Addiction Medicine

In the United States, opioid use by patients who are pregnant more than quadrupled from 1999 to 2014.¹ Opioid use disorder (OUD) in the perinatal period is associated with a higher risk for depression, suicide, malnutrition, domestic violence, and obstetric complications such as spontaneous abortion, preeclampsia, and premature delivery.² Buprenorphine and methadone are the standard of care for treating OUD in pregnancy.^3,4 While a literature review found that maternal treatment with buprenorphine has comparable efficacy to treatment with methadone,⁵ a small randomized, double-blind study found that compared to buprenorphine, methadone was associated with significantly lower use of additional opioids (P = .047).⁶ This suggests methadone has therapeutic value for patients who are pregnant.

Despite the benefits of methadone for treating perinatal OUD, the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Patients typically take methadone once a day, and the dose is titrated every 3 to 5 days to allow serum levels to reach steady state.⁷ During pregnancy, there are increases in both the volume of distribution and medication metabolism secondary to increased expression of the cytochrome P450 3A4 enzyme by the liver, intestine, and placenta.⁸ Additionally, as the pregnancy progresses, the rate of methadone metabolism increases.⁹ Methadone’s half-life (20 to 35 hours) leads to its accumulation in tissue and slow release into the blood.¹⁰ As a result, patients with OUD who are pregnant often require higher doses of methadone or divided dosing, particularly in the second and third trimesters.¹¹

In this article, we provide a strategy for divided dosing of methadone for managing opioid withdrawal symptoms in the acute care setting. We present 2 cases of women with OUD who are pregnant and describe the collaboration of addiction medicine, consultation-liaison psychiatry, and obstetrics services.

CASE 1

Ms. H, age 29, is G3P2 and presents to the emergency department (ED) during her fourth pregnancy at 31 weeks, 1 day gestation. She has a history of opioid, cocaine, and benzodiazepine use disorders and chronic hepatitis C. Ms. H is enrolled in an opioid treatment program and takes methadone 190 mg/d in addition to nonprescribed opioids. In the ED, Ms. H requests medically supervised withdrawal management. Her urine toxicology is positive for cocaine, benzodiazepines, methadone, and opiates. Her laboratory results and electrocardiogram (ECG) are unremarkable. On admission, Ms. H’s Clinical Opiate Withdrawal Scale (COWS) score is 3, indicating minimal symptoms (5 to 12: mild; 13 to 24: moderate; 25 to 36: moderately severe; >36: severe). Fetal monitoring is reassuring.

Ms. H’s withdrawal is monitored with COWS every 4 hours. The treatment team initiates methadone 170 mg/d, with an additional 10 mg/d as needed to keep her COWS score <8, and daily QTc monitoring. Ms. H also receives lorazepam 2 to 4 mg/d as needed for benzodiazepine withdrawal. Despite the increase in her daily methadone dose, Ms. H continues to experience opioid withdrawal in the early evening and overnight. As a result, the treatment team increases Ms. H’s morning methadone dose to 190 mg and schedules an afternoon dose of 30 mg. Despite this adjustment, her COWS scores remain elevated in the afternoon and evening, and she requires additional as-needed doses of methadone. Methadone peak and trough levels are ordered to assess for rapid metabolism. The serum trough level is 190 ng/mL, which is low, and a serum peak level is not reported. Despite titration, Ms. H has a self-directed premature discharge.

Five days later at 32 weeks, 2 days gestation, Ms. H is readmitted after she had resumed use of opioids, benzodiazepines, and cocaine. Her vital signs are stable, and her laboratory results and ECG are unremarkable. Fetal monitoring is reassuring. Given Ms. H’s low methadone serum trough level and overall concern for rapid methadone metabolism, the treatment team decides to divide dosing of methadone. Over 9 days, the team titrates methadone to 170 mg twice daily on the day of discharge, which resolves Ms. H’s withdrawal symptoms.

At 38 weeks, 5 days gestation, Ms. H returns to the ED after experiencing labor contractions and opiate withdrawal symptoms after she resumed use of heroin, cocaine, and benzodiazepines. During this admission, Ms. H’s methadone is increased to 180 mg twice daily with additional as-needed doses for ongoing withdrawal symptoms. At 39 weeks, 2 days gestation, Ms. H has a scheduled cesarean delivery.

Her infant has a normal weight but is transferred to the neonatal intensive care unit (NICU) for management of neonatal opioid withdrawal syndrome (NOWS) and receives morphine. The baby remains in the NICU for 35 days and is discharged home without further treatment. When Ms. H is discharged, her methadone dose is 170 mg twice daily, which resolves her opioid withdrawal symptoms. The treatment team directs her to continue care in her methadone outpatient program and receive treatment for her cocaine and benzodiazepine use disorders. She declines residential or inpatient substance use treatment.

Continue to: CASE 2

Ms. M, age 39, is G4P2 and presents to the hospital during her fifth pregnancy at 27 weeks gestation. She has not received prenatal care for this pregnancy. She has a history of OUD and major depressive disorder (MDD). Ms. M’s urine toxicology is positive for opiates, fentanyl, and oxycodone. Her laboratory results are notable for mildly elevated alanine aminotransferase, positive hepatitis C antibody, and a hepatitis C viral load of 91,000, consistent with chronic hepatitis C infection. On admission, her COWS score is 14, indicating moderate withdrawal symptoms. Her ECG is unremarkable, and fetal monitoring is reassuring.

Ms. M had received methadone during a prior pregnancy and opts to reinitiate treatment with methadone during her current admission. The team initiates methadone 20 mg/d with additional as-needed doses for ongoing withdrawal symptoms. Due to a persistently elevated COWS score, Ms. M’s methadone is increased to 90 mg/d, which resolves her withdrawal symptoms. However, on Day 4, Ms. M reports having anxiety, refuses bloodwork to obtain methadone peak and trough levels, and prematurely discharges from the hospital.

One day later at 27 weeks, 5 days gestation, Ms. M is readmitted for continued management of opioid withdrawal. She presents with stable vital signs, an unremarkable ECG, and reassuring fetal monitoring. Her COWS score is 5. The treatment team reinitiates methadone at 80 mg/d and titrates it to 100 mg/d on Day 7. Given Ms. M’s ongoing evening cravings and concern for rapid methadone metabolism, on Day 10 the team switches the methadone dosing to 50 mg twice daily to maintain steady-state levels and promote patient comfort. Fluoxetine 20 mg/d is started for comorbid MDD and eventually increased to 80 mg/d. Ms. M is discharged on Day 15 with a regimen of methadone 60 mg/d in the morning and 70 mg/d at night. She plans to resume care in an opioid treatment program and follow up with psychiatry and hepatology for her anxiety and hepatitis C.

A need for aggressive treatment

Given the rising rates of opioid use by patients who are pregnant, harmful behavior related to opioid use, and a wealth of evidence supporting opioid agonist treatment for OUD in pregnancy, there is a growing need for guidance in managing perinatal OUD. A systematic approach to using methadone to treat OUD in patients who are pregnant is essential; the lack of data surrounding use of this medication in such patients may cause overall harm.¹² Limited guidelines and a lack of familiarity with prescribing methadone to patients who are pregnant may lead clinicians to underdose patients, which can result in ongoing withdrawal, premature patient-directed discharges, and poor engagement in care.¹³ Both patients in the 2 cases described in this article experienced ongoing withdrawal symptoms despite daily titration of methadone. This suggests rapid metabolism, which was successfully managed by dividing the dosing of methadone, particularly in the latter trimesters.

These cases illustrate the need for aggressive perinatal opioid withdrawal management through rapid escalation of divided doses of methadone in a monitored acute care setting. Because methadone elimination is more rapid and clearance rates increase during the perinatal period, divided methadone dosing allows for sustained plasma methadone concentrations and improved outpatient treatment adherence.^9,14,15

Continue to: Decreasing the rate of premature discharges

Decreasing the rate of premature discharges

In both cases, the patients discharged from the hospital prematurely, likely related to incomplete management of their opioid withdrawal or other withdrawal syndromes (both patients had multiple substance use disorders [SUDs]). Compared to patients without an SUD, patients with SUDs are 3 times more likely to have a self-directed discharge.¹⁶ Patients report leaving the hospital prematurely due to undertreated withdrawal, uncontrolled pain, discrimination by staff, and hospital restrictions.¹⁶ Recommendations to decrease the rates of premature patient-directed discharges in this population include providing patient-centered and harm reduction–oriented care in addition to adequate management of pain and withdrawal.¹⁷

Impact of methadone on fetal outcomes

Approximately 55% to 94% of infants born to patients who are opioid-dependent will develop NOWS. However, there is no relationship between this syndrome and therapeutic doses of methadone.¹⁸ Moreover, long-term research has found that after adjusting for socioeconomic factors, methadone treatment during pregnancy does not have an adverse effect on postnatal development. Divided dosing in maternal methadone administration is also shown to have less of an impact on fetal neurobehavior and NOWS.¹⁹

Our recommendations for methadone treatment for perinatal patients are outlined in the Table. Aggressive treatment of opioid withdrawal in the hospital can promote treatment engagement and prevent premature discharges. Clinicians should assess for other withdrawal syndromes when a patient has multiple SUDs and collaborate with an interdisciplinary team to improve patient outcomes.

Bottom Line

The prevalence of opioid use disorder (OUD) in patients who are pregnant is increasing. Methadone is an option for treating perinatal OUD, but the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Using divided doses of methadone can ensure the comfort and safety of the patient and their baby and improve adherence and outcomes.

Related Resources

• Chaney L, Mathia C, Cole T. Transitioning patients with opioid use disorder from methadone to buprenorphine. Current Psychiatry. 2022;21(12):23-24,28. doi:10.12788/cp.0305
• Townsel C, Irani S, Buis C, et al. Partnering for the future clinic: a multidisciplinary perinatal substance use program. Gen Hosp Psychiatry. 2023;85:220-228. doi:10.1016/j. genhosppsych.2023.10.009

Drug Brand Names

Buprenorphine • Buprenex, Suboxone, Zubsolv, Sublocade
Fentanyl • Abstral, Actiq
Fluoxetine • Prozac
Lorazepam • Ativan
Methadone • Methadose, Dolophine
Oxycodone • Oxycontin

In the United States, opioid use by patients who are pregnant more than quadrupled from 1999 to 2014.¹ Opioid use disorder (OUD) in the perinatal period is associated with a higher risk for depression, suicide, malnutrition, domestic violence, and obstetric complications such as spontaneous abortion, preeclampsia, and premature delivery.² Buprenorphine and methadone are the standard of care for treating OUD in pregnancy.^3,4 While a literature review found that maternal treatment with buprenorphine has comparable efficacy to treatment with methadone,⁵ a small randomized, double-blind study found that compared to buprenorphine, methadone was associated with significantly lower use of additional opioids (P = .047).⁶ This suggests methadone has therapeutic value for patients who are pregnant.

Despite the benefits of methadone for treating perinatal OUD, the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Patients typically take methadone once a day, and the dose is titrated every 3 to 5 days to allow serum levels to reach steady state.⁷ During pregnancy, there are increases in both the volume of distribution and medication metabolism secondary to increased expression of the cytochrome P450 3A4 enzyme by the liver, intestine, and placenta.⁸ Additionally, as the pregnancy progresses, the rate of methadone metabolism increases.⁹ Methadone’s half-life (20 to 35 hours) leads to its accumulation in tissue and slow release into the blood.¹⁰ As a result, patients with OUD who are pregnant often require higher doses of methadone or divided dosing, particularly in the second and third trimesters.¹¹

In this article, we provide a strategy for divided dosing of methadone for managing opioid withdrawal symptoms in the acute care setting. We present 2 cases of women with OUD who are pregnant and describe the collaboration of addiction medicine, consultation-liaison psychiatry, and obstetrics services.

CASE 1

Ms. H, age 29, is G3P2 and presents to the emergency department (ED) during her fourth pregnancy at 31 weeks, 1 day gestation. She has a history of opioid, cocaine, and benzodiazepine use disorders and chronic hepatitis C. Ms. H is enrolled in an opioid treatment program and takes methadone 190 mg/d in addition to nonprescribed opioids. In the ED, Ms. H requests medically supervised withdrawal management. Her urine toxicology is positive for cocaine, benzodiazepines, methadone, and opiates. Her laboratory results and electrocardiogram (ECG) are unremarkable. On admission, Ms. H’s Clinical Opiate Withdrawal Scale (COWS) score is 3, indicating minimal symptoms (5 to 12: mild; 13 to 24: moderate; 25 to 36: moderately severe; >36: severe). Fetal monitoring is reassuring.

Ms. H’s withdrawal is monitored with COWS every 4 hours. The treatment team initiates methadone 170 mg/d, with an additional 10 mg/d as needed to keep her COWS score <8, and daily QTc monitoring. Ms. H also receives lorazepam 2 to 4 mg/d as needed for benzodiazepine withdrawal. Despite the increase in her daily methadone dose, Ms. H continues to experience opioid withdrawal in the early evening and overnight. As a result, the treatment team increases Ms. H’s morning methadone dose to 190 mg and schedules an afternoon dose of 30 mg. Despite this adjustment, her COWS scores remain elevated in the afternoon and evening, and she requires additional as-needed doses of methadone. Methadone peak and trough levels are ordered to assess for rapid metabolism. The serum trough level is 190 ng/mL, which is low, and a serum peak level is not reported. Despite titration, Ms. H has a self-directed premature discharge.

Five days later at 32 weeks, 2 days gestation, Ms. H is readmitted after she had resumed use of opioids, benzodiazepines, and cocaine. Her vital signs are stable, and her laboratory results and ECG are unremarkable. Fetal monitoring is reassuring. Given Ms. H’s low methadone serum trough level and overall concern for rapid methadone metabolism, the treatment team decides to divide dosing of methadone. Over 9 days, the team titrates methadone to 170 mg twice daily on the day of discharge, which resolves Ms. H’s withdrawal symptoms.

At 38 weeks, 5 days gestation, Ms. H returns to the ED after experiencing labor contractions and opiate withdrawal symptoms after she resumed use of heroin, cocaine, and benzodiazepines. During this admission, Ms. H’s methadone is increased to 180 mg twice daily with additional as-needed doses for ongoing withdrawal symptoms. At 39 weeks, 2 days gestation, Ms. H has a scheduled cesarean delivery.

Her infant has a normal weight but is transferred to the neonatal intensive care unit (NICU) for management of neonatal opioid withdrawal syndrome (NOWS) and receives morphine. The baby remains in the NICU for 35 days and is discharged home without further treatment. When Ms. H is discharged, her methadone dose is 170 mg twice daily, which resolves her opioid withdrawal symptoms. The treatment team directs her to continue care in her methadone outpatient program and receive treatment for her cocaine and benzodiazepine use disorders. She declines residential or inpatient substance use treatment.

Continue to: CASE 2

Ms. M, age 39, is G4P2 and presents to the hospital during her fifth pregnancy at 27 weeks gestation. She has not received prenatal care for this pregnancy. She has a history of OUD and major depressive disorder (MDD). Ms. M’s urine toxicology is positive for opiates, fentanyl, and oxycodone. Her laboratory results are notable for mildly elevated alanine aminotransferase, positive hepatitis C antibody, and a hepatitis C viral load of 91,000, consistent with chronic hepatitis C infection. On admission, her COWS score is 14, indicating moderate withdrawal symptoms. Her ECG is unremarkable, and fetal monitoring is reassuring.

Ms. M had received methadone during a prior pregnancy and opts to reinitiate treatment with methadone during her current admission. The team initiates methadone 20 mg/d with additional as-needed doses for ongoing withdrawal symptoms. Due to a persistently elevated COWS score, Ms. M’s methadone is increased to 90 mg/d, which resolves her withdrawal symptoms. However, on Day 4, Ms. M reports having anxiety, refuses bloodwork to obtain methadone peak and trough levels, and prematurely discharges from the hospital.

One day later at 27 weeks, 5 days gestation, Ms. M is readmitted for continued management of opioid withdrawal. She presents with stable vital signs, an unremarkable ECG, and reassuring fetal monitoring. Her COWS score is 5. The treatment team reinitiates methadone at 80 mg/d and titrates it to 100 mg/d on Day 7. Given Ms. M’s ongoing evening cravings and concern for rapid methadone metabolism, on Day 10 the team switches the methadone dosing to 50 mg twice daily to maintain steady-state levels and promote patient comfort. Fluoxetine 20 mg/d is started for comorbid MDD and eventually increased to 80 mg/d. Ms. M is discharged on Day 15 with a regimen of methadone 60 mg/d in the morning and 70 mg/d at night. She plans to resume care in an opioid treatment program and follow up with psychiatry and hepatology for her anxiety and hepatitis C.

A need for aggressive treatment

Given the rising rates of opioid use by patients who are pregnant, harmful behavior related to opioid use, and a wealth of evidence supporting opioid agonist treatment for OUD in pregnancy, there is a growing need for guidance in managing perinatal OUD. A systematic approach to using methadone to treat OUD in patients who are pregnant is essential; the lack of data surrounding use of this medication in such patients may cause overall harm.¹² Limited guidelines and a lack of familiarity with prescribing methadone to patients who are pregnant may lead clinicians to underdose patients, which can result in ongoing withdrawal, premature patient-directed discharges, and poor engagement in care.¹³ Both patients in the 2 cases described in this article experienced ongoing withdrawal symptoms despite daily titration of methadone. This suggests rapid metabolism, which was successfully managed by dividing the dosing of methadone, particularly in the latter trimesters.

These cases illustrate the need for aggressive perinatal opioid withdrawal management through rapid escalation of divided doses of methadone in a monitored acute care setting. Because methadone elimination is more rapid and clearance rates increase during the perinatal period, divided methadone dosing allows for sustained plasma methadone concentrations and improved outpatient treatment adherence.^9,14,15

Continue to: Decreasing the rate of premature discharges

Decreasing the rate of premature discharges

In both cases, the patients discharged from the hospital prematurely, likely related to incomplete management of their opioid withdrawal or other withdrawal syndromes (both patients had multiple substance use disorders [SUDs]). Compared to patients without an SUD, patients with SUDs are 3 times more likely to have a self-directed discharge.¹⁶ Patients report leaving the hospital prematurely due to undertreated withdrawal, uncontrolled pain, discrimination by staff, and hospital restrictions.¹⁶ Recommendations to decrease the rates of premature patient-directed discharges in this population include providing patient-centered and harm reduction–oriented care in addition to adequate management of pain and withdrawal.¹⁷

Impact of methadone on fetal outcomes

Approximately 55% to 94% of infants born to patients who are opioid-dependent will develop NOWS. However, there is no relationship between this syndrome and therapeutic doses of methadone.¹⁸ Moreover, long-term research has found that after adjusting for socioeconomic factors, methadone treatment during pregnancy does not have an adverse effect on postnatal development. Divided dosing in maternal methadone administration is also shown to have less of an impact on fetal neurobehavior and NOWS.¹⁹

Our recommendations for methadone treatment for perinatal patients are outlined in the Table. Aggressive treatment of opioid withdrawal in the hospital can promote treatment engagement and prevent premature discharges. Clinicians should assess for other withdrawal syndromes when a patient has multiple SUDs and collaborate with an interdisciplinary team to improve patient outcomes.

Bottom Line

The prevalence of opioid use disorder (OUD) in patients who are pregnant is increasing. Methadone is an option for treating perinatal OUD, but the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Using divided doses of methadone can ensure the comfort and safety of the patient and their baby and improve adherence and outcomes.

Related Resources

• Chaney L, Mathia C, Cole T. Transitioning patients with opioid use disorder from methadone to buprenorphine. Current Psychiatry. 2022;21(12):23-24,28. doi:10.12788/cp.0305
• Townsel C, Irani S, Buis C, et al. Partnering for the future clinic: a multidisciplinary perinatal substance use program. Gen Hosp Psychiatry. 2023;85:220-228. doi:10.1016/j. genhosppsych.2023.10.009

Drug Brand Names

Buprenorphine • Buprenex, Suboxone, Zubsolv, Sublocade
Fentanyl • Abstral, Actiq
Fluoxetine • Prozac
Lorazepam • Ativan
Methadone • Methadose, Dolophine
Oxycodone • Oxycontin

In the United States, opioid use by patients who are pregnant more than quadrupled from 1999 to 2014.¹ Opioid use disorder (OUD) in the perinatal period is associated with a higher risk for depression, suicide, malnutrition, domestic violence, and obstetric complications such as spontaneous abortion, preeclampsia, and premature delivery.² Buprenorphine and methadone are the standard of care for treating OUD in pregnancy.^3,4 While a literature review found that maternal treatment with buprenorphine has comparable efficacy to treatment with methadone,⁵ a small randomized, double-blind study found that compared to buprenorphine, methadone was associated with significantly lower use of additional opioids (P = .047).⁶ This suggests methadone has therapeutic value for patients who are pregnant.

Despite the benefits of methadone for treating perinatal OUD, the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Patients typically take methadone once a day, and the dose is titrated every 3 to 5 days to allow serum levels to reach steady state.⁷ During pregnancy, there are increases in both the volume of distribution and medication metabolism secondary to increased expression of the cytochrome P450 3A4 enzyme by the liver, intestine, and placenta.⁸ Additionally, as the pregnancy progresses, the rate of methadone metabolism increases.⁹ Methadone’s half-life (20 to 35 hours) leads to its accumulation in tissue and slow release into the blood.¹⁰ As a result, patients with OUD who are pregnant often require higher doses of methadone or divided dosing, particularly in the second and third trimesters.¹¹

In this article, we provide a strategy for divided dosing of methadone for managing opioid withdrawal symptoms in the acute care setting. We present 2 cases of women with OUD who are pregnant and describe the collaboration of addiction medicine, consultation-liaison psychiatry, and obstetrics services.

CASE 1

Ms. H, age 29, is G3P2 and presents to the emergency department (ED) during her fourth pregnancy at 31 weeks, 1 day gestation. She has a history of opioid, cocaine, and benzodiazepine use disorders and chronic hepatitis C. Ms. H is enrolled in an opioid treatment program and takes methadone 190 mg/d in addition to nonprescribed opioids. In the ED, Ms. H requests medically supervised withdrawal management. Her urine toxicology is positive for cocaine, benzodiazepines, methadone, and opiates. Her laboratory results and electrocardiogram (ECG) are unremarkable. On admission, Ms. H’s Clinical Opiate Withdrawal Scale (COWS) score is 3, indicating minimal symptoms (5 to 12: mild; 13 to 24: moderate; 25 to 36: moderately severe; >36: severe). Fetal monitoring is reassuring.

Ms. H’s withdrawal is monitored with COWS every 4 hours. The treatment team initiates methadone 170 mg/d, with an additional 10 mg/d as needed to keep her COWS score <8, and daily QTc monitoring. Ms. H also receives lorazepam 2 to 4 mg/d as needed for benzodiazepine withdrawal. Despite the increase in her daily methadone dose, Ms. H continues to experience opioid withdrawal in the early evening and overnight. As a result, the treatment team increases Ms. H’s morning methadone dose to 190 mg and schedules an afternoon dose of 30 mg. Despite this adjustment, her COWS scores remain elevated in the afternoon and evening, and she requires additional as-needed doses of methadone. Methadone peak and trough levels are ordered to assess for rapid metabolism. The serum trough level is 190 ng/mL, which is low, and a serum peak level is not reported. Despite titration, Ms. H has a self-directed premature discharge.

Five days later at 32 weeks, 2 days gestation, Ms. H is readmitted after she had resumed use of opioids, benzodiazepines, and cocaine. Her vital signs are stable, and her laboratory results and ECG are unremarkable. Fetal monitoring is reassuring. Given Ms. H’s low methadone serum trough level and overall concern for rapid methadone metabolism, the treatment team decides to divide dosing of methadone. Over 9 days, the team titrates methadone to 170 mg twice daily on the day of discharge, which resolves Ms. H’s withdrawal symptoms.

At 38 weeks, 5 days gestation, Ms. H returns to the ED after experiencing labor contractions and opiate withdrawal symptoms after she resumed use of heroin, cocaine, and benzodiazepines. During this admission, Ms. H’s methadone is increased to 180 mg twice daily with additional as-needed doses for ongoing withdrawal symptoms. At 39 weeks, 2 days gestation, Ms. H has a scheduled cesarean delivery.

Her infant has a normal weight but is transferred to the neonatal intensive care unit (NICU) for management of neonatal opioid withdrawal syndrome (NOWS) and receives morphine. The baby remains in the NICU for 35 days and is discharged home without further treatment. When Ms. H is discharged, her methadone dose is 170 mg twice daily, which resolves her opioid withdrawal symptoms. The treatment team directs her to continue care in her methadone outpatient program and receive treatment for her cocaine and benzodiazepine use disorders. She declines residential or inpatient substance use treatment.

Continue to: CASE 2

Ms. M, age 39, is G4P2 and presents to the hospital during her fifth pregnancy at 27 weeks gestation. She has not received prenatal care for this pregnancy. She has a history of OUD and major depressive disorder (MDD). Ms. M’s urine toxicology is positive for opiates, fentanyl, and oxycodone. Her laboratory results are notable for mildly elevated alanine aminotransferase, positive hepatitis C antibody, and a hepatitis C viral load of 91,000, consistent with chronic hepatitis C infection. On admission, her COWS score is 14, indicating moderate withdrawal symptoms. Her ECG is unremarkable, and fetal monitoring is reassuring.

Ms. M had received methadone during a prior pregnancy and opts to reinitiate treatment with methadone during her current admission. The team initiates methadone 20 mg/d with additional as-needed doses for ongoing withdrawal symptoms. Due to a persistently elevated COWS score, Ms. M’s methadone is increased to 90 mg/d, which resolves her withdrawal symptoms. However, on Day 4, Ms. M reports having anxiety, refuses bloodwork to obtain methadone peak and trough levels, and prematurely discharges from the hospital.

One day later at 27 weeks, 5 days gestation, Ms. M is readmitted for continued management of opioid withdrawal. She presents with stable vital signs, an unremarkable ECG, and reassuring fetal monitoring. Her COWS score is 5. The treatment team reinitiates methadone at 80 mg/d and titrates it to 100 mg/d on Day 7. Given Ms. M’s ongoing evening cravings and concern for rapid methadone metabolism, on Day 10 the team switches the methadone dosing to 50 mg twice daily to maintain steady-state levels and promote patient comfort. Fluoxetine 20 mg/d is started for comorbid MDD and eventually increased to 80 mg/d. Ms. M is discharged on Day 15 with a regimen of methadone 60 mg/d in the morning and 70 mg/d at night. She plans to resume care in an opioid treatment program and follow up with psychiatry and hepatology for her anxiety and hepatitis C.

A need for aggressive treatment

Given the rising rates of opioid use by patients who are pregnant, harmful behavior related to opioid use, and a wealth of evidence supporting opioid agonist treatment for OUD in pregnancy, there is a growing need for guidance in managing perinatal OUD. A systematic approach to using methadone to treat OUD in patients who are pregnant is essential; the lack of data surrounding use of this medication in such patients may cause overall harm.¹² Limited guidelines and a lack of familiarity with prescribing methadone to patients who are pregnant may lead clinicians to underdose patients, which can result in ongoing withdrawal, premature patient-directed discharges, and poor engagement in care.¹³ Both patients in the 2 cases described in this article experienced ongoing withdrawal symptoms despite daily titration of methadone. This suggests rapid metabolism, which was successfully managed by dividing the dosing of methadone, particularly in the latter trimesters.

These cases illustrate the need for aggressive perinatal opioid withdrawal management through rapid escalation of divided doses of methadone in a monitored acute care setting. Because methadone elimination is more rapid and clearance rates increase during the perinatal period, divided methadone dosing allows for sustained plasma methadone concentrations and improved outpatient treatment adherence.^9,14,15

Continue to: Decreasing the rate of premature discharges

Decreasing the rate of premature discharges

In both cases, the patients discharged from the hospital prematurely, likely related to incomplete management of their opioid withdrawal or other withdrawal syndromes (both patients had multiple substance use disorders [SUDs]). Compared to patients without an SUD, patients with SUDs are 3 times more likely to have a self-directed discharge.¹⁶ Patients report leaving the hospital prematurely due to undertreated withdrawal, uncontrolled pain, discrimination by staff, and hospital restrictions.¹⁶ Recommendations to decrease the rates of premature patient-directed discharges in this population include providing patient-centered and harm reduction–oriented care in addition to adequate management of pain and withdrawal.¹⁷

Impact of methadone on fetal outcomes

Approximately 55% to 94% of infants born to patients who are opioid-dependent will develop NOWS. However, there is no relationship between this syndrome and therapeutic doses of methadone.¹⁸ Moreover, long-term research has found that after adjusting for socioeconomic factors, methadone treatment during pregnancy does not have an adverse effect on postnatal development. Divided dosing in maternal methadone administration is also shown to have less of an impact on fetal neurobehavior and NOWS.¹⁹

Our recommendations for methadone treatment for perinatal patients are outlined in the Table. Aggressive treatment of opioid withdrawal in the hospital can promote treatment engagement and prevent premature discharges. Clinicians should assess for other withdrawal syndromes when a patient has multiple SUDs and collaborate with an interdisciplinary team to improve patient outcomes.

Bottom Line

The prevalence of opioid use disorder (OUD) in patients who are pregnant is increasing. Methadone is an option for treating perinatal OUD, but the physiological changes that occur in patients who are pregnant—coupled with methadone’s unique pharmacologic properties—may complicate its use. Using divided doses of methadone can ensure the comfort and safety of the patient and their baby and improve adherence and outcomes.

Related Resources

• Chaney L, Mathia C, Cole T. Transitioning patients with opioid use disorder from methadone to buprenorphine. Current Psychiatry. 2022;21(12):23-24,28. doi:10.12788/cp.0305
• Townsel C, Irani S, Buis C, et al. Partnering for the future clinic: a multidisciplinary perinatal substance use program. Gen Hosp Psychiatry. 2023;85:220-228. doi:10.1016/j. genhosppsych.2023.10.009

Drug Brand Names

Buprenorphine • Buprenex, Suboxone, Zubsolv, Sublocade
Fentanyl • Abstral, Actiq
Fluoxetine • Prozac
Lorazepam • Ativan
Methadone • Methadose, Dolophine
Oxycodone • Oxycontin

Our psychiatric research, which found a high incidence of undiagnosed mental illness in mass shooters, was recently awarded the esteemed Psychodynamic Psychiatry Journal Prize for best paper published in the last 2 years (2022-2023). The editors noted our integrity in using quantitative data to argue against the common, careless assumption that mass shooters are not mentally ill.

Some of the mass shooters we studied were motivated by religious or political ideologies that were considered forms of terrorism. Given the current tragically violent landscape both at home and in Israel/Palestine, the “desire for destruction” is vital to understand.

Although there have been a limited number of psychiatric studies of perpetrators of mass shootings, our team took the first step to lay the groundwork by conducting a systematic, quantitative study. Our psychiatric research team’s research findings were published in the Journal of Clinical Psychopharmacology and then in greater detail in Psychodynamic Psychiatry,^1,2 which provided important context to the complicated backgrounds of these mass shooters who suffer from abuse, marginalization, and severe undiagnosed brain illness.³

Dr. Cerfolio

The Mother Jones database of 115 mass shootings from 1982 to 2019 was used to study retrospectively 55 shooters in the United States. We developed a uniform, comprehensive, 62-item questionnaire to compile the data collection from multiple sources and record our psychiatric assessments of the assailants, using DSM-5 criteria. After developing this detailed psychiatric assessment questionnaire, psychiatric researchers evaluated the weight and quality of clinical evidence by (1) interviewing forensic psychiatrists who had assessed the assailant following the crime, and/or (2) reviewing court records of psychiatric evaluations conducted during the postcrime judicial proceedings to determine the prevalence of psychiatric illness. Rather than accepting diagnoses from forensic psychiatrists and/or court records, our team independently reviewed the clinical data gathered from multiple sources to apply the DSM-5 criteria to diagnose mental illness.

In most incidents in the database, the perpetrator died either during or shortly after the crime. We examined every case (n=35) in which the assailant survived, and criminal proceedings were instituted.

Of the 35 cases in which the assailant survived and criminal proceedings were instituted, there was insufficient information to make a diagnosis in 3 cases. Of the remaining 32 cases in which we had sufficient information, we determined that 87.5% had the following psychiatric diagnosis: 18 assailants (56%) had schizophrenia, while 10 assailants (31%) had other psychiatric diagnoses: 3 had bipolar I disorder, 2 had delusional disorders (persecutory), 2 had personality disorders (1 paranoid, 1 borderline), 2 had substance-related disorders without other psychiatric diagnosis, and 1 had post-traumatic stress disorder (PTSD).

Out of the 32 surviving assailants for whom we have sufficient evidence, 87.5% of perpetrators of mass shootings were diagnosed with major psychiatric illness, and none were treated appropriately with medication at the time of the crime. Four assailants (12.5%) had no psychiatric diagnosis that we could discern. Of the 18 surviving assailants with schizophrenia, no assailant was on antipsychotic medication for the treatment of schizophrenia prior to the crime. Of the 10 surviving assailants with other psychiatric illnesses, no assailant was on antipsychotic and/or appropriate medication.

In addition, we found that the clinical misdiagnosis of early-onset schizophrenia was associated with the worsening of many of these assailants’ psychotic symptoms. Many of our adolescent shooters prior to the massacre had been misdiagnosed with attention-deficit disorder (ADD), major depression disorder (MDD), or autism spectrum disorder.

Though the vast majority of those suffering from psychiatric illnesses who are appropriately treated are not violent, there is a growing body of scientific research that indicates a strong association of untreated brain illness with those who commit mass shootings.^4,5,6 This research demonstrates that such untreated illness combined with access to firearms poses a lethal threat to society.

Stanford University

Most of the assailants also experienced profound estrangement, not only from families and friends, but most importantly from themselves. Being marginalized rendered them more vulnerable to their untreated psychiatric illness and to radicalization online, which fostered their violence. While there are complex reasons that a person is not diagnosed, there remains a vital need to decrease the stigma of mental illness to enable those with psychiatric illness to be more respected, less marginalized, and encouraged to receive effective psychiatric treatments.

Dr. Cerfolio is author of “Psychoanalytic and Spiritual Perspectives on Terrorism: Desire for Destruction.” She is clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Dr. Glick is Professor Emeritus, Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, Calif.

References

1. Glick ID, et al. Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):366-369. doi: 10.1097/JCP.0000000000001417.

2. Cerfolio NE, et al. A Retrospective Observational Study of Psychosocial Determinants and Psychiatric Diagnoses of Mass Shooters in the United States. Psychodyn Psychiatry. 2022 Fall;50(3):1-16. doi: 10.1521/pdps.2022.50.5.001.

3. Cerfolio NE. The Parkland gunman, a horrific crime, and mental illness. The New York Times. 2022 Oct 14. www.nytimes.com/2022/10/14/opinion/letters/jan-6-panel-trump.html#link-5e2ccc1.

4. Corner E, et al. Mental Health Disorders and the Terrorist: A Research Note Probing Selection Effects and Disorder Prevalence. Stud Confl Terror. 2016 Jan;39(6):560–568. doi: 10.1080/1057610X.2015.1120099.

5. Gruenewald J, et al. Distinguishing “Loner” Attacks from Other Domestic Extremist Violence. Criminol Public Policy. 2013 Feb;12(1):65–91. doi: 10.1111/1745-9133.12008.

6. Lankford A. Detecting mental health problems and suicidal motives among terrorists and mass shooters. Crim Behav Ment Health. 2016 Dec;26(5):315-321. doi: 10.1002/cbm.2020.

Our psychiatric research, which found a high incidence of undiagnosed mental illness in mass shooters, was recently awarded the esteemed Psychodynamic Psychiatry Journal Prize for best paper published in the last 2 years (2022-2023). The editors noted our integrity in using quantitative data to argue against the common, careless assumption that mass shooters are not mentally ill.

Some of the mass shooters we studied were motivated by religious or political ideologies that were considered forms of terrorism. Given the current tragically violent landscape both at home and in Israel/Palestine, the “desire for destruction” is vital to understand.

Although there have been a limited number of psychiatric studies of perpetrators of mass shootings, our team took the first step to lay the groundwork by conducting a systematic, quantitative study. Our psychiatric research team’s research findings were published in the Journal of Clinical Psychopharmacology and then in greater detail in Psychodynamic Psychiatry,^1,2 which provided important context to the complicated backgrounds of these mass shooters who suffer from abuse, marginalization, and severe undiagnosed brain illness.³

Dr. Cerfolio

The Mother Jones database of 115 mass shootings from 1982 to 2019 was used to study retrospectively 55 shooters in the United States. We developed a uniform, comprehensive, 62-item questionnaire to compile the data collection from multiple sources and record our psychiatric assessments of the assailants, using DSM-5 criteria. After developing this detailed psychiatric assessment questionnaire, psychiatric researchers evaluated the weight and quality of clinical evidence by (1) interviewing forensic psychiatrists who had assessed the assailant following the crime, and/or (2) reviewing court records of psychiatric evaluations conducted during the postcrime judicial proceedings to determine the prevalence of psychiatric illness. Rather than accepting diagnoses from forensic psychiatrists and/or court records, our team independently reviewed the clinical data gathered from multiple sources to apply the DSM-5 criteria to diagnose mental illness.

In most incidents in the database, the perpetrator died either during or shortly after the crime. We examined every case (n=35) in which the assailant survived, and criminal proceedings were instituted.

Of the 35 cases in which the assailant survived and criminal proceedings were instituted, there was insufficient information to make a diagnosis in 3 cases. Of the remaining 32 cases in which we had sufficient information, we determined that 87.5% had the following psychiatric diagnosis: 18 assailants (56%) had schizophrenia, while 10 assailants (31%) had other psychiatric diagnoses: 3 had bipolar I disorder, 2 had delusional disorders (persecutory), 2 had personality disorders (1 paranoid, 1 borderline), 2 had substance-related disorders without other psychiatric diagnosis, and 1 had post-traumatic stress disorder (PTSD).

Out of the 32 surviving assailants for whom we have sufficient evidence, 87.5% of perpetrators of mass shootings were diagnosed with major psychiatric illness, and none were treated appropriately with medication at the time of the crime. Four assailants (12.5%) had no psychiatric diagnosis that we could discern. Of the 18 surviving assailants with schizophrenia, no assailant was on antipsychotic medication for the treatment of schizophrenia prior to the crime. Of the 10 surviving assailants with other psychiatric illnesses, no assailant was on antipsychotic and/or appropriate medication.

In addition, we found that the clinical misdiagnosis of early-onset schizophrenia was associated with the worsening of many of these assailants’ psychotic symptoms. Many of our adolescent shooters prior to the massacre had been misdiagnosed with attention-deficit disorder (ADD), major depression disorder (MDD), or autism spectrum disorder.

Though the vast majority of those suffering from psychiatric illnesses who are appropriately treated are not violent, there is a growing body of scientific research that indicates a strong association of untreated brain illness with those who commit mass shootings.^4,5,6 This research demonstrates that such untreated illness combined with access to firearms poses a lethal threat to society.

Stanford University

Most of the assailants also experienced profound estrangement, not only from families and friends, but most importantly from themselves. Being marginalized rendered them more vulnerable to their untreated psychiatric illness and to radicalization online, which fostered their violence. While there are complex reasons that a person is not diagnosed, there remains a vital need to decrease the stigma of mental illness to enable those with psychiatric illness to be more respected, less marginalized, and encouraged to receive effective psychiatric treatments.

Dr. Cerfolio is author of “Psychoanalytic and Spiritual Perspectives on Terrorism: Desire for Destruction.” She is clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Dr. Glick is Professor Emeritus, Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, Calif.

References

1. Glick ID, et al. Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):366-369. doi: 10.1097/JCP.0000000000001417.

2. Cerfolio NE, et al. A Retrospective Observational Study of Psychosocial Determinants and Psychiatric Diagnoses of Mass Shooters in the United States. Psychodyn Psychiatry. 2022 Fall;50(3):1-16. doi: 10.1521/pdps.2022.50.5.001.

3. Cerfolio NE. The Parkland gunman, a horrific crime, and mental illness. The New York Times. 2022 Oct 14. www.nytimes.com/2022/10/14/opinion/letters/jan-6-panel-trump.html#link-5e2ccc1.

4. Corner E, et al. Mental Health Disorders and the Terrorist: A Research Note Probing Selection Effects and Disorder Prevalence. Stud Confl Terror. 2016 Jan;39(6):560–568. doi: 10.1080/1057610X.2015.1120099.

5. Gruenewald J, et al. Distinguishing “Loner” Attacks from Other Domestic Extremist Violence. Criminol Public Policy. 2013 Feb;12(1):65–91. doi: 10.1111/1745-9133.12008.

6. Lankford A. Detecting mental health problems and suicidal motives among terrorists and mass shooters. Crim Behav Ment Health. 2016 Dec;26(5):315-321. doi: 10.1002/cbm.2020.

Our psychiatric research, which found a high incidence of undiagnosed mental illness in mass shooters, was recently awarded the esteemed Psychodynamic Psychiatry Journal Prize for best paper published in the last 2 years (2022-2023). The editors noted our integrity in using quantitative data to argue against the common, careless assumption that mass shooters are not mentally ill.

Some of the mass shooters we studied were motivated by religious or political ideologies that were considered forms of terrorism. Given the current tragically violent landscape both at home and in Israel/Palestine, the “desire for destruction” is vital to understand.

Although there have been a limited number of psychiatric studies of perpetrators of mass shootings, our team took the first step to lay the groundwork by conducting a systematic, quantitative study. Our psychiatric research team’s research findings were published in the Journal of Clinical Psychopharmacology and then in greater detail in Psychodynamic Psychiatry,^1,2 which provided important context to the complicated backgrounds of these mass shooters who suffer from abuse, marginalization, and severe undiagnosed brain illness.³

Dr. Cerfolio

The Mother Jones database of 115 mass shootings from 1982 to 2019 was used to study retrospectively 55 shooters in the United States. We developed a uniform, comprehensive, 62-item questionnaire to compile the data collection from multiple sources and record our psychiatric assessments of the assailants, using DSM-5 criteria. After developing this detailed psychiatric assessment questionnaire, psychiatric researchers evaluated the weight and quality of clinical evidence by (1) interviewing forensic psychiatrists who had assessed the assailant following the crime, and/or (2) reviewing court records of psychiatric evaluations conducted during the postcrime judicial proceedings to determine the prevalence of psychiatric illness. Rather than accepting diagnoses from forensic psychiatrists and/or court records, our team independently reviewed the clinical data gathered from multiple sources to apply the DSM-5 criteria to diagnose mental illness.

In most incidents in the database, the perpetrator died either during or shortly after the crime. We examined every case (n=35) in which the assailant survived, and criminal proceedings were instituted.

Of the 35 cases in which the assailant survived and criminal proceedings were instituted, there was insufficient information to make a diagnosis in 3 cases. Of the remaining 32 cases in which we had sufficient information, we determined that 87.5% had the following psychiatric diagnosis: 18 assailants (56%) had schizophrenia, while 10 assailants (31%) had other psychiatric diagnoses: 3 had bipolar I disorder, 2 had delusional disorders (persecutory), 2 had personality disorders (1 paranoid, 1 borderline), 2 had substance-related disorders without other psychiatric diagnosis, and 1 had post-traumatic stress disorder (PTSD).

Out of the 32 surviving assailants for whom we have sufficient evidence, 87.5% of perpetrators of mass shootings were diagnosed with major psychiatric illness, and none were treated appropriately with medication at the time of the crime. Four assailants (12.5%) had no psychiatric diagnosis that we could discern. Of the 18 surviving assailants with schizophrenia, no assailant was on antipsychotic medication for the treatment of schizophrenia prior to the crime. Of the 10 surviving assailants with other psychiatric illnesses, no assailant was on antipsychotic and/or appropriate medication.

In addition, we found that the clinical misdiagnosis of early-onset schizophrenia was associated with the worsening of many of these assailants’ psychotic symptoms. Many of our adolescent shooters prior to the massacre had been misdiagnosed with attention-deficit disorder (ADD), major depression disorder (MDD), or autism spectrum disorder.

Though the vast majority of those suffering from psychiatric illnesses who are appropriately treated are not violent, there is a growing body of scientific research that indicates a strong association of untreated brain illness with those who commit mass shootings.^4,5,6 This research demonstrates that such untreated illness combined with access to firearms poses a lethal threat to society.

Stanford University

Most of the assailants also experienced profound estrangement, not only from families and friends, but most importantly from themselves. Being marginalized rendered them more vulnerable to their untreated psychiatric illness and to radicalization online, which fostered their violence. While there are complex reasons that a person is not diagnosed, there remains a vital need to decrease the stigma of mental illness to enable those with psychiatric illness to be more respected, less marginalized, and encouraged to receive effective psychiatric treatments.

Dr. Cerfolio is author of “Psychoanalytic and Spiritual Perspectives on Terrorism: Desire for Destruction.” She is clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Dr. Glick is Professor Emeritus, Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, Calif.

References

1. Glick ID, et al. Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):366-369. doi: 10.1097/JCP.0000000000001417.

2. Cerfolio NE, et al. A Retrospective Observational Study of Psychosocial Determinants and Psychiatric Diagnoses of Mass Shooters in the United States. Psychodyn Psychiatry. 2022 Fall;50(3):1-16. doi: 10.1521/pdps.2022.50.5.001.

3. Cerfolio NE. The Parkland gunman, a horrific crime, and mental illness. The New York Times. 2022 Oct 14. www.nytimes.com/2022/10/14/opinion/letters/jan-6-panel-trump.html#link-5e2ccc1.

4. Corner E, et al. Mental Health Disorders and the Terrorist: A Research Note Probing Selection Effects and Disorder Prevalence. Stud Confl Terror. 2016 Jan;39(6):560–568. doi: 10.1080/1057610X.2015.1120099.

5. Gruenewald J, et al. Distinguishing “Loner” Attacks from Other Domestic Extremist Violence. Criminol Public Policy. 2013 Feb;12(1):65–91. doi: 10.1111/1745-9133.12008.

6. Lankford A. Detecting mental health problems and suicidal motives among terrorists and mass shooters. Crim Behav Ment Health. 2016 Dec;26(5):315-321. doi: 10.1002/cbm.2020.

TOPLINE:

Salivary microbiota changes caused by cigarette smoking may affect metabolic pathways and increase disease risk.

METHODOLOGY:

The researchers analyzed health information and data on the composition of salivary microbiota from 1601 adult participants in the Cooperative Health Research in South Tyrol (CHRIS) microbiome study (CHRISMB); CHRIS is an ongoing study in Italy.

The average age of the study population was 45 years; 53% were female, and 45% were current or former smokers.

The researchers hypothesized that changes in salivary microbial composition would be associated with smoking, with more nitrate-reducing bacteria present, and that nitrate reduction pathways would be reduced in smokers.

TAKEAWAY:

The researchers identified 44 genera that differed in the salivary microbiota of current smokers and nonsmokers. In smokers, seven genera in the phylum Proteobacteria were decreased and six in the phylum Actinobacteria were increased compared with nonsmokers; these phyla contain primarily aerobic and anaerobic taxa, respectively.

Some microbiota changes were significantly associated with daily smoking intensity; genera from the classes Betaproteobacteria (Lautropia or Neisseria), Gammaproteobacteria (Cardiobacterium), and Flavobacteriia (Capnocytophaga) decreased significantly with increased grams of tobacco smoked per day, measured in 5-g increments.

Smoking was associated with changes in the salivary microbiota; the nitrate reduction pathway was significantly lower in smokers compared with nonsmokers, and these decreases were consistent with previous studies of decreased cardiovascular events in former smokers.

However, the salivary microbiota of smokers who had quit for at least 5 years resembled that of individuals who had never smoked.

IN PRACTICE:

“Decreased microbial nitrate reduction pathway abundance in smokers may provide an additional explanation for the effect of smoking on cardiovascular and periodontal diseases risk, a hypothesis which should be tested in future studies,” the researchers wrote.

SOURCE:

The lead author of the study was Giacomo Antonello, MD, of Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. The study was published online in Scientific Reports (a Nature journal) on November 2, 2023.

LIMITATIONS:

The cross-sectional design and lack of professional assessment of tooth and gum health were limiting factors, as were potential confounding factors including medication use, diet, and alcohol intake.

DISCLOSURES:

The study was supported by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and by the European Regional Development Fund. The CHRISMB microbiota data generation was funded by the National Institute of Dental and Craniofacial Research. The researchers had no financial conflicts to disclose.

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

TOPLINE:

Salivary microbiota changes caused by cigarette smoking may affect metabolic pathways and increase disease risk.

METHODOLOGY:

The researchers analyzed health information and data on the composition of salivary microbiota from 1601 adult participants in the Cooperative Health Research in South Tyrol (CHRIS) microbiome study (CHRISMB); CHRIS is an ongoing study in Italy.

The average age of the study population was 45 years; 53% were female, and 45% were current or former smokers.

The researchers hypothesized that changes in salivary microbial composition would be associated with smoking, with more nitrate-reducing bacteria present, and that nitrate reduction pathways would be reduced in smokers.

TAKEAWAY:

The researchers identified 44 genera that differed in the salivary microbiota of current smokers and nonsmokers. In smokers, seven genera in the phylum Proteobacteria were decreased and six in the phylum Actinobacteria were increased compared with nonsmokers; these phyla contain primarily aerobic and anaerobic taxa, respectively.

Some microbiota changes were significantly associated with daily smoking intensity; genera from the classes Betaproteobacteria (Lautropia or Neisseria), Gammaproteobacteria (Cardiobacterium), and Flavobacteriia (Capnocytophaga) decreased significantly with increased grams of tobacco smoked per day, measured in 5-g increments.

Smoking was associated with changes in the salivary microbiota; the nitrate reduction pathway was significantly lower in smokers compared with nonsmokers, and these decreases were consistent with previous studies of decreased cardiovascular events in former smokers.

However, the salivary microbiota of smokers who had quit for at least 5 years resembled that of individuals who had never smoked.

IN PRACTICE:

“Decreased microbial nitrate reduction pathway abundance in smokers may provide an additional explanation for the effect of smoking on cardiovascular and periodontal diseases risk, a hypothesis which should be tested in future studies,” the researchers wrote.

SOURCE:

The lead author of the study was Giacomo Antonello, MD, of Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. The study was published online in Scientific Reports (a Nature journal) on November 2, 2023.

LIMITATIONS:

The cross-sectional design and lack of professional assessment of tooth and gum health were limiting factors, as were potential confounding factors including medication use, diet, and alcohol intake.

DISCLOSURES:

The study was supported by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and by the European Regional Development Fund. The CHRISMB microbiota data generation was funded by the National Institute of Dental and Craniofacial Research. The researchers had no financial conflicts to disclose.

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

TOPLINE:

Salivary microbiota changes caused by cigarette smoking may affect metabolic pathways and increase disease risk.

METHODOLOGY:

The researchers analyzed health information and data on the composition of salivary microbiota from 1601 adult participants in the Cooperative Health Research in South Tyrol (CHRIS) microbiome study (CHRISMB); CHRIS is an ongoing study in Italy.

The average age of the study population was 45 years; 53% were female, and 45% were current or former smokers.

The researchers hypothesized that changes in salivary microbial composition would be associated with smoking, with more nitrate-reducing bacteria present, and that nitrate reduction pathways would be reduced in smokers.

TAKEAWAY:

The researchers identified 44 genera that differed in the salivary microbiota of current smokers and nonsmokers. In smokers, seven genera in the phylum Proteobacteria were decreased and six in the phylum Actinobacteria were increased compared with nonsmokers; these phyla contain primarily aerobic and anaerobic taxa, respectively.

Some microbiota changes were significantly associated with daily smoking intensity; genera from the classes Betaproteobacteria (Lautropia or Neisseria), Gammaproteobacteria (Cardiobacterium), and Flavobacteriia (Capnocytophaga) decreased significantly with increased grams of tobacco smoked per day, measured in 5-g increments.

Smoking was associated with changes in the salivary microbiota; the nitrate reduction pathway was significantly lower in smokers compared with nonsmokers, and these decreases were consistent with previous studies of decreased cardiovascular events in former smokers.

However, the salivary microbiota of smokers who had quit for at least 5 years resembled that of individuals who had never smoked.

IN PRACTICE:

“Decreased microbial nitrate reduction pathway abundance in smokers may provide an additional explanation for the effect of smoking on cardiovascular and periodontal diseases risk, a hypothesis which should be tested in future studies,” the researchers wrote.

SOURCE:

The lead author of the study was Giacomo Antonello, MD, of Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. The study was published online in Scientific Reports (a Nature journal) on November 2, 2023.

LIMITATIONS:

The cross-sectional design and lack of professional assessment of tooth and gum health were limiting factors, as were potential confounding factors including medication use, diet, and alcohol intake.

DISCLOSURES:

The study was supported by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and by the European Regional Development Fund. The CHRISMB microbiota data generation was funded by the National Institute of Dental and Craniofacial Research. The researchers had no financial conflicts to disclose.

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

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style.

Working closely with individuals with substance use disorders (SUDs), we’ve observed a worrisome trend of patients leaving the hospital against medical advice (AMA). This issue is not only prevalent in psychiatric settings, but also in emergency departments, medical and surgical floors, and even intensive care units.¹

Compared to individuals without such disorders, individuals with SUDs—particularly those with opioid use disorders—are up to 3 times more likely to leave the hospital AMA.^1,2 Leaving AMA can lead to multiple complications, including an increased risk of readmission, suboptimal treatment outcomes, and an increased use of health care resources.^1-3

It is critical to understand why patients elect to leave a hospital AMA. In a qualitative study, Simon et al¹ found that individuals with SUDs often leave AMA due to uncontrolled withdrawal symptoms and pain, perceived stigma and discrimination, and dissatisfaction with care. Predictors of patients leaving the hospital AMA include the severity of their drug dependence and previous negative treatment experiences.⁴ A systematic review found housing instability and a lack of social support influence an individual’s decision to leave AMA.⁵

Recommendations for managing patients who leave AMA

Enhancing your understanding of withdrawal symptoms may allow you to offer patients more effective symptom control, possibly with methadone or buprenorphine.² Injectable opioid agonist treatment may also help to retain a patient in care. In a case report, a 47-year-old man with a severe opioid use disorder who had left the hospital AMA due to uncontrolled opioid withdrawal was readmitted, treated with IV hydromorphone, and enrolled in ongoing community injectable opioid agonist treatment.⁶

Clinicians must address the stigma and discrimination patients with SUDs often face in health care institutions. Additional training for clinicians to improve their understanding of these disorders and foster a more compassionate and nonjudgmental approach to care may be beneficial.

Like most medicolegal conflicts, leaving AMA is often a clinical and interpersonal problem disguised as a legal one. When assessing these patients’ decision-making capacity, we often find they are angry and dissatisfied with the care they have (or have not) received. The most useful intervention may be to restore communication between the patient and their treatment team.

Even after a patient leaves AMA, the treatment team may experience countertransference issues, such as heightened emotional reactions or biases, that could compromise their clinical judgment. Addressing these dynamics may require team debriefings, supervision, or further training in managing transference and countertransference, particularly since patients who leave AMA may return for subsequent care.⁷

Integrated care models, which feature close collaboration between clinicians from different specialties, can help ensure that a patient’s diverse health needs are met and reduce the likelihood of them leaving AMA. Integrated care models may be particularly effective for patients with co-occurring conditions such as HIV and SUDs.⁸

Implementing these recommendations can be challenging. Barriers to addressing AMA departures span several domains, including patient-specific barriers (eg, stigma and discrimination), clinical barriers (eg, lack of resources and training for clinicians), institutional hurdles (eg, systemic inefficiencies), and broader social barriers (eg, housing instability and inadequate social support). Overcoming these barriers requires a multifaceted approach involving clinicians, policymakers, and the community that considers medical, psychological, and social factors.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style.

Working closely with individuals with substance use disorders (SUDs), we’ve observed a worrisome trend of patients leaving the hospital against medical advice (AMA). This issue is not only prevalent in psychiatric settings, but also in emergency departments, medical and surgical floors, and even intensive care units.¹

Compared to individuals without such disorders, individuals with SUDs—particularly those with opioid use disorders—are up to 3 times more likely to leave the hospital AMA.^1,2 Leaving AMA can lead to multiple complications, including an increased risk of readmission, suboptimal treatment outcomes, and an increased use of health care resources.^1-3

It is critical to understand why patients elect to leave a hospital AMA. In a qualitative study, Simon et al¹ found that individuals with SUDs often leave AMA due to uncontrolled withdrawal symptoms and pain, perceived stigma and discrimination, and dissatisfaction with care. Predictors of patients leaving the hospital AMA include the severity of their drug dependence and previous negative treatment experiences.⁴ A systematic review found housing instability and a lack of social support influence an individual’s decision to leave AMA.⁵

Recommendations for managing patients who leave AMA

Enhancing your understanding of withdrawal symptoms may allow you to offer patients more effective symptom control, possibly with methadone or buprenorphine.² Injectable opioid agonist treatment may also help to retain a patient in care. In a case report, a 47-year-old man with a severe opioid use disorder who had left the hospital AMA due to uncontrolled opioid withdrawal was readmitted, treated with IV hydromorphone, and enrolled in ongoing community injectable opioid agonist treatment.⁶

Clinicians must address the stigma and discrimination patients with SUDs often face in health care institutions. Additional training for clinicians to improve their understanding of these disorders and foster a more compassionate and nonjudgmental approach to care may be beneficial.

Like most medicolegal conflicts, leaving AMA is often a clinical and interpersonal problem disguised as a legal one. When assessing these patients’ decision-making capacity, we often find they are angry and dissatisfied with the care they have (or have not) received. The most useful intervention may be to restore communication between the patient and their treatment team.

Even after a patient leaves AMA, the treatment team may experience countertransference issues, such as heightened emotional reactions or biases, that could compromise their clinical judgment. Addressing these dynamics may require team debriefings, supervision, or further training in managing transference and countertransference, particularly since patients who leave AMA may return for subsequent care.⁷

Integrated care models, which feature close collaboration between clinicians from different specialties, can help ensure that a patient’s diverse health needs are met and reduce the likelihood of them leaving AMA. Integrated care models may be particularly effective for patients with co-occurring conditions such as HIV and SUDs.⁸

Implementing these recommendations can be challenging. Barriers to addressing AMA departures span several domains, including patient-specific barriers (eg, stigma and discrimination), clinical barriers (eg, lack of resources and training for clinicians), institutional hurdles (eg, systemic inefficiencies), and broader social barriers (eg, housing instability and inadequate social support). Overcoming these barriers requires a multifaceted approach involving clinicians, policymakers, and the community that considers medical, psychological, and social factors.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style.

Working closely with individuals with substance use disorders (SUDs), we’ve observed a worrisome trend of patients leaving the hospital against medical advice (AMA). This issue is not only prevalent in psychiatric settings, but also in emergency departments, medical and surgical floors, and even intensive care units.¹

Compared to individuals without such disorders, individuals with SUDs—particularly those with opioid use disorders—are up to 3 times more likely to leave the hospital AMA.^1,2 Leaving AMA can lead to multiple complications, including an increased risk of readmission, suboptimal treatment outcomes, and an increased use of health care resources.^1-3

It is critical to understand why patients elect to leave a hospital AMA. In a qualitative study, Simon et al¹ found that individuals with SUDs often leave AMA due to uncontrolled withdrawal symptoms and pain, perceived stigma and discrimination, and dissatisfaction with care. Predictors of patients leaving the hospital AMA include the severity of their drug dependence and previous negative treatment experiences.⁴ A systematic review found housing instability and a lack of social support influence an individual’s decision to leave AMA.⁵

Recommendations for managing patients who leave AMA

Enhancing your understanding of withdrawal symptoms may allow you to offer patients more effective symptom control, possibly with methadone or buprenorphine.² Injectable opioid agonist treatment may also help to retain a patient in care. In a case report, a 47-year-old man with a severe opioid use disorder who had left the hospital AMA due to uncontrolled opioid withdrawal was readmitted, treated with IV hydromorphone, and enrolled in ongoing community injectable opioid agonist treatment.⁶

Clinicians must address the stigma and discrimination patients with SUDs often face in health care institutions. Additional training for clinicians to improve their understanding of these disorders and foster a more compassionate and nonjudgmental approach to care may be beneficial.

Like most medicolegal conflicts, leaving AMA is often a clinical and interpersonal problem disguised as a legal one. When assessing these patients’ decision-making capacity, we often find they are angry and dissatisfied with the care they have (or have not) received. The most useful intervention may be to restore communication between the patient and their treatment team.

Even after a patient leaves AMA, the treatment team may experience countertransference issues, such as heightened emotional reactions or biases, that could compromise their clinical judgment. Addressing these dynamics may require team debriefings, supervision, or further training in managing transference and countertransference, particularly since patients who leave AMA may return for subsequent care.⁷

Integrated care models, which feature close collaboration between clinicians from different specialties, can help ensure that a patient’s diverse health needs are met and reduce the likelihood of them leaving AMA. Integrated care models may be particularly effective for patients with co-occurring conditions such as HIV and SUDs.⁸

Implementing these recommendations can be challenging. Barriers to addressing AMA departures span several domains, including patient-specific barriers (eg, stigma and discrimination), clinical barriers (eg, lack of resources and training for clinicians), institutional hurdles (eg, systemic inefficiencies), and broader social barriers (eg, housing instability and inadequate social support). Overcoming these barriers requires a multifaceted approach involving clinicians, policymakers, and the community that considers medical, psychological, and social factors.

TOPLINE:

Among children with urine drug screens that are positive for cannabinoids, confirmatory testing based on liquid chromatography–mass spectrometry (LC-MS) may be negative despite detectable concentrations of a cannabis metabolite, according to a research letter published online in JAMA Pediatrics.

METHODOLOGY:

• After a laboratory changed its reporting threshold for the metabolite 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) from 5 ng/mL to 15 ng/mL in 2019 to match federal standards, researchers examined the rate of false positives for the initial urine drug screen and the false-negative rate with LC-MS.
• Their study focused on 976 cannabinoid-positive drug screens conducted at a pediatric hospital between Nov. 18, 2019, and May 31, 2021, that had confirmatory LC-MS to rule out false-positive results.
• Patients had a median age of 16 years.

TAKEAWAY:

• The false-positive rate was 10.1% based on the 15 ng/mL threshold compared with 2% based on the 5 ng/mL limit of quantification.
• About 81% of samples with negative LC-MS reports had detectable concentrations of THC-COOH.

IN PRACTICE:

“Confirming THC-COOH in children’s and adolescents’ urine may be relevant at concentrations less than 15 ng/mL, particularly if child protection is pertinent,” according to the study authors.

“Confirmatory testing should be reserved for select cases and must be interpreted with caution,” they added. “Laboratories should report down to the limit of quantification on request.”

SOURCE:

Christopher J. Watson, MD, emergency medicine physician, Maine Medical Center, Portland, is the study’s corresponding author.

LIMITATIONS:

The researchers lacked information about the clinical context in which patients underwent drug screening.

DISCLOSURES:

A coauthor disclosed royalties from UpToDate outside of the study.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Among children with urine drug screens that are positive for cannabinoids, confirmatory testing based on liquid chromatography–mass spectrometry (LC-MS) may be negative despite detectable concentrations of a cannabis metabolite, according to a research letter published online in JAMA Pediatrics.

METHODOLOGY:

• After a laboratory changed its reporting threshold for the metabolite 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) from 5 ng/mL to 15 ng/mL in 2019 to match federal standards, researchers examined the rate of false positives for the initial urine drug screen and the false-negative rate with LC-MS.
• Their study focused on 976 cannabinoid-positive drug screens conducted at a pediatric hospital between Nov. 18, 2019, and May 31, 2021, that had confirmatory LC-MS to rule out false-positive results.
• Patients had a median age of 16 years.

TAKEAWAY:

• The false-positive rate was 10.1% based on the 15 ng/mL threshold compared with 2% based on the 5 ng/mL limit of quantification.
• About 81% of samples with negative LC-MS reports had detectable concentrations of THC-COOH.

IN PRACTICE:

“Confirming THC-COOH in children’s and adolescents’ urine may be relevant at concentrations less than 15 ng/mL, particularly if child protection is pertinent,” according to the study authors.

“Confirmatory testing should be reserved for select cases and must be interpreted with caution,” they added. “Laboratories should report down to the limit of quantification on request.”

SOURCE:

Christopher J. Watson, MD, emergency medicine physician, Maine Medical Center, Portland, is the study’s corresponding author.

LIMITATIONS:

The researchers lacked information about the clinical context in which patients underwent drug screening.

DISCLOSURES:

A coauthor disclosed royalties from UpToDate outside of the study.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Among children with urine drug screens that are positive for cannabinoids, confirmatory testing based on liquid chromatography–mass spectrometry (LC-MS) may be negative despite detectable concentrations of a cannabis metabolite, according to a research letter published online in JAMA Pediatrics.

METHODOLOGY:

• After a laboratory changed its reporting threshold for the metabolite 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) from 5 ng/mL to 15 ng/mL in 2019 to match federal standards, researchers examined the rate of false positives for the initial urine drug screen and the false-negative rate with LC-MS.
• Their study focused on 976 cannabinoid-positive drug screens conducted at a pediatric hospital between Nov. 18, 2019, and May 31, 2021, that had confirmatory LC-MS to rule out false-positive results.
• Patients had a median age of 16 years.

TAKEAWAY:

• The false-positive rate was 10.1% based on the 15 ng/mL threshold compared with 2% based on the 5 ng/mL limit of quantification.
• About 81% of samples with negative LC-MS reports had detectable concentrations of THC-COOH.

IN PRACTICE:

“Confirming THC-COOH in children’s and adolescents’ urine may be relevant at concentrations less than 15 ng/mL, particularly if child protection is pertinent,” according to the study authors.

“Confirmatory testing should be reserved for select cases and must be interpreted with caution,” they added. “Laboratories should report down to the limit of quantification on request.”

SOURCE:

Christopher J. Watson, MD, emergency medicine physician, Maine Medical Center, Portland, is the study’s corresponding author.

LIMITATIONS:

The researchers lacked information about the clinical context in which patients underwent drug screening.

DISCLOSURES:

A coauthor disclosed royalties from UpToDate outside of the study.
 

A version of this article appeared on Medscape.com.

TOPLINE:

In conjunction with psychosocial interventions, oral naltrexone and acamprosate are both effective first-line drug therapies for alcohol use disorder (AUD), results of a systematic review and meta-analysis found.

METHODOLOGY:

• Researchers evaluated efficacy and comparative efficacy of three therapies for AUD that are approved in the United States (acamprosate, naltrexone, and disulfiram) and six that are commonly used off-label (baclofen, gabapentin, varenicline, topiramate, prazosin, and ondansetron).
• Data came from 118 randomized clinical trials lasting at least 12 weeks with 20,976 participants.
• 74% of these studies included psychosocial co-interventions, and the primary outcome was alcohol consumption.
• Numbers needed to treat (NNT) were calculated for medications with at least moderate strength of evidence for benefit.

TAKEAWAY:

• Acamprosate (NNT = 11) and naltrexone (50 mg/day; NNT = 18) had the highest strength of evidence and were both associated with statistically significant improvement in drinking outcomes.
• Oral naltrexone but not acamprosate was also associated with lower rates of return to heavy drinking (NNT = 11), compared with placebo.
• Injectable naltrexone was not associated with return to any or heavy drinking but was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, –4.99 days).
• The four trials that directly compared acamprosate with oral naltrexone did not consistently establish superiority of either medication for alcohol use outcomes, and among off-label drugs, only topiramate had moderate strength of evidence for benefit.

IN PRACTICE:

“Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. In conjunction with psychosocial interventions, these findings support the use of oral naltrexone, 50 mg/day, and acamprosate as first-line pharmacotherapies for alcohol use disorder,” the authors write.

SOURCE:

The study, with first author Melissa McPheeters, PhD, MPH, RTI International, Research Triangle Park, North Carolina, was published online in JAMA.

LIMITATIONS:

Most study participants had moderate to severe AUD, and the applicability of the findings to people with mild AUD is uncertain. The mean age of participants was typically between ages 40 and 49 years, and it’s unclear whether the medications have similar efficacy for older or younger age groups. Information on adverse effects was limited.

DISCLOSURES:

Funding for the study was provided by the Agency for Healthcare Research and Quality of the U.S. Department of Health & Human Services. The authors have disclosed no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

In conjunction with psychosocial interventions, oral naltrexone and acamprosate are both effective first-line drug therapies for alcohol use disorder (AUD), results of a systematic review and meta-analysis found.

METHODOLOGY:

• Researchers evaluated efficacy and comparative efficacy of three therapies for AUD that are approved in the United States (acamprosate, naltrexone, and disulfiram) and six that are commonly used off-label (baclofen, gabapentin, varenicline, topiramate, prazosin, and ondansetron).
• Data came from 118 randomized clinical trials lasting at least 12 weeks with 20,976 participants.
• 74% of these studies included psychosocial co-interventions, and the primary outcome was alcohol consumption.
• Numbers needed to treat (NNT) were calculated for medications with at least moderate strength of evidence for benefit.

TAKEAWAY:

• Acamprosate (NNT = 11) and naltrexone (50 mg/day; NNT = 18) had the highest strength of evidence and were both associated with statistically significant improvement in drinking outcomes.
• Oral naltrexone but not acamprosate was also associated with lower rates of return to heavy drinking (NNT = 11), compared with placebo.
• Injectable naltrexone was not associated with return to any or heavy drinking but was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, –4.99 days).
• The four trials that directly compared acamprosate with oral naltrexone did not consistently establish superiority of either medication for alcohol use outcomes, and among off-label drugs, only topiramate had moderate strength of evidence for benefit.

IN PRACTICE:

“Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. In conjunction with psychosocial interventions, these findings support the use of oral naltrexone, 50 mg/day, and acamprosate as first-line pharmacotherapies for alcohol use disorder,” the authors write.

SOURCE:

The study, with first author Melissa McPheeters, PhD, MPH, RTI International, Research Triangle Park, North Carolina, was published online in JAMA.

LIMITATIONS:

Most study participants had moderate to severe AUD, and the applicability of the findings to people with mild AUD is uncertain. The mean age of participants was typically between ages 40 and 49 years, and it’s unclear whether the medications have similar efficacy for older or younger age groups. Information on adverse effects was limited.

DISCLOSURES:

Funding for the study was provided by the Agency for Healthcare Research and Quality of the U.S. Department of Health & Human Services. The authors have disclosed no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

In conjunction with psychosocial interventions, oral naltrexone and acamprosate are both effective first-line drug therapies for alcohol use disorder (AUD), results of a systematic review and meta-analysis found.

METHODOLOGY:

• Researchers evaluated efficacy and comparative efficacy of three therapies for AUD that are approved in the United States (acamprosate, naltrexone, and disulfiram) and six that are commonly used off-label (baclofen, gabapentin, varenicline, topiramate, prazosin, and ondansetron).
• Data came from 118 randomized clinical trials lasting at least 12 weeks with 20,976 participants.
• 74% of these studies included psychosocial co-interventions, and the primary outcome was alcohol consumption.
• Numbers needed to treat (NNT) were calculated for medications with at least moderate strength of evidence for benefit.

TAKEAWAY:

• Acamprosate (NNT = 11) and naltrexone (50 mg/day; NNT = 18) had the highest strength of evidence and were both associated with statistically significant improvement in drinking outcomes.
• Oral naltrexone but not acamprosate was also associated with lower rates of return to heavy drinking (NNT = 11), compared with placebo.
• Injectable naltrexone was not associated with return to any or heavy drinking but was associated with fewer drinking days over the 30-day treatment period (weighted mean difference, –4.99 days).
• The four trials that directly compared acamprosate with oral naltrexone did not consistently establish superiority of either medication for alcohol use outcomes, and among off-label drugs, only topiramate had moderate strength of evidence for benefit.

IN PRACTICE:

“Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality. In conjunction with psychosocial interventions, these findings support the use of oral naltrexone, 50 mg/day, and acamprosate as first-line pharmacotherapies for alcohol use disorder,” the authors write.

SOURCE:

The study, with first author Melissa McPheeters, PhD, MPH, RTI International, Research Triangle Park, North Carolina, was published online in JAMA.

LIMITATIONS:

Most study participants had moderate to severe AUD, and the applicability of the findings to people with mild AUD is uncertain. The mean age of participants was typically between ages 40 and 49 years, and it’s unclear whether the medications have similar efficacy for older or younger age groups. Information on adverse effects was limited.

DISCLOSURES:

Funding for the study was provided by the Agency for Healthcare Research and Quality of the U.S. Department of Health & Human Services. The authors have disclosed no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Use of e-cigarettes among U.S. teens was down sharply, dropping from 14.1% in 2022 to 10% in 2023, government figures show, but the majority of these youth still used flavored products, which have been shown to both entice teens and keep them vaping.

METHODOLOGY:

• The MMRW report from the U.S. Centers for Disease Control and Prevention presents data from an annual survey of U.S. middle and high school students of their use of tobacco products, including vapes.
• The survey is a cross-sectional, school-based, self-administered web-based questionnaire that uses a stratified, three-stage cluster sampling procedure to generate a nationally representative sample based off the responses of 22,069 students in 2023.
• The overall response rate was 30.5%.
• “Ever use” was defined as using a product once or twice previously, and “current use” was defined as use in the past 30 days.
• The survey queried students on their use of e-cigarettes, traditional cigarettes, cigars, smokeless tobacco, nicotine pouches, hookahs, pipe tobacco, and other oral nicotine products.

TAKEAWAY:

• The use of tobacco products by high school students decreased by 540,000 people from 2022 to 2023 (2.51 million vs. 1.97 million students).
• From 2022 to 2023, current e-cigarette use among high school students declined from 14.1% to 10.0%.
• Among middle and high school students, e-cigarettes were the most used nicotine product in 2023 (7.7%; 2.13 million), followed by cigarettes (1.6%), cigars (1.6%), nicotine pouches (1.5%), smokeless tobacco (1.2%), other oral nicotine products (1.2%), hookahs (1.1%), heated tobacco products (1.0%), and pipe tobacco (0.5%).
• Among students reporting current e-cigarette use, 89.4% said that they used flavored products, and 25.2% said they used an e-cigarette daily. The most commonly reported brands were Elf Bar, Esco Bar, Vuse, JUUL, and Mr. Fog. Fruit (63.4%) and candy (35%) were the most commonly reported flavors.

IN PRACTICE:

“Sustained efforts to prevent initiation of tobacco product use among young persons and strategies to help young tobacco users quit are critical to reducing U.S. youth tobacco product use,” the report states.

SOURCE:

The report was produced by the CDC and published in the Morbidity and Mortality Weekly Report for Nov. 3, 2023.

LIMITATIONS:

Data were obtained by students self-reporting their tobacco use, which can result in social desirability and recall biases, the report states. In addition, the responses were from students enrolled in school settings and may not be representative of teens who are in detention centers, alternative schools, have dropped out of school or are homeschooled. The response rate for the 2023 survey was also lower than in the previous year (30.5% in 2023 vs. 45.2% in 2022), increasing the potential for higher standard errors and reducing the power to detect significant differences.

DISCLOSURES:

No potential conflicts of interest were disclosed.

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

TOPLINE:

Use of e-cigarettes among U.S. teens was down sharply, dropping from 14.1% in 2022 to 10% in 2023, government figures show, but the majority of these youth still used flavored products, which have been shown to both entice teens and keep them vaping.

METHODOLOGY:

• The MMRW report from the U.S. Centers for Disease Control and Prevention presents data from an annual survey of U.S. middle and high school students of their use of tobacco products, including vapes.
• The survey is a cross-sectional, school-based, self-administered web-based questionnaire that uses a stratified, three-stage cluster sampling procedure to generate a nationally representative sample based off the responses of 22,069 students in 2023.
• The overall response rate was 30.5%.
• “Ever use” was defined as using a product once or twice previously, and “current use” was defined as use in the past 30 days.
• The survey queried students on their use of e-cigarettes, traditional cigarettes, cigars, smokeless tobacco, nicotine pouches, hookahs, pipe tobacco, and other oral nicotine products.

TAKEAWAY:

• The use of tobacco products by high school students decreased by 540,000 people from 2022 to 2023 (2.51 million vs. 1.97 million students).
• From 2022 to 2023, current e-cigarette use among high school students declined from 14.1% to 10.0%.
• Among middle and high school students, e-cigarettes were the most used nicotine product in 2023 (7.7%; 2.13 million), followed by cigarettes (1.6%), cigars (1.6%), nicotine pouches (1.5%), smokeless tobacco (1.2%), other oral nicotine products (1.2%), hookahs (1.1%), heated tobacco products (1.0%), and pipe tobacco (0.5%).
• Among students reporting current e-cigarette use, 89.4% said that they used flavored products, and 25.2% said they used an e-cigarette daily. The most commonly reported brands were Elf Bar, Esco Bar, Vuse, JUUL, and Mr. Fog. Fruit (63.4%) and candy (35%) were the most commonly reported flavors.

IN PRACTICE:

“Sustained efforts to prevent initiation of tobacco product use among young persons and strategies to help young tobacco users quit are critical to reducing U.S. youth tobacco product use,” the report states.

SOURCE:

The report was produced by the CDC and published in the Morbidity and Mortality Weekly Report for Nov. 3, 2023.

LIMITATIONS:

Data were obtained by students self-reporting their tobacco use, which can result in social desirability and recall biases, the report states. In addition, the responses were from students enrolled in school settings and may not be representative of teens who are in detention centers, alternative schools, have dropped out of school or are homeschooled. The response rate for the 2023 survey was also lower than in the previous year (30.5% in 2023 vs. 45.2% in 2022), increasing the potential for higher standard errors and reducing the power to detect significant differences.

DISCLOSURES:

No potential conflicts of interest were disclosed.

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

TOPLINE:

Use of e-cigarettes among U.S. teens was down sharply, dropping from 14.1% in 2022 to 10% in 2023, government figures show, but the majority of these youth still used flavored products, which have been shown to both entice teens and keep them vaping.

METHODOLOGY:

• The MMRW report from the U.S. Centers for Disease Control and Prevention presents data from an annual survey of U.S. middle and high school students of their use of tobacco products, including vapes.
• The survey is a cross-sectional, school-based, self-administered web-based questionnaire that uses a stratified, three-stage cluster sampling procedure to generate a nationally representative sample based off the responses of 22,069 students in 2023.
• The overall response rate was 30.5%.
• “Ever use” was defined as using a product once or twice previously, and “current use” was defined as use in the past 30 days.
• The survey queried students on their use of e-cigarettes, traditional cigarettes, cigars, smokeless tobacco, nicotine pouches, hookahs, pipe tobacco, and other oral nicotine products.

TAKEAWAY:

• The use of tobacco products by high school students decreased by 540,000 people from 2022 to 2023 (2.51 million vs. 1.97 million students).
• From 2022 to 2023, current e-cigarette use among high school students declined from 14.1% to 10.0%.
• Among middle and high school students, e-cigarettes were the most used nicotine product in 2023 (7.7%; 2.13 million), followed by cigarettes (1.6%), cigars (1.6%), nicotine pouches (1.5%), smokeless tobacco (1.2%), other oral nicotine products (1.2%), hookahs (1.1%), heated tobacco products (1.0%), and pipe tobacco (0.5%).
• Among students reporting current e-cigarette use, 89.4% said that they used flavored products, and 25.2% said they used an e-cigarette daily. The most commonly reported brands were Elf Bar, Esco Bar, Vuse, JUUL, and Mr. Fog. Fruit (63.4%) and candy (35%) were the most commonly reported flavors.

IN PRACTICE:

“Sustained efforts to prevent initiation of tobacco product use among young persons and strategies to help young tobacco users quit are critical to reducing U.S. youth tobacco product use,” the report states.

SOURCE:

The report was produced by the CDC and published in the Morbidity and Mortality Weekly Report for Nov. 3, 2023.

LIMITATIONS:

Data were obtained by students self-reporting their tobacco use, which can result in social desirability and recall biases, the report states. In addition, the responses were from students enrolled in school settings and may not be representative of teens who are in detention centers, alternative schools, have dropped out of school or are homeschooled. The response rate for the 2023 survey was also lower than in the previous year (30.5% in 2023 vs. 45.2% in 2022), increasing the potential for higher standard errors and reducing the power to detect significant differences.

DISCLOSURES:

No potential conflicts of interest were disclosed.

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

The American Cancer Society has updated its screening guidelines for lung cancer, the leading cause of cancer-specific deaths in the United States and the largest driver of potential years of life lost from cancer.

The 2023 screening guidance, aimed principally at reducing lung cancer mortality in asymptomatic but high-risk, tobacco-exposed individuals, expands the age eligibility and lowers both the former smoking history and the years since quitting threshold for screening with low-dose CT (LDCT).

It is based on the most recent evidence on the efficacy and effectiveness of screening and lung cancer risk in persons who formerly smoked, wrote the ACS’s Guideline Development Group led by Robert A. Smith, PhD, senior vice president of early cancer detection science. The new guidelines, which replace the 2013 statement, appear in CA: A Cancer Journal for Physicians.

The primary evidence source for the update was a systematic review of LDCT lung cancer screening conducted for the U.S. Preventive Services Task Force and published in 2021.

The new guideline continues a trend of expanding eligibility for lung cancer screening, which has had low uptake, to prevent more deaths. “Recent studies have shown that extending the age for persons who smoked and formerly smoked, eliminating the ‘years since quitting’ requirement, and lowering the pack-per-year recommendation could make a real difference in saving lives,” Dr. Smith said. “The relative risk of developing lung cancer in people who have smoked most of their life compared to people who never smoked is very high – about 70 times the risk.” Although lung cancer is the third most common malignancy in the United States, it accounts for more deaths than colorectal, breast, prostate, and cervical cancers combined.

The recommendation for annual LDCT for at-risk persons remains unchanged from 2013.

Among the 2023 eligibility changes:

• Age: Expanded to 50-80 years from 55-74 years.
• Smoking status: Changed to current or previous smoker from current smoker or smoker who quit within past 15 years (number of years since quitting no longer a criterion to start or stop screening). Dr. Smith noted that both the 2013 guidelines and other groups’ updated recommendations retained the eligibility cutoff of 15 years since smoking cessation. “But had their risk declined to a level that just did not justify continuing screening?” he asked. “There wasn’t an answer to that question, so we needed to look carefully at the absolute risk of lung cancer in persons who formerly smoked compared with people who currently smoked and people who never smoked.”
• Smoking history: Reduced to 20 or more pack-years (average of 20 cigarettes a day) versus 30 or more pack-years.
• Exclusions: Expanded to health conditions that may increase harm or hinder further evaluation, surgery, or treatment; comorbidities limiting life expectancy to fewer than 5 years; unwillingness to accept treatment for screen‐detected cancer, which was changed from 2013’s life‐limiting comorbid conditions, metallic implants or devices in the chest or back, home oxygen supplementation.

In addition, decision-making should be a shared process with a health professional providing the patient with information on the benefits, limitations, and harms of LDCT screening, as well as prescreening advice on smoking cessation and the offer of assistive counseling and pharmocotherapy.

“Overall, lung cancer screening remains one of the least used early cancer detection modalities in clinical practice. The new guidance opens up lung cancer screening to all former smokers regardless of time of cessation,” said internist William E. Golden, MD, MACP, a professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock. “This may promote greater uptake in concert with greater availability of low-radiation CT scanning.”

While agreeing the expanded criteria will enfranchise nearly 5 million current and former U.S. smokers for screening and may reduce deaths, internist Aarati D. Didwania, MD, MMSCI, MACP, a professor of medicine and medical education at Northwestern University, Chicago, warned that increasing actual uptake may be an uphill battle. “The practical part of the equation is seeing that the scans get done. There is often a lag between a recommendation of a yearly test and getting insurance coverage for it, and many disadvantaged people face barriers.” Then there’s the knowledge gap. “Patients and doctors have to know what the new guidelines are and who has access,” she said.

Reaching the target population in rural areas is particularly challenging with the greater distances to imaging centers. Another barrier is that most electronic health records do not identify eligible patients based on smoking and pack‐year history.

In Dr. Didwania’s view, professional medical societies have an important role to play in educating their members, and through them, patients. “Disseminating information about the new recommendations is the first step and would be incredibly helpful.”
 

A brief history of lung cancer screening

1950s: By mid-20th century, the causal association between tobacco exposure and lung cancer became clear and by the late 1950s attempts were made to develop a lung cancer screening strategy for high‐risk individuals, commonly with the combination of sputum cytology and chest x-ray.

1970s: The ACS recommended annual testing for current or former smokers with chest x-ray (and sometimes sputum cytology).

1980: The ACS withdrew the above recommendation for regular radiographic screening after randomized controlled trials failed to yield convincing evidence that such screening saved lives.

2013: After the National Lung Screening Trial found three annual LDCT screenings were associated with a 20% relative mortality reduction, compared with annual chest x-ray, the ACS issued a recommendation for annual screening with LDCT: in persons 55-74 years with a pack‐year history of 30 or more who currently smoke or formerly smoked but had not exceeded 15 years since quitting and had no life-limiting morbidity.
 

Future mortality

Although tobacco controls are expected to reduce age‐adjusted lung cancer mortality in the United States by 79% from 2015 to 2065, 4.4 million lung cancer deaths are projected to occur in this period, the authors stated. “A large fraction of these deaths can be prevented if we embrace the urgent challenge to improve our ability to identify the population at risk and apply our knowledge to achieve high rates of participation in regular [lung cancer screening].”

The study was funded by the American Cancer Society Guideline Development Group and the National Comprehensive Cancer Network. The authors disclosed no relevant competing interests. Dr. Golden and Dr. Didwania had no relevant conflicts of interest to declare with regard to their comments.

The American Cancer Society has updated its screening guidelines for lung cancer, the leading cause of cancer-specific deaths in the United States and the largest driver of potential years of life lost from cancer.

The 2023 screening guidance, aimed principally at reducing lung cancer mortality in asymptomatic but high-risk, tobacco-exposed individuals, expands the age eligibility and lowers both the former smoking history and the years since quitting threshold for screening with low-dose CT (LDCT).

It is based on the most recent evidence on the efficacy and effectiveness of screening and lung cancer risk in persons who formerly smoked, wrote the ACS’s Guideline Development Group led by Robert A. Smith, PhD, senior vice president of early cancer detection science. The new guidelines, which replace the 2013 statement, appear in CA: A Cancer Journal for Physicians.

The primary evidence source for the update was a systematic review of LDCT lung cancer screening conducted for the U.S. Preventive Services Task Force and published in 2021.

The new guideline continues a trend of expanding eligibility for lung cancer screening, which has had low uptake, to prevent more deaths. “Recent studies have shown that extending the age for persons who smoked and formerly smoked, eliminating the ‘years since quitting’ requirement, and lowering the pack-per-year recommendation could make a real difference in saving lives,” Dr. Smith said. “The relative risk of developing lung cancer in people who have smoked most of their life compared to people who never smoked is very high – about 70 times the risk.” Although lung cancer is the third most common malignancy in the United States, it accounts for more deaths than colorectal, breast, prostate, and cervical cancers combined.

The recommendation for annual LDCT for at-risk persons remains unchanged from 2013.

Among the 2023 eligibility changes:

• Age: Expanded to 50-80 years from 55-74 years.
• Smoking status: Changed to current or previous smoker from current smoker or smoker who quit within past 15 years (number of years since quitting no longer a criterion to start or stop screening). Dr. Smith noted that both the 2013 guidelines and other groups’ updated recommendations retained the eligibility cutoff of 15 years since smoking cessation. “But had their risk declined to a level that just did not justify continuing screening?” he asked. “There wasn’t an answer to that question, so we needed to look carefully at the absolute risk of lung cancer in persons who formerly smoked compared with people who currently smoked and people who never smoked.”
• Smoking history: Reduced to 20 or more pack-years (average of 20 cigarettes a day) versus 30 or more pack-years.
• Exclusions: Expanded to health conditions that may increase harm or hinder further evaluation, surgery, or treatment; comorbidities limiting life expectancy to fewer than 5 years; unwillingness to accept treatment for screen‐detected cancer, which was changed from 2013’s life‐limiting comorbid conditions, metallic implants or devices in the chest or back, home oxygen supplementation.

In addition, decision-making should be a shared process with a health professional providing the patient with information on the benefits, limitations, and harms of LDCT screening, as well as prescreening advice on smoking cessation and the offer of assistive counseling and pharmocotherapy.

“Overall, lung cancer screening remains one of the least used early cancer detection modalities in clinical practice. The new guidance opens up lung cancer screening to all former smokers regardless of time of cessation,” said internist William E. Golden, MD, MACP, a professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock. “This may promote greater uptake in concert with greater availability of low-radiation CT scanning.”

While agreeing the expanded criteria will enfranchise nearly 5 million current and former U.S. smokers for screening and may reduce deaths, internist Aarati D. Didwania, MD, MMSCI, MACP, a professor of medicine and medical education at Northwestern University, Chicago, warned that increasing actual uptake may be an uphill battle. “The practical part of the equation is seeing that the scans get done. There is often a lag between a recommendation of a yearly test and getting insurance coverage for it, and many disadvantaged people face barriers.” Then there’s the knowledge gap. “Patients and doctors have to know what the new guidelines are and who has access,” she said.

Reaching the target population in rural areas is particularly challenging with the greater distances to imaging centers. Another barrier is that most electronic health records do not identify eligible patients based on smoking and pack‐year history.

In Dr. Didwania’s view, professional medical societies have an important role to play in educating their members, and through them, patients. “Disseminating information about the new recommendations is the first step and would be incredibly helpful.”
 

A brief history of lung cancer screening

1950s: By mid-20th century, the causal association between tobacco exposure and lung cancer became clear and by the late 1950s attempts were made to develop a lung cancer screening strategy for high‐risk individuals, commonly with the combination of sputum cytology and chest x-ray.

1970s: The ACS recommended annual testing for current or former smokers with chest x-ray (and sometimes sputum cytology).

1980: The ACS withdrew the above recommendation for regular radiographic screening after randomized controlled trials failed to yield convincing evidence that such screening saved lives.

2013: After the National Lung Screening Trial found three annual LDCT screenings were associated with a 20% relative mortality reduction, compared with annual chest x-ray, the ACS issued a recommendation for annual screening with LDCT: in persons 55-74 years with a pack‐year history of 30 or more who currently smoke or formerly smoked but had not exceeded 15 years since quitting and had no life-limiting morbidity.
 

Future mortality

Although tobacco controls are expected to reduce age‐adjusted lung cancer mortality in the United States by 79% from 2015 to 2065, 4.4 million lung cancer deaths are projected to occur in this period, the authors stated. “A large fraction of these deaths can be prevented if we embrace the urgent challenge to improve our ability to identify the population at risk and apply our knowledge to achieve high rates of participation in regular [lung cancer screening].”

The study was funded by the American Cancer Society Guideline Development Group and the National Comprehensive Cancer Network. The authors disclosed no relevant competing interests. Dr. Golden and Dr. Didwania had no relevant conflicts of interest to declare with regard to their comments.

The American Cancer Society has updated its screening guidelines for lung cancer, the leading cause of cancer-specific deaths in the United States and the largest driver of potential years of life lost from cancer.

The 2023 screening guidance, aimed principally at reducing lung cancer mortality in asymptomatic but high-risk, tobacco-exposed individuals, expands the age eligibility and lowers both the former smoking history and the years since quitting threshold for screening with low-dose CT (LDCT).

It is based on the most recent evidence on the efficacy and effectiveness of screening and lung cancer risk in persons who formerly smoked, wrote the ACS’s Guideline Development Group led by Robert A. Smith, PhD, senior vice president of early cancer detection science. The new guidelines, which replace the 2013 statement, appear in CA: A Cancer Journal for Physicians.

The primary evidence source for the update was a systematic review of LDCT lung cancer screening conducted for the U.S. Preventive Services Task Force and published in 2021.

The new guideline continues a trend of expanding eligibility for lung cancer screening, which has had low uptake, to prevent more deaths. “Recent studies have shown that extending the age for persons who smoked and formerly smoked, eliminating the ‘years since quitting’ requirement, and lowering the pack-per-year recommendation could make a real difference in saving lives,” Dr. Smith said. “The relative risk of developing lung cancer in people who have smoked most of their life compared to people who never smoked is very high – about 70 times the risk.” Although lung cancer is the third most common malignancy in the United States, it accounts for more deaths than colorectal, breast, prostate, and cervical cancers combined.

The recommendation for annual LDCT for at-risk persons remains unchanged from 2013.

Among the 2023 eligibility changes:

• Age: Expanded to 50-80 years from 55-74 years.
• Smoking status: Changed to current or previous smoker from current smoker or smoker who quit within past 15 years (number of years since quitting no longer a criterion to start or stop screening). Dr. Smith noted that both the 2013 guidelines and other groups’ updated recommendations retained the eligibility cutoff of 15 years since smoking cessation. “But had their risk declined to a level that just did not justify continuing screening?” he asked. “There wasn’t an answer to that question, so we needed to look carefully at the absolute risk of lung cancer in persons who formerly smoked compared with people who currently smoked and people who never smoked.”
• Smoking history: Reduced to 20 or more pack-years (average of 20 cigarettes a day) versus 30 or more pack-years.
• Exclusions: Expanded to health conditions that may increase harm or hinder further evaluation, surgery, or treatment; comorbidities limiting life expectancy to fewer than 5 years; unwillingness to accept treatment for screen‐detected cancer, which was changed from 2013’s life‐limiting comorbid conditions, metallic implants or devices in the chest or back, home oxygen supplementation.

In addition, decision-making should be a shared process with a health professional providing the patient with information on the benefits, limitations, and harms of LDCT screening, as well as prescreening advice on smoking cessation and the offer of assistive counseling and pharmocotherapy.

“Overall, lung cancer screening remains one of the least used early cancer detection modalities in clinical practice. The new guidance opens up lung cancer screening to all former smokers regardless of time of cessation,” said internist William E. Golden, MD, MACP, a professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock. “This may promote greater uptake in concert with greater availability of low-radiation CT scanning.”

While agreeing the expanded criteria will enfranchise nearly 5 million current and former U.S. smokers for screening and may reduce deaths, internist Aarati D. Didwania, MD, MMSCI, MACP, a professor of medicine and medical education at Northwestern University, Chicago, warned that increasing actual uptake may be an uphill battle. “The practical part of the equation is seeing that the scans get done. There is often a lag between a recommendation of a yearly test and getting insurance coverage for it, and many disadvantaged people face barriers.” Then there’s the knowledge gap. “Patients and doctors have to know what the new guidelines are and who has access,” she said.

Reaching the target population in rural areas is particularly challenging with the greater distances to imaging centers. Another barrier is that most electronic health records do not identify eligible patients based on smoking and pack‐year history.

In Dr. Didwania’s view, professional medical societies have an important role to play in educating their members, and through them, patients. “Disseminating information about the new recommendations is the first step and would be incredibly helpful.”
 

A brief history of lung cancer screening

1950s: By mid-20th century, the causal association between tobacco exposure and lung cancer became clear and by the late 1950s attempts were made to develop a lung cancer screening strategy for high‐risk individuals, commonly with the combination of sputum cytology and chest x-ray.

1970s: The ACS recommended annual testing for current or former smokers with chest x-ray (and sometimes sputum cytology).

1980: The ACS withdrew the above recommendation for regular radiographic screening after randomized controlled trials failed to yield convincing evidence that such screening saved lives.

2013: After the National Lung Screening Trial found three annual LDCT screenings were associated with a 20% relative mortality reduction, compared with annual chest x-ray, the ACS issued a recommendation for annual screening with LDCT: in persons 55-74 years with a pack‐year history of 30 or more who currently smoke or formerly smoked but had not exceeded 15 years since quitting and had no life-limiting morbidity.
 

Future mortality

Although tobacco controls are expected to reduce age‐adjusted lung cancer mortality in the United States by 79% from 2015 to 2065, 4.4 million lung cancer deaths are projected to occur in this period, the authors stated. “A large fraction of these deaths can be prevented if we embrace the urgent challenge to improve our ability to identify the population at risk and apply our knowledge to achieve high rates of participation in regular [lung cancer screening].”

The study was funded by the American Cancer Society Guideline Development Group and the National Comprehensive Cancer Network. The authors disclosed no relevant competing interests. Dr. Golden and Dr. Didwania had no relevant conflicts of interest to declare with regard to their comments.

Mental health conditions are the leading cause of pregnancy-related death in Illinois (40%) and across the United States (21%).^1,2There is increasing recognition in primary care that major depressive disorder (MDD) often co-occurs with other mental health conditions. Funding bodies, such as the Agency for Healthcare Research and Quality³ and the Health Resources and Service Administration,⁴ have spotlights on improving screening and access to care for depression and substance use disorders (SUDs). However, the needs of individuals with multiple mental health conditions still often go unrecognized and unaddressed in perinatal health settings.

The U.S. Preventive Services Task Force recommends that all adults be screened for depression, alcohol use, and drug use, and will be recommending screening for anxiety.^5,6 The American College of Obstetrics and Gynecology recommends screening for perinatal mental health conditions including depression, anxiety, bipolar disorder, acute postpartum psychosis, and suicidality; however, despite these recommendations, screening and treatment for comorbid mental health disorders during pregnancy and the postpartum is not standard practice.⁷

Addressing perinatal mental health is critical because untreated mental health conditions during the perinatal period can cause long-term adverse psychiatric and medical outcomes for the birthing person, the baby, and the family.⁸ This commentary highlights the importance of recognizing and screening for perinatal mental health comorbidities, improving referral rates for mental health treatment, and raising awareness of the importance of addressing rural perinatal mental health.
 

Perinatal mental health comorbidities

Major depressive disorder is the most common mental health condition during the perinatal period⁹ and is often comorbid.^10-12 In “Perinatal mental health in low-income urban and rural patients: The importance of screening for comorbidities,” Craemer et al.¹³ reported that nearly half of the perinatal patients who screened positive for MDD also screened positive for at least one other mental health condition, among them general anxiety disorder (GAD), SUD, posttraumatic stress disorder (PTSD), and suicidality.

Many (9%) of the perinatal patients with MDD had a severe comorbidity profile characterized by four diagnoses – MDD, GAD, SUD, and PTSD. In routine medical care these comorbidities often go undetected even though the risk to mothers and babies increases with more severe mental health symptoms.⁸

The high frequency of perinatal mental health comorbidities Craemer et al.¹³ found demonstrates a compelling need for comorbid mental health screening during the perinatal period, particularly for low-income Black, Hispanic, and rural birthing persons. Positive screens for perinatal mental health disorders may reflect the onset of these disorders in pregnancy or the postpartum, or preexisting disorders that have gone undetected or untreated before pregnancy.

For many patients, the perinatal period is the first time they are screened for any mental health disorder; typically, they are screened solely for depression. Screening alone can have a positive impact on perinatal mental health. In fact, the USPSTF found that programs to screen perinatal patients, with or without treatment-related support, resulted in a 2%-9% absolute reduction in depression prevalence.¹⁴ However, screening for MDD is too infrequent for many reasons, including the logistics of integrating screening into the clinic workflow and limited provider availability, time, and training in mental health.

We recommend screening perinatal patients for mental health comorbidities. This recommendation may seem impractical given the lack of screening tools for comorbid mental health conditions; however, the Computerized Adaptive Test for Mental Health (CAT-MH), the validated tool^15-17 used in this study, is an ideal option. CAT-MH is uniquely capable of screening for MDD, GAD, PTSD, SUD, and suicidality in one platform and is routinely used in diverse settings including the Veterans Administration,¹⁸ foster care,¹⁹ and universities.²⁰ The main limitation of this more comprehensive screening is that it takes about 10 minutes per patient. However, CAT-MH is self-administered and can be done in the waiting room or on a mobile device prior to a clinic visit.

CAT-MH can also be easily integrated into clinical workflow when added to the Electronic Medical Record²¹, and is a more comprehensive tool than existing perinatal depression tools such as the Perinatal Health Questionaire-9 (PHQ-9) and Edinburgh Perinatal Depression Scale (EPDS).²² Another limitation is cost – currently $5.00 per assessment – however, this is less than routine blood work.²³ If CAT-MH is not an option, we recommend a stepped approach of screening for GAD when perinatal patients screen positive for MDD, as this is the most common comorbidity profile. The GAD-7 is a free and widely available tool.²⁴

Barriers to care

In Craemer et al,¹³ nearly two-thirds (64.9%) of perinatal patients with a positive screen did not receive a referral to follow-up care or a medication prescription. These low referral rates may reflect a variety of widely recognized barriers to care, including lack of referral options, provider and/or patient reluctance to pursue referrals, barriers to insurance coverage, or inadequate behavioral health infrastructure to ensure referral and diagnostic follow-up.

Further, rural residing perinatal patients are an underserved population that need more resources and screening. Despite an on-site behavioral specialist at the rural clinic, Craemer et al¹³ found a stark disparity in referral rates: referrals to treatment for a positive diagnosis was over two times less at the rural clinic (23.9%), compared with the urban clinics (51.6%). The most common treatment offered at the rural clinic was a prescription for medication (17.4%), while referral to follow-up care was the most common at the urban clinics (35.5%). Rural areas not only have a shortage of health care providers, but community members seeking mental health care often encounter greater stigma, compared with urban residents.^25,26

These data highlight an unmet need for referrals to treatment for patients in rural communities, particularly in Illinois where the pregnancy-related mortality ratio attributable to mental health conditions is three times greater in rural areas, compared with those residing in urban Cook County (Chicago).² Increasing access and availability to mental health treatment and prevention resources in Illinois, especially in rural areas, is an opportunity to prevent pregnancy-related mortality attributable to mental health conditions.

Overall, there is a critical need for screening for perinatal mental health comorbidities, increased attention to low rates of referral to mental health treatment, and investing in rural perinatal mental health. Addressing perinatal mental health disorders is key to decreasing the burden of maternal mortality, particularly in Illinois.

Ms. Craemer and Ms. Sayah are senior research specialists at the Center for Research on Women & Gender, University of Illinois at Chicago. Dr. Duffecy is a professor of clinical psychiatry at the University of Illinois at Chicago. Dr. Geller is a professor of obstetrics & gynecology and director of the Center for Research on Women & Gender, University of Illinois at Chicago. Dr. Maki is a professor of psychiatry, psychology, and obstetrics & gynecology at the University of Illinois at Chicago.

References

1. Trost S et al. Pregnancy-related deaths: Data from maternal mortality review committees in 36 states, 2017-2019. Atlanta: Centers for Disease Control and Prevention, U.S. Department of Health & Human Services, 2022.

2. Illinois Department of Public Health. Illinois maternal morbidity and mortality report 2016-2017. 2021.

3. AHRQ. Funding opportunities to address opioid and other substance use disorders. Updated 2023.

4. HRSA. Screening and treatment for maternal mental health and substance use disorders.

5. U.S. Preventive Services Task Force. Recommendations for primary care practice. Accessed May 26, 2023.

6. U.S. Preventive Services Task Force. Draft recommendation statement: Anxiety in adults: Screening. 2022.

7. ACOG. Screening and diagnosis of mental health conditions during pregnancy and postpartum. Clinical Practice Guideline. Number 4. 2023 June.

8. Meltzer-Brody S and Stuebe A. The long-term psychiatric and medical prognosis of perinatal mental illness. Best Pract Res Clin Obstet Gynaecol. 2014 Jan. doi: 10.1016/j.bpobgyn.2013.08.009.

9. Van Niel MS and Payne JL. Perinatal depression: A review. Cleve Clin J Med. 2020 May. doi: 10.3949/ccjm.87a.19054.

10. Wisner KL et al. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. 2013 May. doi: 10.1001/jamapsychiatry.2013.87.

11. Falah-Hassani K et al. The prevalence of antenatal and postnatal co-morbid anxiety and depression: A meta-analysis. Psychol Med. 2017 Sep. doi: 10.1017/S0033291717000617.

12. Pentecost R et al. Scoping review of the associations between perinatal substance use and perinatal depression and anxiety. J Obstet Gynecol Neonatal Nurs. 2021 Jul. doi: 10.1016/j.jogn.2021.02.008.

13. Craemer KA et al. Perinatal mental health in low-income urban and rural patients: The importance of screening for comorbidities. Gen Hosp Psychiatry. 2023 Jul-Aug. doi: 10.1016/j.genhosppsych.2023.05.007.

14. O’Connor E et al. Primary care screening for and treatment of depression in pregnant and postpartum women: Evidence report and systematic review for the U.S. Preventive Services Task Force. JAMA. 2016 Jan 26. doi: 10.1001/jama.2015.18948.

15. Kozhimannil KB et al. Racial and ethnic disparities in postpartum depression care among low-income women. Psychiatr Serv. 2011 Jun. doi: 10.1176/ps.62.6.pss6206_0619.

16. Wenzel ES et al. Depression and anxiety symptoms across pregnancy and the postpartum in low-income Black and Latina women. Arch Womens Ment Health. 2021 Dec. doi: 10.1007/s00737-021-01139-y.

17. Gibbons RD et al. Development of a computerized adaptive substance use disorder scale for screening and measurement: The CAT‐SUD. Addiction. 2020 Jul. doi: 10.1111/add.14938.

18. Brenner LA et al. Validation of a computerized adaptive test suicide scale (CAT-SS) among united states military veterans. PloS One. 2022 Jan 21. doi: 10.1371/journal.pone.0261920.

19. The Center for State Child Welfare Data. Using technology to diagnose and report on behavioral health challenges facing foster youth. 2018.

20. Kim JJ et al. The experience of depression, anxiety, and mania among perinatal women. Arch Womens Ment Health. 2016 Oct. doi: 10.1007/s00737-016-0632-6.

21. Tepper MC et al. Toward population health: Using a learning behavioral health system and measurement-based care to improve access, care, outcomes, and disparities. Community Ment Health J. 2022 Nov. doi: 10.1007/s10597-022-00957-3.

22. Wenzel E et al. Using computerised adaptive tests to screen for perinatal depression in underserved women of colour. Evid Based Ment Health. 2022 Feb. doi: 10.1136/ebmental-2021-300262.

23. Sanger-Katz M. They want it to be secret: How a common blood test can cost $11 or almost $1,000. New York Times. 2019 Apr 19.

24. Spitzer RL et al. A brief measure for assessing generalized anxiety disorder: The GAD-7. Arch Intern Med. 2006 May 22. doi: 10.1001/archinte.166.10.1092.

25. Mollard E et al. An integrative review of postpartum depression in rural US communities. Arch Psychiatr Nurs. 2016 Jun. doi: 10.1016/j.apnu.2015.12.003.

26. Anglim AJ and Radke SM. Rural maternal health care outcomes, drivers, and patient perspectives. Clin Obstet Gynecol. 2022 Dec 1. doi: 10.1097/GRF.0000000000000753.

Mental health conditions are the leading cause of pregnancy-related death in Illinois (40%) and across the United States (21%).^1,2There is increasing recognition in primary care that major depressive disorder (MDD) often co-occurs with other mental health conditions. Funding bodies, such as the Agency for Healthcare Research and Quality³ and the Health Resources and Service Administration,⁴ have spotlights on improving screening and access to care for depression and substance use disorders (SUDs). However, the needs of individuals with multiple mental health conditions still often go unrecognized and unaddressed in perinatal health settings.

The U.S. Preventive Services Task Force recommends that all adults be screened for depression, alcohol use, and drug use, and will be recommending screening for anxiety.^5,6 The American College of Obstetrics and Gynecology recommends screening for perinatal mental health conditions including depression, anxiety, bipolar disorder, acute postpartum psychosis, and suicidality; however, despite these recommendations, screening and treatment for comorbid mental health disorders during pregnancy and the postpartum is not standard practice.⁷

Addressing perinatal mental health is critical because untreated mental health conditions during the perinatal period can cause long-term adverse psychiatric and medical outcomes for the birthing person, the baby, and the family.⁸ This commentary highlights the importance of recognizing and screening for perinatal mental health comorbidities, improving referral rates for mental health treatment, and raising awareness of the importance of addressing rural perinatal mental health.
 

Perinatal mental health comorbidities

Major depressive disorder is the most common mental health condition during the perinatal period⁹ and is often comorbid.^10-12 In “Perinatal mental health in low-income urban and rural patients: The importance of screening for comorbidities,” Craemer et al.¹³ reported that nearly half of the perinatal patients who screened positive for MDD also screened positive for at least one other mental health condition, among them general anxiety disorder (GAD), SUD, posttraumatic stress disorder (PTSD), and suicidality.

Many (9%) of the perinatal patients with MDD had a severe comorbidity profile characterized by four diagnoses – MDD, GAD, SUD, and PTSD. In routine medical care these comorbidities often go undetected even though the risk to mothers and babies increases with more severe mental health symptoms.⁸

The high frequency of perinatal mental health comorbidities Craemer et al.¹³ found demonstrates a compelling need for comorbid mental health screening during the perinatal period, particularly for low-income Black, Hispanic, and rural birthing persons. Positive screens for perinatal mental health disorders may reflect the onset of these disorders in pregnancy or the postpartum, or preexisting disorders that have gone undetected or untreated before pregnancy.

For many patients, the perinatal period is the first time they are screened for any mental health disorder; typically, they are screened solely for depression. Screening alone can have a positive impact on perinatal mental health. In fact, the USPSTF found that programs to screen perinatal patients, with or without treatment-related support, resulted in a 2%-9% absolute reduction in depression prevalence.¹⁴ However, screening for MDD is too infrequent for many reasons, including the logistics of integrating screening into the clinic workflow and limited provider availability, time, and training in mental health.

We recommend screening perinatal patients for mental health comorbidities. This recommendation may seem impractical given the lack of screening tools for comorbid mental health conditions; however, the Computerized Adaptive Test for Mental Health (CAT-MH), the validated tool^15-17 used in this study, is an ideal option. CAT-MH is uniquely capable of screening for MDD, GAD, PTSD, SUD, and suicidality in one platform and is routinely used in diverse settings including the Veterans Administration,¹⁸ foster care,¹⁹ and universities.²⁰ The main limitation of this more comprehensive screening is that it takes about 10 minutes per patient. However, CAT-MH is self-administered and can be done in the waiting room or on a mobile device prior to a clinic visit.

CAT-MH can also be easily integrated into clinical workflow when added to the Electronic Medical Record²¹, and is a more comprehensive tool than existing perinatal depression tools such as the Perinatal Health Questionaire-9 (PHQ-9) and Edinburgh Perinatal Depression Scale (EPDS).²² Another limitation is cost – currently $5.00 per assessment – however, this is less than routine blood work.²³ If CAT-MH is not an option, we recommend a stepped approach of screening for GAD when perinatal patients screen positive for MDD, as this is the most common comorbidity profile. The GAD-7 is a free and widely available tool.²⁴

Barriers to care

In Craemer et al,¹³ nearly two-thirds (64.9%) of perinatal patients with a positive screen did not receive a referral to follow-up care or a medication prescription. These low referral rates may reflect a variety of widely recognized barriers to care, including lack of referral options, provider and/or patient reluctance to pursue referrals, barriers to insurance coverage, or inadequate behavioral health infrastructure to ensure referral and diagnostic follow-up.

Further, rural residing perinatal patients are an underserved population that need more resources and screening. Despite an on-site behavioral specialist at the rural clinic, Craemer et al¹³ found a stark disparity in referral rates: referrals to treatment for a positive diagnosis was over two times less at the rural clinic (23.9%), compared with the urban clinics (51.6%). The most common treatment offered at the rural clinic was a prescription for medication (17.4%), while referral to follow-up care was the most common at the urban clinics (35.5%). Rural areas not only have a shortage of health care providers, but community members seeking mental health care often encounter greater stigma, compared with urban residents.^25,26

These data highlight an unmet need for referrals to treatment for patients in rural communities, particularly in Illinois where the pregnancy-related mortality ratio attributable to mental health conditions is three times greater in rural areas, compared with those residing in urban Cook County (Chicago).² Increasing access and availability to mental health treatment and prevention resources in Illinois, especially in rural areas, is an opportunity to prevent pregnancy-related mortality attributable to mental health conditions.

Overall, there is a critical need for screening for perinatal mental health comorbidities, increased attention to low rates of referral to mental health treatment, and investing in rural perinatal mental health. Addressing perinatal mental health disorders is key to decreasing the burden of maternal mortality, particularly in Illinois.

Ms. Craemer and Ms. Sayah are senior research specialists at the Center for Research on Women & Gender, University of Illinois at Chicago. Dr. Duffecy is a professor of clinical psychiatry at the University of Illinois at Chicago. Dr. Geller is a professor of obstetrics & gynecology and director of the Center for Research on Women & Gender, University of Illinois at Chicago. Dr. Maki is a professor of psychiatry, psychology, and obstetrics & gynecology at the University of Illinois at Chicago.

References

1. Trost S et al. Pregnancy-related deaths: Data from maternal mortality review committees in 36 states, 2017-2019. Atlanta: Centers for Disease Control and Prevention, U.S. Department of Health & Human Services, 2022.

2. Illinois Department of Public Health. Illinois maternal morbidity and mortality report 2016-2017. 2021.

3. AHRQ. Funding opportunities to address opioid and other substance use disorders. Updated 2023.

4. HRSA. Screening and treatment for maternal mental health and substance use disorders.

5. U.S. Preventive Services Task Force. Recommendations for primary care practice. Accessed May 26, 2023.

6. U.S. Preventive Services Task Force. Draft recommendation statement: Anxiety in adults: Screening. 2022.

7. ACOG. Screening and diagnosis of mental health conditions during pregnancy and postpartum. Clinical Practice Guideline. Number 4. 2023 June.

8. Meltzer-Brody S and Stuebe A. The long-term psychiatric and medical prognosis of perinatal mental illness. Best Pract Res Clin Obstet Gynaecol. 2014 Jan. doi: 10.1016/j.bpobgyn.2013.08.009.

9. Van Niel MS and Payne JL. Perinatal depression: A review. Cleve Clin J Med. 2020 May. doi: 10.3949/ccjm.87a.19054.

10. Wisner KL et al. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. 2013 May. doi: 10.1001/jamapsychiatry.2013.87.

11. Falah-Hassani K et al. The prevalence of antenatal and postnatal co-morbid anxiety and depression: A meta-analysis. Psychol Med. 2017 Sep. doi: 10.1017/S0033291717000617.

12. Pentecost R et al. Scoping review of the associations between perinatal substance use and perinatal depression and anxiety. J Obstet Gynecol Neonatal Nurs. 2021 Jul. doi: 10.1016/j.jogn.2021.02.008.

13. Craemer KA et al. Perinatal mental health in low-income urban and rural patients: The importance of screening for comorbidities. Gen Hosp Psychiatry. 2023 Jul-Aug. doi: 10.1016/j.genhosppsych.2023.05.007.

14. O’Connor E et al. Primary care screening for and treatment of depression in pregnant and postpartum women: Evidence report and systematic review for the U.S. Preventive Services Task Force. JAMA. 2016 Jan 26. doi: 10.1001/jama.2015.18948.

15. Kozhimannil KB et al. Racial and ethnic disparities in postpartum depression care among low-income women. Psychiatr Serv. 2011 Jun. doi: 10.1176/ps.62.6.pss6206_0619.

16. Wenzel ES et al. Depression and anxiety symptoms across pregnancy and the postpartum in low-income Black and Latina women. Arch Womens Ment Health. 2021 Dec. doi: 10.1007/s00737-021-01139-y.

17. Gibbons RD et al. Development of a computerized adaptive substance use disorder scale for screening and measurement: The CAT‐SUD. Addiction. 2020 Jul. doi: 10.1111/add.14938.

18. Brenner LA et al. Validation of a computerized adaptive test suicide scale (CAT-SS) among united states military veterans. PloS One. 2022 Jan 21. doi: 10.1371/journal.pone.0261920.

19. The Center for State Child Welfare Data. Using technology to diagnose and report on behavioral health challenges facing foster youth. 2018.

20. Kim JJ et al. The experience of depression, anxiety, and mania among perinatal women. Arch Womens Ment Health. 2016 Oct. doi: 10.1007/s00737-016-0632-6.

21. Tepper MC et al. Toward population health: Using a learning behavioral health system and measurement-based care to improve access, care, outcomes, and disparities. Community Ment Health J. 2022 Nov. doi: 10.1007/s10597-022-00957-3.

22. Wenzel E et al. Using computerised adaptive tests to screen for perinatal depression in underserved women of colour. Evid Based Ment Health. 2022 Feb. doi: 10.1136/ebmental-2021-300262.

23. Sanger-Katz M. They want it to be secret: How a common blood test can cost $11 or almost $1,000. New York Times. 2019 Apr 19.

24. Spitzer RL et al. A brief measure for assessing generalized anxiety disorder: The GAD-7. Arch Intern Med. 2006 May 22. doi: 10.1001/archinte.166.10.1092.

25. Mollard E et al. An integrative review of postpartum depression in rural US communities. Arch Psychiatr Nurs. 2016 Jun. doi: 10.1016/j.apnu.2015.12.003.

26. Anglim AJ and Radke SM. Rural maternal health care outcomes, drivers, and patient perspectives. Clin Obstet Gynecol. 2022 Dec 1. doi: 10.1097/GRF.0000000000000753.

Mental health conditions are the leading cause of pregnancy-related death in Illinois (40%) and across the United States (21%).^1,2There is increasing recognition in primary care that major depressive disorder (MDD) often co-occurs with other mental health conditions. Funding bodies, such as the Agency for Healthcare Research and Quality³ and the Health Resources and Service Administration,⁴ have spotlights on improving screening and access to care for depression and substance use disorders (SUDs). However, the needs of individuals with multiple mental health conditions still often go unrecognized and unaddressed in perinatal health settings.

The U.S. Preventive Services Task Force recommends that all adults be screened for depression, alcohol use, and drug use, and will be recommending screening for anxiety.^5,6 The American College of Obstetrics and Gynecology recommends screening for perinatal mental health conditions including depression, anxiety, bipolar disorder, acute postpartum psychosis, and suicidality; however, despite these recommendations, screening and treatment for comorbid mental health disorders during pregnancy and the postpartum is not standard practice.⁷

Addressing perinatal mental health is critical because untreated mental health conditions during the perinatal period can cause long-term adverse psychiatric and medical outcomes for the birthing person, the baby, and the family.⁸ This commentary highlights the importance of recognizing and screening for perinatal mental health comorbidities, improving referral rates for mental health treatment, and raising awareness of the importance of addressing rural perinatal mental health.
 

Perinatal mental health comorbidities

Major depressive disorder is the most common mental health condition during the perinatal period⁹ and is often comorbid.^10-12 In “Perinatal mental health in low-income urban and rural patients: The importance of screening for comorbidities,” Craemer et al.¹³ reported that nearly half of the perinatal patients who screened positive for MDD also screened positive for at least one other mental health condition, among them general anxiety disorder (GAD), SUD, posttraumatic stress disorder (PTSD), and suicidality.

Many (9%) of the perinatal patients with MDD had a severe comorbidity profile characterized by four diagnoses – MDD, GAD, SUD, and PTSD. In routine medical care these comorbidities often go undetected even though the risk to mothers and babies increases with more severe mental health symptoms.⁸

The high frequency of perinatal mental health comorbidities Craemer et al.¹³ found demonstrates a compelling need for comorbid mental health screening during the perinatal period, particularly for low-income Black, Hispanic, and rural birthing persons. Positive screens for perinatal mental health disorders may reflect the onset of these disorders in pregnancy or the postpartum, or preexisting disorders that have gone undetected or untreated before pregnancy.

For many patients, the perinatal period is the first time they are screened for any mental health disorder; typically, they are screened solely for depression. Screening alone can have a positive impact on perinatal mental health. In fact, the USPSTF found that programs to screen perinatal patients, with or without treatment-related support, resulted in a 2%-9% absolute reduction in depression prevalence.¹⁴ However, screening for MDD is too infrequent for many reasons, including the logistics of integrating screening into the clinic workflow and limited provider availability, time, and training in mental health.

We recommend screening perinatal patients for mental health comorbidities. This recommendation may seem impractical given the lack of screening tools for comorbid mental health conditions; however, the Computerized Adaptive Test for Mental Health (CAT-MH), the validated tool^15-17 used in this study, is an ideal option. CAT-MH is uniquely capable of screening for MDD, GAD, PTSD, SUD, and suicidality in one platform and is routinely used in diverse settings including the Veterans Administration,¹⁸ foster care,¹⁹ and universities.²⁰ The main limitation of this more comprehensive screening is that it takes about 10 minutes per patient. However, CAT-MH is self-administered and can be done in the waiting room or on a mobile device prior to a clinic visit.

CAT-MH can also be easily integrated into clinical workflow when added to the Electronic Medical Record²¹, and is a more comprehensive tool than existing perinatal depression tools such as the Perinatal Health Questionaire-9 (PHQ-9) and Edinburgh Perinatal Depression Scale (EPDS).²² Another limitation is cost – currently $5.00 per assessment – however, this is less than routine blood work.²³ If CAT-MH is not an option, we recommend a stepped approach of screening for GAD when perinatal patients screen positive for MDD, as this is the most common comorbidity profile. The GAD-7 is a free and widely available tool.²⁴

Barriers to care

In Craemer et al,¹³ nearly two-thirds (64.9%) of perinatal patients with a positive screen did not receive a referral to follow-up care or a medication prescription. These low referral rates may reflect a variety of widely recognized barriers to care, including lack of referral options, provider and/or patient reluctance to pursue referrals, barriers to insurance coverage, or inadequate behavioral health infrastructure to ensure referral and diagnostic follow-up.

Further, rural residing perinatal patients are an underserved population that need more resources and screening. Despite an on-site behavioral specialist at the rural clinic, Craemer et al¹³ found a stark disparity in referral rates: referrals to treatment for a positive diagnosis was over two times less at the rural clinic (23.9%), compared with the urban clinics (51.6%). The most common treatment offered at the rural clinic was a prescription for medication (17.4%), while referral to follow-up care was the most common at the urban clinics (35.5%). Rural areas not only have a shortage of health care providers, but community members seeking mental health care often encounter greater stigma, compared with urban residents.^25,26

These data highlight an unmet need for referrals to treatment for patients in rural communities, particularly in Illinois where the pregnancy-related mortality ratio attributable to mental health conditions is three times greater in rural areas, compared with those residing in urban Cook County (Chicago).² Increasing access and availability to mental health treatment and prevention resources in Illinois, especially in rural areas, is an opportunity to prevent pregnancy-related mortality attributable to mental health conditions.

Overall, there is a critical need for screening for perinatal mental health comorbidities, increased attention to low rates of referral to mental health treatment, and investing in rural perinatal mental health. Addressing perinatal mental health disorders is key to decreasing the burden of maternal mortality, particularly in Illinois.

Ms. Craemer and Ms. Sayah are senior research specialists at the Center for Research on Women & Gender, University of Illinois at Chicago. Dr. Duffecy is a professor of clinical psychiatry at the University of Illinois at Chicago. Dr. Geller is a professor of obstetrics & gynecology and director of the Center for Research on Women & Gender, University of Illinois at Chicago. Dr. Maki is a professor of psychiatry, psychology, and obstetrics & gynecology at the University of Illinois at Chicago.

References

1. Trost S et al. Pregnancy-related deaths: Data from maternal mortality review committees in 36 states, 2017-2019. Atlanta: Centers for Disease Control and Prevention, U.S. Department of Health & Human Services, 2022.

2. Illinois Department of Public Health. Illinois maternal morbidity and mortality report 2016-2017. 2021.

3. AHRQ. Funding opportunities to address opioid and other substance use disorders. Updated 2023.

4. HRSA. Screening and treatment for maternal mental health and substance use disorders.

5. U.S. Preventive Services Task Force. Recommendations for primary care practice. Accessed May 26, 2023.

6. U.S. Preventive Services Task Force. Draft recommendation statement: Anxiety in adults: Screening. 2022.

7. ACOG. Screening and diagnosis of mental health conditions during pregnancy and postpartum. Clinical Practice Guideline. Number 4. 2023 June.

8. Meltzer-Brody S and Stuebe A. The long-term psychiatric and medical prognosis of perinatal mental illness. Best Pract Res Clin Obstet Gynaecol. 2014 Jan. doi: 10.1016/j.bpobgyn.2013.08.009.

9. Van Niel MS and Payne JL. Perinatal depression: A review. Cleve Clin J Med. 2020 May. doi: 10.3949/ccjm.87a.19054.

10. Wisner KL et al. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. 2013 May. doi: 10.1001/jamapsychiatry.2013.87.

11. Falah-Hassani K et al. The prevalence of antenatal and postnatal co-morbid anxiety and depression: A meta-analysis. Psychol Med. 2017 Sep. doi: 10.1017/S0033291717000617.

12. Pentecost R et al. Scoping review of the associations between perinatal substance use and perinatal depression and anxiety. J Obstet Gynecol Neonatal Nurs. 2021 Jul. doi: 10.1016/j.jogn.2021.02.008.

13. Craemer KA et al. Perinatal mental health in low-income urban and rural patients: The importance of screening for comorbidities. Gen Hosp Psychiatry. 2023 Jul-Aug. doi: 10.1016/j.genhosppsych.2023.05.007.

14. O’Connor E et al. Primary care screening for and treatment of depression in pregnant and postpartum women: Evidence report and systematic review for the U.S. Preventive Services Task Force. JAMA. 2016 Jan 26. doi: 10.1001/jama.2015.18948.

15. Kozhimannil KB et al. Racial and ethnic disparities in postpartum depression care among low-income women. Psychiatr Serv. 2011 Jun. doi: 10.1176/ps.62.6.pss6206_0619.

16. Wenzel ES et al. Depression and anxiety symptoms across pregnancy and the postpartum in low-income Black and Latina women. Arch Womens Ment Health. 2021 Dec. doi: 10.1007/s00737-021-01139-y.

17. Gibbons RD et al. Development of a computerized adaptive substance use disorder scale for screening and measurement: The CAT‐SUD. Addiction. 2020 Jul. doi: 10.1111/add.14938.

18. Brenner LA et al. Validation of a computerized adaptive test suicide scale (CAT-SS) among united states military veterans. PloS One. 2022 Jan 21. doi: 10.1371/journal.pone.0261920.

19. The Center for State Child Welfare Data. Using technology to diagnose and report on behavioral health challenges facing foster youth. 2018.

20. Kim JJ et al. The experience of depression, anxiety, and mania among perinatal women. Arch Womens Ment Health. 2016 Oct. doi: 10.1007/s00737-016-0632-6.

21. Tepper MC et al. Toward population health: Using a learning behavioral health system and measurement-based care to improve access, care, outcomes, and disparities. Community Ment Health J. 2022 Nov. doi: 10.1007/s10597-022-00957-3.

22. Wenzel E et al. Using computerised adaptive tests to screen for perinatal depression in underserved women of colour. Evid Based Ment Health. 2022 Feb. doi: 10.1136/ebmental-2021-300262.

23. Sanger-Katz M. They want it to be secret: How a common blood test can cost $11 or almost $1,000. New York Times. 2019 Apr 19.

24. Spitzer RL et al. A brief measure for assessing generalized anxiety disorder: The GAD-7. Arch Intern Med. 2006 May 22. doi: 10.1001/archinte.166.10.1092.

25. Mollard E et al. An integrative review of postpartum depression in rural US communities. Arch Psychiatr Nurs. 2016 Jun. doi: 10.1016/j.apnu.2015.12.003.

26. Anglim AJ and Radke SM. Rural maternal health care outcomes, drivers, and patient perspectives. Clin Obstet Gynecol. 2022 Dec 1. doi: 10.1097/GRF.0000000000000753.