Women giving birth for the first time have significantly higher odds of developing gestational diabetes if they have a high polygenic risk score (PRS) and low physical activity, new data suggest.

Researchers, led by Kymberleigh A. Pagel, PhD, with the department of computer science, Indiana University, Bloomington, concluded that physical activity early in pregnancy is associated with reduced risk of gestational diabetes and may help women who are at high risk because of genetic predisposition, age, family history of diabetes, and body mass index.

The researchers included 3,533 women in the analysis (average age, 28.6 years) which was a subcohort of a larger study. They found that physical activity’s association with lower gestational diabetes risk “was particularly significant in individuals who were genetically predisposed to diabetes through PRS or family history,” the authors wrote.

Women with high PRS and low level of physical activity had three times the odds of developing gestational diabetes (odds ratio, 3.4; 95% confidence interval, 2.3-5.3).

Those with high PRS and moderate to high activity levels in early pregnancy (metabolic equivalents of task [METs] of at least 450) had gestational diabetes risk similar to that of the general population, according to the researchers.

The findings were published in JAMA Network Open.

Maisa Feghali, MD, a maternal-fetal specialist at the University of Pittsburgh Medical Center, who was not part of the study, said in an interview she found the link of physical activity and compensation for high predisposition to gestational diabetes most interesting.

“That’s interesting because a lot of studies that have looked at prevention of gestational diabetes either through limited weight gain or through some form of counseling on physical activity have not really shown any benefit,” she noted. “It might just be it’s not just one size fits all and it may be that physical activity is mostly beneficial in those with a high predisposition.”

Research in this area is particularly important as 7% of pregnancies in the United States each year are affected by gestational diabetes and the risk for developing type 2 diabetes “has doubled in the past decade among patients with GD [gestational diabetes],” the authors wrote.

Researchers looked at risks for gestational diabetes in high-risk subgroups, including women who had a body mass index of more than 25 kg/m² or were at least 35 years old. In that group, women who were either in the in the top 25th percentile for PRS or had low physical activity (METs less than 450) had from 25% to 75% greater risk of developing gestational diabetes.

The findings are consistent with previous research and suggest exercise interventions may be important in improving pregnancy outcomes, the authors wrote.

Christina Han, MD, division director for maternal-fetal medicine at University of California, Los Angeles, who was not part of the study, pointed out several limitations of the study, however.

One of the biggest limitations, she said, was that “they excluded two-thirds of the original study. Essentially, they took only Caucasian [White] patients, which is about one-third of the study.” Additionally, the cohort was made up of people who had never had babies.

“Lots of our gestational diabetes patients are not first-time moms, so this makes the generalizability of the study very limited,” Dr. Han said.

She added that none of the sites where the study was conducted were in the South or Northwest, which also adds questions about generalizability.

Dr. Feghali and Dr. Han reported no relevant financial relationships.

Women giving birth for the first time have significantly higher odds of developing gestational diabetes if they have a high polygenic risk score (PRS) and low physical activity, new data suggest.

Researchers, led by Kymberleigh A. Pagel, PhD, with the department of computer science, Indiana University, Bloomington, concluded that physical activity early in pregnancy is associated with reduced risk of gestational diabetes and may help women who are at high risk because of genetic predisposition, age, family history of diabetes, and body mass index.

The researchers included 3,533 women in the analysis (average age, 28.6 years) which was a subcohort of a larger study. They found that physical activity’s association with lower gestational diabetes risk “was particularly significant in individuals who were genetically predisposed to diabetes through PRS or family history,” the authors wrote.

Women with high PRS and low level of physical activity had three times the odds of developing gestational diabetes (odds ratio, 3.4; 95% confidence interval, 2.3-5.3).

Those with high PRS and moderate to high activity levels in early pregnancy (metabolic equivalents of task [METs] of at least 450) had gestational diabetes risk similar to that of the general population, according to the researchers.

The findings were published in JAMA Network Open.

Maisa Feghali, MD, a maternal-fetal specialist at the University of Pittsburgh Medical Center, who was not part of the study, said in an interview she found the link of physical activity and compensation for high predisposition to gestational diabetes most interesting.

“That’s interesting because a lot of studies that have looked at prevention of gestational diabetes either through limited weight gain or through some form of counseling on physical activity have not really shown any benefit,” she noted. “It might just be it’s not just one size fits all and it may be that physical activity is mostly beneficial in those with a high predisposition.”

Research in this area is particularly important as 7% of pregnancies in the United States each year are affected by gestational diabetes and the risk for developing type 2 diabetes “has doubled in the past decade among patients with GD [gestational diabetes],” the authors wrote.

Researchers looked at risks for gestational diabetes in high-risk subgroups, including women who had a body mass index of more than 25 kg/m² or were at least 35 years old. In that group, women who were either in the in the top 25th percentile for PRS or had low physical activity (METs less than 450) had from 25% to 75% greater risk of developing gestational diabetes.

The findings are consistent with previous research and suggest exercise interventions may be important in improving pregnancy outcomes, the authors wrote.

Christina Han, MD, division director for maternal-fetal medicine at University of California, Los Angeles, who was not part of the study, pointed out several limitations of the study, however.

One of the biggest limitations, she said, was that “they excluded two-thirds of the original study. Essentially, they took only Caucasian [White] patients, which is about one-third of the study.” Additionally, the cohort was made up of people who had never had babies.

“Lots of our gestational diabetes patients are not first-time moms, so this makes the generalizability of the study very limited,” Dr. Han said.

She added that none of the sites where the study was conducted were in the South or Northwest, which also adds questions about generalizability.

Dr. Feghali and Dr. Han reported no relevant financial relationships.

Women giving birth for the first time have significantly higher odds of developing gestational diabetes if they have a high polygenic risk score (PRS) and low physical activity, new data suggest.

Researchers, led by Kymberleigh A. Pagel, PhD, with the department of computer science, Indiana University, Bloomington, concluded that physical activity early in pregnancy is associated with reduced risk of gestational diabetes and may help women who are at high risk because of genetic predisposition, age, family history of diabetes, and body mass index.

The researchers included 3,533 women in the analysis (average age, 28.6 years) which was a subcohort of a larger study. They found that physical activity’s association with lower gestational diabetes risk “was particularly significant in individuals who were genetically predisposed to diabetes through PRS or family history,” the authors wrote.

Women with high PRS and low level of physical activity had three times the odds of developing gestational diabetes (odds ratio, 3.4; 95% confidence interval, 2.3-5.3).

Those with high PRS and moderate to high activity levels in early pregnancy (metabolic equivalents of task [METs] of at least 450) had gestational diabetes risk similar to that of the general population, according to the researchers.

The findings were published in JAMA Network Open.

Maisa Feghali, MD, a maternal-fetal specialist at the University of Pittsburgh Medical Center, who was not part of the study, said in an interview she found the link of physical activity and compensation for high predisposition to gestational diabetes most interesting.

“That’s interesting because a lot of studies that have looked at prevention of gestational diabetes either through limited weight gain or through some form of counseling on physical activity have not really shown any benefit,” she noted. “It might just be it’s not just one size fits all and it may be that physical activity is mostly beneficial in those with a high predisposition.”

Research in this area is particularly important as 7% of pregnancies in the United States each year are affected by gestational diabetes and the risk for developing type 2 diabetes “has doubled in the past decade among patients with GD [gestational diabetes],” the authors wrote.

Researchers looked at risks for gestational diabetes in high-risk subgroups, including women who had a body mass index of more than 25 kg/m² or were at least 35 years old. In that group, women who were either in the in the top 25th percentile for PRS or had low physical activity (METs less than 450) had from 25% to 75% greater risk of developing gestational diabetes.

The findings are consistent with previous research and suggest exercise interventions may be important in improving pregnancy outcomes, the authors wrote.

Christina Han, MD, division director for maternal-fetal medicine at University of California, Los Angeles, who was not part of the study, pointed out several limitations of the study, however.

One of the biggest limitations, she said, was that “they excluded two-thirds of the original study. Essentially, they took only Caucasian [White] patients, which is about one-third of the study.” Additionally, the cohort was made up of people who had never had babies.

“Lots of our gestational diabetes patients are not first-time moms, so this makes the generalizability of the study very limited,” Dr. Han said.

She added that none of the sites where the study was conducted were in the South or Northwest, which also adds questions about generalizability.

Dr. Feghali and Dr. Han reported no relevant financial relationships.

Living-donor liver transplant recipients gained an additional 13-17 years of life, compared with patients who remained on the wait list, according to a retrospective case-control study.

The data suggest that the life-years gained are comparable to or greater than those conferred by either other lifesaving procedures or liver transplant from a deceased donor, wrote the researchers, led by Whitney Jackson, MD, assistant professor of gastroenterology and medical director of living-donor liver transplantation at the University of Colorado Anschutz Medical Campus.

“Despite the acceptance of living-donor liver transplant as a lifesaving procedure for end-stage liver disease, it remains underused in the United States,” the authors wrote in JAMA Surgery. “This study’s findings challenge current perceptions regarding when the survival benefit of a living-donor transplant occurs.”

Dr. Jackson and colleagues conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients database for 119,275 U.S. liver transplant candidates and recipients from January 2012 to September 2021. They assessed the survival benefit, life-years saved, and the Model for End-Stage Liver Disease incorporating sodium levels (MELD-Na) score at which the survival benefit was obtained, compared with those who remained on the wait list.

The research team included 116,455 liver transplant candidates who were 18 and older and assigned to the wait list, as well as 2,820 patients who received a living-donor liver transplant. Patients listed for retransplant or multiorgan transplant were excluded, as were those with prior kidney or liver transplants.

The mean age of the study participants was 55 years, and 63% were men. Overall, 70.2% were White, 15.8% were Hispanic or Latinx, 8.2% were Black or African American, 4.3% were Asian, 0.9% were American Indian or Alaska Native, and 0.2% were Native Hawaiian or Pacific Islander. The most common etiologies were alcoholic cirrhosis (23.8%) and nonalcoholic steatohepatitis (15.9%).

Compared with patients on the wait list, recipients of a living-donor liver transplant were younger, more often women, more educated, and more often White. A greater proportion of transplant recipients had a primary etiology of nonalcoholic steatohepatitis (19.8%) and cholestatic liver disease (24.1%). At wait list placement, one-third of candidates had a MELD-Na score of 14 or higher.

The research team found a significant survival benefit for patients receiving a living-donor liver transplant based on mortality risk and survival scores. The survival benefit was significant at a MELD-Na score as low as 11, with a 34% decrease(95% confidence interval [CI], 17.4%-52.0%) in mortality compared with the wait list. In addition, mortality risk models confirmed a survival benefit for patients with a MELD-Na score of 11 or higher at 1 year after transplant (adjusted hazard ratio, 0.64; 95% CI, 0.47-0.88; P = .006). At a MELD-Na score of 14-16, mortality decreased by about 50% (aHR, 0.47; 95% CI, 0.34-0.66; P < .001).

The probability of death from a living-donor liver transplant for patients with very low MELD-Na scores (between 6 and 10) was greater than that for patients on the wait list for the first 259 days, at which point the risk of death for both groups was equal. At 471 days, the probability of survival in both groups was equal. As the MELD-Na score increased, both the time to equal risk of death and the time to equal survival decreased, demonstrating that the survival benefit occurs much earlier for patients with a higher MELD-Na score.

Analysis of life-years from transplant showed living-donor transplant recipients gained 13-17 life-years compared to those who didn’t receive one.

“Living-donor liver transplantation is a valuable yet underutilized strategy to address the significant organ shortage and long waiting times on the transplant list in the U.S.,” said Renu Dhanasekaran, MD, PhD, assistant professor of gastroenterology and hepatology at Stanford (Calif.) University.

Dr. Dhanasekaran, who wasn’t involved with this study, also welcomed the finding that living-donor liver transplantation can benefit patients with low MELD-Na scores, even below the expected cutoff at 15. According to the study authors, previous research had suggested benefit would be seen only at MELD-Na 15 and above.

“In my practice, I have several patients whose symptoms are out of proportion to their MELD score, and data like this will convince them and their potential donors to avail a transplant at an earlier stage,” she said.

The findings challenge the current paradigm around the timing of referral for a liver transplant and may have ramifications for allocation policies for deceased donors, the study authors wrote. The data can also help to contextualize risk-benefit discussions for donors and recipients.

“Donating a part of one’s liver to save a patient suffering from end-stage liver disease is an incredible act of selfless love,” Dr. Dhanasekaran said. “I hope strong positive data from studies like this one encourage more donors, patients, and transplant centers to expand the use of [living-donor liver transplant].”

The authors reported no grant support or funding sources for this study. One author disclosed being married to the current chair of the United Network for Organ Sharing’s Liver and Intestinal Organ Transplantation Committee. No other conflicts of interest were reported. Dr. Dhanasekaran reported no relevant disclosures.

Living-donor liver transplant recipients gained an additional 13-17 years of life, compared with patients who remained on the wait list, according to a retrospective case-control study.

The data suggest that the life-years gained are comparable to or greater than those conferred by either other lifesaving procedures or liver transplant from a deceased donor, wrote the researchers, led by Whitney Jackson, MD, assistant professor of gastroenterology and medical director of living-donor liver transplantation at the University of Colorado Anschutz Medical Campus.

“Despite the acceptance of living-donor liver transplant as a lifesaving procedure for end-stage liver disease, it remains underused in the United States,” the authors wrote in JAMA Surgery. “This study’s findings challenge current perceptions regarding when the survival benefit of a living-donor transplant occurs.”

Dr. Jackson and colleagues conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients database for 119,275 U.S. liver transplant candidates and recipients from January 2012 to September 2021. They assessed the survival benefit, life-years saved, and the Model for End-Stage Liver Disease incorporating sodium levels (MELD-Na) score at which the survival benefit was obtained, compared with those who remained on the wait list.

The research team included 116,455 liver transplant candidates who were 18 and older and assigned to the wait list, as well as 2,820 patients who received a living-donor liver transplant. Patients listed for retransplant or multiorgan transplant were excluded, as were those with prior kidney or liver transplants.

The mean age of the study participants was 55 years, and 63% were men. Overall, 70.2% were White, 15.8% were Hispanic or Latinx, 8.2% were Black or African American, 4.3% were Asian, 0.9% were American Indian or Alaska Native, and 0.2% were Native Hawaiian or Pacific Islander. The most common etiologies were alcoholic cirrhosis (23.8%) and nonalcoholic steatohepatitis (15.9%).

Compared with patients on the wait list, recipients of a living-donor liver transplant were younger, more often women, more educated, and more often White. A greater proportion of transplant recipients had a primary etiology of nonalcoholic steatohepatitis (19.8%) and cholestatic liver disease (24.1%). At wait list placement, one-third of candidates had a MELD-Na score of 14 or higher.

The research team found a significant survival benefit for patients receiving a living-donor liver transplant based on mortality risk and survival scores. The survival benefit was significant at a MELD-Na score as low as 11, with a 34% decrease(95% confidence interval [CI], 17.4%-52.0%) in mortality compared with the wait list. In addition, mortality risk models confirmed a survival benefit for patients with a MELD-Na score of 11 or higher at 1 year after transplant (adjusted hazard ratio, 0.64; 95% CI, 0.47-0.88; P = .006). At a MELD-Na score of 14-16, mortality decreased by about 50% (aHR, 0.47; 95% CI, 0.34-0.66; P < .001).

The probability of death from a living-donor liver transplant for patients with very low MELD-Na scores (between 6 and 10) was greater than that for patients on the wait list for the first 259 days, at which point the risk of death for both groups was equal. At 471 days, the probability of survival in both groups was equal. As the MELD-Na score increased, both the time to equal risk of death and the time to equal survival decreased, demonstrating that the survival benefit occurs much earlier for patients with a higher MELD-Na score.

Analysis of life-years from transplant showed living-donor transplant recipients gained 13-17 life-years compared to those who didn’t receive one.

“Living-donor liver transplantation is a valuable yet underutilized strategy to address the significant organ shortage and long waiting times on the transplant list in the U.S.,” said Renu Dhanasekaran, MD, PhD, assistant professor of gastroenterology and hepatology at Stanford (Calif.) University.

Dr. Dhanasekaran, who wasn’t involved with this study, also welcomed the finding that living-donor liver transplantation can benefit patients with low MELD-Na scores, even below the expected cutoff at 15. According to the study authors, previous research had suggested benefit would be seen only at MELD-Na 15 and above.

“In my practice, I have several patients whose symptoms are out of proportion to their MELD score, and data like this will convince them and their potential donors to avail a transplant at an earlier stage,” she said.

The findings challenge the current paradigm around the timing of referral for a liver transplant and may have ramifications for allocation policies for deceased donors, the study authors wrote. The data can also help to contextualize risk-benefit discussions for donors and recipients.

“Donating a part of one’s liver to save a patient suffering from end-stage liver disease is an incredible act of selfless love,” Dr. Dhanasekaran said. “I hope strong positive data from studies like this one encourage more donors, patients, and transplant centers to expand the use of [living-donor liver transplant].”

The authors reported no grant support or funding sources for this study. One author disclosed being married to the current chair of the United Network for Organ Sharing’s Liver and Intestinal Organ Transplantation Committee. No other conflicts of interest were reported. Dr. Dhanasekaran reported no relevant disclosures.

Living-donor liver transplant recipients gained an additional 13-17 years of life, compared with patients who remained on the wait list, according to a retrospective case-control study.

The data suggest that the life-years gained are comparable to or greater than those conferred by either other lifesaving procedures or liver transplant from a deceased donor, wrote the researchers, led by Whitney Jackson, MD, assistant professor of gastroenterology and medical director of living-donor liver transplantation at the University of Colorado Anschutz Medical Campus.

“Despite the acceptance of living-donor liver transplant as a lifesaving procedure for end-stage liver disease, it remains underused in the United States,” the authors wrote in JAMA Surgery. “This study’s findings challenge current perceptions regarding when the survival benefit of a living-donor transplant occurs.”

Dr. Jackson and colleagues conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients database for 119,275 U.S. liver transplant candidates and recipients from January 2012 to September 2021. They assessed the survival benefit, life-years saved, and the Model for End-Stage Liver Disease incorporating sodium levels (MELD-Na) score at which the survival benefit was obtained, compared with those who remained on the wait list.

The research team included 116,455 liver transplant candidates who were 18 and older and assigned to the wait list, as well as 2,820 patients who received a living-donor liver transplant. Patients listed for retransplant or multiorgan transplant were excluded, as were those with prior kidney or liver transplants.

The mean age of the study participants was 55 years, and 63% were men. Overall, 70.2% were White, 15.8% were Hispanic or Latinx, 8.2% were Black or African American, 4.3% were Asian, 0.9% were American Indian or Alaska Native, and 0.2% were Native Hawaiian or Pacific Islander. The most common etiologies were alcoholic cirrhosis (23.8%) and nonalcoholic steatohepatitis (15.9%).

Compared with patients on the wait list, recipients of a living-donor liver transplant were younger, more often women, more educated, and more often White. A greater proportion of transplant recipients had a primary etiology of nonalcoholic steatohepatitis (19.8%) and cholestatic liver disease (24.1%). At wait list placement, one-third of candidates had a MELD-Na score of 14 or higher.

The research team found a significant survival benefit for patients receiving a living-donor liver transplant based on mortality risk and survival scores. The survival benefit was significant at a MELD-Na score as low as 11, with a 34% decrease(95% confidence interval [CI], 17.4%-52.0%) in mortality compared with the wait list. In addition, mortality risk models confirmed a survival benefit for patients with a MELD-Na score of 11 or higher at 1 year after transplant (adjusted hazard ratio, 0.64; 95% CI, 0.47-0.88; P = .006). At a MELD-Na score of 14-16, mortality decreased by about 50% (aHR, 0.47; 95% CI, 0.34-0.66; P < .001).

The probability of death from a living-donor liver transplant for patients with very low MELD-Na scores (between 6 and 10) was greater than that for patients on the wait list for the first 259 days, at which point the risk of death for both groups was equal. At 471 days, the probability of survival in both groups was equal. As the MELD-Na score increased, both the time to equal risk of death and the time to equal survival decreased, demonstrating that the survival benefit occurs much earlier for patients with a higher MELD-Na score.

Analysis of life-years from transplant showed living-donor transplant recipients gained 13-17 life-years compared to those who didn’t receive one.

“Living-donor liver transplantation is a valuable yet underutilized strategy to address the significant organ shortage and long waiting times on the transplant list in the U.S.,” said Renu Dhanasekaran, MD, PhD, assistant professor of gastroenterology and hepatology at Stanford (Calif.) University.

Dr. Dhanasekaran, who wasn’t involved with this study, also welcomed the finding that living-donor liver transplantation can benefit patients with low MELD-Na scores, even below the expected cutoff at 15. According to the study authors, previous research had suggested benefit would be seen only at MELD-Na 15 and above.

“In my practice, I have several patients whose symptoms are out of proportion to their MELD score, and data like this will convince them and their potential donors to avail a transplant at an earlier stage,” she said.

The findings challenge the current paradigm around the timing of referral for a liver transplant and may have ramifications for allocation policies for deceased donors, the study authors wrote. The data can also help to contextualize risk-benefit discussions for donors and recipients.

“Donating a part of one’s liver to save a patient suffering from end-stage liver disease is an incredible act of selfless love,” Dr. Dhanasekaran said. “I hope strong positive data from studies like this one encourage more donors, patients, and transplant centers to expand the use of [living-donor liver transplant].”

The authors reported no grant support or funding sources for this study. One author disclosed being married to the current chair of the United Network for Organ Sharing’s Liver and Intestinal Organ Transplantation Committee. No other conflicts of interest were reported. Dr. Dhanasekaran reported no relevant disclosures.

Borderline personality disorder was significantly associated with relapse after 6 months in adults with major depressive disorder who underwent electroconvulsive therapy (ECT), based on data from 109 individuals.

ECT has demonstrated effectiveness for treatment of unipolar and bipolar major depression, but relapses within 6 months are frequent, and potential factors affecting relapse have not been well studied, wrote Matthieu Hein, MD, PhD, of Erasme Hospital, Université Libre de Bruxelles, and colleagues.

Borderline personality disorder (BPD) is a common comorbidity among individuals with major depressive disorder, and previous research suggests a possible negative effect of BPD on ECT response in MDD patients, they wrote.

In a study published in Psychiatry Research, the researchers recruited 68 females and 41 males aged 18 years and older with diagnosed MDD who had partial or complete response to ECT after receiving treatment at a single center. Approximately two-thirds of the patients were aged 50 years and older, and 22 met criteria for BPD. The ECT consisted of three sessions per week; the total number of sessions ranged from 6 to 18.

The primary outcome was relapse at 6 months after ECT treatment. Relapse was defined as a score of 16 or higher on the Hamilton Depression Rating Scale in combination with a mean absolute increase of at least 10 points from the psychiatric interview at the end of the ECT.

Relapse rates at 6 months were 37.6% for the study population overall, but significantly higher for those with BPD, compared with those without BPD (72.7% vs. 28.7%; P < .001).

In a multivariate analysis, adjusting for age, gender, and mood stabilizer use after ECT, relapse was approximately four times more likely among individuals with BPD, compared with those without (hazard ratio, 4.14). No significant association appeared between increased relapse and other comorbid personality disorders, anxiety disorders, alcohol or substance use disorders, or hospitalization during the ECT treatment period.

Potential reasons for the increased relapse risk among individuals with MDD and BPD include the younger age of the individuals with BPD, which has been shown to increase MDD relapse risk; the direct negative impact of BPD on mental functioning; and the documented tendency to poor treatment adherence, the researchers wrote in their discussion.

“Given these different elements, it seems important to screen more systematically for BPD in major depressed individuals treated with ECT in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation,” they emphasized.

“The demonstration of this higher risk of relapse within 6 months associated with BPD in major depressed individuals treated with ECT could open new therapeutic perspectives to allow better maintenance of euthymia in this particular subpopulation,” they added.

The study findings were limited by several factors including the retrospective design and the focus on only BPD, which may not generalize to other personality disorders, the researchers noted.

However, the results support data from previous studies and highlight the need for more systematic BPD screening in MDD patients to prevent relapse after ECT, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.
 

Borderline personality disorder was significantly associated with relapse after 6 months in adults with major depressive disorder who underwent electroconvulsive therapy (ECT), based on data from 109 individuals.

ECT has demonstrated effectiveness for treatment of unipolar and bipolar major depression, but relapses within 6 months are frequent, and potential factors affecting relapse have not been well studied, wrote Matthieu Hein, MD, PhD, of Erasme Hospital, Université Libre de Bruxelles, and colleagues.

Borderline personality disorder (BPD) is a common comorbidity among individuals with major depressive disorder, and previous research suggests a possible negative effect of BPD on ECT response in MDD patients, they wrote.

In a study published in Psychiatry Research, the researchers recruited 68 females and 41 males aged 18 years and older with diagnosed MDD who had partial or complete response to ECT after receiving treatment at a single center. Approximately two-thirds of the patients were aged 50 years and older, and 22 met criteria for BPD. The ECT consisted of three sessions per week; the total number of sessions ranged from 6 to 18.

The primary outcome was relapse at 6 months after ECT treatment. Relapse was defined as a score of 16 or higher on the Hamilton Depression Rating Scale in combination with a mean absolute increase of at least 10 points from the psychiatric interview at the end of the ECT.

Relapse rates at 6 months were 37.6% for the study population overall, but significantly higher for those with BPD, compared with those without BPD (72.7% vs. 28.7%; P < .001).

In a multivariate analysis, adjusting for age, gender, and mood stabilizer use after ECT, relapse was approximately four times more likely among individuals with BPD, compared with those without (hazard ratio, 4.14). No significant association appeared between increased relapse and other comorbid personality disorders, anxiety disorders, alcohol or substance use disorders, or hospitalization during the ECT treatment period.

Potential reasons for the increased relapse risk among individuals with MDD and BPD include the younger age of the individuals with BPD, which has been shown to increase MDD relapse risk; the direct negative impact of BPD on mental functioning; and the documented tendency to poor treatment adherence, the researchers wrote in their discussion.

“Given these different elements, it seems important to screen more systematically for BPD in major depressed individuals treated with ECT in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation,” they emphasized.

“The demonstration of this higher risk of relapse within 6 months associated with BPD in major depressed individuals treated with ECT could open new therapeutic perspectives to allow better maintenance of euthymia in this particular subpopulation,” they added.

The study findings were limited by several factors including the retrospective design and the focus on only BPD, which may not generalize to other personality disorders, the researchers noted.

However, the results support data from previous studies and highlight the need for more systematic BPD screening in MDD patients to prevent relapse after ECT, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.
 

Borderline personality disorder was significantly associated with relapse after 6 months in adults with major depressive disorder who underwent electroconvulsive therapy (ECT), based on data from 109 individuals.

ECT has demonstrated effectiveness for treatment of unipolar and bipolar major depression, but relapses within 6 months are frequent, and potential factors affecting relapse have not been well studied, wrote Matthieu Hein, MD, PhD, of Erasme Hospital, Université Libre de Bruxelles, and colleagues.

Borderline personality disorder (BPD) is a common comorbidity among individuals with major depressive disorder, and previous research suggests a possible negative effect of BPD on ECT response in MDD patients, they wrote.

In a study published in Psychiatry Research, the researchers recruited 68 females and 41 males aged 18 years and older with diagnosed MDD who had partial or complete response to ECT after receiving treatment at a single center. Approximately two-thirds of the patients were aged 50 years and older, and 22 met criteria for BPD. The ECT consisted of three sessions per week; the total number of sessions ranged from 6 to 18.

The primary outcome was relapse at 6 months after ECT treatment. Relapse was defined as a score of 16 or higher on the Hamilton Depression Rating Scale in combination with a mean absolute increase of at least 10 points from the psychiatric interview at the end of the ECT.

Relapse rates at 6 months were 37.6% for the study population overall, but significantly higher for those with BPD, compared with those without BPD (72.7% vs. 28.7%; P < .001).

In a multivariate analysis, adjusting for age, gender, and mood stabilizer use after ECT, relapse was approximately four times more likely among individuals with BPD, compared with those without (hazard ratio, 4.14). No significant association appeared between increased relapse and other comorbid personality disorders, anxiety disorders, alcohol or substance use disorders, or hospitalization during the ECT treatment period.

Potential reasons for the increased relapse risk among individuals with MDD and BPD include the younger age of the individuals with BPD, which has been shown to increase MDD relapse risk; the direct negative impact of BPD on mental functioning; and the documented tendency to poor treatment adherence, the researchers wrote in their discussion.

“Given these different elements, it seems important to screen more systematically for BPD in major depressed individuals treated with ECT in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation,” they emphasized.

“The demonstration of this higher risk of relapse within 6 months associated with BPD in major depressed individuals treated with ECT could open new therapeutic perspectives to allow better maintenance of euthymia in this particular subpopulation,” they added.

The study findings were limited by several factors including the retrospective design and the focus on only BPD, which may not generalize to other personality disorders, the researchers noted.

However, the results support data from previous studies and highlight the need for more systematic BPD screening in MDD patients to prevent relapse after ECT, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.
 

Many patients experience neuropsychiatric symptoms following stroke. There is tremendous variation in the type, severity, and timeline of these symptoms, which have the potential to significantly impact patients’ quality of life. Some symptoms occur as a direct result of ischemic injury to brain structures regulating behavior, executive function, perception, or affect. Other symptoms occur indirectly due to the patient’s often-difficult experiences with the health care system, disrupted routines, or altered poststroke functional abilities. Psychiatric symptoms are not as easily recognized as classic stroke symptoms (such as hemiparesis) and are frequently overlooked, especially in the acute phase. However, these symptoms can negatively influence patients’ interpersonal relationships, rehabilitation, and employment.

Patients and families may not realize certain symptoms are stroke-related and may not discuss them with their clinicians. It is important to ask about and recognize psychiatric symptoms in patients who have experienced a stroke so you can provide optimal education and treatment. In this article, we review the types of psychiatric symptoms associated with strokes in specific brain regions (Table^1-10). We also describe symptoms that do not appear directly related to the anatomical structures affected by the infarct, including delirium, psychosis, depression, anxiety, and posttraumatic stress.

Symptoms associated with stroke in specific regions

Frontal lobe strokes

The frontal lobes are the largest lobes in the brain, and damage to areas within these lobes can cause behavioral and personality changes. Lesions in the lateral frontal cortex can cause aprosodia (difficulty expressing or comprehending variations in tone of voice), which can lead to communication errors. Lateral frontal cortex injury can cause executive dysfunction and a lack of empathy¹ as well as trouble with attention, planning, and self-regulation that may affect daily functioning. Strokes affecting the superior and inferior mesial cortices may result in apathy, lack of motivation, altered self-regulation, altered emotional processing, and disinhibition. Patients who experience a basal forebrain stroke may exhibit confabulation, reduced motivation, and delusions such as Capgras syndrome (the belief that a person or place has been replaced by an exact copy) and reduplicative paramnesia (the belief that a place has been either moved, duplicated, or exists in 2 places simultaneously). Strokes involving the orbital cortex can be associated with personality changes, impulsivity, poor social judgment, reduced empathy, altered self-regulation, lack of goal-directed behavior, and environmental dependency.

Some strokes may occur primarily in the subcortical white matter within the frontal lobes. Symptoms may be due to a single stroke with sudden onset, or due to repeated ischemic events that accumulate over time, as seen with microvascular disease. In the case of microvascular disease, the onset of symptoms may be insidious and the course progressive. Infarcts in the subcortical area can also cause personality changes (though typically more subtle when compared to orbitofrontal strokes), reduced emotions, poor empathy, and irritability.¹ Patients may lack insight into some of or all these symptoms following a frontal lobe infarct, which makes it critical to gather collateral information from the patient’s friends or family.

Parietal lobe strokes

Symptomatology from parietal strokes depends on whether the stroke affects the dominant or nondominant hemisphere. Dominant parietal lesions cause language deficits, and psychiatric symptoms may be difficult to elucidate due to the patient’s inability to communicate.² On the other hand, patients with nondominant parietal stroke may have neglect of, or inattention to, the opposite (typically left) side.³ This often manifests as a reluctance to use the affected limb or limbs, in some cases despite a lack of true weakness or motor dysfunction. In addition, patients may also have visual and/or tactile inattention towards the affected side, despite a lack of gross visual or sensory impairment.² In rare cases, a patient’s stroke may be misdiagnosed as a functional disorder due to the perceived unwillingness to use a neurologically intact limb. In severe cases, patients may not recognize an affected extremity as their own. Patients are also frequently unaware of deficits affecting their nondominant side and may argue with those attempting to explain their deficit. Anosodiaphoria—an abnormal lack of concern regarding their deficits—may also be observed. Additionally, aprosodia, flat affect, and personality changes may result from strokes affecting the nondominant hemisphere, which can impact the patient’s relationships and social functioning.³

Occipital lobe strokes

While negative or loss-of-function symptomatology is one of the hallmarks of stroke, occipital lobe infarcts can pose an exception. Although vision loss is the most common symptom with occipital lobe strokes, some patients experience visual hallucinations that may occur acutely or subacutely. In the acute phase, patients may report hallucinations of varied description,⁴ including poorly formed areas of color, scotomas, metamorphopsia (visual distortion in which straight lines appear curved), more complex and formed hallucinations and/or palinoptic images (images or brief scenes that continue to be perceived after looking away). These hallucinations, often referred to as release phenomena or release hallucinations, are thought to result from disinhibition of the visual cortex, which then fires spontaneously.

Hallucinations are associated with either infarction or hemorrhage in the posterior cerebral artery territory. In some cases, the hallucinations may take on a formed, complex appearance, and Charles Bonnet syndrome (visual hallucinations in the setting of vision loss, with insight into the hallucinations) has been identified in a small portion of patients.⁵

Continue to: The duration of these...

The duration of these hallucinations varies. Some patients describe very short periods of the disturbance, lasting minutes to hours and corresponding with the onset of their stroke. Others experience prolonged hallucinations, which frequently evolve into formed, complex images, lasting from days to months.⁶ In the setting of cortical stroke, patients may be at risk for seizures, which could manifest as visual hallucinations. It is essential to ensure that epileptic causes of hallucinations have been ruled out, because seizures may require treatment and other precautions.

Other stroke locations

Strokes in other locations also can result in psychiatric or behavioral symptoms. Acute stroke in the subcortical midbrain or thalamus may result in peduncular hallucinosis, a syndrome of vivid visual hallucinations.⁷ The midbrain (most commonly the reticular formation) is usually affected; however, certain lesions of the thalamus may also cause peduncular hallucinosis. This phenomenon is theorized to be due to an increase in serotonin activity relative to acetylcholine and is often accompanied by drowsiness.

The subthalamic nucleus is most frequently associated with disordered movement such as hemiballismus, but also causes disturbances in mood and behavior, including hyperphagia and personality changes.⁸ Irritability, aggressiveness, disinhibition, anxiety, and obscene speech may also be seen with lesions of the subthalamic nucleus.

Finally, the caudate nucleus may cause alterations in executive functioning and behavior.⁹ A stroke in the dorsolateral caudate may cause abulia and psychic akinesia, decreased problem-solving ability, reduced abstract thinking, and/or diminished spontaneity, whereas an infarct in the ventromedial region of the nucleus may cause disinhibition, disorganization, impulsiveness, and, in severe cases, affective symptoms with psychosis.¹⁰ Strokes in any of these areas are at risk for being misdiagnosed because patients may not have a hemiparesis, and isolated positive or psychiatric symptoms may not be recognized as stroke.

Symptoms not related to stroke location

Delirium and psychosis

Following a stroke, a patient may exhibit neuropsychiatric symptoms that do not appear to relate directly to the anatomical structures affected by the infarct. In the acute phase, factors such as older age and medical complications (including infection, metabolic derangement, and lack of sleep due to frequent neurologic checks) create a high risk of delirium.¹¹ Differentiating delirium from alterations in mental status due to seizure, cerebral edema, or other medical complications is essential, and delirium precautions should be exercised to the greatest extent possible. Other neuropsychiatric symptoms may manifest following hospitalization.

Continue to: Poststroke psychosis...

Poststroke psychosis often presents subacutely. Among these patients, the most common psychosis is delusion disorder, followed by schizophrenia-like psychosis and mood disorder with psychotic features.¹² Some evidence suggests antipsychotics may be highly effective for many of these patients.¹² Poststroke psychosis does appear to correlate somewhat with nondominant hemisphere lesions, including the frontal lobe, parietal lobe, temporal lobe, and/or caudate nucleus. Because high mortality and poor functional outcomes have been associated with poststroke psychosis, early intervention is essential.

Depression

Depression is a common problem following stroke, affecting approximately 35% of stroke patients.¹³ In addition to impairing quality of life, depression negatively impacts rehabilitation and increases caregiver burden. There is significant variability regarding risk factors that increases the likelihood of poststroke depression; however, psychiatric history, dysphagia, and poor social support consistently correlate with a higher risk.^14,15 Characteristics of a patient’s stroke, such as lesion volume and the ability to perform activities of daily living, are also risk factors. Identifying depression among patients who recently had a stroke is sometimes difficult due to a plethora of confounding factors. Patients may not communicate well due to aphasia, while strokes in other locations may result in an altered affect. Depending on the stroke location, patients may also suffer anosognosia (a lack of awareness of their deficits), which may impair their ability to learn and use adaptive strategies and equipment. An additional confounder is the significant overlap between depressive symptoms and those seen in the setting of a major medical event or hospitalization (decreased appetite, fatigue, etc). The prevalence of depression peaks approximately 3 to 6 months after stroke, with symptoms lasting 9 to 12 months on average, although many patients experience symptoms significantly longer.¹⁴ Because symptoms can begin within hours to days following a stroke, it is essential that both hospital and outpatient clinicians assess for depression when indicated. Patients with poststroke depression should receive prompt treatment because appropriate treatment correlates with improved rehabilitation, and most patients respond well to antidepressants.¹⁶ Early treatment reduces mortality and improves compliance with secondary stroke prevention measures, including pharmacotherapy.¹⁷

Anxiety and posttraumatic stress

Anxiety and anxiety-related disorders are additional potential complications following stroke that significantly influence patient outcomes and well-being. The abrupt, unexpected onset of stroke is often frightening to patients and families. The potential for life-altering deficits as well as intense, often invasive, interactions with the health care system does little to assuage patients’ fear. Stroke patients must contend with a change in neurologic function while processing their difficult experiences, and may develop profound fear of a recurrent stroke. As many as 22% of patients have an anxiety disorder 3 months after they have a stroke.¹⁸ Phobic disorder is the most prevalent subtype, followed by generalized anxiety disorder. Younger age and previous anxiety or depression place patients at greater risk of developing poststroke anxiety. Patients suffering from poststroke anxiety have a reduced quality of life, are more dependent, and show restricted participation in rehabilitation, all of which culminate in poorer outcomes.

Many patients describe their experiences surrounding their stroke as traumatic, and posttraumatic stress disorder (PTSD) is increasingly acknowledged as a potential complication for patients with recent stroke.¹⁹ PTSD profoundly impacts patient quality of life. Interestingly, most patients who develop poststroke PTSD do not have a history of other psychiatric illness, and it is difficult to predict who may develop PTSD. Relatively little is known regarding optimal treatment strategies for poststroke PTSD, or the efficacy of pharma­cotherapy and psychotherapeutic strategies to treat it.

Goals: Improve recovery and quality of life

Neuropsychiatric symptoms are common following a stroke and may manifest in a variety of ways. While some symptoms are a direct consequence of injury to a specific brain region, other symptoms may be a response to loss of independence, disability, experience with the medical system, or fear of recurrent stroke. The onset of psychiatric symptoms can be acute, beginning during hospitalization, or delayed. Understanding the association of psychiatric symptoms with the anatomical location of stroke may assist clinicians in identifying such symptoms. This knowledge informs conversations with patients and their caregivers, who may benefit from understanding that such symptoms are common after stroke. Furthermore, identifying psychiatric complications following stroke may affect rehabilitation. Additional investigation is necessary to find more effective treatment modalities and improve early intervention.

Continue to: Bottom Line

Neuropsychiatric symptoms are frequently overlooked in patients with recent stroke. These symptoms include delirium, psychosis, depression, anxiety, and posttraumatic stress disorder, and can be the direct result of injury to neuroanatomical structures or a consequence of the patient’s experience. Prompt treatment can maximize stroke recovery and quality of life.

Related Resources

• Zhang S, Xu M, Liu ZJ, et al. Neuropsychiatric issues after stroke: clinical significance and therapeutic implications. World J Psychiatry. 2020;10(6):125-138. doi:10.5498/wjp. v10.i6.125
• Saha G, Chakraborty K, Pattojoshi A. Management of psychiatric disorders in patients with stroke and traumatic brain injury. Indian J Psychiatry. 2022;64(Suppl 2): S344-S354.

Many patients experience neuropsychiatric symptoms following stroke. There is tremendous variation in the type, severity, and timeline of these symptoms, which have the potential to significantly impact patients’ quality of life. Some symptoms occur as a direct result of ischemic injury to brain structures regulating behavior, executive function, perception, or affect. Other symptoms occur indirectly due to the patient’s often-difficult experiences with the health care system, disrupted routines, or altered poststroke functional abilities. Psychiatric symptoms are not as easily recognized as classic stroke symptoms (such as hemiparesis) and are frequently overlooked, especially in the acute phase. However, these symptoms can negatively influence patients’ interpersonal relationships, rehabilitation, and employment.

Patients and families may not realize certain symptoms are stroke-related and may not discuss them with their clinicians. It is important to ask about and recognize psychiatric symptoms in patients who have experienced a stroke so you can provide optimal education and treatment. In this article, we review the types of psychiatric symptoms associated with strokes in specific brain regions (Table^1-10). We also describe symptoms that do not appear directly related to the anatomical structures affected by the infarct, including delirium, psychosis, depression, anxiety, and posttraumatic stress.

Symptoms associated with stroke in specific regions

Frontal lobe strokes

The frontal lobes are the largest lobes in the brain, and damage to areas within these lobes can cause behavioral and personality changes. Lesions in the lateral frontal cortex can cause aprosodia (difficulty expressing or comprehending variations in tone of voice), which can lead to communication errors. Lateral frontal cortex injury can cause executive dysfunction and a lack of empathy¹ as well as trouble with attention, planning, and self-regulation that may affect daily functioning. Strokes affecting the superior and inferior mesial cortices may result in apathy, lack of motivation, altered self-regulation, altered emotional processing, and disinhibition. Patients who experience a basal forebrain stroke may exhibit confabulation, reduced motivation, and delusions such as Capgras syndrome (the belief that a person or place has been replaced by an exact copy) and reduplicative paramnesia (the belief that a place has been either moved, duplicated, or exists in 2 places simultaneously). Strokes involving the orbital cortex can be associated with personality changes, impulsivity, poor social judgment, reduced empathy, altered self-regulation, lack of goal-directed behavior, and environmental dependency.

Some strokes may occur primarily in the subcortical white matter within the frontal lobes. Symptoms may be due to a single stroke with sudden onset, or due to repeated ischemic events that accumulate over time, as seen with microvascular disease. In the case of microvascular disease, the onset of symptoms may be insidious and the course progressive. Infarcts in the subcortical area can also cause personality changes (though typically more subtle when compared to orbitofrontal strokes), reduced emotions, poor empathy, and irritability.¹ Patients may lack insight into some of or all these symptoms following a frontal lobe infarct, which makes it critical to gather collateral information from the patient’s friends or family.

Parietal lobe strokes

Symptomatology from parietal strokes depends on whether the stroke affects the dominant or nondominant hemisphere. Dominant parietal lesions cause language deficits, and psychiatric symptoms may be difficult to elucidate due to the patient’s inability to communicate.² On the other hand, patients with nondominant parietal stroke may have neglect of, or inattention to, the opposite (typically left) side.³ This often manifests as a reluctance to use the affected limb or limbs, in some cases despite a lack of true weakness or motor dysfunction. In addition, patients may also have visual and/or tactile inattention towards the affected side, despite a lack of gross visual or sensory impairment.² In rare cases, a patient’s stroke may be misdiagnosed as a functional disorder due to the perceived unwillingness to use a neurologically intact limb. In severe cases, patients may not recognize an affected extremity as their own. Patients are also frequently unaware of deficits affecting their nondominant side and may argue with those attempting to explain their deficit. Anosodiaphoria—an abnormal lack of concern regarding their deficits—may also be observed. Additionally, aprosodia, flat affect, and personality changes may result from strokes affecting the nondominant hemisphere, which can impact the patient’s relationships and social functioning.³

Occipital lobe strokes

While negative or loss-of-function symptomatology is one of the hallmarks of stroke, occipital lobe infarcts can pose an exception. Although vision loss is the most common symptom with occipital lobe strokes, some patients experience visual hallucinations that may occur acutely or subacutely. In the acute phase, patients may report hallucinations of varied description,⁴ including poorly formed areas of color, scotomas, metamorphopsia (visual distortion in which straight lines appear curved), more complex and formed hallucinations and/or palinoptic images (images or brief scenes that continue to be perceived after looking away). These hallucinations, often referred to as release phenomena or release hallucinations, are thought to result from disinhibition of the visual cortex, which then fires spontaneously.

Hallucinations are associated with either infarction or hemorrhage in the posterior cerebral artery territory. In some cases, the hallucinations may take on a formed, complex appearance, and Charles Bonnet syndrome (visual hallucinations in the setting of vision loss, with insight into the hallucinations) has been identified in a small portion of patients.⁵

Continue to: The duration of these...

The duration of these hallucinations varies. Some patients describe very short periods of the disturbance, lasting minutes to hours and corresponding with the onset of their stroke. Others experience prolonged hallucinations, which frequently evolve into formed, complex images, lasting from days to months.⁶ In the setting of cortical stroke, patients may be at risk for seizures, which could manifest as visual hallucinations. It is essential to ensure that epileptic causes of hallucinations have been ruled out, because seizures may require treatment and other precautions.

Other stroke locations

Strokes in other locations also can result in psychiatric or behavioral symptoms. Acute stroke in the subcortical midbrain or thalamus may result in peduncular hallucinosis, a syndrome of vivid visual hallucinations.⁷ The midbrain (most commonly the reticular formation) is usually affected; however, certain lesions of the thalamus may also cause peduncular hallucinosis. This phenomenon is theorized to be due to an increase in serotonin activity relative to acetylcholine and is often accompanied by drowsiness.

The subthalamic nucleus is most frequently associated with disordered movement such as hemiballismus, but also causes disturbances in mood and behavior, including hyperphagia and personality changes.⁸ Irritability, aggressiveness, disinhibition, anxiety, and obscene speech may also be seen with lesions of the subthalamic nucleus.

Finally, the caudate nucleus may cause alterations in executive functioning and behavior.⁹ A stroke in the dorsolateral caudate may cause abulia and psychic akinesia, decreased problem-solving ability, reduced abstract thinking, and/or diminished spontaneity, whereas an infarct in the ventromedial region of the nucleus may cause disinhibition, disorganization, impulsiveness, and, in severe cases, affective symptoms with psychosis.¹⁰ Strokes in any of these areas are at risk for being misdiagnosed because patients may not have a hemiparesis, and isolated positive or psychiatric symptoms may not be recognized as stroke.

Symptoms not related to stroke location

Delirium and psychosis

Following a stroke, a patient may exhibit neuropsychiatric symptoms that do not appear to relate directly to the anatomical structures affected by the infarct. In the acute phase, factors such as older age and medical complications (including infection, metabolic derangement, and lack of sleep due to frequent neurologic checks) create a high risk of delirium.¹¹ Differentiating delirium from alterations in mental status due to seizure, cerebral edema, or other medical complications is essential, and delirium precautions should be exercised to the greatest extent possible. Other neuropsychiatric symptoms may manifest following hospitalization.

Continue to: Poststroke psychosis...

Poststroke psychosis often presents subacutely. Among these patients, the most common psychosis is delusion disorder, followed by schizophrenia-like psychosis and mood disorder with psychotic features.¹² Some evidence suggests antipsychotics may be highly effective for many of these patients.¹² Poststroke psychosis does appear to correlate somewhat with nondominant hemisphere lesions, including the frontal lobe, parietal lobe, temporal lobe, and/or caudate nucleus. Because high mortality and poor functional outcomes have been associated with poststroke psychosis, early intervention is essential.

Depression

Depression is a common problem following stroke, affecting approximately 35% of stroke patients.¹³ In addition to impairing quality of life, depression negatively impacts rehabilitation and increases caregiver burden. There is significant variability regarding risk factors that increases the likelihood of poststroke depression; however, psychiatric history, dysphagia, and poor social support consistently correlate with a higher risk.^14,15 Characteristics of a patient’s stroke, such as lesion volume and the ability to perform activities of daily living, are also risk factors. Identifying depression among patients who recently had a stroke is sometimes difficult due to a plethora of confounding factors. Patients may not communicate well due to aphasia, while strokes in other locations may result in an altered affect. Depending on the stroke location, patients may also suffer anosognosia (a lack of awareness of their deficits), which may impair their ability to learn and use adaptive strategies and equipment. An additional confounder is the significant overlap between depressive symptoms and those seen in the setting of a major medical event or hospitalization (decreased appetite, fatigue, etc). The prevalence of depression peaks approximately 3 to 6 months after stroke, with symptoms lasting 9 to 12 months on average, although many patients experience symptoms significantly longer.¹⁴ Because symptoms can begin within hours to days following a stroke, it is essential that both hospital and outpatient clinicians assess for depression when indicated. Patients with poststroke depression should receive prompt treatment because appropriate treatment correlates with improved rehabilitation, and most patients respond well to antidepressants.¹⁶ Early treatment reduces mortality and improves compliance with secondary stroke prevention measures, including pharmacotherapy.¹⁷

Anxiety and posttraumatic stress

Anxiety and anxiety-related disorders are additional potential complications following stroke that significantly influence patient outcomes and well-being. The abrupt, unexpected onset of stroke is often frightening to patients and families. The potential for life-altering deficits as well as intense, often invasive, interactions with the health care system does little to assuage patients’ fear. Stroke patients must contend with a change in neurologic function while processing their difficult experiences, and may develop profound fear of a recurrent stroke. As many as 22% of patients have an anxiety disorder 3 months after they have a stroke.¹⁸ Phobic disorder is the most prevalent subtype, followed by generalized anxiety disorder. Younger age and previous anxiety or depression place patients at greater risk of developing poststroke anxiety. Patients suffering from poststroke anxiety have a reduced quality of life, are more dependent, and show restricted participation in rehabilitation, all of which culminate in poorer outcomes.

Many patients describe their experiences surrounding their stroke as traumatic, and posttraumatic stress disorder (PTSD) is increasingly acknowledged as a potential complication for patients with recent stroke.¹⁹ PTSD profoundly impacts patient quality of life. Interestingly, most patients who develop poststroke PTSD do not have a history of other psychiatric illness, and it is difficult to predict who may develop PTSD. Relatively little is known regarding optimal treatment strategies for poststroke PTSD, or the efficacy of pharma­cotherapy and psychotherapeutic strategies to treat it.

Goals: Improve recovery and quality of life

Neuropsychiatric symptoms are common following a stroke and may manifest in a variety of ways. While some symptoms are a direct consequence of injury to a specific brain region, other symptoms may be a response to loss of independence, disability, experience with the medical system, or fear of recurrent stroke. The onset of psychiatric symptoms can be acute, beginning during hospitalization, or delayed. Understanding the association of psychiatric symptoms with the anatomical location of stroke may assist clinicians in identifying such symptoms. This knowledge informs conversations with patients and their caregivers, who may benefit from understanding that such symptoms are common after stroke. Furthermore, identifying psychiatric complications following stroke may affect rehabilitation. Additional investigation is necessary to find more effective treatment modalities and improve early intervention.

Continue to: Bottom Line

Neuropsychiatric symptoms are frequently overlooked in patients with recent stroke. These symptoms include delirium, psychosis, depression, anxiety, and posttraumatic stress disorder, and can be the direct result of injury to neuroanatomical structures or a consequence of the patient’s experience. Prompt treatment can maximize stroke recovery and quality of life.

Related Resources

• Zhang S, Xu M, Liu ZJ, et al. Neuropsychiatric issues after stroke: clinical significance and therapeutic implications. World J Psychiatry. 2020;10(6):125-138. doi:10.5498/wjp. v10.i6.125
• Saha G, Chakraborty K, Pattojoshi A. Management of psychiatric disorders in patients with stroke and traumatic brain injury. Indian J Psychiatry. 2022;64(Suppl 2): S344-S354.

Many patients experience neuropsychiatric symptoms following stroke. There is tremendous variation in the type, severity, and timeline of these symptoms, which have the potential to significantly impact patients’ quality of life. Some symptoms occur as a direct result of ischemic injury to brain structures regulating behavior, executive function, perception, or affect. Other symptoms occur indirectly due to the patient’s often-difficult experiences with the health care system, disrupted routines, or altered poststroke functional abilities. Psychiatric symptoms are not as easily recognized as classic stroke symptoms (such as hemiparesis) and are frequently overlooked, especially in the acute phase. However, these symptoms can negatively influence patients’ interpersonal relationships, rehabilitation, and employment.

Patients and families may not realize certain symptoms are stroke-related and may not discuss them with their clinicians. It is important to ask about and recognize psychiatric symptoms in patients who have experienced a stroke so you can provide optimal education and treatment. In this article, we review the types of psychiatric symptoms associated with strokes in specific brain regions (Table^1-10). We also describe symptoms that do not appear directly related to the anatomical structures affected by the infarct, including delirium, psychosis, depression, anxiety, and posttraumatic stress.

Symptoms associated with stroke in specific regions

Frontal lobe strokes

The frontal lobes are the largest lobes in the brain, and damage to areas within these lobes can cause behavioral and personality changes. Lesions in the lateral frontal cortex can cause aprosodia (difficulty expressing or comprehending variations in tone of voice), which can lead to communication errors. Lateral frontal cortex injury can cause executive dysfunction and a lack of empathy¹ as well as trouble with attention, planning, and self-regulation that may affect daily functioning. Strokes affecting the superior and inferior mesial cortices may result in apathy, lack of motivation, altered self-regulation, altered emotional processing, and disinhibition. Patients who experience a basal forebrain stroke may exhibit confabulation, reduced motivation, and delusions such as Capgras syndrome (the belief that a person or place has been replaced by an exact copy) and reduplicative paramnesia (the belief that a place has been either moved, duplicated, or exists in 2 places simultaneously). Strokes involving the orbital cortex can be associated with personality changes, impulsivity, poor social judgment, reduced empathy, altered self-regulation, lack of goal-directed behavior, and environmental dependency.

Some strokes may occur primarily in the subcortical white matter within the frontal lobes. Symptoms may be due to a single stroke with sudden onset, or due to repeated ischemic events that accumulate over time, as seen with microvascular disease. In the case of microvascular disease, the onset of symptoms may be insidious and the course progressive. Infarcts in the subcortical area can also cause personality changes (though typically more subtle when compared to orbitofrontal strokes), reduced emotions, poor empathy, and irritability.¹ Patients may lack insight into some of or all these symptoms following a frontal lobe infarct, which makes it critical to gather collateral information from the patient’s friends or family.

Parietal lobe strokes

Symptomatology from parietal strokes depends on whether the stroke affects the dominant or nondominant hemisphere. Dominant parietal lesions cause language deficits, and psychiatric symptoms may be difficult to elucidate due to the patient’s inability to communicate.² On the other hand, patients with nondominant parietal stroke may have neglect of, or inattention to, the opposite (typically left) side.³ This often manifests as a reluctance to use the affected limb or limbs, in some cases despite a lack of true weakness or motor dysfunction. In addition, patients may also have visual and/or tactile inattention towards the affected side, despite a lack of gross visual or sensory impairment.² In rare cases, a patient’s stroke may be misdiagnosed as a functional disorder due to the perceived unwillingness to use a neurologically intact limb. In severe cases, patients may not recognize an affected extremity as their own. Patients are also frequently unaware of deficits affecting their nondominant side and may argue with those attempting to explain their deficit. Anosodiaphoria—an abnormal lack of concern regarding their deficits—may also be observed. Additionally, aprosodia, flat affect, and personality changes may result from strokes affecting the nondominant hemisphere, which can impact the patient’s relationships and social functioning.³

Occipital lobe strokes

While negative or loss-of-function symptomatology is one of the hallmarks of stroke, occipital lobe infarcts can pose an exception. Although vision loss is the most common symptom with occipital lobe strokes, some patients experience visual hallucinations that may occur acutely or subacutely. In the acute phase, patients may report hallucinations of varied description,⁴ including poorly formed areas of color, scotomas, metamorphopsia (visual distortion in which straight lines appear curved), more complex and formed hallucinations and/or palinoptic images (images or brief scenes that continue to be perceived after looking away). These hallucinations, often referred to as release phenomena or release hallucinations, are thought to result from disinhibition of the visual cortex, which then fires spontaneously.

Hallucinations are associated with either infarction or hemorrhage in the posterior cerebral artery territory. In some cases, the hallucinations may take on a formed, complex appearance, and Charles Bonnet syndrome (visual hallucinations in the setting of vision loss, with insight into the hallucinations) has been identified in a small portion of patients.⁵

Continue to: The duration of these...

The duration of these hallucinations varies. Some patients describe very short periods of the disturbance, lasting minutes to hours and corresponding with the onset of their stroke. Others experience prolonged hallucinations, which frequently evolve into formed, complex images, lasting from days to months.⁶ In the setting of cortical stroke, patients may be at risk for seizures, which could manifest as visual hallucinations. It is essential to ensure that epileptic causes of hallucinations have been ruled out, because seizures may require treatment and other precautions.

Other stroke locations

Strokes in other locations also can result in psychiatric or behavioral symptoms. Acute stroke in the subcortical midbrain or thalamus may result in peduncular hallucinosis, a syndrome of vivid visual hallucinations.⁷ The midbrain (most commonly the reticular formation) is usually affected; however, certain lesions of the thalamus may also cause peduncular hallucinosis. This phenomenon is theorized to be due to an increase in serotonin activity relative to acetylcholine and is often accompanied by drowsiness.

The subthalamic nucleus is most frequently associated with disordered movement such as hemiballismus, but also causes disturbances in mood and behavior, including hyperphagia and personality changes.⁸ Irritability, aggressiveness, disinhibition, anxiety, and obscene speech may also be seen with lesions of the subthalamic nucleus.

Finally, the caudate nucleus may cause alterations in executive functioning and behavior.⁹ A stroke in the dorsolateral caudate may cause abulia and psychic akinesia, decreased problem-solving ability, reduced abstract thinking, and/or diminished spontaneity, whereas an infarct in the ventromedial region of the nucleus may cause disinhibition, disorganization, impulsiveness, and, in severe cases, affective symptoms with psychosis.¹⁰ Strokes in any of these areas are at risk for being misdiagnosed because patients may not have a hemiparesis, and isolated positive or psychiatric symptoms may not be recognized as stroke.

Symptoms not related to stroke location

Delirium and psychosis

Following a stroke, a patient may exhibit neuropsychiatric symptoms that do not appear to relate directly to the anatomical structures affected by the infarct. In the acute phase, factors such as older age and medical complications (including infection, metabolic derangement, and lack of sleep due to frequent neurologic checks) create a high risk of delirium.¹¹ Differentiating delirium from alterations in mental status due to seizure, cerebral edema, or other medical complications is essential, and delirium precautions should be exercised to the greatest extent possible. Other neuropsychiatric symptoms may manifest following hospitalization.

Continue to: Poststroke psychosis...

Poststroke psychosis often presents subacutely. Among these patients, the most common psychosis is delusion disorder, followed by schizophrenia-like psychosis and mood disorder with psychotic features.¹² Some evidence suggests antipsychotics may be highly effective for many of these patients.¹² Poststroke psychosis does appear to correlate somewhat with nondominant hemisphere lesions, including the frontal lobe, parietal lobe, temporal lobe, and/or caudate nucleus. Because high mortality and poor functional outcomes have been associated with poststroke psychosis, early intervention is essential.

Depression

Depression is a common problem following stroke, affecting approximately 35% of stroke patients.¹³ In addition to impairing quality of life, depression negatively impacts rehabilitation and increases caregiver burden. There is significant variability regarding risk factors that increases the likelihood of poststroke depression; however, psychiatric history, dysphagia, and poor social support consistently correlate with a higher risk.^14,15 Characteristics of a patient’s stroke, such as lesion volume and the ability to perform activities of daily living, are also risk factors. Identifying depression among patients who recently had a stroke is sometimes difficult due to a plethora of confounding factors. Patients may not communicate well due to aphasia, while strokes in other locations may result in an altered affect. Depending on the stroke location, patients may also suffer anosognosia (a lack of awareness of their deficits), which may impair their ability to learn and use adaptive strategies and equipment. An additional confounder is the significant overlap between depressive symptoms and those seen in the setting of a major medical event or hospitalization (decreased appetite, fatigue, etc). The prevalence of depression peaks approximately 3 to 6 months after stroke, with symptoms lasting 9 to 12 months on average, although many patients experience symptoms significantly longer.¹⁴ Because symptoms can begin within hours to days following a stroke, it is essential that both hospital and outpatient clinicians assess for depression when indicated. Patients with poststroke depression should receive prompt treatment because appropriate treatment correlates with improved rehabilitation, and most patients respond well to antidepressants.¹⁶ Early treatment reduces mortality and improves compliance with secondary stroke prevention measures, including pharmacotherapy.¹⁷

Anxiety and posttraumatic stress

Anxiety and anxiety-related disorders are additional potential complications following stroke that significantly influence patient outcomes and well-being. The abrupt, unexpected onset of stroke is often frightening to patients and families. The potential for life-altering deficits as well as intense, often invasive, interactions with the health care system does little to assuage patients’ fear. Stroke patients must contend with a change in neurologic function while processing their difficult experiences, and may develop profound fear of a recurrent stroke. As many as 22% of patients have an anxiety disorder 3 months after they have a stroke.¹⁸ Phobic disorder is the most prevalent subtype, followed by generalized anxiety disorder. Younger age and previous anxiety or depression place patients at greater risk of developing poststroke anxiety. Patients suffering from poststroke anxiety have a reduced quality of life, are more dependent, and show restricted participation in rehabilitation, all of which culminate in poorer outcomes.

Many patients describe their experiences surrounding their stroke as traumatic, and posttraumatic stress disorder (PTSD) is increasingly acknowledged as a potential complication for patients with recent stroke.¹⁹ PTSD profoundly impacts patient quality of life. Interestingly, most patients who develop poststroke PTSD do not have a history of other psychiatric illness, and it is difficult to predict who may develop PTSD. Relatively little is known regarding optimal treatment strategies for poststroke PTSD, or the efficacy of pharma­cotherapy and psychotherapeutic strategies to treat it.

Goals: Improve recovery and quality of life

Neuropsychiatric symptoms are common following a stroke and may manifest in a variety of ways. While some symptoms are a direct consequence of injury to a specific brain region, other symptoms may be a response to loss of independence, disability, experience with the medical system, or fear of recurrent stroke. The onset of psychiatric symptoms can be acute, beginning during hospitalization, or delayed. Understanding the association of psychiatric symptoms with the anatomical location of stroke may assist clinicians in identifying such symptoms. This knowledge informs conversations with patients and their caregivers, who may benefit from understanding that such symptoms are common after stroke. Furthermore, identifying psychiatric complications following stroke may affect rehabilitation. Additional investigation is necessary to find more effective treatment modalities and improve early intervention.

Continue to: Bottom Line

Neuropsychiatric symptoms are frequently overlooked in patients with recent stroke. These symptoms include delirium, psychosis, depression, anxiety, and posttraumatic stress disorder, and can be the direct result of injury to neuroanatomical structures or a consequence of the patient’s experience. Prompt treatment can maximize stroke recovery and quality of life.

Related Resources

• Zhang S, Xu M, Liu ZJ, et al. Neuropsychiatric issues after stroke: clinical significance and therapeutic implications. World J Psychiatry. 2020;10(6):125-138. doi:10.5498/wjp. v10.i6.125
• Saha G, Chakraborty K, Pattojoshi A. Management of psychiatric disorders in patients with stroke and traumatic brain injury. Indian J Psychiatry. 2022;64(Suppl 2): S344-S354.

The opioid use disorder (OUD) epidemic is a major public health crisis in the United States.¹ Naltrexone, methadone, and buprenorphine are first-line therapies for OUD and have high success rates.² While studies have shown that naltrexone is effective, patients must achieve opioid detoxification and maintain 7 to 10 days of total abstinence to avoid a precipitated opioid withdrawal before it can be prescribed.³ Methadone does not require detoxification or a period of complete abstinence, but must be prescribed in special clinics and requires daily observed dosing for the first 90 days,⁴ though these requirements have been relaxed during the COVID-19 pandemic. In contrast, buprenorphine (with or without naloxone) can be used in office-based settings, which significantly improves the accessibility and availability of treatment for patients with OUD. Clinician knowledge and comfort prescribing buprenorphine are limiting factors to treatment.⁵ Increasing the number of clinicians proficient with buprenorphine management can improve access to effective treatment and recovery services, which is critical for patients with OUD.

Multiple resources are available for clinicians to learn how to prescribe buprenorphine, but clear guidance on laboratory testing for patients receiving buprenorphine is limited. To safely and effectively prescribe buprenorphine, clinicians need to understand its pharmacology (Box 1^6-9) and how laboratory testing influences treatment. In an effort to increase clinician knowledge of and proficiency with buprenorphine, this article answers 10 common questions about laboratory monitoring of patients receiving this medication.

Box 1

1. Why is laboratory monitoring important?

Proper laboratory monitoring discourages illicit substance use, encourages medication adherence, and influences treatment modifications. Patient self-reporting on medication compliance may be inaccurate or unreliable.¹⁰ Patients who relapse or use other illicit substances may also be reluctant to disclose their substance use.¹¹

On the other hand, laboratory tests are objective markers of treatment outcome and adherence, and can verify a patient’s self-report.¹² When used appropriately, laboratory monitoring can be therapeutic. It holds patients accountable, especially when used in conjunction with contingency management or other behavioral therapies.¹³ Laboratory monitoring is the most reliable method of determining if patients are abstaining from opioids and other illicit substances, or if the treatment plan requires revision.

2. Which tests should I order?

When initiating or maintaining a patient on buprenorphine, order a general urine drug screen (UDS), urine opioid screen (availability varies by institution), urine creatinine levels, urine buprenorphine/norbuprenorphine/naloxone/creatinine levels, urine alcohol metabolite levels, and a urine general toxicology test. It is also recommended to obtain a comprehensive metabolic panel (CMP) before starting buprenorphine,^14,15 and to monitor CMP values at least once annually following treatment. Patients with a history of IV drug use or other high-risk factors should also be screened for hepatitis B, hepatitis C, and HIV.^14,15

A general UDS can determine if opiates, amphetamines, cocaine, marijuana, or other common illicit substances are present to identify additional substance use. The proficiency of a general UDS may vary depending on the panels used at the respective institution. Some clinics use point-of-care UDS as part of their clinical management; these tests are inexpensive and provide immediate results.¹⁶ A basic UDS typically does not detect synthetic opioids due to the specificity of conventional immunoassays. As a result, specific tests for opioids such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, and methadone should also be considered, depending on their availability. Though buprenorphine treatment may trigger a positive opiate or other opioid screen,¹⁷ buprenorphine adherence should be confirmed using several urine tests, including creatinine, buprenorphine, norbuprenorphine, and naloxone urine levels.

In addition to screening for illicit substances and buprenorphine adherence, it is important to also screen for alcohol. Alcohol use disorder (AUD) is highly comorbid with OUD,¹⁸ and is associated with worse OUD treatment outcomes.¹⁹ Alcohol use may also affect liver function necessary for buprenorphine metabolism,⁸ so urine alcohol metabolites such as ethyl glucuronide and ethyl sulfate, serum transaminases, and gamma-glutamyl transferase should also be obtained.

Continue to: How frequently should patients be tested?

3. How frequently should patients be tested?

As part of the initial assessment, it is recommended to order CMP, UDS, and urine general toxicology.¹⁴ If indicated, specific laboratory tests such as specific opioid and alcohol metabolites screens can be ordered. After starting buprenorphine, the frequency of monitoring urine laboratory tests—including UDS, general drug toxicology, buprenorphine/norbuprenorphine/naloxone/creatinine, and alcohol and its metabolites—depends on a variety of factors, including a patient’s treatment response and stability as well as availability and cost of the tests. Ultimately, the frequency of laboratory monitoring should be determined on a patient-by-patient basis and clinicians should use their judgment.

The American Society of Addiction Medicine suggests testing more frequently earlier in the course of treatment (eg, weekly or biweekly), then spacing it out over time (eg, monthly or quarterly) as the patient’s recovery progresses.^14,15 To conserve resources and reduce spending, some clinicians and guidelines recommend random monitoring as opposed to monitoring at every follow-up visit (eg, once out of every 3 to 5 visits, on average), which allows for longer intervals between testing while ensuring consistency with medication and abstinence from illicit substances.^15,16 We suggest screening every 2 weeks for the first month, then spacing out to monthly and quarterly as patients demonstrate stability, with random screening as indicated. Monitoring of liver function should be done at least once annually.

4. How should urine buprenorphine and other results be interpreted?

There are several issues to consider when interpreting laboratory results. The clinician needs to know what to expect in the sample, and what approximate levels should be detected. To check treatment adherence, laboratory data should include stable urine buprenorphine and norbuprenorphine levels and negative urine screening for other illicit substances.^14,15 While urine buprenorphine and norbuprenorphine levels have great interindividual variability due to genetic differences in hepatic metabolism, unusually high levels of buprenorphine (≥700 ng/mL) without norbuprenorphine suggests “urine spiking,” where patients put buprenorphine directly into their urine sample.^20,21 Abnormally low or undetectable levels raise concern for medication nonadherence or diversion.

Though urine buprenorphine levels do not reliably correlate with dose, because there is typically not much intraindividual variability, patients should have relatively stable levels on each screen once a maintenance dose has been established.²² Furthermore, the buprenorphine-to-norbuprenorphine ratio (ie, “the metabolic ratio”) typically ranges from 1:2 to 1:4 across all individuals,^20,21,23 regardless of dose or metabolic rate. Urine naloxone levels, which typically are included in commercial urine buprenorphine laboratory panels, also may aid in identifying tampered urine specimens when buprenorphine-to-norbuprenorphine ratios are abnormal or inconsistent with an individual’s prior ratio. Naloxone is typically (but not always) poorly absorbed and minimally detected in urine specimens.²⁰ A high level of naloxone coupled with unusually high buprenorphine levels, particularly in the absence of norbuprenorphine in the urine, may indicate urine spiking.^20,21,23

Urine creatinine is used to establish the reliability of the specimen. When urine creatinine concentration is <20 mg/dL, the concentration of most substances typically falls to subthreshold levels of detection.²⁴ If a UDS is negative and the urine has a creatinine concentration <20 mg/dL, the patient should provide a new sample, because the urine was likely too diluted to detect any substances.

Continue to: The presence of alcohol...

The presence of alcohol metabolites can alert the clinician to recent alcohol use and possible AUD, which should be assessed and treated if indicated.

Liver enzymes should be normal or unchanged with short- and long-term buprenorphine use when taken as prescribed.^25,26 However, acute liver injury may occur if patients inject buprenorphine intravenously, especially in those with underlying hepatitis C.²⁵

5. What can cause a false negative result on UDS?

Laboratory monitoring may occasionally yield false negative drug screens. For urine buprenorphine levels, false negatives may occur in patients who are “rapid metabolizers,” infrequent or as-needed usage of the medication, patient mix-up, or laboratory error.²⁷ For other substances, a false negative result may occur if the patient used the substance(s) outside the window of detection. The most common causes of false negative results, however, are overly diluted urine samples (eg, due to rapid water ingestion), or the use of an inappropriate test to measure a specific opioid or substance.²⁷

Many laboratories use conventional immunoassays with morphine antibodies that react with various opioid substrates to determine the presence of a specific opioid. Some opioids—particularly synthetics such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, buprenorphine, and methadone—have poor cross-reactivity with the morphine antibody due to their distinct chemical structures, so standard immunoassays used to detect opioids may result in a false negative result.²⁸ In such situations, a discussion with a clinical pathologist familiar with the laboratory detection method can help ensure proper testing. Additional tests for specific opioids should be ordered to more specifically target substances prone to false negative results.²⁷

6. What can cause a false positive result on UDS?

The cross-reactivity of the morphine substrate may also result in a false positive result.²⁸ Other over-the-counter (OTC) or prescription medications that have cross-reactivity with the morphine antibody include dextromethorphan, verapamil, quinine, fluoroquinolones, and rifampin, which can normally be found in urine 2 to 3 days after consumption.^17,27 Poppy seeds have long been known to result in positive opiate screens on urine testing, particularly when laboratories use lower cutoff values (eg, 300 ng/mL), so advise patients to avoid consuming poppy seeds.²⁹

Continue to: For other drugs of abuse...

For other drugs of abuse, false positives are typically caused by cross-reactivity with other prescription or OTC medications. Numerous substances cross-react with amphetamines and produce false positive results on amphetamine immunoassays, including amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone.²⁷ Sertraline and efavirenz are known to produce false positive results on benzodiazepine UDS, and ibuprofen, naproxen, and efavirenz can produce false positive results for cannabinoids.²⁷

7. How do I communicate the results to patients?

Effectively communicating test results to patients is just as important as the results themselves. A trusting, therapeutic alliance between patient and clinician is highly predictive of successful treatment,³⁰ and how the clinician communicates affects the strength of this collaboration. A principle of addiction treatment is the use of neutral language when discussing laboratory results.^31,32 To avoid unintentional shaming or moral judgment, use words such as “positive” or “negative” rather than stigmatizing terms such as “clean” or “dirty.”³³

Additionally, make it clear that laboratory findings are not used to punish patients, but rather to improve treatment.³⁴ Reassuring the patient that a positive screen will not result in withdrawal of care encourages a working relationship.¹⁴ All patients who receive buprenorphine treatment should be informed that collecting a UDS is the standard of care used to monitor their progress. You might want to compare using UDS in patients with OUD to monitoring HbA1c levels in patients with diabetes as an example to demonstrate how laboratory values inform treatment.^35,36

Before reporting the results, a helpful strategy to maintain the therapeutic alliance in the face of a positive UDS is to ask the patient what they expect their UDS to show. When the patient has been reassured that treatment will not be withdrawn due to a positive result, they may be more likely to fully disclose substance use. This allows them the opportunity to self-disclose rather than be “called out” by the clinician.³⁵

8. What happens when a patient tests positive for drugs of abuse?

If a patient tests positive for opioids or other drugs of abuse, convey this information to them, ideally by asking them what they expect to see on laboratory findings. Patients may have “slip ups” or relapses, or use certain prescription medications for medical reasons with the intention of establishing abstinence. It is essential to convey laboratory findings in a nonjudgmental tone while maintaining a supportive stance with clear boundaries.

Continue to: Though addiction specialists...

Though addiction specialists often advise complete abstinence from all substances, including alcohol, cannabis, and tobacco, the harm-reduction model emphasizes “meeting patients where they are” in terms of continued substance use.³⁷ If a patient can reduce their substance use or abstain from some substances while continuing others, these accomplishments should be acknowledged.

For patients who continue to test positive for illicit substances (>3 instances) without a clear explanation, schedule an appointment to re-educate them about buprenorphine treatment and reassess the patient’s treatment goals. Consider changing the current treatment plan, such as by having more frequent follow-ups, increasing the dose of the buprenorphine for patients whose cravings are not sufficiently suppressed, switching to another medication such as methadone or naltrexone, or referring the patient to a higher level of care, such as intensive outpatient or residential treatment.

9. What should I do if the results indicate abnormal levels of buprenorphine, norbuprenorphine, and naloxone?

When urine buprenorphine, norbuprenorphine, or naloxone levels appear low or the results indicate a likely “spiking,” clarify whether the sample tampering is due to poor adherence or diversion. Similar to dealing with a positive result for substances of abuse, ask the patient what they expect to find in their urine, and discuss the results in a nonjudgmental manner. Patients who admit to difficulty following their medication regimen may require additional psychoeducation and motivational interviewing to identify and address barriers. Strategies to improve adherence include setting an alarm, involving the family, using a pillbox, or simplifying the regimen.³⁸ A long-acting injectable form of buprenorphine is also available.

If you suspect diversion, refer to your clinic’s policy and use other clinical management skills, such as increasing the frequency of visits, random pill counts, and supervised medication administration in the clinic.³⁹ If diversion occurs repetitively and the patient is not appropriate for or benefiting from buprenorphine treatment, it may make sense to terminate treatment and consider other treatment options (such as methadone or residential treatment).³⁹

10. What should I do if a patient disagrees with laboratory findings?

It is common for patients to disagree with laboratory results. Maintaining an attitude of neutrality and allowing the patient to speak and provide explanations is necessary to ensure they feel heard. Explanations patients frequently provide include passive exposure (“I was around someone who was using it”) or accidental ingestion, when a patient reports taking a medication they were not aware was a substance of concern. In a calm and nonjudgmental manner, provide education on what leads to a positive drug screen, including the possibility of false positive findings.

Continue to: Because a screening test...

Because a screening test has high sensitivity and low specificity, false positives may occur.^17,27 Therefore, when a result is in dispute, the use of a high-specificity confirmatory test is often needed (many laboratories have reflex confirmatory testing). However, in the case of diluted urine (urine creatinine concentrations <20 mg/dL), patients should be told the findings are physiologically implausible, and a new urine sample should be obtained.²⁴

Goals of laboratory monitoring

Laboratory monitoring, including UDS and urine buprenorphine levels, is a mainstay of treatment for patients with OUD. The increased use of telehealth has affected how laboratory testing is conducted (Box 2^40,41). The goal of laboratory testing is to influence treatment and improve patient outcomes. Clinical data such as clinician assessment, patient self-reporting, and collateral information provide essential details for patient management. However, laboratory monitoring is often the most reliable and objective source by which to influence treatment.

Box 2

An increased understanding of recommended laboratory monitoring practices may improve your comfort with OUD treatment and motivate more clinicians to offer buprenorphine, a life-saving and disease-modifying treatment for OUD. Doing so would increase access to OUD treatment for patients to reduce the individual and public health risks associated with untreated OUD.

Bottom Line

Laboratory monitoring, particularly urine drug screens and urine buprenorphine levels, is the most reliable source of information in the treatment of patients with opioid use disorder (OUD). An increased understanding of monitoring practices may improve a clinician’s willingness to offer buprenorphine as an option for therapy and their ability to properly treat patients with OUD.

Related Resources

• Li X, Moore S, Olson C. Urine drug tests: how to make the most of them. Current Psychiatry. 2019;18(8):10-18,20.
• Moreno JL, Johnson JL, Peckham AM. Sublingual buprenorphine plus buprenorphine XR for opioid use disorder. Current Psychiatry. 2022;21(6):39-42,49. doi:10.12788/cp.0244

Drug Brand Names

Amantadine • Gocovri
Buprenorphine • Subutex, Sublocade
Bupropion • Wellbutrin, Zyban
Efavirenz • Sustiva
Fentanyl • Actiq
Hydrocodone • Hysingla
Hydromorphone • Dilaudid
Methadone • Methadose
Naloxone • Evzio
Naltrexone • Vivitrol
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Ionamin
Quinine • Qualaquin
Ranitidine • Zantac
Rifampin • Rifadin
Selegiline • Eldepryl
Sertraline • Zoloft
Trazodone • Oleptro
Verapamil • Verelan

The opioid use disorder (OUD) epidemic is a major public health crisis in the United States.¹ Naltrexone, methadone, and buprenorphine are first-line therapies for OUD and have high success rates.² While studies have shown that naltrexone is effective, patients must achieve opioid detoxification and maintain 7 to 10 days of total abstinence to avoid a precipitated opioid withdrawal before it can be prescribed.³ Methadone does not require detoxification or a period of complete abstinence, but must be prescribed in special clinics and requires daily observed dosing for the first 90 days,⁴ though these requirements have been relaxed during the COVID-19 pandemic. In contrast, buprenorphine (with or without naloxone) can be used in office-based settings, which significantly improves the accessibility and availability of treatment for patients with OUD. Clinician knowledge and comfort prescribing buprenorphine are limiting factors to treatment.⁵ Increasing the number of clinicians proficient with buprenorphine management can improve access to effective treatment and recovery services, which is critical for patients with OUD.

Multiple resources are available for clinicians to learn how to prescribe buprenorphine, but clear guidance on laboratory testing for patients receiving buprenorphine is limited. To safely and effectively prescribe buprenorphine, clinicians need to understand its pharmacology (Box 1^6-9) and how laboratory testing influences treatment. In an effort to increase clinician knowledge of and proficiency with buprenorphine, this article answers 10 common questions about laboratory monitoring of patients receiving this medication.

Box 1

1. Why is laboratory monitoring important?

Proper laboratory monitoring discourages illicit substance use, encourages medication adherence, and influences treatment modifications. Patient self-reporting on medication compliance may be inaccurate or unreliable.¹⁰ Patients who relapse or use other illicit substances may also be reluctant to disclose their substance use.¹¹

On the other hand, laboratory tests are objective markers of treatment outcome and adherence, and can verify a patient’s self-report.¹² When used appropriately, laboratory monitoring can be therapeutic. It holds patients accountable, especially when used in conjunction with contingency management or other behavioral therapies.¹³ Laboratory monitoring is the most reliable method of determining if patients are abstaining from opioids and other illicit substances, or if the treatment plan requires revision.

2. Which tests should I order?

When initiating or maintaining a patient on buprenorphine, order a general urine drug screen (UDS), urine opioid screen (availability varies by institution), urine creatinine levels, urine buprenorphine/norbuprenorphine/naloxone/creatinine levels, urine alcohol metabolite levels, and a urine general toxicology test. It is also recommended to obtain a comprehensive metabolic panel (CMP) before starting buprenorphine,^14,15 and to monitor CMP values at least once annually following treatment. Patients with a history of IV drug use or other high-risk factors should also be screened for hepatitis B, hepatitis C, and HIV.^14,15

A general UDS can determine if opiates, amphetamines, cocaine, marijuana, or other common illicit substances are present to identify additional substance use. The proficiency of a general UDS may vary depending on the panels used at the respective institution. Some clinics use point-of-care UDS as part of their clinical management; these tests are inexpensive and provide immediate results.¹⁶ A basic UDS typically does not detect synthetic opioids due to the specificity of conventional immunoassays. As a result, specific tests for opioids such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, and methadone should also be considered, depending on their availability. Though buprenorphine treatment may trigger a positive opiate or other opioid screen,¹⁷ buprenorphine adherence should be confirmed using several urine tests, including creatinine, buprenorphine, norbuprenorphine, and naloxone urine levels.

In addition to screening for illicit substances and buprenorphine adherence, it is important to also screen for alcohol. Alcohol use disorder (AUD) is highly comorbid with OUD,¹⁸ and is associated with worse OUD treatment outcomes.¹⁹ Alcohol use may also affect liver function necessary for buprenorphine metabolism,⁸ so urine alcohol metabolites such as ethyl glucuronide and ethyl sulfate, serum transaminases, and gamma-glutamyl transferase should also be obtained.

Continue to: How frequently should patients be tested?

3. How frequently should patients be tested?

As part of the initial assessment, it is recommended to order CMP, UDS, and urine general toxicology.¹⁴ If indicated, specific laboratory tests such as specific opioid and alcohol metabolites screens can be ordered. After starting buprenorphine, the frequency of monitoring urine laboratory tests—including UDS, general drug toxicology, buprenorphine/norbuprenorphine/naloxone/creatinine, and alcohol and its metabolites—depends on a variety of factors, including a patient’s treatment response and stability as well as availability and cost of the tests. Ultimately, the frequency of laboratory monitoring should be determined on a patient-by-patient basis and clinicians should use their judgment.

The American Society of Addiction Medicine suggests testing more frequently earlier in the course of treatment (eg, weekly or biweekly), then spacing it out over time (eg, monthly or quarterly) as the patient’s recovery progresses.^14,15 To conserve resources and reduce spending, some clinicians and guidelines recommend random monitoring as opposed to monitoring at every follow-up visit (eg, once out of every 3 to 5 visits, on average), which allows for longer intervals between testing while ensuring consistency with medication and abstinence from illicit substances.^15,16 We suggest screening every 2 weeks for the first month, then spacing out to monthly and quarterly as patients demonstrate stability, with random screening as indicated. Monitoring of liver function should be done at least once annually.

4. How should urine buprenorphine and other results be interpreted?

There are several issues to consider when interpreting laboratory results. The clinician needs to know what to expect in the sample, and what approximate levels should be detected. To check treatment adherence, laboratory data should include stable urine buprenorphine and norbuprenorphine levels and negative urine screening for other illicit substances.^14,15 While urine buprenorphine and norbuprenorphine levels have great interindividual variability due to genetic differences in hepatic metabolism, unusually high levels of buprenorphine (≥700 ng/mL) without norbuprenorphine suggests “urine spiking,” where patients put buprenorphine directly into their urine sample.^20,21 Abnormally low or undetectable levels raise concern for medication nonadherence or diversion.

Though urine buprenorphine levels do not reliably correlate with dose, because there is typically not much intraindividual variability, patients should have relatively stable levels on each screen once a maintenance dose has been established.²² Furthermore, the buprenorphine-to-norbuprenorphine ratio (ie, “the metabolic ratio”) typically ranges from 1:2 to 1:4 across all individuals,^20,21,23 regardless of dose or metabolic rate. Urine naloxone levels, which typically are included in commercial urine buprenorphine laboratory panels, also may aid in identifying tampered urine specimens when buprenorphine-to-norbuprenorphine ratios are abnormal or inconsistent with an individual’s prior ratio. Naloxone is typically (but not always) poorly absorbed and minimally detected in urine specimens.²⁰ A high level of naloxone coupled with unusually high buprenorphine levels, particularly in the absence of norbuprenorphine in the urine, may indicate urine spiking.^20,21,23

Urine creatinine is used to establish the reliability of the specimen. When urine creatinine concentration is <20 mg/dL, the concentration of most substances typically falls to subthreshold levels of detection.²⁴ If a UDS is negative and the urine has a creatinine concentration <20 mg/dL, the patient should provide a new sample, because the urine was likely too diluted to detect any substances.

Continue to: The presence of alcohol...

The presence of alcohol metabolites can alert the clinician to recent alcohol use and possible AUD, which should be assessed and treated if indicated.

Liver enzymes should be normal or unchanged with short- and long-term buprenorphine use when taken as prescribed.^25,26 However, acute liver injury may occur if patients inject buprenorphine intravenously, especially in those with underlying hepatitis C.²⁵

5. What can cause a false negative result on UDS?

Laboratory monitoring may occasionally yield false negative drug screens. For urine buprenorphine levels, false negatives may occur in patients who are “rapid metabolizers,” infrequent or as-needed usage of the medication, patient mix-up, or laboratory error.²⁷ For other substances, a false negative result may occur if the patient used the substance(s) outside the window of detection. The most common causes of false negative results, however, are overly diluted urine samples (eg, due to rapid water ingestion), or the use of an inappropriate test to measure a specific opioid or substance.²⁷

Many laboratories use conventional immunoassays with morphine antibodies that react with various opioid substrates to determine the presence of a specific opioid. Some opioids—particularly synthetics such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, buprenorphine, and methadone—have poor cross-reactivity with the morphine antibody due to their distinct chemical structures, so standard immunoassays used to detect opioids may result in a false negative result.²⁸ In such situations, a discussion with a clinical pathologist familiar with the laboratory detection method can help ensure proper testing. Additional tests for specific opioids should be ordered to more specifically target substances prone to false negative results.²⁷

6. What can cause a false positive result on UDS?

The cross-reactivity of the morphine substrate may also result in a false positive result.²⁸ Other over-the-counter (OTC) or prescription medications that have cross-reactivity with the morphine antibody include dextromethorphan, verapamil, quinine, fluoroquinolones, and rifampin, which can normally be found in urine 2 to 3 days after consumption.^17,27 Poppy seeds have long been known to result in positive opiate screens on urine testing, particularly when laboratories use lower cutoff values (eg, 300 ng/mL), so advise patients to avoid consuming poppy seeds.²⁹

Continue to: For other drugs of abuse...

For other drugs of abuse, false positives are typically caused by cross-reactivity with other prescription or OTC medications. Numerous substances cross-react with amphetamines and produce false positive results on amphetamine immunoassays, including amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone.²⁷ Sertraline and efavirenz are known to produce false positive results on benzodiazepine UDS, and ibuprofen, naproxen, and efavirenz can produce false positive results for cannabinoids.²⁷

7. How do I communicate the results to patients?

Effectively communicating test results to patients is just as important as the results themselves. A trusting, therapeutic alliance between patient and clinician is highly predictive of successful treatment,³⁰ and how the clinician communicates affects the strength of this collaboration. A principle of addiction treatment is the use of neutral language when discussing laboratory results.^31,32 To avoid unintentional shaming or moral judgment, use words such as “positive” or “negative” rather than stigmatizing terms such as “clean” or “dirty.”³³

Additionally, make it clear that laboratory findings are not used to punish patients, but rather to improve treatment.³⁴ Reassuring the patient that a positive screen will not result in withdrawal of care encourages a working relationship.¹⁴ All patients who receive buprenorphine treatment should be informed that collecting a UDS is the standard of care used to monitor their progress. You might want to compare using UDS in patients with OUD to monitoring HbA1c levels in patients with diabetes as an example to demonstrate how laboratory values inform treatment.^35,36

Before reporting the results, a helpful strategy to maintain the therapeutic alliance in the face of a positive UDS is to ask the patient what they expect their UDS to show. When the patient has been reassured that treatment will not be withdrawn due to a positive result, they may be more likely to fully disclose substance use. This allows them the opportunity to self-disclose rather than be “called out” by the clinician.³⁵

8. What happens when a patient tests positive for drugs of abuse?

If a patient tests positive for opioids or other drugs of abuse, convey this information to them, ideally by asking them what they expect to see on laboratory findings. Patients may have “slip ups” or relapses, or use certain prescription medications for medical reasons with the intention of establishing abstinence. It is essential to convey laboratory findings in a nonjudgmental tone while maintaining a supportive stance with clear boundaries.

Continue to: Though addiction specialists...

Though addiction specialists often advise complete abstinence from all substances, including alcohol, cannabis, and tobacco, the harm-reduction model emphasizes “meeting patients where they are” in terms of continued substance use.³⁷ If a patient can reduce their substance use or abstain from some substances while continuing others, these accomplishments should be acknowledged.

For patients who continue to test positive for illicit substances (>3 instances) without a clear explanation, schedule an appointment to re-educate them about buprenorphine treatment and reassess the patient’s treatment goals. Consider changing the current treatment plan, such as by having more frequent follow-ups, increasing the dose of the buprenorphine for patients whose cravings are not sufficiently suppressed, switching to another medication such as methadone or naltrexone, or referring the patient to a higher level of care, such as intensive outpatient or residential treatment.

9. What should I do if the results indicate abnormal levels of buprenorphine, norbuprenorphine, and naloxone?

When urine buprenorphine, norbuprenorphine, or naloxone levels appear low or the results indicate a likely “spiking,” clarify whether the sample tampering is due to poor adherence or diversion. Similar to dealing with a positive result for substances of abuse, ask the patient what they expect to find in their urine, and discuss the results in a nonjudgmental manner. Patients who admit to difficulty following their medication regimen may require additional psychoeducation and motivational interviewing to identify and address barriers. Strategies to improve adherence include setting an alarm, involving the family, using a pillbox, or simplifying the regimen.³⁸ A long-acting injectable form of buprenorphine is also available.

If you suspect diversion, refer to your clinic’s policy and use other clinical management skills, such as increasing the frequency of visits, random pill counts, and supervised medication administration in the clinic.³⁹ If diversion occurs repetitively and the patient is not appropriate for or benefiting from buprenorphine treatment, it may make sense to terminate treatment and consider other treatment options (such as methadone or residential treatment).³⁹

10. What should I do if a patient disagrees with laboratory findings?

It is common for patients to disagree with laboratory results. Maintaining an attitude of neutrality and allowing the patient to speak and provide explanations is necessary to ensure they feel heard. Explanations patients frequently provide include passive exposure (“I was around someone who was using it”) or accidental ingestion, when a patient reports taking a medication they were not aware was a substance of concern. In a calm and nonjudgmental manner, provide education on what leads to a positive drug screen, including the possibility of false positive findings.

Continue to: Because a screening test...

Because a screening test has high sensitivity and low specificity, false positives may occur.^17,27 Therefore, when a result is in dispute, the use of a high-specificity confirmatory test is often needed (many laboratories have reflex confirmatory testing). However, in the case of diluted urine (urine creatinine concentrations <20 mg/dL), patients should be told the findings are physiologically implausible, and a new urine sample should be obtained.²⁴

Goals of laboratory monitoring

Laboratory monitoring, including UDS and urine buprenorphine levels, is a mainstay of treatment for patients with OUD. The increased use of telehealth has affected how laboratory testing is conducted (Box 2^40,41). The goal of laboratory testing is to influence treatment and improve patient outcomes. Clinical data such as clinician assessment, patient self-reporting, and collateral information provide essential details for patient management. However, laboratory monitoring is often the most reliable and objective source by which to influence treatment.

Box 2

An increased understanding of recommended laboratory monitoring practices may improve your comfort with OUD treatment and motivate more clinicians to offer buprenorphine, a life-saving and disease-modifying treatment for OUD. Doing so would increase access to OUD treatment for patients to reduce the individual and public health risks associated with untreated OUD.

Bottom Line

Laboratory monitoring, particularly urine drug screens and urine buprenorphine levels, is the most reliable source of information in the treatment of patients with opioid use disorder (OUD). An increased understanding of monitoring practices may improve a clinician’s willingness to offer buprenorphine as an option for therapy and their ability to properly treat patients with OUD.

Related Resources

• Li X, Moore S, Olson C. Urine drug tests: how to make the most of them. Current Psychiatry. 2019;18(8):10-18,20.
• Moreno JL, Johnson JL, Peckham AM. Sublingual buprenorphine plus buprenorphine XR for opioid use disorder. Current Psychiatry. 2022;21(6):39-42,49. doi:10.12788/cp.0244

Drug Brand Names

Amantadine • Gocovri
Buprenorphine • Subutex, Sublocade
Bupropion • Wellbutrin, Zyban
Efavirenz • Sustiva
Fentanyl • Actiq
Hydrocodone • Hysingla
Hydromorphone • Dilaudid
Methadone • Methadose
Naloxone • Evzio
Naltrexone • Vivitrol
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Ionamin
Quinine • Qualaquin
Ranitidine • Zantac
Rifampin • Rifadin
Selegiline • Eldepryl
Sertraline • Zoloft
Trazodone • Oleptro
Verapamil • Verelan

The opioid use disorder (OUD) epidemic is a major public health crisis in the United States.¹ Naltrexone, methadone, and buprenorphine are first-line therapies for OUD and have high success rates.² While studies have shown that naltrexone is effective, patients must achieve opioid detoxification and maintain 7 to 10 days of total abstinence to avoid a precipitated opioid withdrawal before it can be prescribed.³ Methadone does not require detoxification or a period of complete abstinence, but must be prescribed in special clinics and requires daily observed dosing for the first 90 days,⁴ though these requirements have been relaxed during the COVID-19 pandemic. In contrast, buprenorphine (with or without naloxone) can be used in office-based settings, which significantly improves the accessibility and availability of treatment for patients with OUD. Clinician knowledge and comfort prescribing buprenorphine are limiting factors to treatment.⁵ Increasing the number of clinicians proficient with buprenorphine management can improve access to effective treatment and recovery services, which is critical for patients with OUD.

Multiple resources are available for clinicians to learn how to prescribe buprenorphine, but clear guidance on laboratory testing for patients receiving buprenorphine is limited. To safely and effectively prescribe buprenorphine, clinicians need to understand its pharmacology (Box 1^6-9) and how laboratory testing influences treatment. In an effort to increase clinician knowledge of and proficiency with buprenorphine, this article answers 10 common questions about laboratory monitoring of patients receiving this medication.

Box 1

1. Why is laboratory monitoring important?

Proper laboratory monitoring discourages illicit substance use, encourages medication adherence, and influences treatment modifications. Patient self-reporting on medication compliance may be inaccurate or unreliable.¹⁰ Patients who relapse or use other illicit substances may also be reluctant to disclose their substance use.¹¹

On the other hand, laboratory tests are objective markers of treatment outcome and adherence, and can verify a patient’s self-report.¹² When used appropriately, laboratory monitoring can be therapeutic. It holds patients accountable, especially when used in conjunction with contingency management or other behavioral therapies.¹³ Laboratory monitoring is the most reliable method of determining if patients are abstaining from opioids and other illicit substances, or if the treatment plan requires revision.

2. Which tests should I order?

When initiating or maintaining a patient on buprenorphine, order a general urine drug screen (UDS), urine opioid screen (availability varies by institution), urine creatinine levels, urine buprenorphine/norbuprenorphine/naloxone/creatinine levels, urine alcohol metabolite levels, and a urine general toxicology test. It is also recommended to obtain a comprehensive metabolic panel (CMP) before starting buprenorphine,^14,15 and to monitor CMP values at least once annually following treatment. Patients with a history of IV drug use or other high-risk factors should also be screened for hepatitis B, hepatitis C, and HIV.^14,15

A general UDS can determine if opiates, amphetamines, cocaine, marijuana, or other common illicit substances are present to identify additional substance use. The proficiency of a general UDS may vary depending on the panels used at the respective institution. Some clinics use point-of-care UDS as part of their clinical management; these tests are inexpensive and provide immediate results.¹⁶ A basic UDS typically does not detect synthetic opioids due to the specificity of conventional immunoassays. As a result, specific tests for opioids such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, and methadone should also be considered, depending on their availability. Though buprenorphine treatment may trigger a positive opiate or other opioid screen,¹⁷ buprenorphine adherence should be confirmed using several urine tests, including creatinine, buprenorphine, norbuprenorphine, and naloxone urine levels.

In addition to screening for illicit substances and buprenorphine adherence, it is important to also screen for alcohol. Alcohol use disorder (AUD) is highly comorbid with OUD,¹⁸ and is associated with worse OUD treatment outcomes.¹⁹ Alcohol use may also affect liver function necessary for buprenorphine metabolism,⁸ so urine alcohol metabolites such as ethyl glucuronide and ethyl sulfate, serum transaminases, and gamma-glutamyl transferase should also be obtained.

Continue to: How frequently should patients be tested?

3. How frequently should patients be tested?

As part of the initial assessment, it is recommended to order CMP, UDS, and urine general toxicology.¹⁴ If indicated, specific laboratory tests such as specific opioid and alcohol metabolites screens can be ordered. After starting buprenorphine, the frequency of monitoring urine laboratory tests—including UDS, general drug toxicology, buprenorphine/norbuprenorphine/naloxone/creatinine, and alcohol and its metabolites—depends on a variety of factors, including a patient’s treatment response and stability as well as availability and cost of the tests. Ultimately, the frequency of laboratory monitoring should be determined on a patient-by-patient basis and clinicians should use their judgment.

The American Society of Addiction Medicine suggests testing more frequently earlier in the course of treatment (eg, weekly or biweekly), then spacing it out over time (eg, monthly or quarterly) as the patient’s recovery progresses.^14,15 To conserve resources and reduce spending, some clinicians and guidelines recommend random monitoring as opposed to monitoring at every follow-up visit (eg, once out of every 3 to 5 visits, on average), which allows for longer intervals between testing while ensuring consistency with medication and abstinence from illicit substances.^15,16 We suggest screening every 2 weeks for the first month, then spacing out to monthly and quarterly as patients demonstrate stability, with random screening as indicated. Monitoring of liver function should be done at least once annually.

4. How should urine buprenorphine and other results be interpreted?

There are several issues to consider when interpreting laboratory results. The clinician needs to know what to expect in the sample, and what approximate levels should be detected. To check treatment adherence, laboratory data should include stable urine buprenorphine and norbuprenorphine levels and negative urine screening for other illicit substances.^14,15 While urine buprenorphine and norbuprenorphine levels have great interindividual variability due to genetic differences in hepatic metabolism, unusually high levels of buprenorphine (≥700 ng/mL) without norbuprenorphine suggests “urine spiking,” where patients put buprenorphine directly into their urine sample.^20,21 Abnormally low or undetectable levels raise concern for medication nonadherence or diversion.

Though urine buprenorphine levels do not reliably correlate with dose, because there is typically not much intraindividual variability, patients should have relatively stable levels on each screen once a maintenance dose has been established.²² Furthermore, the buprenorphine-to-norbuprenorphine ratio (ie, “the metabolic ratio”) typically ranges from 1:2 to 1:4 across all individuals,^20,21,23 regardless of dose or metabolic rate. Urine naloxone levels, which typically are included in commercial urine buprenorphine laboratory panels, also may aid in identifying tampered urine specimens when buprenorphine-to-norbuprenorphine ratios are abnormal or inconsistent with an individual’s prior ratio. Naloxone is typically (but not always) poorly absorbed and minimally detected in urine specimens.²⁰ A high level of naloxone coupled with unusually high buprenorphine levels, particularly in the absence of norbuprenorphine in the urine, may indicate urine spiking.^20,21,23

Urine creatinine is used to establish the reliability of the specimen. When urine creatinine concentration is <20 mg/dL, the concentration of most substances typically falls to subthreshold levels of detection.²⁴ If a UDS is negative and the urine has a creatinine concentration <20 mg/dL, the patient should provide a new sample, because the urine was likely too diluted to detect any substances.

Continue to: The presence of alcohol...

The presence of alcohol metabolites can alert the clinician to recent alcohol use and possible AUD, which should be assessed and treated if indicated.

Liver enzymes should be normal or unchanged with short- and long-term buprenorphine use when taken as prescribed.^25,26 However, acute liver injury may occur if patients inject buprenorphine intravenously, especially in those with underlying hepatitis C.²⁵

5. What can cause a false negative result on UDS?

Laboratory monitoring may occasionally yield false negative drug screens. For urine buprenorphine levels, false negatives may occur in patients who are “rapid metabolizers,” infrequent or as-needed usage of the medication, patient mix-up, or laboratory error.²⁷ For other substances, a false negative result may occur if the patient used the substance(s) outside the window of detection. The most common causes of false negative results, however, are overly diluted urine samples (eg, due to rapid water ingestion), or the use of an inappropriate test to measure a specific opioid or substance.²⁷

Many laboratories use conventional immunoassays with morphine antibodies that react with various opioid substrates to determine the presence of a specific opioid. Some opioids—particularly synthetics such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, buprenorphine, and methadone—have poor cross-reactivity with the morphine antibody due to their distinct chemical structures, so standard immunoassays used to detect opioids may result in a false negative result.²⁸ In such situations, a discussion with a clinical pathologist familiar with the laboratory detection method can help ensure proper testing. Additional tests for specific opioids should be ordered to more specifically target substances prone to false negative results.²⁷

6. What can cause a false positive result on UDS?

The cross-reactivity of the morphine substrate may also result in a false positive result.²⁸ Other over-the-counter (OTC) or prescription medications that have cross-reactivity with the morphine antibody include dextromethorphan, verapamil, quinine, fluoroquinolones, and rifampin, which can normally be found in urine 2 to 3 days after consumption.^17,27 Poppy seeds have long been known to result in positive opiate screens on urine testing, particularly when laboratories use lower cutoff values (eg, 300 ng/mL), so advise patients to avoid consuming poppy seeds.²⁹

Continue to: For other drugs of abuse...

For other drugs of abuse, false positives are typically caused by cross-reactivity with other prescription or OTC medications. Numerous substances cross-react with amphetamines and produce false positive results on amphetamine immunoassays, including amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone.²⁷ Sertraline and efavirenz are known to produce false positive results on benzodiazepine UDS, and ibuprofen, naproxen, and efavirenz can produce false positive results for cannabinoids.²⁷

7. How do I communicate the results to patients?

Effectively communicating test results to patients is just as important as the results themselves. A trusting, therapeutic alliance between patient and clinician is highly predictive of successful treatment,³⁰ and how the clinician communicates affects the strength of this collaboration. A principle of addiction treatment is the use of neutral language when discussing laboratory results.^31,32 To avoid unintentional shaming or moral judgment, use words such as “positive” or “negative” rather than stigmatizing terms such as “clean” or “dirty.”³³

Additionally, make it clear that laboratory findings are not used to punish patients, but rather to improve treatment.³⁴ Reassuring the patient that a positive screen will not result in withdrawal of care encourages a working relationship.¹⁴ All patients who receive buprenorphine treatment should be informed that collecting a UDS is the standard of care used to monitor their progress. You might want to compare using UDS in patients with OUD to monitoring HbA1c levels in patients with diabetes as an example to demonstrate how laboratory values inform treatment.^35,36

Before reporting the results, a helpful strategy to maintain the therapeutic alliance in the face of a positive UDS is to ask the patient what they expect their UDS to show. When the patient has been reassured that treatment will not be withdrawn due to a positive result, they may be more likely to fully disclose substance use. This allows them the opportunity to self-disclose rather than be “called out” by the clinician.³⁵

8. What happens when a patient tests positive for drugs of abuse?

If a patient tests positive for opioids or other drugs of abuse, convey this information to them, ideally by asking them what they expect to see on laboratory findings. Patients may have “slip ups” or relapses, or use certain prescription medications for medical reasons with the intention of establishing abstinence. It is essential to convey laboratory findings in a nonjudgmental tone while maintaining a supportive stance with clear boundaries.

Continue to: Though addiction specialists...

Though addiction specialists often advise complete abstinence from all substances, including alcohol, cannabis, and tobacco, the harm-reduction model emphasizes “meeting patients where they are” in terms of continued substance use.³⁷ If a patient can reduce their substance use or abstain from some substances while continuing others, these accomplishments should be acknowledged.

For patients who continue to test positive for illicit substances (>3 instances) without a clear explanation, schedule an appointment to re-educate them about buprenorphine treatment and reassess the patient’s treatment goals. Consider changing the current treatment plan, such as by having more frequent follow-ups, increasing the dose of the buprenorphine for patients whose cravings are not sufficiently suppressed, switching to another medication such as methadone or naltrexone, or referring the patient to a higher level of care, such as intensive outpatient or residential treatment.

9. What should I do if the results indicate abnormal levels of buprenorphine, norbuprenorphine, and naloxone?

When urine buprenorphine, norbuprenorphine, or naloxone levels appear low or the results indicate a likely “spiking,” clarify whether the sample tampering is due to poor adherence or diversion. Similar to dealing with a positive result for substances of abuse, ask the patient what they expect to find in their urine, and discuss the results in a nonjudgmental manner. Patients who admit to difficulty following their medication regimen may require additional psychoeducation and motivational interviewing to identify and address barriers. Strategies to improve adherence include setting an alarm, involving the family, using a pillbox, or simplifying the regimen.³⁸ A long-acting injectable form of buprenorphine is also available.

If you suspect diversion, refer to your clinic’s policy and use other clinical management skills, such as increasing the frequency of visits, random pill counts, and supervised medication administration in the clinic.³⁹ If diversion occurs repetitively and the patient is not appropriate for or benefiting from buprenorphine treatment, it may make sense to terminate treatment and consider other treatment options (such as methadone or residential treatment).³⁹

10. What should I do if a patient disagrees with laboratory findings?

It is common for patients to disagree with laboratory results. Maintaining an attitude of neutrality and allowing the patient to speak and provide explanations is necessary to ensure they feel heard. Explanations patients frequently provide include passive exposure (“I was around someone who was using it”) or accidental ingestion, when a patient reports taking a medication they were not aware was a substance of concern. In a calm and nonjudgmental manner, provide education on what leads to a positive drug screen, including the possibility of false positive findings.

Continue to: Because a screening test...

Because a screening test has high sensitivity and low specificity, false positives may occur.^17,27 Therefore, when a result is in dispute, the use of a high-specificity confirmatory test is often needed (many laboratories have reflex confirmatory testing). However, in the case of diluted urine (urine creatinine concentrations <20 mg/dL), patients should be told the findings are physiologically implausible, and a new urine sample should be obtained.²⁴

Goals of laboratory monitoring

Laboratory monitoring, including UDS and urine buprenorphine levels, is a mainstay of treatment for patients with OUD. The increased use of telehealth has affected how laboratory testing is conducted (Box 2^40,41). The goal of laboratory testing is to influence treatment and improve patient outcomes. Clinical data such as clinician assessment, patient self-reporting, and collateral information provide essential details for patient management. However, laboratory monitoring is often the most reliable and objective source by which to influence treatment.

Box 2

An increased understanding of recommended laboratory monitoring practices may improve your comfort with OUD treatment and motivate more clinicians to offer buprenorphine, a life-saving and disease-modifying treatment for OUD. Doing so would increase access to OUD treatment for patients to reduce the individual and public health risks associated with untreated OUD.

Bottom Line

Laboratory monitoring, particularly urine drug screens and urine buprenorphine levels, is the most reliable source of information in the treatment of patients with opioid use disorder (OUD). An increased understanding of monitoring practices may improve a clinician’s willingness to offer buprenorphine as an option for therapy and their ability to properly treat patients with OUD.

Related Resources

• Li X, Moore S, Olson C. Urine drug tests: how to make the most of them. Current Psychiatry. 2019;18(8):10-18,20.
• Moreno JL, Johnson JL, Peckham AM. Sublingual buprenorphine plus buprenorphine XR for opioid use disorder. Current Psychiatry. 2022;21(6):39-42,49. doi:10.12788/cp.0244

Drug Brand Names

Amantadine • Gocovri
Buprenorphine • Subutex, Sublocade
Bupropion • Wellbutrin, Zyban
Efavirenz • Sustiva
Fentanyl • Actiq
Hydrocodone • Hysingla
Hydromorphone • Dilaudid
Methadone • Methadose
Naloxone • Evzio
Naltrexone • Vivitrol
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Ionamin
Quinine • Qualaquin
Ranitidine • Zantac
Rifampin • Rifadin
Selegiline • Eldepryl
Sertraline • Zoloft
Trazodone • Oleptro
Verapamil • Verelan

One of psychiatry’s long-standing dogmas is that personality disorders are enduring, unchangeable, and not amenable to treatment with potent psychotropics or intensive psychotherapy. I propose that this dogma may soon be shattered.

Several other dogmas in psychiatry have been demolished over the past several decades:

• that “insanity” is completely irreversible and requires lifetime institutionalization. The serendipitous discovery of chlorpromazine¹ annihilated this centuries-old dogma
• that chronic, severe, refractory depression (with ongoing suicidal urges) that fails to improve with pharmacotherapy or electroconvulsive therapy (ECT) is hopeless and untreatable, until ketamine not only pulverized this dogma, but did it with lightning speed, dazzling us all²
• that dissociative agents such as ketamine are dangerous and condemnable drugs of abuse, until the therapeutic effect of ketamine slayed that dragon³
• that ECT “fries” the brain (as malevolently propagated by antipsychiatry cults), which was completely disproven by neuroimaging studies that show the hippocampus (which shrinks during depression) actually grows by >10% after a few ECT sessions⁴
• that psychotherapy is not a “real” treatment because talking cannot reverse a psychiatric brain disorder, until studies showed significant neuroplasticity with psychotherapy and decrease in inflammatory biomarkers with cognitive-behavioral therapy (CBT)⁵
• that persons with refractory hallucinations and delusions are doomed to a life of disability, until clozapine torpedoed that pessimistic dogma⁶
• that hallucinogens/psychedelics are dangerous and should be banned, until a jarring paradigm shift occurred with the discovery of psilocybin’s transformative effects, and the remarkable therapeutic effects of its mystical trips.⁷

Psilocybin’s therapeutic effects

Psilocybin has already proved to have a strong and lasting effect on depression and promises to have therapeutic benefits for patients with substance use disorders, posttraumatic stress disorder (PTSD), and anxiety.⁸ In addition, when the multiple psychological and neuro­biological effects of psilocybin (and of other psychedelics) are examined, I see a very promising path to amelioration of severe personality disorders such as psychopathy, antisocial behavior, and narcissism. The mechanism(s) of action of psilocybin on the human brain are drastically different from any man-made psychotropic agent. As a psychiatric neuroscientist, I envision the neurologic impact of psilocybin to be conducive to a complete transformation of a patient’s view of themself, other people, and the meaning of life. It is reminiscent of religious conversion.

The psychological effects of psilocybin in humans have been described as follows:

• emotional breakthrough⁹
• increased psychological flexibility,^10,11 a very cortical effect
• mystical experience,¹² which results in sudden and significant changes in behavior and perception and includes the following dimensions: sacredness, noetic quality, deeply felt positive mood, ineffability, paradoxicality, and transcendence of time and space¹³
• oceanic boundlessness, feeling “one with the universe”¹⁴
• universal interconnectedness, insightfulness, blissful state, spiritual experience¹⁴
• ego dissolution,¹⁵ with loss of one’s personal identity
• increased neuroplasticity¹⁶
• changes in cognition and increase in insight.¹⁷

The neurobiological effects of psilocybin are mediated by serotonin 5HT2A agonism and include the following¹⁸:

• reduction in the activity of the medial prefrontal cortex, which regulates memory, attention, inhibitory control, and habit
• a decrease in the connectivity between the medial prefrontal cortex and the posterior cingulate cortex, which regulates memory and emotions
• reducing the default mode network, which is active during rest, stimulating internal thoughts and reminiscing about previous feelings and events, sometimes including ruminations. Psilocybin reverses those processes to thinking about others, not just the self, and becoming more open-minded about the world and other people. This can be therapeutic for depression, which is often associated with negative ruminations but also with entrenched habits (addictive behaviors), anxiety, PTSD, and obsessive-compulsive disorders
• increased global functional connectivity among various brain networks, leading to stronger functional integration of behavior
• collapse of major cortical oscillatory rhythms such as alpha and others that perpetuate “prior” beliefs
• extensive neuroplasticity and recalibration of thought processes and decomposition of pathological beliefs, referred to as REBUS (relaxed beliefs under psychedelics).

The bottom line is psilocybin and other psychedelics can dramatically alter, reshape, and relax rigid beliefs and personality traits by decreasing “neuroticism” and increasing “extraversion,” insightfulness, openness, and possibly conscientiousness.¹⁹ Although no studies of psychedelics in psychopathic, antisocial, or narcissistic personality disorders have been conducted, it is very reasonable to speculate that psilocybin may reverse traits of these disorders such as callousness, lack of empathy, and pathological self-centeredness.

Going further, a preliminary report suggests psilocybin can modify political views by decreasing authoritarianism and increasing libertarianism.^20,21 In the current political zeitgeist, could psychedelics such as psilocybin reduce or even eliminate political extremism and visceral hatred on all sides? It would be remarkable research to carry out to heal a politically divided populace.The dogma of untreatable personality disorders or hopelessly entrenched political extremism is on the chopping block, and psychedelics offer hope to splinter those beliefs by concurrently remodeling brain tissue (neuroplasticity) and rectifying the mindset (psychoplasticity).

One of psychiatry’s long-standing dogmas is that personality disorders are enduring, unchangeable, and not amenable to treatment with potent psychotropics or intensive psychotherapy. I propose that this dogma may soon be shattered.

Several other dogmas in psychiatry have been demolished over the past several decades:

• that “insanity” is completely irreversible and requires lifetime institutionalization. The serendipitous discovery of chlorpromazine¹ annihilated this centuries-old dogma
• that chronic, severe, refractory depression (with ongoing suicidal urges) that fails to improve with pharmacotherapy or electroconvulsive therapy (ECT) is hopeless and untreatable, until ketamine not only pulverized this dogma, but did it with lightning speed, dazzling us all²
• that dissociative agents such as ketamine are dangerous and condemnable drugs of abuse, until the therapeutic effect of ketamine slayed that dragon³
• that ECT “fries” the brain (as malevolently propagated by antipsychiatry cults), which was completely disproven by neuroimaging studies that show the hippocampus (which shrinks during depression) actually grows by >10% after a few ECT sessions⁴
• that psychotherapy is not a “real” treatment because talking cannot reverse a psychiatric brain disorder, until studies showed significant neuroplasticity with psychotherapy and decrease in inflammatory biomarkers with cognitive-behavioral therapy (CBT)⁵
• that persons with refractory hallucinations and delusions are doomed to a life of disability, until clozapine torpedoed that pessimistic dogma⁶
• that hallucinogens/psychedelics are dangerous and should be banned, until a jarring paradigm shift occurred with the discovery of psilocybin’s transformative effects, and the remarkable therapeutic effects of its mystical trips.⁷

Psilocybin’s therapeutic effects

Psilocybin has already proved to have a strong and lasting effect on depression and promises to have therapeutic benefits for patients with substance use disorders, posttraumatic stress disorder (PTSD), and anxiety.⁸ In addition, when the multiple psychological and neuro­biological effects of psilocybin (and of other psychedelics) are examined, I see a very promising path to amelioration of severe personality disorders such as psychopathy, antisocial behavior, and narcissism. The mechanism(s) of action of psilocybin on the human brain are drastically different from any man-made psychotropic agent. As a psychiatric neuroscientist, I envision the neurologic impact of psilocybin to be conducive to a complete transformation of a patient’s view of themself, other people, and the meaning of life. It is reminiscent of religious conversion.

The psychological effects of psilocybin in humans have been described as follows:

• emotional breakthrough⁹
• increased psychological flexibility,^10,11 a very cortical effect
• mystical experience,¹² which results in sudden and significant changes in behavior and perception and includes the following dimensions: sacredness, noetic quality, deeply felt positive mood, ineffability, paradoxicality, and transcendence of time and space¹³
• oceanic boundlessness, feeling “one with the universe”¹⁴
• universal interconnectedness, insightfulness, blissful state, spiritual experience¹⁴
• ego dissolution,¹⁵ with loss of one’s personal identity
• increased neuroplasticity¹⁶
• changes in cognition and increase in insight.¹⁷

The neurobiological effects of psilocybin are mediated by serotonin 5HT2A agonism and include the following¹⁸:

• reduction in the activity of the medial prefrontal cortex, which regulates memory, attention, inhibitory control, and habit
• a decrease in the connectivity between the medial prefrontal cortex and the posterior cingulate cortex, which regulates memory and emotions
• reducing the default mode network, which is active during rest, stimulating internal thoughts and reminiscing about previous feelings and events, sometimes including ruminations. Psilocybin reverses those processes to thinking about others, not just the self, and becoming more open-minded about the world and other people. This can be therapeutic for depression, which is often associated with negative ruminations but also with entrenched habits (addictive behaviors), anxiety, PTSD, and obsessive-compulsive disorders
• increased global functional connectivity among various brain networks, leading to stronger functional integration of behavior
• collapse of major cortical oscillatory rhythms such as alpha and others that perpetuate “prior” beliefs
• extensive neuroplasticity and recalibration of thought processes and decomposition of pathological beliefs, referred to as REBUS (relaxed beliefs under psychedelics).

The bottom line is psilocybin and other psychedelics can dramatically alter, reshape, and relax rigid beliefs and personality traits by decreasing “neuroticism” and increasing “extraversion,” insightfulness, openness, and possibly conscientiousness.¹⁹ Although no studies of psychedelics in psychopathic, antisocial, or narcissistic personality disorders have been conducted, it is very reasonable to speculate that psilocybin may reverse traits of these disorders such as callousness, lack of empathy, and pathological self-centeredness.

Going further, a preliminary report suggests psilocybin can modify political views by decreasing authoritarianism and increasing libertarianism.^20,21 In the current political zeitgeist, could psychedelics such as psilocybin reduce or even eliminate political extremism and visceral hatred on all sides? It would be remarkable research to carry out to heal a politically divided populace.The dogma of untreatable personality disorders or hopelessly entrenched political extremism is on the chopping block, and psychedelics offer hope to splinter those beliefs by concurrently remodeling brain tissue (neuroplasticity) and rectifying the mindset (psychoplasticity).

One of psychiatry’s long-standing dogmas is that personality disorders are enduring, unchangeable, and not amenable to treatment with potent psychotropics or intensive psychotherapy. I propose that this dogma may soon be shattered.

Several other dogmas in psychiatry have been demolished over the past several decades:

• that “insanity” is completely irreversible and requires lifetime institutionalization. The serendipitous discovery of chlorpromazine¹ annihilated this centuries-old dogma
• that chronic, severe, refractory depression (with ongoing suicidal urges) that fails to improve with pharmacotherapy or electroconvulsive therapy (ECT) is hopeless and untreatable, until ketamine not only pulverized this dogma, but did it with lightning speed, dazzling us all²
• that dissociative agents such as ketamine are dangerous and condemnable drugs of abuse, until the therapeutic effect of ketamine slayed that dragon³
• that ECT “fries” the brain (as malevolently propagated by antipsychiatry cults), which was completely disproven by neuroimaging studies that show the hippocampus (which shrinks during depression) actually grows by >10% after a few ECT sessions⁴
• that psychotherapy is not a “real” treatment because talking cannot reverse a psychiatric brain disorder, until studies showed significant neuroplasticity with psychotherapy and decrease in inflammatory biomarkers with cognitive-behavioral therapy (CBT)⁵
• that persons with refractory hallucinations and delusions are doomed to a life of disability, until clozapine torpedoed that pessimistic dogma⁶
• that hallucinogens/psychedelics are dangerous and should be banned, until a jarring paradigm shift occurred with the discovery of psilocybin’s transformative effects, and the remarkable therapeutic effects of its mystical trips.⁷

Psilocybin’s therapeutic effects

Psilocybin has already proved to have a strong and lasting effect on depression and promises to have therapeutic benefits for patients with substance use disorders, posttraumatic stress disorder (PTSD), and anxiety.⁸ In addition, when the multiple psychological and neuro­biological effects of psilocybin (and of other psychedelics) are examined, I see a very promising path to amelioration of severe personality disorders such as psychopathy, antisocial behavior, and narcissism. The mechanism(s) of action of psilocybin on the human brain are drastically different from any man-made psychotropic agent. As a psychiatric neuroscientist, I envision the neurologic impact of psilocybin to be conducive to a complete transformation of a patient’s view of themself, other people, and the meaning of life. It is reminiscent of religious conversion.

The psychological effects of psilocybin in humans have been described as follows:

• emotional breakthrough⁹
• increased psychological flexibility,^10,11 a very cortical effect
• mystical experience,¹² which results in sudden and significant changes in behavior and perception and includes the following dimensions: sacredness, noetic quality, deeply felt positive mood, ineffability, paradoxicality, and transcendence of time and space¹³
• oceanic boundlessness, feeling “one with the universe”¹⁴
• universal interconnectedness, insightfulness, blissful state, spiritual experience¹⁴
• ego dissolution,¹⁵ with loss of one’s personal identity
• increased neuroplasticity¹⁶
• changes in cognition and increase in insight.¹⁷

The neurobiological effects of psilocybin are mediated by serotonin 5HT2A agonism and include the following¹⁸:

• reduction in the activity of the medial prefrontal cortex, which regulates memory, attention, inhibitory control, and habit
• a decrease in the connectivity between the medial prefrontal cortex and the posterior cingulate cortex, which regulates memory and emotions
• reducing the default mode network, which is active during rest, stimulating internal thoughts and reminiscing about previous feelings and events, sometimes including ruminations. Psilocybin reverses those processes to thinking about others, not just the self, and becoming more open-minded about the world and other people. This can be therapeutic for depression, which is often associated with negative ruminations but also with entrenched habits (addictive behaviors), anxiety, PTSD, and obsessive-compulsive disorders
• increased global functional connectivity among various brain networks, leading to stronger functional integration of behavior
• collapse of major cortical oscillatory rhythms such as alpha and others that perpetuate “prior” beliefs
• extensive neuroplasticity and recalibration of thought processes and decomposition of pathological beliefs, referred to as REBUS (relaxed beliefs under psychedelics).

The bottom line is psilocybin and other psychedelics can dramatically alter, reshape, and relax rigid beliefs and personality traits by decreasing “neuroticism” and increasing “extraversion,” insightfulness, openness, and possibly conscientiousness.¹⁹ Although no studies of psychedelics in psychopathic, antisocial, or narcissistic personality disorders have been conducted, it is very reasonable to speculate that psilocybin may reverse traits of these disorders such as callousness, lack of empathy, and pathological self-centeredness.

Going further, a preliminary report suggests psilocybin can modify political views by decreasing authoritarianism and increasing libertarianism.^20,21 In the current political zeitgeist, could psychedelics such as psilocybin reduce or even eliminate political extremism and visceral hatred on all sides? It would be remarkable research to carry out to heal a politically divided populace.The dogma of untreatable personality disorders or hopelessly entrenched political extremism is on the chopping block, and psychedelics offer hope to splinter those beliefs by concurrently remodeling brain tissue (neuroplasticity) and rectifying the mindset (psychoplasticity).

The series “Neurotransmitter-based diagnosis and treatment: A hypothesis” (Part 1: Current Psychiatry, May 2022, p. 30-36, doi:10.12788/cp.0242; Part 2: Current Psychiatry, June 2022, p. 28-33, doi:10.12788/cp.0253; and Part 3: Current Psychiatry, July 2022, p. 34-40, doi:10.12788/cp.0260) translated biological psychiatry’s working causal theory into actionable clinical ideas.

The presentation of abnormal neuro­transmission may occur along a continuum. For example, extreme dopamine deficiency can present as catatonia, moderate deficiency may present with inattention, normal activity permits adaptive functioning, and excitatory delirium and sudden death may be at the extreme end of dopa­minergic excess.¹

The amplitude, rate of change, and location of neurotransmitter dysfunction may determine which specialty takes the primary treatment role. Fatigue, pain, sleep difficulty, and emotional distress require clinicians to understand the whole patient, which is why health care professionals need cross training in psychiatry, and psychiatry recognizes multisystem pathology.

The recognition and treatment of substance use disorders requires an understanding of neurotransmitter symptoms, in terms of both acute drug effects and withdrawal. Fallows² provides this information in an accessible chart. Discussions of neurotransmitters also have value in managing psychotropic medication withdrawal.³

Acetylcholine is another neuro­transmitter of importance; it is essential to normal motor, cognitive, and emotional function. Extreme cholinergic deficiency or anticholinergic crisis has symptoms of pupillary dilation, psychosis, and delirium.^4-6 The progressive decline seen in certain dementias is related in part to cholinergic deficit. Dominance of cholinergic activity is associated with depression and biomarkers such as increased rapid eye movement (REM) density, a measure of the frequency of rapid eye movements during REM sleep.⁷ Cholinergic excess or cholinergic crisis may present with symptoms of salivation, lacrimation, muscle weakness, delirium, or paralysis.⁸

The articles alluded to the interaction of neurotransmitter systems (eg, “dopamine blockade helps with endorphin suppression”). Isolating the effects of a single neurotransmitter is useful, but covariance of neurotransmitter activity also has diagnostic and treatment implications.^9-11 Abnormalities in these interactions may be part of the causal process in fundamental cognitive functions.¹² If endorphin suppression is insensitive to dopamine blockade, a relative endorphin excess may create symptoms. If acetylcholine changes are normally balanced by a relative increase in dopamine and norepinephrine, then a weak catecholamine response would fit the catecholamine-cholinergic balance hypothesis of depression. Neurotransmitter interactions are well worked out in the neurology of the basal ganglia but less clear in the frontal and limbic systems.¹³

Quantification has been applied in some areas of clinical care. Morphine equivalents are used to express opiate potency, and there are algorithms to summarize multiple medication effects on respiratory depression/overdose risk.^14,15 Chlorpromazine equivalents were used to translate a range of antipsychotic potencies in the early days of antipsychotic treatment. Adverse effects and some treatment responses partially corresponded to the level of dopamine blockade, but not without noise. There is a wide range of variance as antipsychotic potency is assessed for clinical efficacy.¹⁶ We are still working on the array of medication potency and selectivity across neurotransmitter systems.^17,18 For example, paroxetine is a potent serotonin reuptake blocker but less selective than citalopram, particularly antagonizing cholinergic muscarinic receptors.

The authors noted their hypothesis needs further elaboration and quantification as psychiatry moves from impressionistic practice to firmer science. Measurement of neuro­transmitter activity is an area of intense research. Biomeasures have yet to add much value to the clinical practice of psychiatry, but we hope for progress. Functional neuroimaging with sophisticated algorithms is beginning to detail neocortical activity.¹⁹ CSF measurement of dopamine and serotonin metabolites seem to correlate with severe depression and suicidal behavior. Noninvasive, wearable technologies to measure galvanic skin response, oxygenation, and neurotransmitter metabolic products may add to neuro-transmitter-based assessment and treatment.

Neurotransmitters are one aspect of brain function. Other processes, such as hormonal neuromodulation²⁰ and ion channels, may be over- or underactive. Channelopathies are of particular interest in cardiology and neurology but are also notable in pain and emotional disorders.^21-26 Voltage-gated sodium channels are thought to be involved in general anesthesia.²⁷ Adverse effects of some psychotropic medications are best understood as ion channel dysfunction.²⁸ Using the strategy of this hypothesis applied to activation or inactivation of sodium, potassium, and calcium channels can guide useful diagnostic and treatment ideas for further study.

Mark C. Chandler, MD
Triangle Neuropsychiatry
Durham, North Carolina

Disclosures

The author reports no financial relationships with any companies whose products are mentioned in his letter, or with manufacturers of competing products.

References

1. Mash DC. Excited delirium and sudden death: a syndromal disorder at the extreme end of the neuropsychiatric continuum. Front Physiol. 2016;7:435.

2. Fallows Z. MIT MedLinks. Accessed August 8, 2022. http://web.mit.edu/zakf/www/drugchart/drugchart11.html

3. Groot PC, van Os J. How user knowledge of psychotropic drug withdrawal resulted in the development of person-specific tapering medication. Ther Adv Psychopharmacol. 2020;10:2045125320932452. doi:10.1177/2045125320932452

4. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116-129.

5. Nair VP, Hunter JM. Anticholinesterases and anticholinergic drugs. Continuing Education in Anaesthesia Critical Care & Pain. 2004;4(5):164-168.

6. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium--theory, evidence and practice. Br J Clin Pharmacol. 2016;81(3):516-524.

7. Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol Psychiatry. 2019;24(5):694-709.

8. Adeyinka A, Kondamudi NP. Cholinergic Crisis. StatPearls Publishing; 2022.

9. El Mansari M, Guiard BP, Chernoloz O, et al. Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder. CNS Neurosci Ther. 2010;16(3):e1-e17.

10. Esposito E. Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets. 2006;7(2):177-185.

11. Kringelbach ML, Cruzat J, Cabral J, et al. Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proc Natl Acad Sci U S A. 2020;117(17):9566-9576.

12. Thiele A, Bellgrove MA. Neuromodulation of attention. Neuron. 2018;97(4):769-785.

13. Muñoz A, Lopez-Lopez A, Labandeira CM, et al. Interactions between the serotonergic and other neurotransmitter systems in the basal ganglia: role in Parkinson’s disease and adverse effects of L-DOPA. Front Neuroanat. 2020;14:26.

14. Nielsen S, Degenhardt L, Hoban B, et al. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiol Drug Saf. 2016;25(6):733-737.

15. Lo-Ciganic WH, Huang JL, Zhang HH, et al. Evaluation of machine-learning algorithms for predicting opioid overdose risk among Medicare beneficiaries with opioid prescriptions. JAMA Netw Open. 2019;2(3):e190968. doi:10.1001/jamanetworkopen.2019.0968

16. Dewan MJ, Koss M. The clinical impact of reported variance in potency of antipsychotic agents. Acta Psychiatr Scand. 1995;91(4):229-232.

17. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64(6):663-667.

18. Hayasaka Y, Purgato M, Magni LR, et al. Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials. J Affect Disord. 2015;180:179-184.

19. Hansen JY, Shafiei G, Markello RD, et al. Mapping neurotransmitter systems to the structural and functional organization of the human neocortex. bioRxiv. 2021. https://doi.org/10.1101/2021.10.28.466336

20. Hwang WJ, Lee TY, Kim NS, et al. The role of estrogen receptors and their signaling across psychiatric disorders. Int J Mol Sci. 2020;22(1):373.

21. Lawrence JH, Tomaselli GF, Marban E. Ion channels: structure and function. Heart Dis Stroke. 1993;2(1):75-80.

22. Fedele F, Severino P, Bruno N, et al. Role of ion channels in coronary microcirculation: a review of the literature. Future Cardiol. 2013;9(6):897-905.

23. Kumar P, Kumar D, Jha SK, et al. Ion channels in neurological disorders. Adv Protein Chem Struct Biol. 2016;103:97-136.

24. Quagliato LA, Nardi AE. The role of convergent ion channel pathways in microglial phenotypes: a systematic review of the implications for neurological and psychiatric disorders. Transl Psychiatry. 2018;8(1):259.

25. Bianchi MT, Botzolakis EJ. Targeting ligand-gated ion channels in neurology and psychiatry: is pharmacological promiscuity an obstacle or an opportunity? BMC Pharmacol. 2010;10:3.

26. Imbrici P, Camerino DC, Tricarico D. Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet. 2013;4:76.

27. Xiao J, Chen Z, Yu B. A potential mechanism of sodium channel mediating the general anesthesia induced by propofol. Front Cell Neurosci. 2020;14:593050. doi:10.3389/fncel.2020.593050

28. Kamei S, Sato N, Harayama Y, et al. Molecular analysis of potassium ion channel genes in sudden death cases among patients administered psychotropic drug therapy: are polymorphisms in LQT genes a potential risk factor? J Hum Genet. 2014;59(2):95-99.

The authors respond

Thank you for your thoughtful commen­tary. Our conceptual article was not designed to cover enough ground to be completely thorough. Everything you wrote adds to what we wanted to bring to the reader’s attention. The mechanisms of disease in psychiatry are numerous and still elusive, and the brain’s complexity is staggering. Our main goal was to point out possible correlations between specific symptoms and specific neurotransmitter activity. We had to oversimplify to make the article concise enough for publication. Neurotransmitter effects are based on their synthesis, storage, release, reuptake, and degradation. A receptor’s quantity and quality of function, inhibitors, inducers, and many other factors are involved in neurotransmitter performance. And, of course, there are additional fundamental neurotransmitters beyond the 6 we touched on. Our ability to sort through all of this is still rudimentary. You also reflect on the emerging methods to objectively measure neuro­transmitter activity, which will eventually find their way to clinical practice and become invaluable. Still, we treat people, not tests or pictures, so diagnostic thinking based on clinical presentation will forever remain a cornerstone of dealing with individual patients.

We hope scientists and clinicians such as yourself will improve our concept and make it truly practical.

Dmitry M. Arbuck, MD
Clinical Assistant Professor of Psychiatry and Medicine
Indiana University School of Medicine
Indianapolis, Indiana
President and Medical Director
Indiana Polyclinic
Carmel, Indiana

José Miguel Salmerón, MD
Professor
Department of Psychiatry
Universidad del Valle School of Medicine/Hospital
Universitario del Valle
Cali, Colombia

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their response, or with manufacturers of competing products.

The series “Neurotransmitter-based diagnosis and treatment: A hypothesis” (Part 1: Current Psychiatry, May 2022, p. 30-36, doi:10.12788/cp.0242; Part 2: Current Psychiatry, June 2022, p. 28-33, doi:10.12788/cp.0253; and Part 3: Current Psychiatry, July 2022, p. 34-40, doi:10.12788/cp.0260) translated biological psychiatry’s working causal theory into actionable clinical ideas.

The presentation of abnormal neuro­transmission may occur along a continuum. For example, extreme dopamine deficiency can present as catatonia, moderate deficiency may present with inattention, normal activity permits adaptive functioning, and excitatory delirium and sudden death may be at the extreme end of dopa­minergic excess.¹

The amplitude, rate of change, and location of neurotransmitter dysfunction may determine which specialty takes the primary treatment role. Fatigue, pain, sleep difficulty, and emotional distress require clinicians to understand the whole patient, which is why health care professionals need cross training in psychiatry, and psychiatry recognizes multisystem pathology.

The recognition and treatment of substance use disorders requires an understanding of neurotransmitter symptoms, in terms of both acute drug effects and withdrawal. Fallows² provides this information in an accessible chart. Discussions of neurotransmitters also have value in managing psychotropic medication withdrawal.³

Acetylcholine is another neuro­transmitter of importance; it is essential to normal motor, cognitive, and emotional function. Extreme cholinergic deficiency or anticholinergic crisis has symptoms of pupillary dilation, psychosis, and delirium.^4-6 The progressive decline seen in certain dementias is related in part to cholinergic deficit. Dominance of cholinergic activity is associated with depression and biomarkers such as increased rapid eye movement (REM) density, a measure of the frequency of rapid eye movements during REM sleep.⁷ Cholinergic excess or cholinergic crisis may present with symptoms of salivation, lacrimation, muscle weakness, delirium, or paralysis.⁸

The articles alluded to the interaction of neurotransmitter systems (eg, “dopamine blockade helps with endorphin suppression”). Isolating the effects of a single neurotransmitter is useful, but covariance of neurotransmitter activity also has diagnostic and treatment implications.^9-11 Abnormalities in these interactions may be part of the causal process in fundamental cognitive functions.¹² If endorphin suppression is insensitive to dopamine blockade, a relative endorphin excess may create symptoms. If acetylcholine changes are normally balanced by a relative increase in dopamine and norepinephrine, then a weak catecholamine response would fit the catecholamine-cholinergic balance hypothesis of depression. Neurotransmitter interactions are well worked out in the neurology of the basal ganglia but less clear in the frontal and limbic systems.¹³

Quantification has been applied in some areas of clinical care. Morphine equivalents are used to express opiate potency, and there are algorithms to summarize multiple medication effects on respiratory depression/overdose risk.^14,15 Chlorpromazine equivalents were used to translate a range of antipsychotic potencies in the early days of antipsychotic treatment. Adverse effects and some treatment responses partially corresponded to the level of dopamine blockade, but not without noise. There is a wide range of variance as antipsychotic potency is assessed for clinical efficacy.¹⁶ We are still working on the array of medication potency and selectivity across neurotransmitter systems.^17,18 For example, paroxetine is a potent serotonin reuptake blocker but less selective than citalopram, particularly antagonizing cholinergic muscarinic receptors.

The authors noted their hypothesis needs further elaboration and quantification as psychiatry moves from impressionistic practice to firmer science. Measurement of neuro­transmitter activity is an area of intense research. Biomeasures have yet to add much value to the clinical practice of psychiatry, but we hope for progress. Functional neuroimaging with sophisticated algorithms is beginning to detail neocortical activity.¹⁹ CSF measurement of dopamine and serotonin metabolites seem to correlate with severe depression and suicidal behavior. Noninvasive, wearable technologies to measure galvanic skin response, oxygenation, and neurotransmitter metabolic products may add to neuro-transmitter-based assessment and treatment.

Neurotransmitters are one aspect of brain function. Other processes, such as hormonal neuromodulation²⁰ and ion channels, may be over- or underactive. Channelopathies are of particular interest in cardiology and neurology but are also notable in pain and emotional disorders.^21-26 Voltage-gated sodium channels are thought to be involved in general anesthesia.²⁷ Adverse effects of some psychotropic medications are best understood as ion channel dysfunction.²⁸ Using the strategy of this hypothesis applied to activation or inactivation of sodium, potassium, and calcium channels can guide useful diagnostic and treatment ideas for further study.

Mark C. Chandler, MD
Triangle Neuropsychiatry
Durham, North Carolina

Disclosures

The author reports no financial relationships with any companies whose products are mentioned in his letter, or with manufacturers of competing products.

References

1. Mash DC. Excited delirium and sudden death: a syndromal disorder at the extreme end of the neuropsychiatric continuum. Front Physiol. 2016;7:435.

2. Fallows Z. MIT MedLinks. Accessed August 8, 2022. http://web.mit.edu/zakf/www/drugchart/drugchart11.html

3. Groot PC, van Os J. How user knowledge of psychotropic drug withdrawal resulted in the development of person-specific tapering medication. Ther Adv Psychopharmacol. 2020;10:2045125320932452. doi:10.1177/2045125320932452

4. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116-129.

5. Nair VP, Hunter JM. Anticholinesterases and anticholinergic drugs. Continuing Education in Anaesthesia Critical Care & Pain. 2004;4(5):164-168.

6. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium--theory, evidence and practice. Br J Clin Pharmacol. 2016;81(3):516-524.

7. Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol Psychiatry. 2019;24(5):694-709.

8. Adeyinka A, Kondamudi NP. Cholinergic Crisis. StatPearls Publishing; 2022.

9. El Mansari M, Guiard BP, Chernoloz O, et al. Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder. CNS Neurosci Ther. 2010;16(3):e1-e17.

10. Esposito E. Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets. 2006;7(2):177-185.

11. Kringelbach ML, Cruzat J, Cabral J, et al. Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proc Natl Acad Sci U S A. 2020;117(17):9566-9576.

12. Thiele A, Bellgrove MA. Neuromodulation of attention. Neuron. 2018;97(4):769-785.

13. Muñoz A, Lopez-Lopez A, Labandeira CM, et al. Interactions between the serotonergic and other neurotransmitter systems in the basal ganglia: role in Parkinson’s disease and adverse effects of L-DOPA. Front Neuroanat. 2020;14:26.

14. Nielsen S, Degenhardt L, Hoban B, et al. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiol Drug Saf. 2016;25(6):733-737.

15. Lo-Ciganic WH, Huang JL, Zhang HH, et al. Evaluation of machine-learning algorithms for predicting opioid overdose risk among Medicare beneficiaries with opioid prescriptions. JAMA Netw Open. 2019;2(3):e190968. doi:10.1001/jamanetworkopen.2019.0968

16. Dewan MJ, Koss M. The clinical impact of reported variance in potency of antipsychotic agents. Acta Psychiatr Scand. 1995;91(4):229-232.

17. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64(6):663-667.

18. Hayasaka Y, Purgato M, Magni LR, et al. Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials. J Affect Disord. 2015;180:179-184.

19. Hansen JY, Shafiei G, Markello RD, et al. Mapping neurotransmitter systems to the structural and functional organization of the human neocortex. bioRxiv. 2021. https://doi.org/10.1101/2021.10.28.466336

20. Hwang WJ, Lee TY, Kim NS, et al. The role of estrogen receptors and their signaling across psychiatric disorders. Int J Mol Sci. 2020;22(1):373.

21. Lawrence JH, Tomaselli GF, Marban E. Ion channels: structure and function. Heart Dis Stroke. 1993;2(1):75-80.

22. Fedele F, Severino P, Bruno N, et al. Role of ion channels in coronary microcirculation: a review of the literature. Future Cardiol. 2013;9(6):897-905.

23. Kumar P, Kumar D, Jha SK, et al. Ion channels in neurological disorders. Adv Protein Chem Struct Biol. 2016;103:97-136.

24. Quagliato LA, Nardi AE. The role of convergent ion channel pathways in microglial phenotypes: a systematic review of the implications for neurological and psychiatric disorders. Transl Psychiatry. 2018;8(1):259.

25. Bianchi MT, Botzolakis EJ. Targeting ligand-gated ion channels in neurology and psychiatry: is pharmacological promiscuity an obstacle or an opportunity? BMC Pharmacol. 2010;10:3.

26. Imbrici P, Camerino DC, Tricarico D. Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet. 2013;4:76.

27. Xiao J, Chen Z, Yu B. A potential mechanism of sodium channel mediating the general anesthesia induced by propofol. Front Cell Neurosci. 2020;14:593050. doi:10.3389/fncel.2020.593050

28. Kamei S, Sato N, Harayama Y, et al. Molecular analysis of potassium ion channel genes in sudden death cases among patients administered psychotropic drug therapy: are polymorphisms in LQT genes a potential risk factor? J Hum Genet. 2014;59(2):95-99.

The authors respond

Thank you for your thoughtful commen­tary. Our conceptual article was not designed to cover enough ground to be completely thorough. Everything you wrote adds to what we wanted to bring to the reader’s attention. The mechanisms of disease in psychiatry are numerous and still elusive, and the brain’s complexity is staggering. Our main goal was to point out possible correlations between specific symptoms and specific neurotransmitter activity. We had to oversimplify to make the article concise enough for publication. Neurotransmitter effects are based on their synthesis, storage, release, reuptake, and degradation. A receptor’s quantity and quality of function, inhibitors, inducers, and many other factors are involved in neurotransmitter performance. And, of course, there are additional fundamental neurotransmitters beyond the 6 we touched on. Our ability to sort through all of this is still rudimentary. You also reflect on the emerging methods to objectively measure neuro­transmitter activity, which will eventually find their way to clinical practice and become invaluable. Still, we treat people, not tests or pictures, so diagnostic thinking based on clinical presentation will forever remain a cornerstone of dealing with individual patients.

We hope scientists and clinicians such as yourself will improve our concept and make it truly practical.

Dmitry M. Arbuck, MD
Clinical Assistant Professor of Psychiatry and Medicine
Indiana University School of Medicine
Indianapolis, Indiana
President and Medical Director
Indiana Polyclinic
Carmel, Indiana

José Miguel Salmerón, MD
Professor
Department of Psychiatry
Universidad del Valle School of Medicine/Hospital
Universitario del Valle
Cali, Colombia

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their response, or with manufacturers of competing products.

The series “Neurotransmitter-based diagnosis and treatment: A hypothesis” (Part 1: Current Psychiatry, May 2022, p. 30-36, doi:10.12788/cp.0242; Part 2: Current Psychiatry, June 2022, p. 28-33, doi:10.12788/cp.0253; and Part 3: Current Psychiatry, July 2022, p. 34-40, doi:10.12788/cp.0260) translated biological psychiatry’s working causal theory into actionable clinical ideas.

The presentation of abnormal neuro­transmission may occur along a continuum. For example, extreme dopamine deficiency can present as catatonia, moderate deficiency may present with inattention, normal activity permits adaptive functioning, and excitatory delirium and sudden death may be at the extreme end of dopa­minergic excess.¹

The amplitude, rate of change, and location of neurotransmitter dysfunction may determine which specialty takes the primary treatment role. Fatigue, pain, sleep difficulty, and emotional distress require clinicians to understand the whole patient, which is why health care professionals need cross training in psychiatry, and psychiatry recognizes multisystem pathology.

The recognition and treatment of substance use disorders requires an understanding of neurotransmitter symptoms, in terms of both acute drug effects and withdrawal. Fallows² provides this information in an accessible chart. Discussions of neurotransmitters also have value in managing psychotropic medication withdrawal.³

Acetylcholine is another neuro­transmitter of importance; it is essential to normal motor, cognitive, and emotional function. Extreme cholinergic deficiency or anticholinergic crisis has symptoms of pupillary dilation, psychosis, and delirium.^4-6 The progressive decline seen in certain dementias is related in part to cholinergic deficit. Dominance of cholinergic activity is associated with depression and biomarkers such as increased rapid eye movement (REM) density, a measure of the frequency of rapid eye movements during REM sleep.⁷ Cholinergic excess or cholinergic crisis may present with symptoms of salivation, lacrimation, muscle weakness, delirium, or paralysis.⁸

The articles alluded to the interaction of neurotransmitter systems (eg, “dopamine blockade helps with endorphin suppression”). Isolating the effects of a single neurotransmitter is useful, but covariance of neurotransmitter activity also has diagnostic and treatment implications.^9-11 Abnormalities in these interactions may be part of the causal process in fundamental cognitive functions.¹² If endorphin suppression is insensitive to dopamine blockade, a relative endorphin excess may create symptoms. If acetylcholine changes are normally balanced by a relative increase in dopamine and norepinephrine, then a weak catecholamine response would fit the catecholamine-cholinergic balance hypothesis of depression. Neurotransmitter interactions are well worked out in the neurology of the basal ganglia but less clear in the frontal and limbic systems.¹³

Quantification has been applied in some areas of clinical care. Morphine equivalents are used to express opiate potency, and there are algorithms to summarize multiple medication effects on respiratory depression/overdose risk.^14,15 Chlorpromazine equivalents were used to translate a range of antipsychotic potencies in the early days of antipsychotic treatment. Adverse effects and some treatment responses partially corresponded to the level of dopamine blockade, but not without noise. There is a wide range of variance as antipsychotic potency is assessed for clinical efficacy.¹⁶ We are still working on the array of medication potency and selectivity across neurotransmitter systems.^17,18 For example, paroxetine is a potent serotonin reuptake blocker but less selective than citalopram, particularly antagonizing cholinergic muscarinic receptors.

The authors noted their hypothesis needs further elaboration and quantification as psychiatry moves from impressionistic practice to firmer science. Measurement of neuro­transmitter activity is an area of intense research. Biomeasures have yet to add much value to the clinical practice of psychiatry, but we hope for progress. Functional neuroimaging with sophisticated algorithms is beginning to detail neocortical activity.¹⁹ CSF measurement of dopamine and serotonin metabolites seem to correlate with severe depression and suicidal behavior. Noninvasive, wearable technologies to measure galvanic skin response, oxygenation, and neurotransmitter metabolic products may add to neuro-transmitter-based assessment and treatment.

Neurotransmitters are one aspect of brain function. Other processes, such as hormonal neuromodulation²⁰ and ion channels, may be over- or underactive. Channelopathies are of particular interest in cardiology and neurology but are also notable in pain and emotional disorders.^21-26 Voltage-gated sodium channels are thought to be involved in general anesthesia.²⁷ Adverse effects of some psychotropic medications are best understood as ion channel dysfunction.²⁸ Using the strategy of this hypothesis applied to activation or inactivation of sodium, potassium, and calcium channels can guide useful diagnostic and treatment ideas for further study.

Mark C. Chandler, MD
Triangle Neuropsychiatry
Durham, North Carolina

Disclosures

The author reports no financial relationships with any companies whose products are mentioned in his letter, or with manufacturers of competing products.

References

1. Mash DC. Excited delirium and sudden death: a syndromal disorder at the extreme end of the neuropsychiatric continuum. Front Physiol. 2016;7:435.

2. Fallows Z. MIT MedLinks. Accessed August 8, 2022. http://web.mit.edu/zakf/www/drugchart/drugchart11.html

3. Groot PC, van Os J. How user knowledge of psychotropic drug withdrawal resulted in the development of person-specific tapering medication. Ther Adv Psychopharmacol. 2020;10:2045125320932452. doi:10.1177/2045125320932452

4. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116-129.

5. Nair VP, Hunter JM. Anticholinesterases and anticholinergic drugs. Continuing Education in Anaesthesia Critical Care & Pain. 2004;4(5):164-168.

6. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium--theory, evidence and practice. Br J Clin Pharmacol. 2016;81(3):516-524.

7. Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol Psychiatry. 2019;24(5):694-709.

8. Adeyinka A, Kondamudi NP. Cholinergic Crisis. StatPearls Publishing; 2022.

9. El Mansari M, Guiard BP, Chernoloz O, et al. Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder. CNS Neurosci Ther. 2010;16(3):e1-e17.

10. Esposito E. Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets. 2006;7(2):177-185.

11. Kringelbach ML, Cruzat J, Cabral J, et al. Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proc Natl Acad Sci U S A. 2020;117(17):9566-9576.

12. Thiele A, Bellgrove MA. Neuromodulation of attention. Neuron. 2018;97(4):769-785.

13. Muñoz A, Lopez-Lopez A, Labandeira CM, et al. Interactions between the serotonergic and other neurotransmitter systems in the basal ganglia: role in Parkinson’s disease and adverse effects of L-DOPA. Front Neuroanat. 2020;14:26.

14. Nielsen S, Degenhardt L, Hoban B, et al. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiol Drug Saf. 2016;25(6):733-737.

15. Lo-Ciganic WH, Huang JL, Zhang HH, et al. Evaluation of machine-learning algorithms for predicting opioid overdose risk among Medicare beneficiaries with opioid prescriptions. JAMA Netw Open. 2019;2(3):e190968. doi:10.1001/jamanetworkopen.2019.0968

16. Dewan MJ, Koss M. The clinical impact of reported variance in potency of antipsychotic agents. Acta Psychiatr Scand. 1995;91(4):229-232.

17. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64(6):663-667.

18. Hayasaka Y, Purgato M, Magni LR, et al. Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials. J Affect Disord. 2015;180:179-184.

19. Hansen JY, Shafiei G, Markello RD, et al. Mapping neurotransmitter systems to the structural and functional organization of the human neocortex. bioRxiv. 2021. https://doi.org/10.1101/2021.10.28.466336

20. Hwang WJ, Lee TY, Kim NS, et al. The role of estrogen receptors and their signaling across psychiatric disorders. Int J Mol Sci. 2020;22(1):373.

21. Lawrence JH, Tomaselli GF, Marban E. Ion channels: structure and function. Heart Dis Stroke. 1993;2(1):75-80.

22. Fedele F, Severino P, Bruno N, et al. Role of ion channels in coronary microcirculation: a review of the literature. Future Cardiol. 2013;9(6):897-905.

23. Kumar P, Kumar D, Jha SK, et al. Ion channels in neurological disorders. Adv Protein Chem Struct Biol. 2016;103:97-136.

24. Quagliato LA, Nardi AE. The role of convergent ion channel pathways in microglial phenotypes: a systematic review of the implications for neurological and psychiatric disorders. Transl Psychiatry. 2018;8(1):259.

25. Bianchi MT, Botzolakis EJ. Targeting ligand-gated ion channels in neurology and psychiatry: is pharmacological promiscuity an obstacle or an opportunity? BMC Pharmacol. 2010;10:3.

26. Imbrici P, Camerino DC, Tricarico D. Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet. 2013;4:76.

27. Xiao J, Chen Z, Yu B. A potential mechanism of sodium channel mediating the general anesthesia induced by propofol. Front Cell Neurosci. 2020;14:593050. doi:10.3389/fncel.2020.593050

28. Kamei S, Sato N, Harayama Y, et al. Molecular analysis of potassium ion channel genes in sudden death cases among patients administered psychotropic drug therapy: are polymorphisms in LQT genes a potential risk factor? J Hum Genet. 2014;59(2):95-99.

The authors respond

Thank you for your thoughtful commen­tary. Our conceptual article was not designed to cover enough ground to be completely thorough. Everything you wrote adds to what we wanted to bring to the reader’s attention. The mechanisms of disease in psychiatry are numerous and still elusive, and the brain’s complexity is staggering. Our main goal was to point out possible correlations between specific symptoms and specific neurotransmitter activity. We had to oversimplify to make the article concise enough for publication. Neurotransmitter effects are based on their synthesis, storage, release, reuptake, and degradation. A receptor’s quantity and quality of function, inhibitors, inducers, and many other factors are involved in neurotransmitter performance. And, of course, there are additional fundamental neurotransmitters beyond the 6 we touched on. Our ability to sort through all of this is still rudimentary. You also reflect on the emerging methods to objectively measure neuro­transmitter activity, which will eventually find their way to clinical practice and become invaluable. Still, we treat people, not tests or pictures, so diagnostic thinking based on clinical presentation will forever remain a cornerstone of dealing with individual patients.

We hope scientists and clinicians such as yourself will improve our concept and make it truly practical.

Dmitry M. Arbuck, MD
Clinical Assistant Professor of Psychiatry and Medicine
Indiana University School of Medicine
Indianapolis, Indiana
President and Medical Director
Indiana Polyclinic
Carmel, Indiana

José Miguel Salmerón, MD
Professor
Department of Psychiatry
Universidad del Valle School of Medicine/Hospital
Universitario del Valle
Cali, Colombia

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their response, or with manufacturers of competing products.

Mr. P, age 67, presents to the clinic with vision changes and memory loss following a fall in his home due to limb weakness. Six years ago, his care team diagnosed him with rheumatoid arthritis (RA). Mr. P’s current medication regimen includes methotrexate 20 mg once weekly and etanercept 50 mg once weekly, and he has been stable on this plan for 3 years. Mr. P also was recently diagnosed with major depressive disorder (MDD), but has not yet started treatment. Following a complete workup, an MRI of Mr. P’s brain revealed white matter demyelination. Due to these findings, he is scheduled for a brain biopsy, which confirms a diagnosis of progressive multifocal leukoencephalopathy (PML).

PML is a demyelinating disease of the central nervous system caused by the John Cunningham virus (JCV), or JC polyomavirus, named for the first patient identified to have contracted the virus.¹ Asymptomatic infection of JCV often occurs in childhood, and antibodies are found in ≤70% of healthy adults. In most individuals, JCV remains latent in the kidneys and lymphoid organs, but immunosuppression can cause it to reactivate.²

JCV infects oligodendrocytes, astrocytes, and neurons, which results in white matter demyelination. Due to this demyelination, individuals can experience visual field defects, speech disturbances, ataxia, paresthesia, and cognitive impairments.² Limb weakness presents in 60% of patients with PML, visual disturbances in 20%, and gait disturbances in 65%.³ Progression of these symptoms can lead to a more severe clinical presentation, including focal seizures in ≤10% of patients, and the mortality rate is 30% to 50%.³ Patients with comorbid HIV have a mortality rate ≤90%.²

Currently, there are no biomarkers that can identify PML in its early stages. A PML diagnosis is typically based on the patient’s clinical presentation, radiological imaging, and detection of JCV DNA. A brain biopsy is the gold standard for PML diagnosis.¹

Interestingly, data suggest that glial cells harboring JCV in the brain express receptors for serotonin and dopamine.⁴ Researchers pinpointed 5HT2A receptors as JCV entry points into cells, and theorized that medications competing for binding, such as certain psychotropic agents, might decrease JCV entry. Cells lacking the 5HT2A receptor have shown immunity to JCV infection and the ability of cells to be infected was restored through transfection of 5HT2A receptors.⁴

Immunosuppressant medications can cause PML

PML was initially seen in individuals with conditions that cause immunosuppression, such as malignancies and HIV. However, “drug-induced PML” refers to cases in which drug-induced immunosuppression creates an environment that allows JCV to reactivate and disseminate back into the CNS.⁴ It is important to emphasize that drug-induced PML is a very rare effect of certain immunosuppressant medications. Medications that can weaken the immune system include glucocorticoids, monoclonal antibodies, alkylating agents, purine analogues, antimetabolites, and immunosuppressants (Table).¹

These medications are used to treat conditions such as multiple sclerosis, RA, psoriatic arthritis, and lupus. Although drug-induced PML can result from the use of any of these agents, the highest incidence (1%) is found with natalizumab. Rates of incidence with other agents are either unknown or as low as .002%.¹ Evidence suggests that the risk for PML increases with the duration of therapy.⁵

Continue to: Management

Management: Stop the offending agent, restore immune function

Specific pharmacologic treatments for PML are lacking. Management of drug-induced PML starts with discontinuing the offending agent. Restoring immune function has been found to be the most effective approach to treat PML.³ Restoration is possible through interleukin-2 (IL-2), IL-7, and T-cell infusions. Other treatment options are theoretical and include the development of a JCV vaccine to stimulate host response, plasma exchange to remove the medication from the host, and antiviral therapy targeting JCV replication. Diclofenac, isotretinoin, and mefloquine can inhibit JCV replication.³

Based on the theory that JCV requires 5HT2A receptors for entry into cells, researchers have studied medications that block this receptor as a treatment for PML. The first-generation antipsychotic chlorpromazine did not show benefit when combined with cidofovir, a replication inhibitor.³ Antipsychotics agents such as ziprasidone and olanzapine have shown in vitro inhibition of JCV, while risperidone has mixed results, with 1 trial failing to find a difference on JCV in fetal glial cells.³ Second-generation antipsychotics may be the preferred option due to more potent antagonism of the 5HT2A receptors and fewer adverse effects compared to agents such as chlorpromazine.⁴ The antidepressant mirtazapine has shown to have promising results, with evidence indicating that earlier initiation is more beneficial.³ Overall, data involving the use of medications that act on the 5HT2A receptor are mixed. Recent data suggest that JCV might enter cells independent of 5HT2A receptors; however, more research in this area is needed.²

The best strategy for treating drug-induced PML has not yet been determined. While combination therapy is thought to be more successful than monotherapy, ultimately, it depends on the patient’s immune response. If a psychotropic medication is chosen as adjunct treatment for drug-induced PML, it is prudent to assess the patient’s entire clinical picture to determine the specific indication for therapy (ie, treating symptomatology or drug-induced PML).

CASE CONTINUED

Following diagnosis, Mr. P is provided supportive therapy, and his care team discontinues methotrexate and etanercept. Although data are mixed on the efficacy of medications that work on 5HT2A receptors, because Mr. P was recently diagnosed with MDD, he is started on mirtazapine 15 mg/d at night in an attempt to manage both MDD and PML. It is possible that his depressive symptoms developed as a result of drug-induced PML rather than major depressive disorder. Discontinuing methotrexate and etanercept stabilizes Mr. P’s PML symptoms but leads to an exacerbation of his RA symptoms. Mr. P is initiated on hydroxychloroquine 400 mg/d for RA management. At a follow-up appointment 4 weeks later, Mr. P reports his sleep, concentration, and overall depressive symptoms have improved. He requests to continue taking mirtazapine.

Related Resources

• Castle D, Robertson NP. Treatment of progressive multifocal leukoencephalopathy. J Neurol. 2019;266(10):2587-2589. doi:10.1007/s00415-019-09501-y

Drug Brand Names

Abatacept • Orencia
Adalimumab • Humira
Alemtuzumab • Campath
Azathioprine • Azasan, Imuran
Basiliximab • Simulect
Belimumab • Benlysta
Bevacizumab • Avastin
Brentuximab vedotin • Adcetris
Cetuximab • Erbitux
Chlorpromazine • Thorazine, Largactil
Cidofovir • Vistide
Cladribine • Mavenclad
Cyclophosphamide • Cytoxan
Cyclosporine • Gengraf, Neoral
Dacarbazine • DTIC-Dome
Diclofenac • Cambia, Zorvolex
Dimethyl fumarate • Tecfidera
Etanercept • Enbrel
Fingolimod • Gilenya
Fludarabine • Fludara
Hydroxychloroquine • Plaquenil
Ibritumomab tiuxetan • Zevalin
Infliximab • Avsola, Inflectra
Isotretinoin • Absorica, Claravis
Mefloquine • Lariam
Methotrexate • Rheumatrex, Trexall
Mirtazapine • Remeron
Mitoxantrone • Novantrone
Muromonab-CD3 • Orthoclone OKT3
Mycophenolate mofetil • CellCept
Natalizumab • Tysabri
Nelarabine • Arranon
Obinutuzumab • Gazyva
Olanzapine • Zyprexa
Risperidone • Risperdal
Tacrolimus • Prograf
Vincristine • Vincasar PFS
Ziprasidone • Geodon

Mr. P, age 67, presents to the clinic with vision changes and memory loss following a fall in his home due to limb weakness. Six years ago, his care team diagnosed him with rheumatoid arthritis (RA). Mr. P’s current medication regimen includes methotrexate 20 mg once weekly and etanercept 50 mg once weekly, and he has been stable on this plan for 3 years. Mr. P also was recently diagnosed with major depressive disorder (MDD), but has not yet started treatment. Following a complete workup, an MRI of Mr. P’s brain revealed white matter demyelination. Due to these findings, he is scheduled for a brain biopsy, which confirms a diagnosis of progressive multifocal leukoencephalopathy (PML).

PML is a demyelinating disease of the central nervous system caused by the John Cunningham virus (JCV), or JC polyomavirus, named for the first patient identified to have contracted the virus.¹ Asymptomatic infection of JCV often occurs in childhood, and antibodies are found in ≤70% of healthy adults. In most individuals, JCV remains latent in the kidneys and lymphoid organs, but immunosuppression can cause it to reactivate.²

JCV infects oligodendrocytes, astrocytes, and neurons, which results in white matter demyelination. Due to this demyelination, individuals can experience visual field defects, speech disturbances, ataxia, paresthesia, and cognitive impairments.² Limb weakness presents in 60% of patients with PML, visual disturbances in 20%, and gait disturbances in 65%.³ Progression of these symptoms can lead to a more severe clinical presentation, including focal seizures in ≤10% of patients, and the mortality rate is 30% to 50%.³ Patients with comorbid HIV have a mortality rate ≤90%.²

Currently, there are no biomarkers that can identify PML in its early stages. A PML diagnosis is typically based on the patient’s clinical presentation, radiological imaging, and detection of JCV DNA. A brain biopsy is the gold standard for PML diagnosis.¹

Interestingly, data suggest that glial cells harboring JCV in the brain express receptors for serotonin and dopamine.⁴ Researchers pinpointed 5HT2A receptors as JCV entry points into cells, and theorized that medications competing for binding, such as certain psychotropic agents, might decrease JCV entry. Cells lacking the 5HT2A receptor have shown immunity to JCV infection and the ability of cells to be infected was restored through transfection of 5HT2A receptors.⁴

Immunosuppressant medications can cause PML

PML was initially seen in individuals with conditions that cause immunosuppression, such as malignancies and HIV. However, “drug-induced PML” refers to cases in which drug-induced immunosuppression creates an environment that allows JCV to reactivate and disseminate back into the CNS.⁴ It is important to emphasize that drug-induced PML is a very rare effect of certain immunosuppressant medications. Medications that can weaken the immune system include glucocorticoids, monoclonal antibodies, alkylating agents, purine analogues, antimetabolites, and immunosuppressants (Table).¹

These medications are used to treat conditions such as multiple sclerosis, RA, psoriatic arthritis, and lupus. Although drug-induced PML can result from the use of any of these agents, the highest incidence (1%) is found with natalizumab. Rates of incidence with other agents are either unknown or as low as .002%.¹ Evidence suggests that the risk for PML increases with the duration of therapy.⁵

Continue to: Management

Management: Stop the offending agent, restore immune function

Specific pharmacologic treatments for PML are lacking. Management of drug-induced PML starts with discontinuing the offending agent. Restoring immune function has been found to be the most effective approach to treat PML.³ Restoration is possible through interleukin-2 (IL-2), IL-7, and T-cell infusions. Other treatment options are theoretical and include the development of a JCV vaccine to stimulate host response, plasma exchange to remove the medication from the host, and antiviral therapy targeting JCV replication. Diclofenac, isotretinoin, and mefloquine can inhibit JCV replication.³

Based on the theory that JCV requires 5HT2A receptors for entry into cells, researchers have studied medications that block this receptor as a treatment for PML. The first-generation antipsychotic chlorpromazine did not show benefit when combined with cidofovir, a replication inhibitor.³ Antipsychotics agents such as ziprasidone and olanzapine have shown in vitro inhibition of JCV, while risperidone has mixed results, with 1 trial failing to find a difference on JCV in fetal glial cells.³ Second-generation antipsychotics may be the preferred option due to more potent antagonism of the 5HT2A receptors and fewer adverse effects compared to agents such as chlorpromazine.⁴ The antidepressant mirtazapine has shown to have promising results, with evidence indicating that earlier initiation is more beneficial.³ Overall, data involving the use of medications that act on the 5HT2A receptor are mixed. Recent data suggest that JCV might enter cells independent of 5HT2A receptors; however, more research in this area is needed.²

The best strategy for treating drug-induced PML has not yet been determined. While combination therapy is thought to be more successful than monotherapy, ultimately, it depends on the patient’s immune response. If a psychotropic medication is chosen as adjunct treatment for drug-induced PML, it is prudent to assess the patient’s entire clinical picture to determine the specific indication for therapy (ie, treating symptomatology or drug-induced PML).

CASE CONTINUED

Following diagnosis, Mr. P is provided supportive therapy, and his care team discontinues methotrexate and etanercept. Although data are mixed on the efficacy of medications that work on 5HT2A receptors, because Mr. P was recently diagnosed with MDD, he is started on mirtazapine 15 mg/d at night in an attempt to manage both MDD and PML. It is possible that his depressive symptoms developed as a result of drug-induced PML rather than major depressive disorder. Discontinuing methotrexate and etanercept stabilizes Mr. P’s PML symptoms but leads to an exacerbation of his RA symptoms. Mr. P is initiated on hydroxychloroquine 400 mg/d for RA management. At a follow-up appointment 4 weeks later, Mr. P reports his sleep, concentration, and overall depressive symptoms have improved. He requests to continue taking mirtazapine.

Related Resources

• Castle D, Robertson NP. Treatment of progressive multifocal leukoencephalopathy. J Neurol. 2019;266(10):2587-2589. doi:10.1007/s00415-019-09501-y

Drug Brand Names

Abatacept • Orencia
Adalimumab • Humira
Alemtuzumab • Campath
Azathioprine • Azasan, Imuran
Basiliximab • Simulect
Belimumab • Benlysta
Bevacizumab • Avastin
Brentuximab vedotin • Adcetris
Cetuximab • Erbitux
Chlorpromazine • Thorazine, Largactil
Cidofovir • Vistide
Cladribine • Mavenclad
Cyclophosphamide • Cytoxan
Cyclosporine • Gengraf, Neoral
Dacarbazine • DTIC-Dome
Diclofenac • Cambia, Zorvolex
Dimethyl fumarate • Tecfidera
Etanercept • Enbrel
Fingolimod • Gilenya
Fludarabine • Fludara
Hydroxychloroquine • Plaquenil
Ibritumomab tiuxetan • Zevalin
Infliximab • Avsola, Inflectra
Isotretinoin • Absorica, Claravis
Mefloquine • Lariam
Methotrexate • Rheumatrex, Trexall
Mirtazapine • Remeron
Mitoxantrone • Novantrone
Muromonab-CD3 • Orthoclone OKT3
Mycophenolate mofetil • CellCept
Natalizumab • Tysabri
Nelarabine • Arranon
Obinutuzumab • Gazyva
Olanzapine • Zyprexa
Risperidone • Risperdal
Tacrolimus • Prograf
Vincristine • Vincasar PFS
Ziprasidone • Geodon

Mr. P, age 67, presents to the clinic with vision changes and memory loss following a fall in his home due to limb weakness. Six years ago, his care team diagnosed him with rheumatoid arthritis (RA). Mr. P’s current medication regimen includes methotrexate 20 mg once weekly and etanercept 50 mg once weekly, and he has been stable on this plan for 3 years. Mr. P also was recently diagnosed with major depressive disorder (MDD), but has not yet started treatment. Following a complete workup, an MRI of Mr. P’s brain revealed white matter demyelination. Due to these findings, he is scheduled for a brain biopsy, which confirms a diagnosis of progressive multifocal leukoencephalopathy (PML).

PML is a demyelinating disease of the central nervous system caused by the John Cunningham virus (JCV), or JC polyomavirus, named for the first patient identified to have contracted the virus.¹ Asymptomatic infection of JCV often occurs in childhood, and antibodies are found in ≤70% of healthy adults. In most individuals, JCV remains latent in the kidneys and lymphoid organs, but immunosuppression can cause it to reactivate.²

JCV infects oligodendrocytes, astrocytes, and neurons, which results in white matter demyelination. Due to this demyelination, individuals can experience visual field defects, speech disturbances, ataxia, paresthesia, and cognitive impairments.² Limb weakness presents in 60% of patients with PML, visual disturbances in 20%, and gait disturbances in 65%.³ Progression of these symptoms can lead to a more severe clinical presentation, including focal seizures in ≤10% of patients, and the mortality rate is 30% to 50%.³ Patients with comorbid HIV have a mortality rate ≤90%.²

Currently, there are no biomarkers that can identify PML in its early stages. A PML diagnosis is typically based on the patient’s clinical presentation, radiological imaging, and detection of JCV DNA. A brain biopsy is the gold standard for PML diagnosis.¹

Interestingly, data suggest that glial cells harboring JCV in the brain express receptors for serotonin and dopamine.⁴ Researchers pinpointed 5HT2A receptors as JCV entry points into cells, and theorized that medications competing for binding, such as certain psychotropic agents, might decrease JCV entry. Cells lacking the 5HT2A receptor have shown immunity to JCV infection and the ability of cells to be infected was restored through transfection of 5HT2A receptors.⁴

Immunosuppressant medications can cause PML

PML was initially seen in individuals with conditions that cause immunosuppression, such as malignancies and HIV. However, “drug-induced PML” refers to cases in which drug-induced immunosuppression creates an environment that allows JCV to reactivate and disseminate back into the CNS.⁴ It is important to emphasize that drug-induced PML is a very rare effect of certain immunosuppressant medications. Medications that can weaken the immune system include glucocorticoids, monoclonal antibodies, alkylating agents, purine analogues, antimetabolites, and immunosuppressants (Table).¹

These medications are used to treat conditions such as multiple sclerosis, RA, psoriatic arthritis, and lupus. Although drug-induced PML can result from the use of any of these agents, the highest incidence (1%) is found with natalizumab. Rates of incidence with other agents are either unknown or as low as .002%.¹ Evidence suggests that the risk for PML increases with the duration of therapy.⁵

Continue to: Management

Management: Stop the offending agent, restore immune function

Specific pharmacologic treatments for PML are lacking. Management of drug-induced PML starts with discontinuing the offending agent. Restoring immune function has been found to be the most effective approach to treat PML.³ Restoration is possible through interleukin-2 (IL-2), IL-7, and T-cell infusions. Other treatment options are theoretical and include the development of a JCV vaccine to stimulate host response, plasma exchange to remove the medication from the host, and antiviral therapy targeting JCV replication. Diclofenac, isotretinoin, and mefloquine can inhibit JCV replication.³

Based on the theory that JCV requires 5HT2A receptors for entry into cells, researchers have studied medications that block this receptor as a treatment for PML. The first-generation antipsychotic chlorpromazine did not show benefit when combined with cidofovir, a replication inhibitor.³ Antipsychotics agents such as ziprasidone and olanzapine have shown in vitro inhibition of JCV, while risperidone has mixed results, with 1 trial failing to find a difference on JCV in fetal glial cells.³ Second-generation antipsychotics may be the preferred option due to more potent antagonism of the 5HT2A receptors and fewer adverse effects compared to agents such as chlorpromazine.⁴ The antidepressant mirtazapine has shown to have promising results, with evidence indicating that earlier initiation is more beneficial.³ Overall, data involving the use of medications that act on the 5HT2A receptor are mixed. Recent data suggest that JCV might enter cells independent of 5HT2A receptors; however, more research in this area is needed.²

The best strategy for treating drug-induced PML has not yet been determined. While combination therapy is thought to be more successful than monotherapy, ultimately, it depends on the patient’s immune response. If a psychotropic medication is chosen as adjunct treatment for drug-induced PML, it is prudent to assess the patient’s entire clinical picture to determine the specific indication for therapy (ie, treating symptomatology or drug-induced PML).

CASE CONTINUED

Following diagnosis, Mr. P is provided supportive therapy, and his care team discontinues methotrexate and etanercept. Although data are mixed on the efficacy of medications that work on 5HT2A receptors, because Mr. P was recently diagnosed with MDD, he is started on mirtazapine 15 mg/d at night in an attempt to manage both MDD and PML. It is possible that his depressive symptoms developed as a result of drug-induced PML rather than major depressive disorder. Discontinuing methotrexate and etanercept stabilizes Mr. P’s PML symptoms but leads to an exacerbation of his RA symptoms. Mr. P is initiated on hydroxychloroquine 400 mg/d for RA management. At a follow-up appointment 4 weeks later, Mr. P reports his sleep, concentration, and overall depressive symptoms have improved. He requests to continue taking mirtazapine.

Related Resources

• Castle D, Robertson NP. Treatment of progressive multifocal leukoencephalopathy. J Neurol. 2019;266(10):2587-2589. doi:10.1007/s00415-019-09501-y

Drug Brand Names

Abatacept • Orencia
Adalimumab • Humira
Alemtuzumab • Campath
Azathioprine • Azasan, Imuran
Basiliximab • Simulect
Belimumab • Benlysta
Bevacizumab • Avastin
Brentuximab vedotin • Adcetris
Cetuximab • Erbitux
Chlorpromazine • Thorazine, Largactil
Cidofovir • Vistide
Cladribine • Mavenclad
Cyclophosphamide • Cytoxan
Cyclosporine • Gengraf, Neoral
Dacarbazine • DTIC-Dome
Diclofenac • Cambia, Zorvolex
Dimethyl fumarate • Tecfidera
Etanercept • Enbrel
Fingolimod • Gilenya
Fludarabine • Fludara
Hydroxychloroquine • Plaquenil
Ibritumomab tiuxetan • Zevalin
Infliximab • Avsola, Inflectra
Isotretinoin • Absorica, Claravis
Mefloquine • Lariam
Methotrexate • Rheumatrex, Trexall
Mirtazapine • Remeron
Mitoxantrone • Novantrone
Muromonab-CD3 • Orthoclone OKT3
Mycophenolate mofetil • CellCept
Natalizumab • Tysabri
Nelarabine • Arranon
Obinutuzumab • Gazyva
Olanzapine • Zyprexa
Risperidone • Risperdal
Tacrolimus • Prograf
Vincristine • Vincasar PFS
Ziprasidone • Geodon

CASE Depressed and suicidal

Police arrive at the home of Mr. H, age 50, after his wife calls 911. She reports he has depression and she saw him in bed brandishing a firearm as if he wanted to hurt himself. Upon arrival, the officers enter the house and find Mr. H in bed without a firearm. Mr. H says little to the officers about the alleged events, but acknowledges he has depression and is willing to go the hospital for further evaluation. Neither his wife nor the officers locate a firearm in the home.

EVALUATION Emergency detention

In the emergency department (ED), Mr. H’s laboratory results and physical examination findings are normal. He acknowledges feeling depressed over the past 2 weeks. Though he cannot identify any precipitants, he says he has experienced anhedonia, lack of appetite, decreased energy, and changes in his sleep patterns. When asked about the day’s events concerning the firearm, Mr. H becomes guarded and does not give a clear answer regarding having thoughts of suicide.

The evaluating psychiatrist obtains collateral from Mr. H’s wife and reviews his medical records. There are no active prescriptions on file and the psychiatrist notices that last year there was a suicide attempt involving a firearm. Following that episode, Mr. H was hospitalized, treated with sertraline 50 mg/d, and discharged with a diagnosis of major depressive disorder. There was no legal or substance abuse history.

In the ED, the psychiatrist conducts a psychiatric evaluation, including a suicide risk assessment, and determines Mr. H is at imminent risk of ending his life. Mr. H’s psychiatrist explains there are 2 treatment options: to be admitted to the hospital or to be discharged. The psychiatrist recommends hospital admission to Mr. H for his safety and stabilization. Mr. H says he prefers to return home.

Because the psychiatrist believes Mr. H is at imminent risk of ending his life and there is no less restrictive setting for treatment, he implements an emergency detention. In Ohio, this allows Mr. H to be held in the hospital for no more than 3 court days in accordance with state law. Before Mr. H’s emergency detention periods ends, the psychiatrist will need to decide whether Mr. H can be safely discharged. If the psychiatrist determines that Mr. H still needs treatment, the court will be petitioned for a civil commitment hearing.

[polldaddy:11189291]

The author’s observations

In some cases, courts allow information a psychiatrist does not directly obtain from a patient to be admitted as testimony in a civil commitment hearing. However, some jurisdictions consider sources of information not obtained directly from the patient as hearsay and thus inadmissible.¹ Though each source listed may provide credible information that could be presented at a hearing, the psychiatrist should discuss with the patient the information obtained from these sources to ensure it is admissable.² A discussion with Mr. H about the factors that led to his hospital arrival will avoid the psychiatrist’s reliance on what another person has heard or seen when providing testimony. Even when a psychiatrist is not faced with an issue of admissibility, caution must be taken with third-party reports.³

TREATMENT Civil commitment hearing

Before the emergency detention period expires, Mr. H’s psychiatrist determines that he remains at imminent risk of self-harm. To continue hospitalization, the psychiatrist files a petition for civil commitment and testifies at the commitment hearing. He reports that Mr. H suffers from a substantial mood disorder that grossly impairs his judgment and behavior. The psychiatrist also testifies that the least restrictive environment for treatment continues to be inpatient hospitalization, because Mr. H is still at imminent risk of harming himself.

Continue to: Following the psychiatrist's...

Following the psychiatrist’s testimony, the magistrate finds that Mr. H is a mentally ill person subject to hospitalization given his mood disorder that grossly impairs his judgment and behavior. The magistrate orders that Mr. H be civilly committed to the hospital.

[polldaddy:11189293]

The author’s observations

The psychiatrist’s testimony mirrors the language regarding civil commitment in the Ohio Revised Code.⁴ Other elements considered for mental illness in Ohio are a substantial disorder of memory, thought, orientation, or perception that grossly impairs one’s capacity to recognize reality or meet the demands of life.⁴ The definition of what constitutes a mental disorder varies by state, but the burden of persuasion—the standard by which the court must be convinced—is generally uniform.⁵ In the 1979 case Addington v Texas, the United States Supreme Court concluded that in a civil commitment hearing, the minimum standard of proof for involuntary commitment must be clear and convincing evidence.⁶ Neither medical certainty nor substantial probability are burdens of persuasions.⁶ Instead, these terms may be presented in a forensic report when an examiner outlines their opinion. Table 1 and the Figure provide more detail on burdens of persuasion.

TREATMENT Civil commitment and patient rights

At a regularly scheduled treatment team meeting, the team informs Mr. H that he has been civilly committed for further treatment. Mr. H becomes upset and tells the team the decision is a complete violation of his rights. After a long rant, Mr. H walks out of the room, saying, “I did not even know when this hearing was.” A member of the treatment team becomes concerned that Mr. H may not have been notified of the hearing.

[polldaddy:11189294]

The author’s observations

It is not clear if Mr. H had been notified of his civil commitment hearing. If Mr. H had not been notified, his rights would have been compromised. Lessard v Schmidt (1972) outlined that individuals involved in a civil commitment hearing should be afforded the same rights as those involved in criminal proceedings.⁷ Mr. H should have been notified of his hearing and afforded the opportunity to have the assignment of counsel, the right to appear, the right to testify, the right to present witnesses and other evidence, and the right to confront witnesses.

Without notification of the hearing, the only right that would have remained intact for Mr. H would have been the assignment of counsel in his absence and without his knowledge. If Mr. H had been notified of the hearing and did not want to attend, yet still desired legal counsel, he could have waived his presence voluntarily after discussing this option with his attorney.^8,9

Continue to: OUTCOME Stabilization and discharge

During his 10-day stay, Mr. H is treated with sertraline 50 mg/d and engages in individual and group therapy. He shows noticeable improvement in his depressive symptoms and reports having no thoughts of suicide or self-harm. The treatment team determines it is appropriate to discharge him home (the firearm was never found) and involves his wife in safety planning and follow-up care. On the day of his discharge, Mr. H reflects on his treatment and civil commitment. He says, “I did not know a judge could order me to be hospitalized.”

[polldaddy:11189297]

The author’s observations

The physician’s decision to pursue civil commitment is best described by the legal doctrines of police powers and parens patriae. Other relevant ethical principles are described in Table 2.¹⁰

Though ethical principles may play a role in civil commitment, parens patriae and police powers is the answer with respect to the State.¹¹Parens patriae is Latin for the “parent of the country” and grants the State the power to protect those residents who are most vulnerable. Police power is the authority of the State to enact and enforce rules that limit the rights of individuals for the greater good of ensuring health, safety, and welfare of all citizens.

Bottom Line

Psychiatrists are entrusted with recognizing when a patient, due to mental illness, is a danger to themselves or others and in need of treatment. After an emergency detention period, if the patient remains a danger to themselves or others and does not want to voluntarily receive treatment, a court hearing is required. As an expert witness, the treating psychiatrist should know the factors of law in their jurisdiction that determine civil commitment.

Related Resources

• Extreme Risk Protection Orders. Johns Hopkins Bloomberg School of Public Health. https://www.jhsph.edu/research/ centers-and-institutes/johns-hopkins-center-for-gun-violenceprevention-and-policy/research/extreme-risk-protectionorders/
• Gutheil TG. The Psychiatrist as Expert Witness. 2nd ed. American Psychiatric Association Publishing; 2009.
• Landmark Cases 2014. American Academy of Psychiatry and the Law. https://www.aapl.org/landmark-cases

Drug Brand Names

Sertraline • Zoloft

CASE Depressed and suicidal

Police arrive at the home of Mr. H, age 50, after his wife calls 911. She reports he has depression and she saw him in bed brandishing a firearm as if he wanted to hurt himself. Upon arrival, the officers enter the house and find Mr. H in bed without a firearm. Mr. H says little to the officers about the alleged events, but acknowledges he has depression and is willing to go the hospital for further evaluation. Neither his wife nor the officers locate a firearm in the home.

EVALUATION Emergency detention

In the emergency department (ED), Mr. H’s laboratory results and physical examination findings are normal. He acknowledges feeling depressed over the past 2 weeks. Though he cannot identify any precipitants, he says he has experienced anhedonia, lack of appetite, decreased energy, and changes in his sleep patterns. When asked about the day’s events concerning the firearm, Mr. H becomes guarded and does not give a clear answer regarding having thoughts of suicide.

The evaluating psychiatrist obtains collateral from Mr. H’s wife and reviews his medical records. There are no active prescriptions on file and the psychiatrist notices that last year there was a suicide attempt involving a firearm. Following that episode, Mr. H was hospitalized, treated with sertraline 50 mg/d, and discharged with a diagnosis of major depressive disorder. There was no legal or substance abuse history.

In the ED, the psychiatrist conducts a psychiatric evaluation, including a suicide risk assessment, and determines Mr. H is at imminent risk of ending his life. Mr. H’s psychiatrist explains there are 2 treatment options: to be admitted to the hospital or to be discharged. The psychiatrist recommends hospital admission to Mr. H for his safety and stabilization. Mr. H says he prefers to return home.

Because the psychiatrist believes Mr. H is at imminent risk of ending his life and there is no less restrictive setting for treatment, he implements an emergency detention. In Ohio, this allows Mr. H to be held in the hospital for no more than 3 court days in accordance with state law. Before Mr. H’s emergency detention periods ends, the psychiatrist will need to decide whether Mr. H can be safely discharged. If the psychiatrist determines that Mr. H still needs treatment, the court will be petitioned for a civil commitment hearing.

[polldaddy:11189291]

The author’s observations

In some cases, courts allow information a psychiatrist does not directly obtain from a patient to be admitted as testimony in a civil commitment hearing. However, some jurisdictions consider sources of information not obtained directly from the patient as hearsay and thus inadmissible.¹ Though each source listed may provide credible information that could be presented at a hearing, the psychiatrist should discuss with the patient the information obtained from these sources to ensure it is admissable.² A discussion with Mr. H about the factors that led to his hospital arrival will avoid the psychiatrist’s reliance on what another person has heard or seen when providing testimony. Even when a psychiatrist is not faced with an issue of admissibility, caution must be taken with third-party reports.³

TREATMENT Civil commitment hearing

Before the emergency detention period expires, Mr. H’s psychiatrist determines that he remains at imminent risk of self-harm. To continue hospitalization, the psychiatrist files a petition for civil commitment and testifies at the commitment hearing. He reports that Mr. H suffers from a substantial mood disorder that grossly impairs his judgment and behavior. The psychiatrist also testifies that the least restrictive environment for treatment continues to be inpatient hospitalization, because Mr. H is still at imminent risk of harming himself.

Continue to: Following the psychiatrist's...

Following the psychiatrist’s testimony, the magistrate finds that Mr. H is a mentally ill person subject to hospitalization given his mood disorder that grossly impairs his judgment and behavior. The magistrate orders that Mr. H be civilly committed to the hospital.

[polldaddy:11189293]

The author’s observations

The psychiatrist’s testimony mirrors the language regarding civil commitment in the Ohio Revised Code.⁴ Other elements considered for mental illness in Ohio are a substantial disorder of memory, thought, orientation, or perception that grossly impairs one’s capacity to recognize reality or meet the demands of life.⁴ The definition of what constitutes a mental disorder varies by state, but the burden of persuasion—the standard by which the court must be convinced—is generally uniform.⁵ In the 1979 case Addington v Texas, the United States Supreme Court concluded that in a civil commitment hearing, the minimum standard of proof for involuntary commitment must be clear and convincing evidence.⁶ Neither medical certainty nor substantial probability are burdens of persuasions.⁶ Instead, these terms may be presented in a forensic report when an examiner outlines their opinion. Table 1 and the Figure provide more detail on burdens of persuasion.

TREATMENT Civil commitment and patient rights

At a regularly scheduled treatment team meeting, the team informs Mr. H that he has been civilly committed for further treatment. Mr. H becomes upset and tells the team the decision is a complete violation of his rights. After a long rant, Mr. H walks out of the room, saying, “I did not even know when this hearing was.” A member of the treatment team becomes concerned that Mr. H may not have been notified of the hearing.

[polldaddy:11189294]

The author’s observations

It is not clear if Mr. H had been notified of his civil commitment hearing. If Mr. H had not been notified, his rights would have been compromised. Lessard v Schmidt (1972) outlined that individuals involved in a civil commitment hearing should be afforded the same rights as those involved in criminal proceedings.⁷ Mr. H should have been notified of his hearing and afforded the opportunity to have the assignment of counsel, the right to appear, the right to testify, the right to present witnesses and other evidence, and the right to confront witnesses.

Without notification of the hearing, the only right that would have remained intact for Mr. H would have been the assignment of counsel in his absence and without his knowledge. If Mr. H had been notified of the hearing and did not want to attend, yet still desired legal counsel, he could have waived his presence voluntarily after discussing this option with his attorney.^8,9

Continue to: OUTCOME Stabilization and discharge

During his 10-day stay, Mr. H is treated with sertraline 50 mg/d and engages in individual and group therapy. He shows noticeable improvement in his depressive symptoms and reports having no thoughts of suicide or self-harm. The treatment team determines it is appropriate to discharge him home (the firearm was never found) and involves his wife in safety planning and follow-up care. On the day of his discharge, Mr. H reflects on his treatment and civil commitment. He says, “I did not know a judge could order me to be hospitalized.”

[polldaddy:11189297]

The author’s observations

The physician’s decision to pursue civil commitment is best described by the legal doctrines of police powers and parens patriae. Other relevant ethical principles are described in Table 2.¹⁰

Though ethical principles may play a role in civil commitment, parens patriae and police powers is the answer with respect to the State.¹¹Parens patriae is Latin for the “parent of the country” and grants the State the power to protect those residents who are most vulnerable. Police power is the authority of the State to enact and enforce rules that limit the rights of individuals for the greater good of ensuring health, safety, and welfare of all citizens.

Bottom Line

Psychiatrists are entrusted with recognizing when a patient, due to mental illness, is a danger to themselves or others and in need of treatment. After an emergency detention period, if the patient remains a danger to themselves or others and does not want to voluntarily receive treatment, a court hearing is required. As an expert witness, the treating psychiatrist should know the factors of law in their jurisdiction that determine civil commitment.

Related Resources

• Extreme Risk Protection Orders. Johns Hopkins Bloomberg School of Public Health. https://www.jhsph.edu/research/ centers-and-institutes/johns-hopkins-center-for-gun-violenceprevention-and-policy/research/extreme-risk-protectionorders/
• Gutheil TG. The Psychiatrist as Expert Witness. 2nd ed. American Psychiatric Association Publishing; 2009.
• Landmark Cases 2014. American Academy of Psychiatry and the Law. https://www.aapl.org/landmark-cases

Drug Brand Names

Sertraline • Zoloft

CASE Depressed and suicidal

Police arrive at the home of Mr. H, age 50, after his wife calls 911. She reports he has depression and she saw him in bed brandishing a firearm as if he wanted to hurt himself. Upon arrival, the officers enter the house and find Mr. H in bed without a firearm. Mr. H says little to the officers about the alleged events, but acknowledges he has depression and is willing to go the hospital for further evaluation. Neither his wife nor the officers locate a firearm in the home.

EVALUATION Emergency detention

In the emergency department (ED), Mr. H’s laboratory results and physical examination findings are normal. He acknowledges feeling depressed over the past 2 weeks. Though he cannot identify any precipitants, he says he has experienced anhedonia, lack of appetite, decreased energy, and changes in his sleep patterns. When asked about the day’s events concerning the firearm, Mr. H becomes guarded and does not give a clear answer regarding having thoughts of suicide.

The evaluating psychiatrist obtains collateral from Mr. H’s wife and reviews his medical records. There are no active prescriptions on file and the psychiatrist notices that last year there was a suicide attempt involving a firearm. Following that episode, Mr. H was hospitalized, treated with sertraline 50 mg/d, and discharged with a diagnosis of major depressive disorder. There was no legal or substance abuse history.

In the ED, the psychiatrist conducts a psychiatric evaluation, including a suicide risk assessment, and determines Mr. H is at imminent risk of ending his life. Mr. H’s psychiatrist explains there are 2 treatment options: to be admitted to the hospital or to be discharged. The psychiatrist recommends hospital admission to Mr. H for his safety and stabilization. Mr. H says he prefers to return home.

Because the psychiatrist believes Mr. H is at imminent risk of ending his life and there is no less restrictive setting for treatment, he implements an emergency detention. In Ohio, this allows Mr. H to be held in the hospital for no more than 3 court days in accordance with state law. Before Mr. H’s emergency detention periods ends, the psychiatrist will need to decide whether Mr. H can be safely discharged. If the psychiatrist determines that Mr. H still needs treatment, the court will be petitioned for a civil commitment hearing.

[polldaddy:11189291]

The author’s observations

In some cases, courts allow information a psychiatrist does not directly obtain from a patient to be admitted as testimony in a civil commitment hearing. However, some jurisdictions consider sources of information not obtained directly from the patient as hearsay and thus inadmissible.¹ Though each source listed may provide credible information that could be presented at a hearing, the psychiatrist should discuss with the patient the information obtained from these sources to ensure it is admissable.² A discussion with Mr. H about the factors that led to his hospital arrival will avoid the psychiatrist’s reliance on what another person has heard or seen when providing testimony. Even when a psychiatrist is not faced with an issue of admissibility, caution must be taken with third-party reports.³

TREATMENT Civil commitment hearing

Before the emergency detention period expires, Mr. H’s psychiatrist determines that he remains at imminent risk of self-harm. To continue hospitalization, the psychiatrist files a petition for civil commitment and testifies at the commitment hearing. He reports that Mr. H suffers from a substantial mood disorder that grossly impairs his judgment and behavior. The psychiatrist also testifies that the least restrictive environment for treatment continues to be inpatient hospitalization, because Mr. H is still at imminent risk of harming himself.

Continue to: Following the psychiatrist's...

Following the psychiatrist’s testimony, the magistrate finds that Mr. H is a mentally ill person subject to hospitalization given his mood disorder that grossly impairs his judgment and behavior. The magistrate orders that Mr. H be civilly committed to the hospital.

[polldaddy:11189293]

The author’s observations

The psychiatrist’s testimony mirrors the language regarding civil commitment in the Ohio Revised Code.⁴ Other elements considered for mental illness in Ohio are a substantial disorder of memory, thought, orientation, or perception that grossly impairs one’s capacity to recognize reality or meet the demands of life.⁴ The definition of what constitutes a mental disorder varies by state, but the burden of persuasion—the standard by which the court must be convinced—is generally uniform.⁵ In the 1979 case Addington v Texas, the United States Supreme Court concluded that in a civil commitment hearing, the minimum standard of proof for involuntary commitment must be clear and convincing evidence.⁶ Neither medical certainty nor substantial probability are burdens of persuasions.⁶ Instead, these terms may be presented in a forensic report when an examiner outlines their opinion. Table 1 and the Figure provide more detail on burdens of persuasion.

TREATMENT Civil commitment and patient rights

At a regularly scheduled treatment team meeting, the team informs Mr. H that he has been civilly committed for further treatment. Mr. H becomes upset and tells the team the decision is a complete violation of his rights. After a long rant, Mr. H walks out of the room, saying, “I did not even know when this hearing was.” A member of the treatment team becomes concerned that Mr. H may not have been notified of the hearing.

[polldaddy:11189294]

The author’s observations

It is not clear if Mr. H had been notified of his civil commitment hearing. If Mr. H had not been notified, his rights would have been compromised. Lessard v Schmidt (1972) outlined that individuals involved in a civil commitment hearing should be afforded the same rights as those involved in criminal proceedings.⁷ Mr. H should have been notified of his hearing and afforded the opportunity to have the assignment of counsel, the right to appear, the right to testify, the right to present witnesses and other evidence, and the right to confront witnesses.

Without notification of the hearing, the only right that would have remained intact for Mr. H would have been the assignment of counsel in his absence and without his knowledge. If Mr. H had been notified of the hearing and did not want to attend, yet still desired legal counsel, he could have waived his presence voluntarily after discussing this option with his attorney.^8,9

Continue to: OUTCOME Stabilization and discharge

During his 10-day stay, Mr. H is treated with sertraline 50 mg/d and engages in individual and group therapy. He shows noticeable improvement in his depressive symptoms and reports having no thoughts of suicide or self-harm. The treatment team determines it is appropriate to discharge him home (the firearm was never found) and involves his wife in safety planning and follow-up care. On the day of his discharge, Mr. H reflects on his treatment and civil commitment. He says, “I did not know a judge could order me to be hospitalized.”

[polldaddy:11189297]

The author’s observations

The physician’s decision to pursue civil commitment is best described by the legal doctrines of police powers and parens patriae. Other relevant ethical principles are described in Table 2.¹⁰

Though ethical principles may play a role in civil commitment, parens patriae and police powers is the answer with respect to the State.¹¹Parens patriae is Latin for the “parent of the country” and grants the State the power to protect those residents who are most vulnerable. Police power is the authority of the State to enact and enforce rules that limit the rights of individuals for the greater good of ensuring health, safety, and welfare of all citizens.

Bottom Line

Psychiatrists are entrusted with recognizing when a patient, due to mental illness, is a danger to themselves or others and in need of treatment. After an emergency detention period, if the patient remains a danger to themselves or others and does not want to voluntarily receive treatment, a court hearing is required. As an expert witness, the treating psychiatrist should know the factors of law in their jurisdiction that determine civil commitment.

Related Resources

• Extreme Risk Protection Orders. Johns Hopkins Bloomberg School of Public Health. https://www.jhsph.edu/research/ centers-and-institutes/johns-hopkins-center-for-gun-violenceprevention-and-policy/research/extreme-risk-protectionorders/
• Gutheil TG. The Psychiatrist as Expert Witness. 2nd ed. American Psychiatric Association Publishing; 2009.
• Landmark Cases 2014. American Academy of Psychiatry and the Law. https://www.aapl.org/landmark-cases

Drug Brand Names

Sertraline • Zoloft

Climate change is causing intense heat waves that threaten human health across the globe.¹ Given their unique biological, behavioral, and social factors, patients with serious mental illness (SMI)—which includes schizophrenia spectrum disorders, bipolar disorder, and severe depression—are at higher risk of developing and dying from heat-related illnesses such as heat exhaustion and heat stroke.¹ In this article, we discuss factors that increase the risk of heat-related illnesses in patients with SMI and outline steps you can take to educate and prepare patients for heat waves.

A confluence of factors increases risk

Thermoregulatory dysfunction is thought to be intrinsic to patients with schizophrenia partly due to dysregulated dopaminergic neurotransmission.² This is compounded by these patients’ higher burden of chronic medical comorbidities such as cardiovascular and respiratory illnesses, which together with psychotropic (ie, antipsychotics, antidepressants, lithium, benzodiazepines) and medical medications (ie, certain antihypertensives, diuretics, treatment for urinary incontinence) further disrupt the body’s cooling strategies and increase vulnerability to heat-related illnesses.^1,3 Antipsychotics commonly prescribed to patients with SMI increase hyperthermia risk largely by 2 mechanisms: central and peripheral thermal dysregulation, and anticholinergic properties (ie, olanzapine, clozapine, chlorpromazine).^2,3 Other anticholinergic medications prescribed to treat extrapyramidal symptoms (ie, diphenhydramine, benztropine, trihexyphenidyl), anxiety, depression, and insomnia (ie, paroxetine, trazodone, doxepin) further add insult to injury because they impair sweating, which decreases the body’s ability to eliminate heat through evaporation.^2,3 Additionally, high temperature exacerbates psychiatric symptoms in patients with SMI, resulting in increased hospitalizations and emergency department visits.¹ Patients with SMI also commonly have cognitive deficits, which may interfere with their ability to prepare for extreme heat and make it difficult for them to protect themselves. Finally, patients with SMI often have lower socioeconomic status with reduced access to air conditioning.^1,2

How to keep patients safe

The acronym HEAT provides a framework that psychiatrists can use to highlight the importance of planning for heat waves in their institution and guiding discussions with individual patients about heat-related illnesses (Table 1).

Help the health care system where you work plan and prepare for heat waves. In-service training in mental health settings such as outpatient clinics, shelters, group homes, and residential programs can help staff identify patients at particular risk and reinforce key prevention messages.

Educate patients and their caregivers on strategies for preventing heat-related illness. Informational materials can be distributed in clinics, residential settings, and day programs. A 1-page downloadable pamphlet available at https://smiadviser.org/wp-content/uploads/2022/08/SMI-Heat-Stroke-ver1.0-FINAL.pdf summarizes key prevention messages of staying hydrated, staying cool, and staying safe.

Assess personalized heat-related risks. Inquire about patients’ daily activities, access to air conditioning, and water intake. Minimize the use of anticholinergic medications. Identify who patients can turn to for assistance, especially for those who struggle with cognitive impairment and social isolation.

Teach patients, caregivers, and staff the signs and symptoms of heat exhaustion and heat stroke and how to respond in such situations.

HEAT focuses psychiatric clinicians on preparing and protecting patients with SMI against dangerous heat waves. Clinicians can take a proactive leadership role in disseminating basic principles of heat-related illness prevention and heat-wave toolkits by using resources available from organizations such as the Climate Psychiatry Alliance (Table 2). They can also initiate advocacy efforts to raise awareness about the elevated risks of heat-related illnesses in this vulnerable population.

Climate change is causing intense heat waves that threaten human health across the globe.¹ Given their unique biological, behavioral, and social factors, patients with serious mental illness (SMI)—which includes schizophrenia spectrum disorders, bipolar disorder, and severe depression—are at higher risk of developing and dying from heat-related illnesses such as heat exhaustion and heat stroke.¹ In this article, we discuss factors that increase the risk of heat-related illnesses in patients with SMI and outline steps you can take to educate and prepare patients for heat waves.

A confluence of factors increases risk

Thermoregulatory dysfunction is thought to be intrinsic to patients with schizophrenia partly due to dysregulated dopaminergic neurotransmission.² This is compounded by these patients’ higher burden of chronic medical comorbidities such as cardiovascular and respiratory illnesses, which together with psychotropic (ie, antipsychotics, antidepressants, lithium, benzodiazepines) and medical medications (ie, certain antihypertensives, diuretics, treatment for urinary incontinence) further disrupt the body’s cooling strategies and increase vulnerability to heat-related illnesses.^1,3 Antipsychotics commonly prescribed to patients with SMI increase hyperthermia risk largely by 2 mechanisms: central and peripheral thermal dysregulation, and anticholinergic properties (ie, olanzapine, clozapine, chlorpromazine).^2,3 Other anticholinergic medications prescribed to treat extrapyramidal symptoms (ie, diphenhydramine, benztropine, trihexyphenidyl), anxiety, depression, and insomnia (ie, paroxetine, trazodone, doxepin) further add insult to injury because they impair sweating, which decreases the body’s ability to eliminate heat through evaporation.^2,3 Additionally, high temperature exacerbates psychiatric symptoms in patients with SMI, resulting in increased hospitalizations and emergency department visits.¹ Patients with SMI also commonly have cognitive deficits, which may interfere with their ability to prepare for extreme heat and make it difficult for them to protect themselves. Finally, patients with SMI often have lower socioeconomic status with reduced access to air conditioning.^1,2

How to keep patients safe

The acronym HEAT provides a framework that psychiatrists can use to highlight the importance of planning for heat waves in their institution and guiding discussions with individual patients about heat-related illnesses (Table 1).

Help the health care system where you work plan and prepare for heat waves. In-service training in mental health settings such as outpatient clinics, shelters, group homes, and residential programs can help staff identify patients at particular risk and reinforce key prevention messages.

Educate patients and their caregivers on strategies for preventing heat-related illness. Informational materials can be distributed in clinics, residential settings, and day programs. A 1-page downloadable pamphlet available at https://smiadviser.org/wp-content/uploads/2022/08/SMI-Heat-Stroke-ver1.0-FINAL.pdf summarizes key prevention messages of staying hydrated, staying cool, and staying safe.

Assess personalized heat-related risks. Inquire about patients’ daily activities, access to air conditioning, and water intake. Minimize the use of anticholinergic medications. Identify who patients can turn to for assistance, especially for those who struggle with cognitive impairment and social isolation.

Teach patients, caregivers, and staff the signs and symptoms of heat exhaustion and heat stroke and how to respond in such situations.

HEAT focuses psychiatric clinicians on preparing and protecting patients with SMI against dangerous heat waves. Clinicians can take a proactive leadership role in disseminating basic principles of heat-related illness prevention and heat-wave toolkits by using resources available from organizations such as the Climate Psychiatry Alliance (Table 2). They can also initiate advocacy efforts to raise awareness about the elevated risks of heat-related illnesses in this vulnerable population.

Climate change is causing intense heat waves that threaten human health across the globe.¹ Given their unique biological, behavioral, and social factors, patients with serious mental illness (SMI)—which includes schizophrenia spectrum disorders, bipolar disorder, and severe depression—are at higher risk of developing and dying from heat-related illnesses such as heat exhaustion and heat stroke.¹ In this article, we discuss factors that increase the risk of heat-related illnesses in patients with SMI and outline steps you can take to educate and prepare patients for heat waves.

A confluence of factors increases risk

Thermoregulatory dysfunction is thought to be intrinsic to patients with schizophrenia partly due to dysregulated dopaminergic neurotransmission.² This is compounded by these patients’ higher burden of chronic medical comorbidities such as cardiovascular and respiratory illnesses, which together with psychotropic (ie, antipsychotics, antidepressants, lithium, benzodiazepines) and medical medications (ie, certain antihypertensives, diuretics, treatment for urinary incontinence) further disrupt the body’s cooling strategies and increase vulnerability to heat-related illnesses.^1,3 Antipsychotics commonly prescribed to patients with SMI increase hyperthermia risk largely by 2 mechanisms: central and peripheral thermal dysregulation, and anticholinergic properties (ie, olanzapine, clozapine, chlorpromazine).^2,3 Other anticholinergic medications prescribed to treat extrapyramidal symptoms (ie, diphenhydramine, benztropine, trihexyphenidyl), anxiety, depression, and insomnia (ie, paroxetine, trazodone, doxepin) further add insult to injury because they impair sweating, which decreases the body’s ability to eliminate heat through evaporation.^2,3 Additionally, high temperature exacerbates psychiatric symptoms in patients with SMI, resulting in increased hospitalizations and emergency department visits.¹ Patients with SMI also commonly have cognitive deficits, which may interfere with their ability to prepare for extreme heat and make it difficult for them to protect themselves. Finally, patients with SMI often have lower socioeconomic status with reduced access to air conditioning.^1,2

How to keep patients safe

The acronym HEAT provides a framework that psychiatrists can use to highlight the importance of planning for heat waves in their institution and guiding discussions with individual patients about heat-related illnesses (Table 1).

Help the health care system where you work plan and prepare for heat waves. In-service training in mental health settings such as outpatient clinics, shelters, group homes, and residential programs can help staff identify patients at particular risk and reinforce key prevention messages.

Educate patients and their caregivers on strategies for preventing heat-related illness. Informational materials can be distributed in clinics, residential settings, and day programs. A 1-page downloadable pamphlet available at https://smiadviser.org/wp-content/uploads/2022/08/SMI-Heat-Stroke-ver1.0-FINAL.pdf summarizes key prevention messages of staying hydrated, staying cool, and staying safe.

Assess personalized heat-related risks. Inquire about patients’ daily activities, access to air conditioning, and water intake. Minimize the use of anticholinergic medications. Identify who patients can turn to for assistance, especially for those who struggle with cognitive impairment and social isolation.

Teach patients, caregivers, and staff the signs and symptoms of heat exhaustion and heat stroke and how to respond in such situations.

HEAT focuses psychiatric clinicians on preparing and protecting patients with SMI against dangerous heat waves. Clinicians can take a proactive leadership role in disseminating basic principles of heat-related illness prevention and heat-wave toolkits by using resources available from organizations such as the Climate Psychiatry Alliance (Table 2). They can also initiate advocacy efforts to raise awareness about the elevated risks of heat-related illnesses in this vulnerable population.