilizing his sodium level and assessing for causes of altered mental status that led to his fall. Psychiatry is consulted for management of his agitation. Following the gradual correction of his sodium level and extubation, his sensorium improves. By hospital Day 5, Mr. F’s delirium resolves.

During this time, Mr. F’s disorganization and religious delusions become apparent. He spends much of his time reading his Bible. He has poor hygiene and limited engagement in activities of daily living. Due to his psychosis and inability to care for himself, Mr. F is transferred to the psychiatric unit with consent from his mother.

Continue to: TREATMENT Olanzapine and fluid restriction

In the psychiatric unit, Mr. F is restarted on olanzapine, but not on perphenazine due to anticholinergic effects and not on propranolol due to continued orthostatic hypotension. Five days later, he is at his baseline level of functioning with residual psychosis. His fluid intake is restricted to <1.5 L per day and he is easily compliant.

Mr. F’s mother is comfortable with his discharge home on a regimen of olanzapine, 25 mg/d, and the team discusses the fluid restrictions with her. The treatment team suggests initiating an LAI before Mr. F is discharged, but this is not pursued because his mother thinks he is doing well with the oral medication. She wants to monitor him with the medication changes in the clinic before pursuing an LAI; however, she is open to it in the future.

The authors’ observations

Approximately 20% of patients with schizophrenia may experience psychogenic polydipsia.^4,5 The cause of psychogenic polydipsia in patients with serious mental illness is multifactorial. It may stem from malfunction of the hypothalamic-pituitary axis, which leads to alterations in antidiuretic hormone secretion and function.^4-6

Mr. F’s case highlights several challenges associated with treating psychogenic polydipsia in patients with serious mental illness. Antipsychotics with high dopamine affinity, such as risperidone and haloperidol, may increase the risk of psychogenic polydipsia, while antipsychotics with lower dopamine affinity, such as clozapine, may decrease the occurrence.⁵ Antipsychotics block postsynaptic dopamine receptors, which can induce supersensitivity by increasing presynaptic dopamine release in the hypothalamic areas, where thirst regulation occurs. This increase in dopamine leads to increased thirst drive and fluid intake.³

Quetiapine or clozapine may have been a better antipsychotic choice because these agents have lower D2 receptor affinity, whereas olanzapine has intermediate binding to D2 receptors.^6,7 However, quetiapine and clozapine are more strongly associated with orthostasis, which was a concern during Mr. F’s hospitalization. The weekly laboratory testing required with clozapine use would have been an unfeasible burden for Mr. F because he lived in a rural environment. Perphenazine was not continued due to higher D2 affinity and anticholinergic effects, which can increase thirst.⁶

Continue to: In addition to switching...

In addition to switching to an antipsychotic with looser D2 binding, other medications for treating polydipsia have been studied. It is hypothesized that the alpha-2 adrenergic system may play a role in thirst regulation. For example, mianserin, an alpha-2 antagonist, may decrease water intake. However, studies have been small and inconsistent.^8,9 Propranolol,¹⁰ a beta adrenergic receptor blocker; irbesartan,¹¹ an angiotensin-II receptor blocker; demeclocycline,¹² a tetracycline that inhibits antidiuretic hormone action; and naltrexone,⁹ a mu opioid antagonist, have been studied with inconclusive results and a variety of adverse effects^5,7,13 (Table 2^8-13).

Behavioral interventions for patients with psychogenic polydipsia include fluid restriction, twice-daily weight checks, cognitive-behavioral therapy, and reinforcement schedules, which may be useful but less realistic due to need for increased supervision.^11,12 Patient and family education on the signs of hyponatremia are important to prevent serious complications, such as those Mr. F experienced.

OUTCOME Repeated hospitalizations

Mr. F is discharged with follow-up in our psychiatry clinic and attends 1 appointment. At that time, his mother reports that Mr. F is compliant with his medication and has limited fluid intake. However, over the next 2 months, he is admitted to our psychiatric unit twice with similar presentations. Each time, the treatment team has extensive discussions with Mr. F’s mother about strategies to limit his water intake and the possibility of residential placement due to his need for a higher level of care. Although she acknowledges that nursing home placement may be needed in the future, she is not ready to take this step.

Three months later, Mr. F returns to our hospital with severe abdominal pain and is found to have a perforated bowel obstruction. His sodium is within normal limits on presentation, and the psychiatry team is not involved during this hospitalization. Mr. F is treated for sepsis and undergoes 3 exploratory laparotomies with continued decline in his health. He dies during this hospitalization. The cause of Mr. F’s perforated bowel obstruction is not determined, and his family does not pursue an autopsy.

The authors’ observations

At Mr. F’s final hospital presentation, his sodium was normal. It is possible Mr. F and his mother had found an acceptable fluid restriction routine, and he may have been doing better from a psychiatric perspective, but this will remain unknown.

Continue to: This case highlights...

This case highlights the clinical and ethical complexity of treating patients with psychogenic polydipsia. Because Mr. F no longer had autonomy, we had to determine if his mother was acting in his best interest as his guardian. Guardianship requirements and expectations vary by state. In our state of Missouri, a guardian is appointed by the court to act in the best interest of the ward, and may be a family member (preferred) or state-appointed. The guardian is responsible for providing the ward’s care and is in charge of financial and medical decisions. In Missouri, the guardian must assure the ward resides in the “least restrictive setting reasonably available,” which is the minimum necessary to provide the ward safe care and housing.¹⁴ Full guardianship, as in Mr. F’s case, is different from limited guardianship, which is an option in states such as Missouri. In limited guardianship, the court decides the extent of the guardian’s role in decisions for the ward.^14,15

Mr. F’s mother believed she was acting in her son’s best interest by having him home with his family. She believed by living at home, he would derive more enjoyment from life than living in a nursing home. By the time Mr. F presented to our hospital, he had been living with decompensated schizophrenia for years, so some level of psychosis was likely to persist, even with treatment. Given his increasingly frequent hospitalizations for hyponatremia due to increased water intake, more intense supervision may have been needed to maintain his safety, in line with nonmaleficence. The treatment team considered Mr. F’s best interest when discussing placement and worked to understand his mother’s preferences.

His mother continued to acknowledge the need for changes and adjustments at home. She was receptive to the need for fluid restriction and increased structure at home. Therefore, we felt she continued to be acting in his best interest, and his home would be the least restrictive setting for his care. If Mr. F had continued to require repeated hospitalizations and had not passed away, we would have pursued an ethics consult to discuss the need for nursing home placement and how to best approach this with Mr. F’s mother.

Bottom Line

Patients with serious mental illness who present with hyponatremia should be evaluated for psychogenic polydipsia by assessing their dietary and fluid intakes, along with collateral from family. The use of antipsychotics with high dopamine affinity may increase the risk of psychogenic polydipsia. Behavioral interventions include fluid restriction, weight checks, cognitive-behavioral therapy, and reinforcement schedules.

Related Resources

• Sharp CS, Wilson MP. Hyponatremia. In: Nordstrom KD, Wilson MP, eds. Quick guide to psychiatric emergencies. Springer International Publishing; 2018:115-119. doi:10.1007/ 978-3-319-58260-3_21
• Sailer C, Winzeler B, Christ-Crain M. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. Swiss Med Wkly. 2017;147:w14514. doi:10.4414/ smw.2017.14514

Drug Brand Names

Amiloride • Midamor
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Demeclocycline • Declomycin
Desmopressin • DDAVP
Haloperidol • Haldol
Irbesartan • Avapro
Lithium • Eskalith, Lithobid
Losartan • Cozaar
Mianserin • Tolvon
Naloxone • Narcan
Naltrexone • Revia
Olanzapine • Zyprexa
Perphenazine • Trilafon
Propranolol • Inderal LA
Quetiapine • Seroquel
Risperidone • Risperda

CASE Unresponsive after a presumed seizure

Mr. F, age 44, has schizophrenia. He is brought to the hospital by ambulance after he is found on the ground outside of his mother’s house following a presumed seizure and fall. On arrival to the emergency department, he is unresponsive. His laboratory values are significant for a sodium level of 110 mEq/L (reference range: 135 to 145 mEq/L), indicating hyponatremia.

HISTORY Fixated on purity

Mr. F’s mother reports that Mr. F had an unremarkable childhood. He was raised in a household with both parents and a younger sister. Mr. F did well academically and studied engineering and physics in college. There was no reported history of trauma or substance use.

During his senior year of college, Mr. F began experiencing paranoia, auditory hallucinations, and religious delusions. He required hospitalization and was diagnosed with schizophrenia. Following multiple hospitalizations over 5 years, he moved in with his mother, who was granted guardianship.

His mother said Mr. F’s religious delusions were of purity and cleansing the soul. He spent hours memorizing the Bible and would go for days without eating but would drink large amounts of water. She said she thought this was due to his desire to flush out imperfections.

In the past 3 years, Mr. F has been hospitalized several times for severe hyponatremia. At home, his mother attempted to restrict his water intake. However, Mr. F would still drink out of sinks and hoses. Mr. F’s mother reports that over the past month he had become more isolated. He would spend entire days reading the Bible, and his water intake had further increased.

Prior medication trials for Mr. F included haloperidol, up to 10 mg twice per day; aripiprazole, up to 20 mg/d; and risperidone, up to 6 mg nightly. These had been effective, but Mr. F had difficulty with adherence. He did not receive a long-acting injectable (LAI) antipsychotic initially due to lack of access at the rural clinic where he was treated, and later due to his mother’s preference for her son to receive oral medications. Prior to his current presentation, Mr. F’s medication regimen was olanzapine, 10 mg twice a day; perphenazine, 8 mg twice a day; and long-acting propranolol, 60 mg/d. Mr. F had no other chronic medical problems.

EVALUATION Hyponatremia, but why?

Mr. F is intubated and admitted to the surgical service for stabilization due to injuries from his fall. He has fractures of his right sinus and bilateral nasal bones, which are managed nonoperatively. He is delirious, with waxing and waning attention, memory disturbances, and disorientation. His psychotropic medications are held.

Continue to: Imaging of his head...

Imaging of his head does not reveal acute abnormalities suggesting a malignant or paraneoplastic process, and there are no concerns for ongoing seizures. An infection workup is negative. His urine toxicology is negative and blood alcohol level is 0. His sodium normalizes after 3 days of IV fluids and fluid restriction. Therefore, further tests to differentiate the causes of hyponatremia, such as urine electrolytes and urine osmolality, are not pursued.

[polldaddy:10910406]

The authors’ observations

The differential diagnosis for hyponatremia is broad in the setting of psychiatric illness. Low sodium levels could be due to psychotropic medications, psychiatrically-driven behaviors, or an underlying medical problem. Our differential diagnosis for Mr. F included iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH), diabetes insipidus, or psychogenic polydipsia, a form of primary polydipsia. Other causes of primary polydipsia are related to substances, such as heavy beer intakeor use of 3,4-methylenedioxymethamphetamine (MDMA, also known as “ecstasy”), or brain lesions,¹ but these causes were less likely given Mr. F’s negative urine toxicology and head imaging.

While psychogenic polydipsia is due to increased water consumption, both SIADH and diabetes insipidus are due to alterations in fluid homeostasis.^2,3 Table 1^2-4 outlines distinguishing characteristics of SIADH, diabetes insipidus, and psychogenic polydipsia. Urine studies were not pursued because Mr. F’s sodium resolved and acute concerns, such as malignancy or infection, were ruled out. Mr. F’s hyponatremia was presumed to be due to psychogenic polydipsia because of his increased fluid intake and normalization of sodium with hypertonic fluids and subsequent fluid restriction. During this time, he was managed on the surgical service; the plan was to pursue urine studies and possibly a fluid challenge if his hyponatremia persisted.

EVALUATION Delirium resolves, delusions persist

While Mr. F is on the surgical service, the treatment team focuses on stabilizing his sodium level and assessing for causes of altered mental status that led to his fall. Psychiatry is consulted for management of his agitation. Following the gradual correction of his sodium level and extubation, his sensorium improves. By hospital Day 5, Mr. F’s delirium resolves.

During this time, Mr. F’s disorganization and religious delusions become apparent. He spends much of his time reading his Bible. He has poor hygiene and limited engagement in activities of daily living. Due to his psychosis and inability to care for himself, Mr. F is transferred to the psychiatric unit with consent from his mother.

Continue to: TREATMENT Olanzapine and fluid restriction

In the psychiatric unit, Mr. F is restarted on olanzapine, but not on perphenazine due to anticholinergic effects and not on propranolol due to continued orthostatic hypotension. Five days later, he is at his baseline level of functioning with residual psychosis. His fluid intake is restricted to <1.5 L per day and he is easily compliant.

Mr. F’s mother is comfortable with his discharge home on a regimen of olanzapine, 25 mg/d, and the team discusses the fluid restrictions with her. The treatment team suggests initiating an LAI before Mr. F is discharged, but this is not pursued because his mother thinks he is doing well with the oral medication. She wants to monitor him with the medication changes in the clinic before pursuing an LAI; however, she is open to it in the future.

The authors’ observations

Approximately 20% of patients with schizophrenia may experience psychogenic polydipsia.^4,5 The cause of psychogenic polydipsia in patients with serious mental illness is multifactorial. It may stem from malfunction of the hypothalamic-pituitary axis, which leads to alterations in antidiuretic hormone secretion and function.^4-6

Mr. F’s case highlights several challenges associated with treating psychogenic polydipsia in patients with serious mental illness. Antipsychotics with high dopamine affinity, such as risperidone and haloperidol, may increase the risk of psychogenic polydipsia, while antipsychotics with lower dopamine affinity, such as clozapine, may decrease the occurrence.⁵ Antipsychotics block postsynaptic dopamine receptors, which can induce supersensitivity by increasing presynaptic dopamine release in the hypothalamic areas, where thirst regulation occurs. This increase in dopamine leads to increased thirst drive and fluid intake.³

Quetiapine or clozapine may have been a better antipsychotic choice because these agents have lower D2 receptor affinity, whereas olanzapine has intermediate binding to D2 receptors.^6,7 However, quetiapine and clozapine are more strongly associated with orthostasis, which was a concern during Mr. F’s hospitalization. The weekly laboratory testing required with clozapine use would have been an unfeasible burden for Mr. F because he lived in a rural environment. Perphenazine was not continued due to higher D2 affinity and anticholinergic effects, which can increase thirst.⁶

Continue to: In addition to switching...

In addition to switching to an antipsychotic with looser D2 binding, other medications for treating polydipsia have been studied. It is hypothesized that the alpha-2 adrenergic system may play a role in thirst regulation. For example, mianserin, an alpha-2 antagonist, may decrease water intake. However, studies have been small and inconsistent.^8,9 Propranolol,¹⁰ a beta adrenergic receptor blocker; irbesartan,¹¹ an angiotensin-II receptor blocker; demeclocycline,¹² a tetracycline that inhibits antidiuretic hormone action; and naltrexone,⁹ a mu opioid antagonist, have been studied with inconclusive results and a variety of adverse effects^5,7,13 (Table 2^8-13).

Behavioral interventions for patients with psychogenic polydipsia include fluid restriction, twice-daily weight checks, cognitive-behavioral therapy, and reinforcement schedules, which may be useful but less realistic due to need for increased supervision.^11,12 Patient and family education on the signs of hyponatremia are important to prevent serious complications, such as those Mr. F experienced.

OUTCOME Repeated hospitalizations

Mr. F is discharged with follow-up in our psychiatry clinic and attends 1 appointment. At that time, his mother reports that Mr. F is compliant with his medication and has limited fluid intake. However, over the next 2 months, he is admitted to our psychiatric unit twice with similar presentations. Each time, the treatment team has extensive discussions with Mr. F’s mother about strategies to limit his water intake and the possibility of residential placement due to his need for a higher level of care. Although she acknowledges that nursing home placement may be needed in the future, she is not ready to take this step.

Three months later, Mr. F returns to our hospital with severe abdominal pain and is found to have a perforated bowel obstruction. His sodium is within normal limits on presentation, and the psychiatry team is not involved during this hospitalization. Mr. F is treated for sepsis and undergoes 3 exploratory laparotomies with continued decline in his health. He dies during this hospitalization. The cause of Mr. F’s perforated bowel obstruction is not determined, and his family does not pursue an autopsy.

The authors’ observations

At Mr. F’s final hospital presentation, his sodium was normal. It is possible Mr. F and his mother had found an acceptable fluid restriction routine, and he may have been doing better from a psychiatric perspective, but this will remain unknown.

Continue to: This case highlights...

This case highlights the clinical and ethical complexity of treating patients with psychogenic polydipsia. Because Mr. F no longer had autonomy, we had to determine if his mother was acting in his best interest as his guardian. Guardianship requirements and expectations vary by state. In our state of Missouri, a guardian is appointed by the court to act in the best interest of the ward, and may be a family member (preferred) or state-appointed. The guardian is responsible for providing the ward’s care and is in charge of financial and medical decisions. In Missouri, the guardian must assure the ward resides in the “least restrictive setting reasonably available,” which is the minimum necessary to provide the ward safe care and housing.¹⁴ Full guardianship, as in Mr. F’s case, is different from limited guardianship, which is an option in states such as Missouri. In limited guardianship, the court decides the extent of the guardian’s role in decisions for the ward.^14,15

Mr. F’s mother believed she was acting in her son’s best interest by having him home with his family. She believed by living at home, he would derive more enjoyment from life than living in a nursing home. By the time Mr. F presented to our hospital, he had been living with decompensated schizophrenia for years, so some level of psychosis was likely to persist, even with treatment. Given his increasingly frequent hospitalizations for hyponatremia due to increased water intake, more intense supervision may have been needed to maintain his safety, in line with nonmaleficence. The treatment team considered Mr. F’s best interest when discussing placement and worked to understand his mother’s preferences.

His mother continued to acknowledge the need for changes and adjustments at home. She was receptive to the need for fluid restriction and increased structure at home. Therefore, we felt she continued to be acting in his best interest, and his home would be the least restrictive setting for his care. If Mr. F had continued to require repeated hospitalizations and had not passed away, we would have pursued an ethics consult to discuss the need for nursing home placement and how to best approach this with Mr. F’s mother.

Bottom Line

Patients with serious mental illness who present with hyponatremia should be evaluated for psychogenic polydipsia by assessing their dietary and fluid intakes, along with collateral from family. The use of antipsychotics with high dopamine affinity may increase the risk of psychogenic polydipsia. Behavioral interventions include fluid restriction, weight checks, cognitive-behavioral therapy, and reinforcement schedules.

Related Resources

• Sharp CS, Wilson MP. Hyponatremia. In: Nordstrom KD, Wilson MP, eds. Quick guide to psychiatric emergencies. Springer International Publishing; 2018:115-119. doi:10.1007/ 978-3-319-58260-3_21
• Sailer C, Winzeler B, Christ-Crain M. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. Swiss Med Wkly. 2017;147:w14514. doi:10.4414/ smw.2017.14514

Drug Brand Names

Amiloride • Midamor
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Demeclocycline • Declomycin
Desmopressin • DDAVP
Haloperidol • Haldol
Irbesartan • Avapro
Lithium • Eskalith, Lithobid
Losartan • Cozaar
Mianserin • Tolvon
Naloxone • Narcan
Naltrexone • Revia
Olanzapine • Zyprexa
Perphenazine • Trilafon
Propranolol • Inderal LA
Quetiapine • Seroquel
Risperidone • Risperda