Schizophrenia & Other Psychotic Disorders

Adults with cerebral palsy, especially those with intellectual disabilities, are significantly more likely to be diagnosed with a psychiatric disorder, compared with the general population, a review of seven datasets shows.

The body of literature on psychiatric issues in children with cerebral palsy (CP) is increasing, but population-based studies of psychiatric issues in adults with CP have been limited in number and in scope. Most of those studies focus mainly on anxiety and depression, rather than on other issues such as psychosis or schizophrenia, Carly A. McMorris, PhD, of the University of Calgary (Alta.) and colleagues wrote.

In a retrospective, cross-sectional study published in Research in Developmental Disabilities, the researchers reviewed information from five health data sets, one registry, and census data for adults aged 18-64 years with a CP diagnosis living in Ontario, including those with and without diagnosed intellectual disabilities (ID) and a comparison group of individuals in the general population. The researchers examined the proportion of individuals with a psychiatric disorder in each of four groups: total CP, CP without ID, CP with ID, and the general population.

The study participants included 9,388 individuals with CP, 4,767 individuals with CP and ID, and a general population of 2,757,744 individuals. About half of the participants were male, and at least 85% lived in urban areas.

Overall, the total CP group was 1.4 times more likely to receive any psychiatric diagnosis, compared with the general population group, over a 2-year period (33.7 % vs. 24.7%). Also, the CP group was more than twice as likely to be diagnosed with a psychotic disorder, schizophrenia, personality disorder, or bipolar disorder, compared with the general population. Individuals with CP were significantly more likely to suffer from mood or affective disorders, and depression and anxiety disorders, compared with the general population, but less likely to suffer from substance use disorders.

When the data were assessed by ID status, disorders such as psychotic disorders, bipolar disorders, and schizophrenia were six times more common among individuals with CP and ID, compared with the general population (adjusted prevalence ratios, 6.26 and 6.46, respectively).

Individuals with CP and ID also had a notably higher prevalence of bipolar disorder (confidence interval, 2.06-2.89) and personality disorder, compared with the general population (aPR, 2.44 and 4.22, respectively), but this subgroup also was less likely than the general population to engage in substance use (aPR, 0.44).

The study findings were limited by several factors, including the absence of universal definitions for some of the conditions studied, potential misclassification of ID, the inclusion of data on specific psychiatric diagnoses but not elevated symptoms, and by the challenges of diagnosing psychiatric disorders in individuals with ID, the researchers noted.

However, “the present study contributes important information to the existing literature, highlighting that psychiatric issues are common in adults with CP, similar to what has been reported in children and youth,” they said. “Further research is needed to determine the validity and reliability of mental health assessment measures for this population, the efficacy of evidence-based psychotherapeutic approaches ... and the underlying causes or mechanisms of psychiatric issues in individuals with CP.”

The findings also highlight the need for health care clinicians to screen for psychiatric issues in CP patients, they said.

The study was supported in part by the Province of Ontario research grants and the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The researchers had no disclosures.

Adults with cerebral palsy, especially those with intellectual disabilities, are significantly more likely to be diagnosed with a psychiatric disorder, compared with the general population, a review of seven datasets shows.

The body of literature on psychiatric issues in children with cerebral palsy (CP) is increasing, but population-based studies of psychiatric issues in adults with CP have been limited in number and in scope. Most of those studies focus mainly on anxiety and depression, rather than on other issues such as psychosis or schizophrenia, Carly A. McMorris, PhD, of the University of Calgary (Alta.) and colleagues wrote.

In a retrospective, cross-sectional study published in Research in Developmental Disabilities, the researchers reviewed information from five health data sets, one registry, and census data for adults aged 18-64 years with a CP diagnosis living in Ontario, including those with and without diagnosed intellectual disabilities (ID) and a comparison group of individuals in the general population. The researchers examined the proportion of individuals with a psychiatric disorder in each of four groups: total CP, CP without ID, CP with ID, and the general population.

The study participants included 9,388 individuals with CP, 4,767 individuals with CP and ID, and a general population of 2,757,744 individuals. About half of the participants were male, and at least 85% lived in urban areas.

Overall, the total CP group was 1.4 times more likely to receive any psychiatric diagnosis, compared with the general population group, over a 2-year period (33.7 % vs. 24.7%). Also, the CP group was more than twice as likely to be diagnosed with a psychotic disorder, schizophrenia, personality disorder, or bipolar disorder, compared with the general population. Individuals with CP were significantly more likely to suffer from mood or affective disorders, and depression and anxiety disorders, compared with the general population, but less likely to suffer from substance use disorders.

When the data were assessed by ID status, disorders such as psychotic disorders, bipolar disorders, and schizophrenia were six times more common among individuals with CP and ID, compared with the general population (adjusted prevalence ratios, 6.26 and 6.46, respectively).

Individuals with CP and ID also had a notably higher prevalence of bipolar disorder (confidence interval, 2.06-2.89) and personality disorder, compared with the general population (aPR, 2.44 and 4.22, respectively), but this subgroup also was less likely than the general population to engage in substance use (aPR, 0.44).

The study findings were limited by several factors, including the absence of universal definitions for some of the conditions studied, potential misclassification of ID, the inclusion of data on specific psychiatric diagnoses but not elevated symptoms, and by the challenges of diagnosing psychiatric disorders in individuals with ID, the researchers noted.

However, “the present study contributes important information to the existing literature, highlighting that psychiatric issues are common in adults with CP, similar to what has been reported in children and youth,” they said. “Further research is needed to determine the validity and reliability of mental health assessment measures for this population, the efficacy of evidence-based psychotherapeutic approaches ... and the underlying causes or mechanisms of psychiatric issues in individuals with CP.”

The findings also highlight the need for health care clinicians to screen for psychiatric issues in CP patients, they said.

The study was supported in part by the Province of Ontario research grants and the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The researchers had no disclosures.

Adults with cerebral palsy, especially those with intellectual disabilities, are significantly more likely to be diagnosed with a psychiatric disorder, compared with the general population, a review of seven datasets shows.

The body of literature on psychiatric issues in children with cerebral palsy (CP) is increasing, but population-based studies of psychiatric issues in adults with CP have been limited in number and in scope. Most of those studies focus mainly on anxiety and depression, rather than on other issues such as psychosis or schizophrenia, Carly A. McMorris, PhD, of the University of Calgary (Alta.) and colleagues wrote.

In a retrospective, cross-sectional study published in Research in Developmental Disabilities, the researchers reviewed information from five health data sets, one registry, and census data for adults aged 18-64 years with a CP diagnosis living in Ontario, including those with and without diagnosed intellectual disabilities (ID) and a comparison group of individuals in the general population. The researchers examined the proportion of individuals with a psychiatric disorder in each of four groups: total CP, CP without ID, CP with ID, and the general population.

The study participants included 9,388 individuals with CP, 4,767 individuals with CP and ID, and a general population of 2,757,744 individuals. About half of the participants were male, and at least 85% lived in urban areas.

Overall, the total CP group was 1.4 times more likely to receive any psychiatric diagnosis, compared with the general population group, over a 2-year period (33.7 % vs. 24.7%). Also, the CP group was more than twice as likely to be diagnosed with a psychotic disorder, schizophrenia, personality disorder, or bipolar disorder, compared with the general population. Individuals with CP were significantly more likely to suffer from mood or affective disorders, and depression and anxiety disorders, compared with the general population, but less likely to suffer from substance use disorders.

When the data were assessed by ID status, disorders such as psychotic disorders, bipolar disorders, and schizophrenia were six times more common among individuals with CP and ID, compared with the general population (adjusted prevalence ratios, 6.26 and 6.46, respectively).

Individuals with CP and ID also had a notably higher prevalence of bipolar disorder (confidence interval, 2.06-2.89) and personality disorder, compared with the general population (aPR, 2.44 and 4.22, respectively), but this subgroup also was less likely than the general population to engage in substance use (aPR, 0.44).

The study findings were limited by several factors, including the absence of universal definitions for some of the conditions studied, potential misclassification of ID, the inclusion of data on specific psychiatric diagnoses but not elevated symptoms, and by the challenges of diagnosing psychiatric disorders in individuals with ID, the researchers noted.

However, “the present study contributes important information to the existing literature, highlighting that psychiatric issues are common in adults with CP, similar to what has been reported in children and youth,” they said. “Further research is needed to determine the validity and reliability of mental health assessment measures for this population, the efficacy of evidence-based psychotherapeutic approaches ... and the underlying causes or mechanisms of psychiatric issues in individuals with CP.”

The findings also highlight the need for health care clinicians to screen for psychiatric issues in CP patients, they said.

The study was supported in part by the Province of Ontario research grants and the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The researchers had no disclosures.

Results from a large study make a strong case for offering long-acting injectable antipsychotics (LAIs) to patients newly diagnosed with schizophrenia.

Investigators found that among patients who switched to LAIs, mortality was lower and there were fewer suicide attempts in comparison with patients who continued taking the corresponding oral antipsychotic (OAP).

In addition, switching to an LAI antipsychotic within the first 2 years of OAP cut the risk for suicide death by 47%.

“With newly diagnosed schizophrenia, more active consideration of LAIs in this stage for better long-term outcomes (i.e., mortality and suicide risk) should be encouraged, particularly for those who have already exhibited poor adherence attitudes,” Cheng-yi Huang, MD, Bali Psychiatric Center, Ministry of Health and Welfare, New Taipei City, Taiwan, said in an interview.

The study was published online May 11 in JAMA Network Open.
 

Powerful incentive to switch

Using data from the Taiwan National Health Insurance Research Database, the investigators identified patients newly diagnosed with schizophrenia who received OAPs from 2002 to 2017.

Within this cohort, they defined the LAI group as patients who switched to LAIs and were prescribed LAIs at least four times within 1 year. The LAI group was propensity matched to patients who continued receiving OAPs of the same compounds. There were 2,614 patients in each group (median age, 30 years).

During the 16-year follow-up period, compared with patients who continued taking the OAP, those who switched to the LAI had a 34% lower risk for all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% confidence interval, 0.54-0.81), a 37% lower risk for natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and a 28% lower risk for suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93).

The risk for suicide mortality was 47% lower for patients who switched to LAIs within the first 2 years of having begun taking the OAP (aHR, 0.53; 95% CI, 0.30-0.92).

A recent study from Canada found that the suicide rate among patients with schizophrenia spectrum disorders was more than 20 times higher than that of the general population.

“Clinically, most psychiatrists use LAIs with a conservative attitude, and the reasons for this attitude are generally not well supported by current scientific evidence,” Dr. Huang and colleagues note in their article.

Dr. Huang said the study provides a powerful incentive to begin treatment with LAIs for patients newly diagnosed with schizophrenia.

“Because this study compared depot versus the same oral compound, as soon as patients show response and tolerability to the OAP, they will benefit much more when switching to LAI of the same compound,” Dr. Huang told this news organization.
 

‘Remarkably underutilized’

Commenting on the study for an interview, William Carpenter Jr., MD, Maryland Psychiatric Research Center, University of Maryland, Baltimore, said this report is “very important and in a high-quality journal.”

“LAIs have been remarkably underutilized in the U.S. and not considered as main line and initial treatment. All of this is unfortunate attitude, not science,” Dr. Carpenter said.

There is now evidence that the field is shifting toward LAIs as frontline treatment, “at least conceptually and by research leaders,” he noted.

“In this report, the health and suicide information is new, extremely important, and robust. This report should alert clinicians to possible advantage of LAI in suicide prevention,” Dr. Carpenter added.

Also commenting for this news organization, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences, Staten Island University Hospital, New York, said the findings provide “another very robust argument for LAIs.”

“The decrease in all-cause mortality is really interesting,” said Dr. Sullivan, “and it would be interesting to find out whether some of this reflects improved metabolic states” with LAIs versus OAPs.

The finding that people who switched to LAIs within 2 years were at much lower risk for suicide and other mortality represents a “powerful argument for switching within 2 years,” Dr. Sullivan said.

However, in current clinical practice, clinicians often don’t suggest LAIs until patients have suffered repeated acute episodes of illness after not taking their oral antipsychotics. Such episodes have an impact on the individual and on their nervous system, Dr. Sullivan explained.

“That’s really undesirable. We know from other data that the more episodes someone has, the harder it is to get the illness symptoms under control,” he noted.

“We really ought to be thinking preventively about approaches that will decrease the risk of recurrence, and the evidence in this study is pretty compelling that the LAI was a significant intervention that decreased the risks. Thinking about LAIs as a preventive measure is a message that hasn’t gotten out to the practice community yet,” Dr. Sullivan added.

The study was supported by the Bali Psychiatric Center, Taiwan, through a grant from the Ministry of Health and Welfare. Dr. Huang, Dr. Carpenter, and Dr. Sullivan have disclosed no relevant financial relationships.

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

Results from a large study make a strong case for offering long-acting injectable antipsychotics (LAIs) to patients newly diagnosed with schizophrenia.

Investigators found that among patients who switched to LAIs, mortality was lower and there were fewer suicide attempts in comparison with patients who continued taking the corresponding oral antipsychotic (OAP).

In addition, switching to an LAI antipsychotic within the first 2 years of OAP cut the risk for suicide death by 47%.

“With newly diagnosed schizophrenia, more active consideration of LAIs in this stage for better long-term outcomes (i.e., mortality and suicide risk) should be encouraged, particularly for those who have already exhibited poor adherence attitudes,” Cheng-yi Huang, MD, Bali Psychiatric Center, Ministry of Health and Welfare, New Taipei City, Taiwan, said in an interview.

The study was published online May 11 in JAMA Network Open.
 

Powerful incentive to switch

Using data from the Taiwan National Health Insurance Research Database, the investigators identified patients newly diagnosed with schizophrenia who received OAPs from 2002 to 2017.

Within this cohort, they defined the LAI group as patients who switched to LAIs and were prescribed LAIs at least four times within 1 year. The LAI group was propensity matched to patients who continued receiving OAPs of the same compounds. There were 2,614 patients in each group (median age, 30 years).

During the 16-year follow-up period, compared with patients who continued taking the OAP, those who switched to the LAI had a 34% lower risk for all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% confidence interval, 0.54-0.81), a 37% lower risk for natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and a 28% lower risk for suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93).

The risk for suicide mortality was 47% lower for patients who switched to LAIs within the first 2 years of having begun taking the OAP (aHR, 0.53; 95% CI, 0.30-0.92).

A recent study from Canada found that the suicide rate among patients with schizophrenia spectrum disorders was more than 20 times higher than that of the general population.

“Clinically, most psychiatrists use LAIs with a conservative attitude, and the reasons for this attitude are generally not well supported by current scientific evidence,” Dr. Huang and colleagues note in their article.

Dr. Huang said the study provides a powerful incentive to begin treatment with LAIs for patients newly diagnosed with schizophrenia.

“Because this study compared depot versus the same oral compound, as soon as patients show response and tolerability to the OAP, they will benefit much more when switching to LAI of the same compound,” Dr. Huang told this news organization.
 

‘Remarkably underutilized’

Commenting on the study for an interview, William Carpenter Jr., MD, Maryland Psychiatric Research Center, University of Maryland, Baltimore, said this report is “very important and in a high-quality journal.”

“LAIs have been remarkably underutilized in the U.S. and not considered as main line and initial treatment. All of this is unfortunate attitude, not science,” Dr. Carpenter said.

There is now evidence that the field is shifting toward LAIs as frontline treatment, “at least conceptually and by research leaders,” he noted.

“In this report, the health and suicide information is new, extremely important, and robust. This report should alert clinicians to possible advantage of LAI in suicide prevention,” Dr. Carpenter added.

Also commenting for this news organization, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences, Staten Island University Hospital, New York, said the findings provide “another very robust argument for LAIs.”

“The decrease in all-cause mortality is really interesting,” said Dr. Sullivan, “and it would be interesting to find out whether some of this reflects improved metabolic states” with LAIs versus OAPs.

The finding that people who switched to LAIs within 2 years were at much lower risk for suicide and other mortality represents a “powerful argument for switching within 2 years,” Dr. Sullivan said.

However, in current clinical practice, clinicians often don’t suggest LAIs until patients have suffered repeated acute episodes of illness after not taking their oral antipsychotics. Such episodes have an impact on the individual and on their nervous system, Dr. Sullivan explained.

“That’s really undesirable. We know from other data that the more episodes someone has, the harder it is to get the illness symptoms under control,” he noted.

“We really ought to be thinking preventively about approaches that will decrease the risk of recurrence, and the evidence in this study is pretty compelling that the LAI was a significant intervention that decreased the risks. Thinking about LAIs as a preventive measure is a message that hasn’t gotten out to the practice community yet,” Dr. Sullivan added.

The study was supported by the Bali Psychiatric Center, Taiwan, through a grant from the Ministry of Health and Welfare. Dr. Huang, Dr. Carpenter, and Dr. Sullivan have disclosed no relevant financial relationships.

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

Results from a large study make a strong case for offering long-acting injectable antipsychotics (LAIs) to patients newly diagnosed with schizophrenia.

Investigators found that among patients who switched to LAIs, mortality was lower and there were fewer suicide attempts in comparison with patients who continued taking the corresponding oral antipsychotic (OAP).

In addition, switching to an LAI antipsychotic within the first 2 years of OAP cut the risk for suicide death by 47%.

“With newly diagnosed schizophrenia, more active consideration of LAIs in this stage for better long-term outcomes (i.e., mortality and suicide risk) should be encouraged, particularly for those who have already exhibited poor adherence attitudes,” Cheng-yi Huang, MD, Bali Psychiatric Center, Ministry of Health and Welfare, New Taipei City, Taiwan, said in an interview.

The study was published online May 11 in JAMA Network Open.
 

Powerful incentive to switch

Using data from the Taiwan National Health Insurance Research Database, the investigators identified patients newly diagnosed with schizophrenia who received OAPs from 2002 to 2017.

Within this cohort, they defined the LAI group as patients who switched to LAIs and were prescribed LAIs at least four times within 1 year. The LAI group was propensity matched to patients who continued receiving OAPs of the same compounds. There were 2,614 patients in each group (median age, 30 years).

During the 16-year follow-up period, compared with patients who continued taking the OAP, those who switched to the LAI had a 34% lower risk for all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% confidence interval, 0.54-0.81), a 37% lower risk for natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and a 28% lower risk for suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93).

The risk for suicide mortality was 47% lower for patients who switched to LAIs within the first 2 years of having begun taking the OAP (aHR, 0.53; 95% CI, 0.30-0.92).

A recent study from Canada found that the suicide rate among patients with schizophrenia spectrum disorders was more than 20 times higher than that of the general population.

“Clinically, most psychiatrists use LAIs with a conservative attitude, and the reasons for this attitude are generally not well supported by current scientific evidence,” Dr. Huang and colleagues note in their article.

Dr. Huang said the study provides a powerful incentive to begin treatment with LAIs for patients newly diagnosed with schizophrenia.

“Because this study compared depot versus the same oral compound, as soon as patients show response and tolerability to the OAP, they will benefit much more when switching to LAI of the same compound,” Dr. Huang told this news organization.
 

‘Remarkably underutilized’

Commenting on the study for an interview, William Carpenter Jr., MD, Maryland Psychiatric Research Center, University of Maryland, Baltimore, said this report is “very important and in a high-quality journal.”

“LAIs have been remarkably underutilized in the U.S. and not considered as main line and initial treatment. All of this is unfortunate attitude, not science,” Dr. Carpenter said.

There is now evidence that the field is shifting toward LAIs as frontline treatment, “at least conceptually and by research leaders,” he noted.

“In this report, the health and suicide information is new, extremely important, and robust. This report should alert clinicians to possible advantage of LAI in suicide prevention,” Dr. Carpenter added.

Also commenting for this news organization, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences, Staten Island University Hospital, New York, said the findings provide “another very robust argument for LAIs.”

“The decrease in all-cause mortality is really interesting,” said Dr. Sullivan, “and it would be interesting to find out whether some of this reflects improved metabolic states” with LAIs versus OAPs.

The finding that people who switched to LAIs within 2 years were at much lower risk for suicide and other mortality represents a “powerful argument for switching within 2 years,” Dr. Sullivan said.

However, in current clinical practice, clinicians often don’t suggest LAIs until patients have suffered repeated acute episodes of illness after not taking their oral antipsychotics. Such episodes have an impact on the individual and on their nervous system, Dr. Sullivan explained.

“That’s really undesirable. We know from other data that the more episodes someone has, the harder it is to get the illness symptoms under control,” he noted.

“We really ought to be thinking preventively about approaches that will decrease the risk of recurrence, and the evidence in this study is pretty compelling that the LAI was a significant intervention that decreased the risks. Thinking about LAIs as a preventive measure is a message that hasn’t gotten out to the practice community yet,” Dr. Sullivan added.

The study was supported by the Bali Psychiatric Center, Taiwan, through a grant from the Ministry of Health and Welfare. Dr. Huang, Dr. Carpenter, and Dr. Sullivan have disclosed no relevant financial relationships.

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

Copeptin, a small peptide secreted with the hormone vasopressin, appears to be one of the first promising biomarkers for predicting psychosis relapse, results of an observational study suggest.

An analysis of plasma copeptin levels in patients with schizophrenia showed those with high plasma levels of the peptide were about three times more likely to experience psychotic relapse, compared with their counterparts with lower levels.

The results suggest, “copeptin could be a promising biomarker in predicting psychotic relapse in schizophrenia spectrum disorder,” said study investigator Jennifer Küster, MD, University Psychiatric Clinics Basel (Switzerland). Measuring copeptin levels upon hospital admission “could help to intensify” the care of at-risk patients, she added.

The findings were presented at the virtual Congress of the Schizophrenia International Research Society 2021.
 

Relapse prevention important

Two-thirds of patients with schizophrenia experience at least one relapse of a psychotic episode, which in turn increases the risk of the disorder having a chronic course, Dr. Küster noted.

In addition, a psychotic relapse is associated with deterioration of function and cognition and reduced treatment response, “so relapse prevention is important,” she said.

Previous research has explored various methods of predicting schizophrenia outcomes. These include measuring inflammatory markers, catecholamines, oxytocin, and cortisol in combination with imaging markers, “but so far no reliable biomarker has been found,” Dr. Küster said.

She noted that psychotic relapse is associated with increased psychological stress – and vasopressin, which is secreted by the pituitary gland, is a known marker of stress. It is involved in sodium homeostasis and higher brain function and is also elevated in acute psychosis.

However, vasopressin “is challenging to measure because assays are complicated and unreliable,” Dr. Küster said.

As a result, the researchers turned their attention to copeptin, a more stable, more reliable surrogate marker for vasopressin. Copeptin has been shown previously to be a predictor of outcomes in somatic diseases and is also increased during psychological distress.

To measure the utility of copeptin in predicting psychotic relapse, the researchers conducted a prospective, explorative, single-center observational study involving inpatients with an acute psychotic episode diagnosed with schizophrenia spectrum disorder or affective disorder.

Baseline characteristics were collected and fasting serum copeptin levels were measured. Disease severity was measured using a range of validated assessment scales.
 

Predictive factor

Among 69 patients available for analysis, 30 experienced psychotic relapse at 1-year follow-up. Relapse was defined as rehospitalization because of an acute psychotic episode.

There were no differences in baseline demographic characteristics between patients with, and without, psychotic relapse. There were also no differences in baseline psychopathology, including scores on the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Global Assessment of Function.

Dr. Küster noted that there were no overall differences between patients with and without psychotic relapse in terms of their plasma copeptin or cortisol levels at baseline.

“The only difference we saw was in diagnosis,” she reported. Patients with psychotic relapse were significantly more likely to have comorbid drug abuse – 43% in patients who relapsed versus 15% of those who did not (P = .02).

However, when the investigators calculated the area under the receiver operating characteristics curve for copeptin levels, they found there was a significant difference in relapse rates in those with copeptin levels >6 pmol/L vs. those with lower levels (hazard ratio, 2.3; P = .039).

When the focus was on only patients with schizophrenia spectrum disorder, the results were even more pronounced. The HR for psychotic relapse in patients with higher vs. lower copeptin levels was 3.2 (P = .028).

“We also looked for other possible predicting factors,” Dr. Küster said. This included sex, age, duration of disease, reason for hospitalization, psychopathology, medication, comorbidities, and cortisol levels. “But none of these factors was associated with psychotic relapse,” she added.

The only factor positively associated with relapse was drug abuse, primarily via marijuana. However, the association with copeptin remained significant even after taking this factor into account.

In future studies, the researchers plan to examine whether copeptin levels could identify which patients at ultra-high risk will transition to first-episode psychosis, as well as to predict development of posttraumatic stress disorder, Dr. Küster said.
 

A proxy for ‘something simpler’?

Commenting on the findings for this news organization, Leah H. Rubin, PhD, associate professor of neurology, Johns Hopkins University, Baltimore, described the study as “interesting” – and noted that her own research has included measuring vasopressin in patients with untreated first-episode psychosis.

Dr. Rubin’s findings showed that levels of the hormone were associated with psychosis severity, and thus she is “not surprised that they found a marker” that may be promising in psychosis relapse prediction.

However, she took issue with the notion that vasopressin is an unreliable marker, pointing out that the work of her team demonstrates that it can be measured. Dr. Rubin added that she found it to be “pretty stable.”

In addition, because the current study had a small sample size, Dr. Rubin said she would be interested to see whether the findings can be replicated on a larger scale.

She also noted that more than two-thirds of the study population were men. “Vasopressin and oxytocin are sexually dimorphic neuropeptides,” she explained, “so I think it becomes important to ensure ... whether it’s the same for men and women.”

“Just from a psychosocial perspective, what’s going on in those folks’ lives?” Dr. Rubin asked. “Is it truly copeptin” or is it high stress levels that facilitate a relapse? Copeptin levels, she added, may be “a proxy for something simpler.”

The study authors and Dr. Rubin have disclosed no relevant financial relationships.

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

Copeptin, a small peptide secreted with the hormone vasopressin, appears to be one of the first promising biomarkers for predicting psychosis relapse, results of an observational study suggest.

An analysis of plasma copeptin levels in patients with schizophrenia showed those with high plasma levels of the peptide were about three times more likely to experience psychotic relapse, compared with their counterparts with lower levels.

The results suggest, “copeptin could be a promising biomarker in predicting psychotic relapse in schizophrenia spectrum disorder,” said study investigator Jennifer Küster, MD, University Psychiatric Clinics Basel (Switzerland). Measuring copeptin levels upon hospital admission “could help to intensify” the care of at-risk patients, she added.

The findings were presented at the virtual Congress of the Schizophrenia International Research Society 2021.
 

Relapse prevention important

Two-thirds of patients with schizophrenia experience at least one relapse of a psychotic episode, which in turn increases the risk of the disorder having a chronic course, Dr. Küster noted.

In addition, a psychotic relapse is associated with deterioration of function and cognition and reduced treatment response, “so relapse prevention is important,” she said.

Previous research has explored various methods of predicting schizophrenia outcomes. These include measuring inflammatory markers, catecholamines, oxytocin, and cortisol in combination with imaging markers, “but so far no reliable biomarker has been found,” Dr. Küster said.

She noted that psychotic relapse is associated with increased psychological stress – and vasopressin, which is secreted by the pituitary gland, is a known marker of stress. It is involved in sodium homeostasis and higher brain function and is also elevated in acute psychosis.

However, vasopressin “is challenging to measure because assays are complicated and unreliable,” Dr. Küster said.

As a result, the researchers turned their attention to copeptin, a more stable, more reliable surrogate marker for vasopressin. Copeptin has been shown previously to be a predictor of outcomes in somatic diseases and is also increased during psychological distress.

To measure the utility of copeptin in predicting psychotic relapse, the researchers conducted a prospective, explorative, single-center observational study involving inpatients with an acute psychotic episode diagnosed with schizophrenia spectrum disorder or affective disorder.

Baseline characteristics were collected and fasting serum copeptin levels were measured. Disease severity was measured using a range of validated assessment scales.
 

Predictive factor

Among 69 patients available for analysis, 30 experienced psychotic relapse at 1-year follow-up. Relapse was defined as rehospitalization because of an acute psychotic episode.

There were no differences in baseline demographic characteristics between patients with, and without, psychotic relapse. There were also no differences in baseline psychopathology, including scores on the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Global Assessment of Function.

Dr. Küster noted that there were no overall differences between patients with and without psychotic relapse in terms of their plasma copeptin or cortisol levels at baseline.

“The only difference we saw was in diagnosis,” she reported. Patients with psychotic relapse were significantly more likely to have comorbid drug abuse – 43% in patients who relapsed versus 15% of those who did not (P = .02).

However, when the investigators calculated the area under the receiver operating characteristics curve for copeptin levels, they found there was a significant difference in relapse rates in those with copeptin levels >6 pmol/L vs. those with lower levels (hazard ratio, 2.3; P = .039).

When the focus was on only patients with schizophrenia spectrum disorder, the results were even more pronounced. The HR for psychotic relapse in patients with higher vs. lower copeptin levels was 3.2 (P = .028).

“We also looked for other possible predicting factors,” Dr. Küster said. This included sex, age, duration of disease, reason for hospitalization, psychopathology, medication, comorbidities, and cortisol levels. “But none of these factors was associated with psychotic relapse,” she added.

The only factor positively associated with relapse was drug abuse, primarily via marijuana. However, the association with copeptin remained significant even after taking this factor into account.

In future studies, the researchers plan to examine whether copeptin levels could identify which patients at ultra-high risk will transition to first-episode psychosis, as well as to predict development of posttraumatic stress disorder, Dr. Küster said.
 

A proxy for ‘something simpler’?

Commenting on the findings for this news organization, Leah H. Rubin, PhD, associate professor of neurology, Johns Hopkins University, Baltimore, described the study as “interesting” – and noted that her own research has included measuring vasopressin in patients with untreated first-episode psychosis.

Dr. Rubin’s findings showed that levels of the hormone were associated with psychosis severity, and thus she is “not surprised that they found a marker” that may be promising in psychosis relapse prediction.

However, she took issue with the notion that vasopressin is an unreliable marker, pointing out that the work of her team demonstrates that it can be measured. Dr. Rubin added that she found it to be “pretty stable.”

In addition, because the current study had a small sample size, Dr. Rubin said she would be interested to see whether the findings can be replicated on a larger scale.

She also noted that more than two-thirds of the study population were men. “Vasopressin and oxytocin are sexually dimorphic neuropeptides,” she explained, “so I think it becomes important to ensure ... whether it’s the same for men and women.”

“Just from a psychosocial perspective, what’s going on in those folks’ lives?” Dr. Rubin asked. “Is it truly copeptin” or is it high stress levels that facilitate a relapse? Copeptin levels, she added, may be “a proxy for something simpler.”

The study authors and Dr. Rubin have disclosed no relevant financial relationships.

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

Copeptin, a small peptide secreted with the hormone vasopressin, appears to be one of the first promising biomarkers for predicting psychosis relapse, results of an observational study suggest.

An analysis of plasma copeptin levels in patients with schizophrenia showed those with high plasma levels of the peptide were about three times more likely to experience psychotic relapse, compared with their counterparts with lower levels.

The results suggest, “copeptin could be a promising biomarker in predicting psychotic relapse in schizophrenia spectrum disorder,” said study investigator Jennifer Küster, MD, University Psychiatric Clinics Basel (Switzerland). Measuring copeptin levels upon hospital admission “could help to intensify” the care of at-risk patients, she added.

The findings were presented at the virtual Congress of the Schizophrenia International Research Society 2021.
 

Relapse prevention important

Two-thirds of patients with schizophrenia experience at least one relapse of a psychotic episode, which in turn increases the risk of the disorder having a chronic course, Dr. Küster noted.

In addition, a psychotic relapse is associated with deterioration of function and cognition and reduced treatment response, “so relapse prevention is important,” she said.

Previous research has explored various methods of predicting schizophrenia outcomes. These include measuring inflammatory markers, catecholamines, oxytocin, and cortisol in combination with imaging markers, “but so far no reliable biomarker has been found,” Dr. Küster said.

She noted that psychotic relapse is associated with increased psychological stress – and vasopressin, which is secreted by the pituitary gland, is a known marker of stress. It is involved in sodium homeostasis and higher brain function and is also elevated in acute psychosis.

However, vasopressin “is challenging to measure because assays are complicated and unreliable,” Dr. Küster said.

As a result, the researchers turned their attention to copeptin, a more stable, more reliable surrogate marker for vasopressin. Copeptin has been shown previously to be a predictor of outcomes in somatic diseases and is also increased during psychological distress.

To measure the utility of copeptin in predicting psychotic relapse, the researchers conducted a prospective, explorative, single-center observational study involving inpatients with an acute psychotic episode diagnosed with schizophrenia spectrum disorder or affective disorder.

Baseline characteristics were collected and fasting serum copeptin levels were measured. Disease severity was measured using a range of validated assessment scales.
 

Predictive factor

Among 69 patients available for analysis, 30 experienced psychotic relapse at 1-year follow-up. Relapse was defined as rehospitalization because of an acute psychotic episode.

There were no differences in baseline demographic characteristics between patients with, and without, psychotic relapse. There were also no differences in baseline psychopathology, including scores on the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Global Assessment of Function.

Dr. Küster noted that there were no overall differences between patients with and without psychotic relapse in terms of their plasma copeptin or cortisol levels at baseline.

“The only difference we saw was in diagnosis,” she reported. Patients with psychotic relapse were significantly more likely to have comorbid drug abuse – 43% in patients who relapsed versus 15% of those who did not (P = .02).

However, when the investigators calculated the area under the receiver operating characteristics curve for copeptin levels, they found there was a significant difference in relapse rates in those with copeptin levels >6 pmol/L vs. those with lower levels (hazard ratio, 2.3; P = .039).

When the focus was on only patients with schizophrenia spectrum disorder, the results were even more pronounced. The HR for psychotic relapse in patients with higher vs. lower copeptin levels was 3.2 (P = .028).

“We also looked for other possible predicting factors,” Dr. Küster said. This included sex, age, duration of disease, reason for hospitalization, psychopathology, medication, comorbidities, and cortisol levels. “But none of these factors was associated with psychotic relapse,” she added.

The only factor positively associated with relapse was drug abuse, primarily via marijuana. However, the association with copeptin remained significant even after taking this factor into account.

In future studies, the researchers plan to examine whether copeptin levels could identify which patients at ultra-high risk will transition to first-episode psychosis, as well as to predict development of posttraumatic stress disorder, Dr. Küster said.
 

A proxy for ‘something simpler’?

Commenting on the findings for this news organization, Leah H. Rubin, PhD, associate professor of neurology, Johns Hopkins University, Baltimore, described the study as “interesting” – and noted that her own research has included measuring vasopressin in patients with untreated first-episode psychosis.

Dr. Rubin’s findings showed that levels of the hormone were associated with psychosis severity, and thus she is “not surprised that they found a marker” that may be promising in psychosis relapse prediction.

However, she took issue with the notion that vasopressin is an unreliable marker, pointing out that the work of her team demonstrates that it can be measured. Dr. Rubin added that she found it to be “pretty stable.”

In addition, because the current study had a small sample size, Dr. Rubin said she would be interested to see whether the findings can be replicated on a larger scale.

She also noted that more than two-thirds of the study population were men. “Vasopressin and oxytocin are sexually dimorphic neuropeptides,” she explained, “so I think it becomes important to ensure ... whether it’s the same for men and women.”

“Just from a psychosocial perspective, what’s going on in those folks’ lives?” Dr. Rubin asked. “Is it truly copeptin” or is it high stress levels that facilitate a relapse? Copeptin levels, she added, may be “a proxy for something simpler.”

The study authors and Dr. Rubin have disclosed no relevant financial relationships.

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

Motor problems in children may be a harbinger of serious mental illness, new research suggests.

Investigators found that motor abnormalities were twice as common among those who develop psychosis or depression, compared with their counterparts in the general population, suggesting that these abnormalities may help predict vulnerability and provide an opportunity for early intervention.

“We have learned there are motor signs that are measurable in adolescence [that are] more prevalent in these disorders,” said lead investigator Katherine S. F. Damme, PhD, adolescent development and preventive treatment program (ADAPT), Northwestern University, Chicago. 

A core symptom

There has been a lot of interest in the pathophysiology of psychosis and in detecting it early, said Dr. Damme. “It has devastating effects, and early intervention is of great importance,” she added.

However, previous research has typically focused on affect or cognition, rather than on motor signs, despite the fact that motor signs are a “core symptom of both psychosis and depression.”

The prevalence and presentation of motor signs in adolescence, which is a “critical time for identifying these risk markers” because of their proximity to the onset of psychosis, has been understudied, Dr. Damme said.

For their study, the investigators gathered motor function data from the Adolescent Brain Cognitive Development Study (ABCD), which included 10,835 children aged 9-11 years with broad demographic diversity from 21 sites across the United States.

Overall, 27.6% of the children were reported to have least one motor sign; approximately 3% were reported to have two or more motor signs.

The most common of these was dyscoordination, which was endorsed by 19.3% of participants. In addition, 8.8% were reported to have had experienced developmental motor delays, 1.5% had psychomotor agitation, and 0.3% had psychomotor retardation.

The investigators determined that 4.6% of participants met criteria for depression, 2.6% for a psychosis, and 1.8% for comorbid psychosis and depression.

Motor signs were much more common among children with depression, psychosis, or both than among those who did not have these conditions; 45.8% reported having at least one motor sign.

Developmental motor delays and dyscoordination occurred at about the same rate in both patients with depression and those with psychosis. Rates were higher among patients with both of these conditions than among those with either condition alone.

In contrast, psychomotor agitation was more common among patients with depression alone and among those with comorbid depression and psychosis than among patients with psychosis alone. The rate of psychomotor retardation was increased among patients with psychosis alone but was less common among patients with comorbidity than in the healthy control group.

Familial vulnerability

The investigators also assessed participants who had not been diagnosed with a mental illness but who had a family history of depression only (28.9%), a relative with psychosis-like experiences (0.6%), or a family history of both depression and psychosis experiences (1.8%).

Although the effect size was smaller, there was a higher rate of motor signs among participants with a family history of these conditions, Dr. Damme said. “Again, we see that it’s elevated across developmental motor delays and at a similar rate in people who have depression and psychosis.”

In addition, psychomotor agitation was linked to depression with psychosis and depression without it.

Sensorimotor connectivity network data for the cohort indicated there was no main effect of diagnosis on corticostriatal connectivity.

However, more depressive symptoms were related to less connectivity (P = .024). There was a similar finding for psychotic-like experiences. The total number of such experiences related to lower connectivity (P < .001).

During the postpresentation discussion, Ian Kelleher, MD, PhD, honorary clinical lecturer in psychiatry at the Royal College of Surgeons in Ireland, Dublin, said he was “surprised” by the finding that the rate of psychomotor retardation was lower among participants with psychosis and depression.

Dr. Damme noted that some of the motor sign item ratings came by way of a child interview and that some of these item ratings came from the adults in the children’s lives.

She added that she was not entirely sure whether asking an 8- to 11-year-old in a clinical interview whether they are experiencing motor signs “might be the best way to get at motor slowing.”

Subtle features

Commenting on the findings in an interview, Peter F. Liddle, MD, PhD, professor of psychiatry, at the University of Nottingham (England), noted that the “features we’re talking about are pretty subtle.

“What I’ve been wondering about for some time is whether we should be getting video recordings and using machine learning approaches to teach a computer to recognize normal movements vs abnormal movements, and particularly facial expression,” said Dr. Liddle, who was not involved with the research.

He called the current study “interesting” but noted several factors that affect the potential utility of the findings in predicting outcomes.

First, they “may not be very good for distinguishing schizophrenia from mood disorders; but if the question is simply determining which young person might go on to develop a significant mental disorder, then it may be useful,” Dr. Liddle said.

He endorsed the investigators’ conclusion that motor abnormalities may be a transdiagnostic marker. Beyond that, they may be “more useful as a predictor of the likely long-term severity, but that’s my own hypothesis based on my work,” he added.

Another question concerns the sensitivity of motor abnormalities as a predictive marker. With the rate of the abnormalities identified in those who developed psychosis and depression about double the rate in the overall population, “it sounds like those assessors were fairly sensitive. … but not all that specific,” said Dr. Liddle.

A third issue relates to treatment. “By the time people get sent to a psychiatrist for assessment for possible impending psychotic illness, they’ve often already had medication,” typically an antidepressant or antipsychotic.

“It’s very well established that dopamine-blocking antipsychotics produce hypokinesia and also dyskinesia,” which could then become a confounding factor, Dr. Liddle said.

The study was funded by grants from the National Institute of Mental Health. The study authors and Dr. Liddle have disclosed no relevant financial relationships.

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

Motor problems in children may be a harbinger of serious mental illness, new research suggests.

Investigators found that motor abnormalities were twice as common among those who develop psychosis or depression, compared with their counterparts in the general population, suggesting that these abnormalities may help predict vulnerability and provide an opportunity for early intervention.

“We have learned there are motor signs that are measurable in adolescence [that are] more prevalent in these disorders,” said lead investigator Katherine S. F. Damme, PhD, adolescent development and preventive treatment program (ADAPT), Northwestern University, Chicago. 

A core symptom

There has been a lot of interest in the pathophysiology of psychosis and in detecting it early, said Dr. Damme. “It has devastating effects, and early intervention is of great importance,” she added.

However, previous research has typically focused on affect or cognition, rather than on motor signs, despite the fact that motor signs are a “core symptom of both psychosis and depression.”

The prevalence and presentation of motor signs in adolescence, which is a “critical time for identifying these risk markers” because of their proximity to the onset of psychosis, has been understudied, Dr. Damme said.

For their study, the investigators gathered motor function data from the Adolescent Brain Cognitive Development Study (ABCD), which included 10,835 children aged 9-11 years with broad demographic diversity from 21 sites across the United States.

Overall, 27.6% of the children were reported to have least one motor sign; approximately 3% were reported to have two or more motor signs.

The most common of these was dyscoordination, which was endorsed by 19.3% of participants. In addition, 8.8% were reported to have had experienced developmental motor delays, 1.5% had psychomotor agitation, and 0.3% had psychomotor retardation.

The investigators determined that 4.6% of participants met criteria for depression, 2.6% for a psychosis, and 1.8% for comorbid psychosis and depression.

Motor signs were much more common among children with depression, psychosis, or both than among those who did not have these conditions; 45.8% reported having at least one motor sign.

Developmental motor delays and dyscoordination occurred at about the same rate in both patients with depression and those with psychosis. Rates were higher among patients with both of these conditions than among those with either condition alone.

In contrast, psychomotor agitation was more common among patients with depression alone and among those with comorbid depression and psychosis than among patients with psychosis alone. The rate of psychomotor retardation was increased among patients with psychosis alone but was less common among patients with comorbidity than in the healthy control group.

Familial vulnerability

The investigators also assessed participants who had not been diagnosed with a mental illness but who had a family history of depression only (28.9%), a relative with psychosis-like experiences (0.6%), or a family history of both depression and psychosis experiences (1.8%).

Although the effect size was smaller, there was a higher rate of motor signs among participants with a family history of these conditions, Dr. Damme said. “Again, we see that it’s elevated across developmental motor delays and at a similar rate in people who have depression and psychosis.”

In addition, psychomotor agitation was linked to depression with psychosis and depression without it.

Sensorimotor connectivity network data for the cohort indicated there was no main effect of diagnosis on corticostriatal connectivity.

However, more depressive symptoms were related to less connectivity (P = .024). There was a similar finding for psychotic-like experiences. The total number of such experiences related to lower connectivity (P < .001).

During the postpresentation discussion, Ian Kelleher, MD, PhD, honorary clinical lecturer in psychiatry at the Royal College of Surgeons in Ireland, Dublin, said he was “surprised” by the finding that the rate of psychomotor retardation was lower among participants with psychosis and depression.

Dr. Damme noted that some of the motor sign item ratings came by way of a child interview and that some of these item ratings came from the adults in the children’s lives.

She added that she was not entirely sure whether asking an 8- to 11-year-old in a clinical interview whether they are experiencing motor signs “might be the best way to get at motor slowing.”

Subtle features

Commenting on the findings in an interview, Peter F. Liddle, MD, PhD, professor of psychiatry, at the University of Nottingham (England), noted that the “features we’re talking about are pretty subtle.

“What I’ve been wondering about for some time is whether we should be getting video recordings and using machine learning approaches to teach a computer to recognize normal movements vs abnormal movements, and particularly facial expression,” said Dr. Liddle, who was not involved with the research.

He called the current study “interesting” but noted several factors that affect the potential utility of the findings in predicting outcomes.

First, they “may not be very good for distinguishing schizophrenia from mood disorders; but if the question is simply determining which young person might go on to develop a significant mental disorder, then it may be useful,” Dr. Liddle said.

He endorsed the investigators’ conclusion that motor abnormalities may be a transdiagnostic marker. Beyond that, they may be “more useful as a predictor of the likely long-term severity, but that’s my own hypothesis based on my work,” he added.

Another question concerns the sensitivity of motor abnormalities as a predictive marker. With the rate of the abnormalities identified in those who developed psychosis and depression about double the rate in the overall population, “it sounds like those assessors were fairly sensitive. … but not all that specific,” said Dr. Liddle.

A third issue relates to treatment. “By the time people get sent to a psychiatrist for assessment for possible impending psychotic illness, they’ve often already had medication,” typically an antidepressant or antipsychotic.

“It’s very well established that dopamine-blocking antipsychotics produce hypokinesia and also dyskinesia,” which could then become a confounding factor, Dr. Liddle said.

The study was funded by grants from the National Institute of Mental Health. The study authors and Dr. Liddle have disclosed no relevant financial relationships.

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

Motor problems in children may be a harbinger of serious mental illness, new research suggests.

Investigators found that motor abnormalities were twice as common among those who develop psychosis or depression, compared with their counterparts in the general population, suggesting that these abnormalities may help predict vulnerability and provide an opportunity for early intervention.

“We have learned there are motor signs that are measurable in adolescence [that are] more prevalent in these disorders,” said lead investigator Katherine S. F. Damme, PhD, adolescent development and preventive treatment program (ADAPT), Northwestern University, Chicago. 

A core symptom

There has been a lot of interest in the pathophysiology of psychosis and in detecting it early, said Dr. Damme. “It has devastating effects, and early intervention is of great importance,” she added.

However, previous research has typically focused on affect or cognition, rather than on motor signs, despite the fact that motor signs are a “core symptom of both psychosis and depression.”

The prevalence and presentation of motor signs in adolescence, which is a “critical time for identifying these risk markers” because of their proximity to the onset of psychosis, has been understudied, Dr. Damme said.

For their study, the investigators gathered motor function data from the Adolescent Brain Cognitive Development Study (ABCD), which included 10,835 children aged 9-11 years with broad demographic diversity from 21 sites across the United States.

Overall, 27.6% of the children were reported to have least one motor sign; approximately 3% were reported to have two or more motor signs.

The most common of these was dyscoordination, which was endorsed by 19.3% of participants. In addition, 8.8% were reported to have had experienced developmental motor delays, 1.5% had psychomotor agitation, and 0.3% had psychomotor retardation.

The investigators determined that 4.6% of participants met criteria for depression, 2.6% for a psychosis, and 1.8% for comorbid psychosis and depression.

Motor signs were much more common among children with depression, psychosis, or both than among those who did not have these conditions; 45.8% reported having at least one motor sign.

Developmental motor delays and dyscoordination occurred at about the same rate in both patients with depression and those with psychosis. Rates were higher among patients with both of these conditions than among those with either condition alone.

In contrast, psychomotor agitation was more common among patients with depression alone and among those with comorbid depression and psychosis than among patients with psychosis alone. The rate of psychomotor retardation was increased among patients with psychosis alone but was less common among patients with comorbidity than in the healthy control group.

Familial vulnerability

The investigators also assessed participants who had not been diagnosed with a mental illness but who had a family history of depression only (28.9%), a relative with psychosis-like experiences (0.6%), or a family history of both depression and psychosis experiences (1.8%).

Although the effect size was smaller, there was a higher rate of motor signs among participants with a family history of these conditions, Dr. Damme said. “Again, we see that it’s elevated across developmental motor delays and at a similar rate in people who have depression and psychosis.”

In addition, psychomotor agitation was linked to depression with psychosis and depression without it.

Sensorimotor connectivity network data for the cohort indicated there was no main effect of diagnosis on corticostriatal connectivity.

However, more depressive symptoms were related to less connectivity (P = .024). There was a similar finding for psychotic-like experiences. The total number of such experiences related to lower connectivity (P < .001).

During the postpresentation discussion, Ian Kelleher, MD, PhD, honorary clinical lecturer in psychiatry at the Royal College of Surgeons in Ireland, Dublin, said he was “surprised” by the finding that the rate of psychomotor retardation was lower among participants with psychosis and depression.

Dr. Damme noted that some of the motor sign item ratings came by way of a child interview and that some of these item ratings came from the adults in the children’s lives.

She added that she was not entirely sure whether asking an 8- to 11-year-old in a clinical interview whether they are experiencing motor signs “might be the best way to get at motor slowing.”

Subtle features

Commenting on the findings in an interview, Peter F. Liddle, MD, PhD, professor of psychiatry, at the University of Nottingham (England), noted that the “features we’re talking about are pretty subtle.

“What I’ve been wondering about for some time is whether we should be getting video recordings and using machine learning approaches to teach a computer to recognize normal movements vs abnormal movements, and particularly facial expression,” said Dr. Liddle, who was not involved with the research.

He called the current study “interesting” but noted several factors that affect the potential utility of the findings in predicting outcomes.

First, they “may not be very good for distinguishing schizophrenia from mood disorders; but if the question is simply determining which young person might go on to develop a significant mental disorder, then it may be useful,” Dr. Liddle said.

He endorsed the investigators’ conclusion that motor abnormalities may be a transdiagnostic marker. Beyond that, they may be “more useful as a predictor of the likely long-term severity, but that’s my own hypothesis based on my work,” he added.

Another question concerns the sensitivity of motor abnormalities as a predictive marker. With the rate of the abnormalities identified in those who developed psychosis and depression about double the rate in the overall population, “it sounds like those assessors were fairly sensitive. … but not all that specific,” said Dr. Liddle.

A third issue relates to treatment. “By the time people get sent to a psychiatrist for assessment for possible impending psychotic illness, they’ve often already had medication,” typically an antidepressant or antipsychotic.

“It’s very well established that dopamine-blocking antipsychotics produce hypokinesia and also dyskinesia,” which could then become a confounding factor, Dr. Liddle said.

The study was funded by grants from the National Institute of Mental Health. The study authors and Dr. Liddle have disclosed no relevant financial relationships.

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

Social and economic disparities are linked to an increased risk for psychosis in Black and Latino communities, new research shows.

Results of a literature review of social and economic disparities in mental illness suggest that “structural racism” contributes to social and environmental conditions that affect psychosis risk.

“Black and Latino people suffer disproportionately from psychosis risk factors, at the neighborhood level and at the individual level, in large part as a result of structural racism,” study investigator Deidre M. Anglin, PhD, associate professor, department of psychology, City College of New York (N.Y.), told reporters attending a press briefing.

The social environment, which, for minorities, involves disadvantage and discrimination, may account for this increased psychosis risk, perhaps even more so than genetics, she said. Structural racism “is a critical public health threat,” Dr. Anglin added.

The findings were presented at the virtual American Psychiatric Association annual meeting and were simultaneously published online May 3 in The American Journal of Psychiatry.
 

Perpetual disadvantage

Dr. Anglin and colleagues examined U.S.-based evidence connecting characteristics of social environments with outcomes across the psychosis continuum – from psychotic experiences to schizophrenia.

Citing numerous studies, the researchers highlighted three key areas that reflect social and environmental conditions that may affect psychosis risk, and that disproportionately affect minorities. These were neighborhood factors, trauma in a U.S. context, and racial disparities during the prenatal and perinatal periods.

The data that were related to neighborhoods revealed “just how much racism has historically structured U.S. neighborhoods in ways that generationally perpetuate disadvantage for racially minoritized communities,” said Dr. Anglin.

“This happens through inequitable access to resources, such as health care, clean air, education, [and] employment, but also in terms of disproportionate exposure to environmental toxins and stressors,” she said.

These neighborhood factors are associated with cumulative stress that may be linked to heightened risk for psychosis, the investigators noted.

U.S. studies show that rates of adverse childhood experiences, such as abuse and emotional and physical neglect, are higher among racial and ethnic minorities.

Police victimization and gun violence disproportionately affect racial minorities and create what the investigators call “a unique type of collective trauma” in the United States. They note that Black men have a 1 in 1,000 chance of being victims of lethal force by police over their lifetimes. By comparison, White men have a 39 in 100,000 chance.

One study of a diverse sample from four large U.S. urban centers showed that those who self-reported different types of police victimization were more likely to report psychotic experiences. Another study showed that greater exposure to gun violence fatalities, regardless of police involvement, was positively associated with psychotic experiences.
 

Obstetric complications

A variety of obstetric complications, including infection, maternal inflammation, and stress, have been associated with increased risk for psychotic disorders in U.S. samples.

“What we saw emerge from the literature is that Black women in the U.S. are at substantially increased risk for many of these obstetrical complications compared to White women, and this is not necessarily explained by socioeconomic status,” said Dr. Anglin.

Neighborhood- and individual-level factors appear to affect the disparity in these outcomes. A recent study revealed that exposure to environmental contaminants such as air pollution is associated with higher rates of preterm birth and low birth weight differentially in Black mothers compared with other mothers, “possibly as a result of an interaction between prenatal stress and contaminants,” the investigators noted.

Research also indicates that Black women are more likely to have lower levels of cortisol during the second trimester of pregnancy compared with women of other racial and ethnic groups. Cortisol is essential for fetal growth. Evidence links lower cortisol levels in later stages of pregnancy with decreased fetal growth in individuals who develop schizophrenia.

Black women have higher levels of certain stress biomarkers, including inflammatory C-reactive protein and adrenocorticotropic hormone, in mid- to late pregnancy, compared with White women of the same socioeconomic status.

Such findings “highlight a complex picture” involving maternal cortisol levels and other stress biomarkers, “potentially leading to poor birth outcomes and subsequent risk for psychotic disorders in adulthood,” the investigators noted.

The researchers call for the dismantling of structural racism and the social policies and norms it shapes. They also recommend changes in health care policy and in the approach to early intervention for psychosis among Black and other racially-minoritized groups.

“Altogether, the current evidence suggests the need to identify, address, and tackle the social determinants deeply ingrained in U.S. society, in tandem with empowering the most marginalized communities,” the researchers wrote.

“We recommend that the field of psychiatry devote considerably more effort to addressing structural racism and social determinants of psychosis in funding priorities, training, and intervention development,” they added.

Dr. Anglin suggests that mental health providers use what she called a “cultural formulation interview” that takes a person’s environmental and social context into consideration. Studies show that incorporating this into clinical practice helps reduce misdiagnosis of mental illness in Black populations, she said.
 

Call to action

Commenting on the findings in an interview, Ned H. Kalin, MD, editor of The American Journal of Psychiatry and professor and chair of the department of psychiatry, University of Wisconsin, Madison, said the study was well done and serves as a “call to action” to address the impact of structural racism on mental health issues and psychiatric diseases.

The article highlights the need for “collecting better data” on structural racism, said Dr. Kalin. “We know it’s a big issue, but we can’t even quantitate it, so we need some fundamental measures to use as a benchmark as we move forward, as we try to make change.”

He noted that racism “is so embedded in one’s experience and in our society that we sort of don’t even think about it as a trauma.”

In psychiatry, for example, trauma is often thought of as a loss or a traumatic event. “We don’t typically think of trauma as an experience that pervades one’s entire life,” but that needs to change, he said. “At the individual level and in the doctor’s office, being sensitive to and aware of these issues is absolutely critical.”

Dr. Anglin and Dr. Kalin have disclosed no relevant financial relationships.

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

Social and economic disparities are linked to an increased risk for psychosis in Black and Latino communities, new research shows.

Results of a literature review of social and economic disparities in mental illness suggest that “structural racism” contributes to social and environmental conditions that affect psychosis risk.

“Black and Latino people suffer disproportionately from psychosis risk factors, at the neighborhood level and at the individual level, in large part as a result of structural racism,” study investigator Deidre M. Anglin, PhD, associate professor, department of psychology, City College of New York (N.Y.), told reporters attending a press briefing.

The social environment, which, for minorities, involves disadvantage and discrimination, may account for this increased psychosis risk, perhaps even more so than genetics, she said. Structural racism “is a critical public health threat,” Dr. Anglin added.

The findings were presented at the virtual American Psychiatric Association annual meeting and were simultaneously published online May 3 in The American Journal of Psychiatry.
 

Perpetual disadvantage

Dr. Anglin and colleagues examined U.S.-based evidence connecting characteristics of social environments with outcomes across the psychosis continuum – from psychotic experiences to schizophrenia.

Citing numerous studies, the researchers highlighted three key areas that reflect social and environmental conditions that may affect psychosis risk, and that disproportionately affect minorities. These were neighborhood factors, trauma in a U.S. context, and racial disparities during the prenatal and perinatal periods.

The data that were related to neighborhoods revealed “just how much racism has historically structured U.S. neighborhoods in ways that generationally perpetuate disadvantage for racially minoritized communities,” said Dr. Anglin.

“This happens through inequitable access to resources, such as health care, clean air, education, [and] employment, but also in terms of disproportionate exposure to environmental toxins and stressors,” she said.

These neighborhood factors are associated with cumulative stress that may be linked to heightened risk for psychosis, the investigators noted.

U.S. studies show that rates of adverse childhood experiences, such as abuse and emotional and physical neglect, are higher among racial and ethnic minorities.

Police victimization and gun violence disproportionately affect racial minorities and create what the investigators call “a unique type of collective trauma” in the United States. They note that Black men have a 1 in 1,000 chance of being victims of lethal force by police over their lifetimes. By comparison, White men have a 39 in 100,000 chance.

One study of a diverse sample from four large U.S. urban centers showed that those who self-reported different types of police victimization were more likely to report psychotic experiences. Another study showed that greater exposure to gun violence fatalities, regardless of police involvement, was positively associated with psychotic experiences.
 

Obstetric complications

A variety of obstetric complications, including infection, maternal inflammation, and stress, have been associated with increased risk for psychotic disorders in U.S. samples.

“What we saw emerge from the literature is that Black women in the U.S. are at substantially increased risk for many of these obstetrical complications compared to White women, and this is not necessarily explained by socioeconomic status,” said Dr. Anglin.

Neighborhood- and individual-level factors appear to affect the disparity in these outcomes. A recent study revealed that exposure to environmental contaminants such as air pollution is associated with higher rates of preterm birth and low birth weight differentially in Black mothers compared with other mothers, “possibly as a result of an interaction between prenatal stress and contaminants,” the investigators noted.

Research also indicates that Black women are more likely to have lower levels of cortisol during the second trimester of pregnancy compared with women of other racial and ethnic groups. Cortisol is essential for fetal growth. Evidence links lower cortisol levels in later stages of pregnancy with decreased fetal growth in individuals who develop schizophrenia.

Black women have higher levels of certain stress biomarkers, including inflammatory C-reactive protein and adrenocorticotropic hormone, in mid- to late pregnancy, compared with White women of the same socioeconomic status.

Such findings “highlight a complex picture” involving maternal cortisol levels and other stress biomarkers, “potentially leading to poor birth outcomes and subsequent risk for psychotic disorders in adulthood,” the investigators noted.

The researchers call for the dismantling of structural racism and the social policies and norms it shapes. They also recommend changes in health care policy and in the approach to early intervention for psychosis among Black and other racially-minoritized groups.

“Altogether, the current evidence suggests the need to identify, address, and tackle the social determinants deeply ingrained in U.S. society, in tandem with empowering the most marginalized communities,” the researchers wrote.

“We recommend that the field of psychiatry devote considerably more effort to addressing structural racism and social determinants of psychosis in funding priorities, training, and intervention development,” they added.

Dr. Anglin suggests that mental health providers use what she called a “cultural formulation interview” that takes a person’s environmental and social context into consideration. Studies show that incorporating this into clinical practice helps reduce misdiagnosis of mental illness in Black populations, she said.
 

Call to action

Commenting on the findings in an interview, Ned H. Kalin, MD, editor of The American Journal of Psychiatry and professor and chair of the department of psychiatry, University of Wisconsin, Madison, said the study was well done and serves as a “call to action” to address the impact of structural racism on mental health issues and psychiatric diseases.

The article highlights the need for “collecting better data” on structural racism, said Dr. Kalin. “We know it’s a big issue, but we can’t even quantitate it, so we need some fundamental measures to use as a benchmark as we move forward, as we try to make change.”

He noted that racism “is so embedded in one’s experience and in our society that we sort of don’t even think about it as a trauma.”

In psychiatry, for example, trauma is often thought of as a loss or a traumatic event. “We don’t typically think of trauma as an experience that pervades one’s entire life,” but that needs to change, he said. “At the individual level and in the doctor’s office, being sensitive to and aware of these issues is absolutely critical.”

Dr. Anglin and Dr. Kalin have disclosed no relevant financial relationships.

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

Social and economic disparities are linked to an increased risk for psychosis in Black and Latino communities, new research shows.

Results of a literature review of social and economic disparities in mental illness suggest that “structural racism” contributes to social and environmental conditions that affect psychosis risk.

“Black and Latino people suffer disproportionately from psychosis risk factors, at the neighborhood level and at the individual level, in large part as a result of structural racism,” study investigator Deidre M. Anglin, PhD, associate professor, department of psychology, City College of New York (N.Y.), told reporters attending a press briefing.

The social environment, which, for minorities, involves disadvantage and discrimination, may account for this increased psychosis risk, perhaps even more so than genetics, she said. Structural racism “is a critical public health threat,” Dr. Anglin added.

The findings were presented at the virtual American Psychiatric Association annual meeting and were simultaneously published online May 3 in The American Journal of Psychiatry.
 

Perpetual disadvantage

Dr. Anglin and colleagues examined U.S.-based evidence connecting characteristics of social environments with outcomes across the psychosis continuum – from psychotic experiences to schizophrenia.

Citing numerous studies, the researchers highlighted three key areas that reflect social and environmental conditions that may affect psychosis risk, and that disproportionately affect minorities. These were neighborhood factors, trauma in a U.S. context, and racial disparities during the prenatal and perinatal periods.

The data that were related to neighborhoods revealed “just how much racism has historically structured U.S. neighborhoods in ways that generationally perpetuate disadvantage for racially minoritized communities,” said Dr. Anglin.

“This happens through inequitable access to resources, such as health care, clean air, education, [and] employment, but also in terms of disproportionate exposure to environmental toxins and stressors,” she said.

These neighborhood factors are associated with cumulative stress that may be linked to heightened risk for psychosis, the investigators noted.

U.S. studies show that rates of adverse childhood experiences, such as abuse and emotional and physical neglect, are higher among racial and ethnic minorities.

Police victimization and gun violence disproportionately affect racial minorities and create what the investigators call “a unique type of collective trauma” in the United States. They note that Black men have a 1 in 1,000 chance of being victims of lethal force by police over their lifetimes. By comparison, White men have a 39 in 100,000 chance.

One study of a diverse sample from four large U.S. urban centers showed that those who self-reported different types of police victimization were more likely to report psychotic experiences. Another study showed that greater exposure to gun violence fatalities, regardless of police involvement, was positively associated with psychotic experiences.
 

Obstetric complications

A variety of obstetric complications, including infection, maternal inflammation, and stress, have been associated with increased risk for psychotic disorders in U.S. samples.

“What we saw emerge from the literature is that Black women in the U.S. are at substantially increased risk for many of these obstetrical complications compared to White women, and this is not necessarily explained by socioeconomic status,” said Dr. Anglin.

Neighborhood- and individual-level factors appear to affect the disparity in these outcomes. A recent study revealed that exposure to environmental contaminants such as air pollution is associated with higher rates of preterm birth and low birth weight differentially in Black mothers compared with other mothers, “possibly as a result of an interaction between prenatal stress and contaminants,” the investigators noted.

Research also indicates that Black women are more likely to have lower levels of cortisol during the second trimester of pregnancy compared with women of other racial and ethnic groups. Cortisol is essential for fetal growth. Evidence links lower cortisol levels in later stages of pregnancy with decreased fetal growth in individuals who develop schizophrenia.

Black women have higher levels of certain stress biomarkers, including inflammatory C-reactive protein and adrenocorticotropic hormone, in mid- to late pregnancy, compared with White women of the same socioeconomic status.

Such findings “highlight a complex picture” involving maternal cortisol levels and other stress biomarkers, “potentially leading to poor birth outcomes and subsequent risk for psychotic disorders in adulthood,” the investigators noted.

The researchers call for the dismantling of structural racism and the social policies and norms it shapes. They also recommend changes in health care policy and in the approach to early intervention for psychosis among Black and other racially-minoritized groups.

“Altogether, the current evidence suggests the need to identify, address, and tackle the social determinants deeply ingrained in U.S. society, in tandem with empowering the most marginalized communities,” the researchers wrote.

“We recommend that the field of psychiatry devote considerably more effort to addressing structural racism and social determinants of psychosis in funding priorities, training, and intervention development,” they added.

Dr. Anglin suggests that mental health providers use what she called a “cultural formulation interview” that takes a person’s environmental and social context into consideration. Studies show that incorporating this into clinical practice helps reduce misdiagnosis of mental illness in Black populations, she said.
 

Call to action

Commenting on the findings in an interview, Ned H. Kalin, MD, editor of The American Journal of Psychiatry and professor and chair of the department of psychiatry, University of Wisconsin, Madison, said the study was well done and serves as a “call to action” to address the impact of structural racism on mental health issues and psychiatric diseases.

The article highlights the need for “collecting better data” on structural racism, said Dr. Kalin. “We know it’s a big issue, but we can’t even quantitate it, so we need some fundamental measures to use as a benchmark as we move forward, as we try to make change.”

He noted that racism “is so embedded in one’s experience and in our society that we sort of don’t even think about it as a trauma.”

In psychiatry, for example, trauma is often thought of as a loss or a traumatic event. “We don’t typically think of trauma as an experience that pervades one’s entire life,” but that needs to change, he said. “At the individual level and in the doctor’s office, being sensitive to and aware of these issues is absolutely critical.”

Dr. Anglin and Dr. Kalin have disclosed no relevant financial relationships.

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

An investigational, orally dissolving film formulation of dexmedetomidine (BXCL501, BioXcel Therapeutics) may offer rapid relief from acute agitation related to schizophrenia or bipolar disorder (BD), results of two phase 3, randomized, placebo-controlled trials show.
 

For both disorders, BXCL501 showed “superiority over placebo” by meeting the primary endpoint of reduction of agitation as measured by the excited component of the Positive and Negative Syndrome Scale (PANSS), study investigator Leslie Citrome, MD, MPH, department of psychiatry and behavioral sciences, New York Medical College, Valhalla, said in an interview.

The findings were presented at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.
 

Noninvasive option

Acute agitation in patients with schizophrenia or BD is often encountered in emergency departments (EDs) and inpatient units. When nondrug tactics fail to calm the patient, drug options include injectable antipsychotics or benzodiazepines. BXCL501 is a thin, orally dissolving film for sublingual or buccal use.

“Dexmedetomidine is a highly-selective alpha-2a receptor agonist and we haven’t really had one of those before in psychiatry for this purpose. And we haven’t had much in the way of orally dissolving thin films that are absorbed in the oral mucosa so this represents an opportunity to provide a potential intervention that does not require an injection and yet could possibly be of use in people who are agitated,” Dr. Citrome said.

The study, known as SERENITY I, included 380 adults (mean age 45.6 years, 63% male) with schizophrenia, schizoaffective disorder, or schizophreniform disorder, and acute agitation in the ED (total score ≥ 14 on the PANSS-Excited Component (PEC) scale at baseline and a score ≥ 4 on at least one of the five PEC items).

Patients were randomly allocated to a single oral dose of BXCL501: 120 mcg, 180 mcg, or placebo. A total of 372 patients (97.9%) completed the study.

Mean PEC total score was 17.6 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -8.5 and -10.3 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.8 for placebo (P < .0001 vs. placebo).

PEC response rates (≥ 40% reduction from baseline) were 80.6% and 89.6% with BXCL501 120 mcg and 180 mcg versus 47.6% with placebo (P < .0001 vs. placebo).

Compared with placebo, significant improvement in the Clinical Global Impression–Improvement scale (CGI-I) was observed with both BXCL501 doses at 1 and 2 hours after dosing and in the Agitation and Calmness Evaluation Scale (ACES) at 2 hours post dosing.

The incidence of adverse events (AE) was 39.5%, 37.3%, and 15.1% with BXCL501 120 mg, 180 mg, and placebo groups.

All AEs were mild or moderate. The most common AEs with BXCL501 were somnolence, dizziness, dry mouth, hypotension, orthostatic hypotension, hypoesthesia, and paresthesia. No drug-related severe or serious AEs occurred.
 

Nipping it in the bud

SERENITY II had a similar design. This study included 380 adults (mean age 48, 55% female) with bipolar I or II disorder and acute agitation in the ED (total score ≥14 on the PEC scale at baseline and a score ≥4 on at least one PEC item). A total of 362 (95.3%) of patients completed the study.

Mean PEC total score was 18 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -9.0 and -10.4 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.9 for placebo (P < .0001 vs. placebo).

Bipolar patients also saw significant improvement on the secondary outcomes of CGI-I and ACES, with an adverse event profile similar to that seen in patients with schizophrenia.

BXCL501 demonstrated “rapid, robust and clinically meaningful efficacy” in both patient populations and represents a “novel, noninvasive and well tolerated treatment of agitation,” the investigators concluded in their APA abstracts.

“Patients who are agitated are in psychic pain and they want relief from this psychic pain. We’re also worried that they might get worse and that agitation escalates to aggression potentially requiring restraints. We want to avoid that,” Dr. Citrome said.

“By nipping it in the bud with a pharmacological intervention, we can ease their psychic pain and we can manage a potentially dangerous situation. Offering an oral medicine that would work quickly would be ideal in my mind and patients might potentially be more accepting of that than an injection,” Dr. Citrome said.

Based on the SERENITY I and II data, BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration.
 

Negotiation first, medication second 

Reached for comment, Samoon Ahmad, MD, professor, department of psychiatry, New York (N.Y.) University, cautioned that, “when we talk about treating an agitated patient, medication is only part of the picture.

“There is a negotiating process with the patient. Number one, you offer them an environment that is conducive to making them feel calm, safe, and secure and that they are being listened to. Providing all of those things sometimes can be very helpful,” said Dr. Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York City.

“If someone starts throwing chairs at you or assaulting you, that is not really the time to negotiate a medicine; you basically have to restrain the patient, and many times give them intramuscular medicine,” Dr. Ahmad said.

He also noted that patients in the SERENITY trials had moderate to severe acute agitation.

“These are people you can potentially negotiate with. But again, when a patient crosses a certain line, you have to immediately do something and that could be intramuscular injection or something oral, which they may spit right in your face, which has happened numerous times,” Dr. Ahmad said.

“I don’t think intramuscular options will ever go away but an oral agent could be a useful tool as well,” said Dr. Ahmad, founder of the Integrative Center for Wellness in New York City.

He cautioned that clinicians are not going to be using this medicine in their offices. “If a patient walks in and is floridly psychotic, you will need to call 911. We’re really talking about its use either in the ED or acute inpatient setting,” Dr. Ahmad said.

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

An investigational, orally dissolving film formulation of dexmedetomidine (BXCL501, BioXcel Therapeutics) may offer rapid relief from acute agitation related to schizophrenia or bipolar disorder (BD), results of two phase 3, randomized, placebo-controlled trials show.
 

For both disorders, BXCL501 showed “superiority over placebo” by meeting the primary endpoint of reduction of agitation as measured by the excited component of the Positive and Negative Syndrome Scale (PANSS), study investigator Leslie Citrome, MD, MPH, department of psychiatry and behavioral sciences, New York Medical College, Valhalla, said in an interview.

The findings were presented at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.
 

Noninvasive option

Acute agitation in patients with schizophrenia or BD is often encountered in emergency departments (EDs) and inpatient units. When nondrug tactics fail to calm the patient, drug options include injectable antipsychotics or benzodiazepines. BXCL501 is a thin, orally dissolving film for sublingual or buccal use.

“Dexmedetomidine is a highly-selective alpha-2a receptor agonist and we haven’t really had one of those before in psychiatry for this purpose. And we haven’t had much in the way of orally dissolving thin films that are absorbed in the oral mucosa so this represents an opportunity to provide a potential intervention that does not require an injection and yet could possibly be of use in people who are agitated,” Dr. Citrome said.

The study, known as SERENITY I, included 380 adults (mean age 45.6 years, 63% male) with schizophrenia, schizoaffective disorder, or schizophreniform disorder, and acute agitation in the ED (total score ≥ 14 on the PANSS-Excited Component (PEC) scale at baseline and a score ≥ 4 on at least one of the five PEC items).

Patients were randomly allocated to a single oral dose of BXCL501: 120 mcg, 180 mcg, or placebo. A total of 372 patients (97.9%) completed the study.

Mean PEC total score was 17.6 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -8.5 and -10.3 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.8 for placebo (P < .0001 vs. placebo).

PEC response rates (≥ 40% reduction from baseline) were 80.6% and 89.6% with BXCL501 120 mcg and 180 mcg versus 47.6% with placebo (P < .0001 vs. placebo).

Compared with placebo, significant improvement in the Clinical Global Impression–Improvement scale (CGI-I) was observed with both BXCL501 doses at 1 and 2 hours after dosing and in the Agitation and Calmness Evaluation Scale (ACES) at 2 hours post dosing.

The incidence of adverse events (AE) was 39.5%, 37.3%, and 15.1% with BXCL501 120 mg, 180 mg, and placebo groups.

All AEs were mild or moderate. The most common AEs with BXCL501 were somnolence, dizziness, dry mouth, hypotension, orthostatic hypotension, hypoesthesia, and paresthesia. No drug-related severe or serious AEs occurred.
 

Nipping it in the bud

SERENITY II had a similar design. This study included 380 adults (mean age 48, 55% female) with bipolar I or II disorder and acute agitation in the ED (total score ≥14 on the PEC scale at baseline and a score ≥4 on at least one PEC item). A total of 362 (95.3%) of patients completed the study.

Mean PEC total score was 18 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -9.0 and -10.4 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.9 for placebo (P < .0001 vs. placebo).

Bipolar patients also saw significant improvement on the secondary outcomes of CGI-I and ACES, with an adverse event profile similar to that seen in patients with schizophrenia.

BXCL501 demonstrated “rapid, robust and clinically meaningful efficacy” in both patient populations and represents a “novel, noninvasive and well tolerated treatment of agitation,” the investigators concluded in their APA abstracts.

“Patients who are agitated are in psychic pain and they want relief from this psychic pain. We’re also worried that they might get worse and that agitation escalates to aggression potentially requiring restraints. We want to avoid that,” Dr. Citrome said.

“By nipping it in the bud with a pharmacological intervention, we can ease their psychic pain and we can manage a potentially dangerous situation. Offering an oral medicine that would work quickly would be ideal in my mind and patients might potentially be more accepting of that than an injection,” Dr. Citrome said.

Based on the SERENITY I and II data, BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration.
 

Negotiation first, medication second 

Reached for comment, Samoon Ahmad, MD, professor, department of psychiatry, New York (N.Y.) University, cautioned that, “when we talk about treating an agitated patient, medication is only part of the picture.

“There is a negotiating process with the patient. Number one, you offer them an environment that is conducive to making them feel calm, safe, and secure and that they are being listened to. Providing all of those things sometimes can be very helpful,” said Dr. Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York City.

“If someone starts throwing chairs at you or assaulting you, that is not really the time to negotiate a medicine; you basically have to restrain the patient, and many times give them intramuscular medicine,” Dr. Ahmad said.

He also noted that patients in the SERENITY trials had moderate to severe acute agitation.

“These are people you can potentially negotiate with. But again, when a patient crosses a certain line, you have to immediately do something and that could be intramuscular injection or something oral, which they may spit right in your face, which has happened numerous times,” Dr. Ahmad said.

“I don’t think intramuscular options will ever go away but an oral agent could be a useful tool as well,” said Dr. Ahmad, founder of the Integrative Center for Wellness in New York City.

He cautioned that clinicians are not going to be using this medicine in their offices. “If a patient walks in and is floridly psychotic, you will need to call 911. We’re really talking about its use either in the ED or acute inpatient setting,” Dr. Ahmad said.

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

An investigational, orally dissolving film formulation of dexmedetomidine (BXCL501, BioXcel Therapeutics) may offer rapid relief from acute agitation related to schizophrenia or bipolar disorder (BD), results of two phase 3, randomized, placebo-controlled trials show.
 

For both disorders, BXCL501 showed “superiority over placebo” by meeting the primary endpoint of reduction of agitation as measured by the excited component of the Positive and Negative Syndrome Scale (PANSS), study investigator Leslie Citrome, MD, MPH, department of psychiatry and behavioral sciences, New York Medical College, Valhalla, said in an interview.

The findings were presented at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.
 

Noninvasive option

Acute agitation in patients with schizophrenia or BD is often encountered in emergency departments (EDs) and inpatient units. When nondrug tactics fail to calm the patient, drug options include injectable antipsychotics or benzodiazepines. BXCL501 is a thin, orally dissolving film for sublingual or buccal use.

“Dexmedetomidine is a highly-selective alpha-2a receptor agonist and we haven’t really had one of those before in psychiatry for this purpose. And we haven’t had much in the way of orally dissolving thin films that are absorbed in the oral mucosa so this represents an opportunity to provide a potential intervention that does not require an injection and yet could possibly be of use in people who are agitated,” Dr. Citrome said.

The study, known as SERENITY I, included 380 adults (mean age 45.6 years, 63% male) with schizophrenia, schizoaffective disorder, or schizophreniform disorder, and acute agitation in the ED (total score ≥ 14 on the PANSS-Excited Component (PEC) scale at baseline and a score ≥ 4 on at least one of the five PEC items).

Patients were randomly allocated to a single oral dose of BXCL501: 120 mcg, 180 mcg, or placebo. A total of 372 patients (97.9%) completed the study.

Mean PEC total score was 17.6 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -8.5 and -10.3 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.8 for placebo (P < .0001 vs. placebo).

PEC response rates (≥ 40% reduction from baseline) were 80.6% and 89.6% with BXCL501 120 mcg and 180 mcg versus 47.6% with placebo (P < .0001 vs. placebo).

Compared with placebo, significant improvement in the Clinical Global Impression–Improvement scale (CGI-I) was observed with both BXCL501 doses at 1 and 2 hours after dosing and in the Agitation and Calmness Evaluation Scale (ACES) at 2 hours post dosing.

The incidence of adverse events (AE) was 39.5%, 37.3%, and 15.1% with BXCL501 120 mg, 180 mg, and placebo groups.

All AEs were mild or moderate. The most common AEs with BXCL501 were somnolence, dizziness, dry mouth, hypotension, orthostatic hypotension, hypoesthesia, and paresthesia. No drug-related severe or serious AEs occurred.
 

Nipping it in the bud

SERENITY II had a similar design. This study included 380 adults (mean age 48, 55% female) with bipolar I or II disorder and acute agitation in the ED (total score ≥14 on the PEC scale at baseline and a score ≥4 on at least one PEC item). A total of 362 (95.3%) of patients completed the study.

Mean PEC total score was 18 at baseline. The mean change from baseline in the PEC total score at 2 hours (primary endpoint) was -9.0 and -10.4 with BXCL501 120 mcg and 180 mcg, respectively, versus -4.9 for placebo (P < .0001 vs. placebo).

Bipolar patients also saw significant improvement on the secondary outcomes of CGI-I and ACES, with an adverse event profile similar to that seen in patients with schizophrenia.

BXCL501 demonstrated “rapid, robust and clinically meaningful efficacy” in both patient populations and represents a “novel, noninvasive and well tolerated treatment of agitation,” the investigators concluded in their APA abstracts.

“Patients who are agitated are in psychic pain and they want relief from this psychic pain. We’re also worried that they might get worse and that agitation escalates to aggression potentially requiring restraints. We want to avoid that,” Dr. Citrome said.

“By nipping it in the bud with a pharmacological intervention, we can ease their psychic pain and we can manage a potentially dangerous situation. Offering an oral medicine that would work quickly would be ideal in my mind and patients might potentially be more accepting of that than an injection,” Dr. Citrome said.

Based on the SERENITY I and II data, BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration.
 

Negotiation first, medication second 

Reached for comment, Samoon Ahmad, MD, professor, department of psychiatry, New York (N.Y.) University, cautioned that, “when we talk about treating an agitated patient, medication is only part of the picture.

“There is a negotiating process with the patient. Number one, you offer them an environment that is conducive to making them feel calm, safe, and secure and that they are being listened to. Providing all of those things sometimes can be very helpful,” said Dr. Ahmad, who serves as unit chief of inpatient psychiatry at Bellevue Hospital Center in New York City.

“If someone starts throwing chairs at you or assaulting you, that is not really the time to negotiate a medicine; you basically have to restrain the patient, and many times give them intramuscular medicine,” Dr. Ahmad said.

He also noted that patients in the SERENITY trials had moderate to severe acute agitation.

“These are people you can potentially negotiate with. But again, when a patient crosses a certain line, you have to immediately do something and that could be intramuscular injection or something oral, which they may spit right in your face, which has happened numerous times,” Dr. Ahmad said.

“I don’t think intramuscular options will ever go away but an oral agent could be a useful tool as well,” said Dr. Ahmad, founder of the Integrative Center for Wellness in New York City.

He cautioned that clinicians are not going to be using this medicine in their offices. “If a patient walks in and is floridly psychotic, you will need to call 911. We’re really talking about its use either in the ED or acute inpatient setting,” Dr. Ahmad said.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

LPETTET/Getty Images

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

LPETTET/Getty Images

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

LPETTET/Getty Images

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

It breaks my heart every time young patients with functional disability and a history of several psychotic episodes are referred to me. It makes me wonder why they weren’t protected from a lifetime of disability with the use of one of the FDA-approved long-acting injectable (LAI) antipsychotics right after discharge from their initial hospitalization for first-episode psychosis (FEP).

Two decades ago, psychiatric research discovered that psychotic episodes are neurotoxic and neurodegenerative, with grave consequences for the brain if they recur. Although many clinicians are aware of the high rate of nonadherence in patients with schizophrenia—which inevitably leads to a psychotic relapse—the vast majority (>99%, in my estimate) never prescribe an LAI after the FEP to guarantee full adherence and protect the patient’s brain from further atrophy due to relapses. The overall rate of LAI antipsychotic use is astonishingly low (approximately 10%), despite the neurologic malignancy of psychotic episodes. Further, LAIs are most often used after a patient has experienced multiple psychotic episodes, at which point the patient has already lost a significant amount of brain tissue and has already descended into a life of permanent disability.

Oral antipsychotics have the same efficacy as their LAI counterparts, and certainly should be used initially in the hospital during FEP to ascertain the absence of an allergic reaction after initial exposure, and to establish tolerability. Inpatient nurses are experts at making sure a reluctant patient actually swallows the pills and does not cheek them to spit them out later. So patients who have had FEP do improve with oral medications in the hospital, but all bets are off that those patients will regularly ingest tablets every day after discharge. Studies show patients have a high rate of nonadherence within days or weeks after leaving the hospital for FEP.¹ This leads to repetitive psychotic relapses and rehospitalizations, with dire consequences for young patients with schizophrenia—a very serious brain disorder that had been labeled “the worst disease of mankind”² in the era before studies showed LAI second-generation antipsychotics for FEP had remarkable rates of relapse prevention and recovery.^3,4

Psychiatrists should approach FEP the same way oncologists approach cancer when it is diagnosed as Stage 1. Oncologists immediately take action to prevent the recurrence of the patient’s cancer with chemotherapy and/or radiation therapy, and do not wait for the cancer to advance to Stage 4, with widespread metastasis, before administering these potentially life-saving therapies (despite their toxic adverse effects). In schizophrenia, functional disability is the equivalent of Stage 4 cancer and should be aggressively prevented by using LAIs at the time of initial diagnosis, which is Stage 1 schizophrenia. Knowing the grave consequences of psychotic relapses, there is no logical reason whatsoever not to switch patients who have had FEP to an LAI before they are discharged from the hospital. A well-known study by a UCLA research group that compared patients who had FEP and were assigned to oral vs LAI antipsychotics at the time of discharge reported a stunning difference at the end of 1 year: a 650% higher relapse rate among the oral medication group compared with the LAI group!⁵ In light of such a massive difference, wouldn’t psychiatrists want to treat their sons or daughters with an LAI antipsychotic right after FEP? I certainly would, and I have always believed in treating every patient like a family member.

Catastrophic consequences

This lack of early intervention with LAI antipsychotics following FEP is the main reason schizophrenia is associated with poor clinical and functional outcomes. Patients are prescribed pills that they often take erratically or not at all, and end up relapsing repeatedly, with multiple catastrophic consequences, such as:

1. Brain tissue loss. Until recently, psychiatry did not know that psychosis destroys gray and white matter in the brain and causes progressive brain atrophy with every psychotic relapse.^6,7 The neurotoxicity of psychosis is attributed to 2 destructive processes: neuro­inflammation^8,9 and free radicals.¹⁰ Approximately 11 cc of brain tissue is lost during FEP and with every subsequent relapse.⁶ Simple math shows that after 3 to 5 relapses, patients’ brains will shrink by 35 cc to 60 cc. No wonder recurrent psychoses lead to a life of permanent disability. As I have said in a past editorial,¹¹ just as cardiologists do everything they can to prevent a second myocardial infarction (“heart attack”), psychiatrists must do the same to prevent a second psychotic episode (“brain attack”).

2. Treatment resistance. With each psychotic episode, the low antipsychotic dose that worked well in FEP is no longer enough and must be increased. The neurodegenerative effects of psychosis implies that the brain structure changes with each episode. Higher and higher doses become necessary with every psychotic recurrence, and studies show that approximately 1 in 8 patients may stop responding altogether after a psychotic relapse.¹²

Continue to: Disability

3. Disability. Functional disability, both vocational and social, usually begins after the second psychotic episode, which is why it is so important to prevent the second episode.¹³ Patients usually must drop out of high school or college or quit the job they held before FEP. Most patients with multiple psychotic episodes will never be able to work, get married, have children, live independently, or develop a circle of friends. Disability in schizophrenia is essentially a functional death sentence.¹⁴

4. Incarceration and criminalization. So many of our patients with schizophrenia get arrested when they become psychotic and behave erratically due to delusions, hallucinations, or both. They typically are taken to jail instead of a hospital because almost all the state hospitals around the country have been closed. It is outrageous that a medical condition of the brain leads to criminalization of patients with schizophrenia.¹⁵ The only solution for this ongoing crisis of incarceration of our patients with schizophrenia is to prevent them from relapsing into psychosis. The so-called deinstitutionalization movement has mutated into trans-institutionalization, moving patients who are medically ill from state hospitals to more restrictive state prisons. Patients with schizophrenia should be surrounded by a mental health team, not by armed prison guards. The rate of recidivism among these individuals is extremely high because patients who are released often stop taking their medications and get re-arrested when their behavior deteriorates.

5. Suicide. The rate of suicide in the first year after FEP is astronomical. A recent study reported an unimaginably high suicide rate: 17,000% higher than that of the general population.¹⁶ Many patients with FEP commit suicide after they stop taking their antipsychotic medication, and often no antipsychotic medication is detected in their postmortem blood samples.

6. Homelessness. A disproportionate number of patients with schizophrenia become homeless.¹⁷ It started in the 1980s, when the shuttering of state hospitals began and patients with chronic illnesses were released into the community to fend for themselves. Many perished. Others became homeless, living on the streets of urban areas.

7. Early mortality. Schizophrenia has repeatedly been shown to be associated with early mortality, with a loss of approximately 25 potential years of life.¹⁷ This is attributed to lifestyle risk factors (eg, sedentary living, poor diet) and multiple medical comorbidities (eg, obesity, diabetes, hypertension). To make things worse, patients with schizophrenia do not receive basic medical care to protect them from cardiovascular morbidity, an appalling disparity of care.¹⁸ Interestingly, a recent 7-year follow-up study of patients with schizophrenia found that the lowest rate of mortality from all causes was among patients receiving a second-generation LAI.¹⁹ Relapse prevention with LAIs can reduce mortality! According to that study, the worst mortality rate was observed in patients with schizophrenia who were not receiving any antipsychotic medication.

Continue to: Posttraumatic stress disorder

8. Posttraumatic stress disorder (PTSD). Many studies report that psychosis triggers PTSD symptoms²⁰ because delusions and hallucinations can represent a life-threatening experience. The symptoms of PTSD get embedded within the positive and negative symptoms of schizophrenia, and every psychotic relapse serves as a “booster shot” for PTSD, leading to depression, anxiety, personality changes, aggressive behavior, and suicide.

9. Hopelessness, depression, and demoralization. The stigma of a severe psychiatric brain disorder such as schizophrenia, with multiple episodes, disability, incarceration, and homelessness, extends to the patients themselves, who become hopeless and demoralized by a chronic illness that marginalizes them into desperately ill individuals.²¹ The more psychotic episodes, the more intense the demoralization, hopelessness, and depression.

10. Family burden. The repercussions of psychotic relapses after FEP leads to significant financial and emotional stress on patients’ families.²² The heavy burden of caregiving among family members can be highly distressing, leading to depression and medical illness due to compromised immune functions.

Preventing relapse: It is not rocket science

It is obvious that the single most important therapeutic action for patients with schizophrenia is to prevent psychotic relapses. Even partial nonadherence must be prevented, because a drop of 25% in a patient’s serum antipsychotic level has been reported to lead to a psychotic relapse.²³ Preventing relapse after FEP is not rocket science: Switch the patient to an LAI before discharge from the hospital,²⁴ and provide the clinically necessary psychosocial treatments at every monthly follow-up visit (supportive psychotherapy, social skill training, vocational rehabilitation, and cognitive remediation). I have witnessed firsthand how stable and functional a patient who has had FEP can become when started on a second-generation LAI very soon after the onset of the illness.

I will finish with a simple question to my clinician readers: given the many devastating consequences of psychotic relapses, what would you do for your young patient with FEP? I hope you will treat them like a family member, and protect them from brain atrophy, disability, incarceration, homelessness, and suicide by starting them on an LAI antipsychotic before they leave the hospital. We must do no less for this highly vulnerable, young patient population.

It breaks my heart every time young patients with functional disability and a history of several psychotic episodes are referred to me. It makes me wonder why they weren’t protected from a lifetime of disability with the use of one of the FDA-approved long-acting injectable (LAI) antipsychotics right after discharge from their initial hospitalization for first-episode psychosis (FEP).

Two decades ago, psychiatric research discovered that psychotic episodes are neurotoxic and neurodegenerative, with grave consequences for the brain if they recur. Although many clinicians are aware of the high rate of nonadherence in patients with schizophrenia—which inevitably leads to a psychotic relapse—the vast majority (>99%, in my estimate) never prescribe an LAI after the FEP to guarantee full adherence and protect the patient’s brain from further atrophy due to relapses. The overall rate of LAI antipsychotic use is astonishingly low (approximately 10%), despite the neurologic malignancy of psychotic episodes. Further, LAIs are most often used after a patient has experienced multiple psychotic episodes, at which point the patient has already lost a significant amount of brain tissue and has already descended into a life of permanent disability.

Oral antipsychotics have the same efficacy as their LAI counterparts, and certainly should be used initially in the hospital during FEP to ascertain the absence of an allergic reaction after initial exposure, and to establish tolerability. Inpatient nurses are experts at making sure a reluctant patient actually swallows the pills and does not cheek them to spit them out later. So patients who have had FEP do improve with oral medications in the hospital, but all bets are off that those patients will regularly ingest tablets every day after discharge. Studies show patients have a high rate of nonadherence within days or weeks after leaving the hospital for FEP.¹ This leads to repetitive psychotic relapses and rehospitalizations, with dire consequences for young patients with schizophrenia—a very serious brain disorder that had been labeled “the worst disease of mankind”² in the era before studies showed LAI second-generation antipsychotics for FEP had remarkable rates of relapse prevention and recovery.^3,4

Psychiatrists should approach FEP the same way oncologists approach cancer when it is diagnosed as Stage 1. Oncologists immediately take action to prevent the recurrence of the patient’s cancer with chemotherapy and/or radiation therapy, and do not wait for the cancer to advance to Stage 4, with widespread metastasis, before administering these potentially life-saving therapies (despite their toxic adverse effects). In schizophrenia, functional disability is the equivalent of Stage 4 cancer and should be aggressively prevented by using LAIs at the time of initial diagnosis, which is Stage 1 schizophrenia. Knowing the grave consequences of psychotic relapses, there is no logical reason whatsoever not to switch patients who have had FEP to an LAI before they are discharged from the hospital. A well-known study by a UCLA research group that compared patients who had FEP and were assigned to oral vs LAI antipsychotics at the time of discharge reported a stunning difference at the end of 1 year: a 650% higher relapse rate among the oral medication group compared with the LAI group!⁵ In light of such a massive difference, wouldn’t psychiatrists want to treat their sons or daughters with an LAI antipsychotic right after FEP? I certainly would, and I have always believed in treating every patient like a family member.

Catastrophic consequences

This lack of early intervention with LAI antipsychotics following FEP is the main reason schizophrenia is associated with poor clinical and functional outcomes. Patients are prescribed pills that they often take erratically or not at all, and end up relapsing repeatedly, with multiple catastrophic consequences, such as:

1. Brain tissue loss. Until recently, psychiatry did not know that psychosis destroys gray and white matter in the brain and causes progressive brain atrophy with every psychotic relapse.^6,7 The neurotoxicity of psychosis is attributed to 2 destructive processes: neuro­inflammation^8,9 and free radicals.¹⁰ Approximately 11 cc of brain tissue is lost during FEP and with every subsequent relapse.⁶ Simple math shows that after 3 to 5 relapses, patients’ brains will shrink by 35 cc to 60 cc. No wonder recurrent psychoses lead to a life of permanent disability. As I have said in a past editorial,¹¹ just as cardiologists do everything they can to prevent a second myocardial infarction (“heart attack”), psychiatrists must do the same to prevent a second psychotic episode (“brain attack”).

2. Treatment resistance. With each psychotic episode, the low antipsychotic dose that worked well in FEP is no longer enough and must be increased. The neurodegenerative effects of psychosis implies that the brain structure changes with each episode. Higher and higher doses become necessary with every psychotic recurrence, and studies show that approximately 1 in 8 patients may stop responding altogether after a psychotic relapse.¹²

Continue to: Disability

3. Disability. Functional disability, both vocational and social, usually begins after the second psychotic episode, which is why it is so important to prevent the second episode.¹³ Patients usually must drop out of high school or college or quit the job they held before FEP. Most patients with multiple psychotic episodes will never be able to work, get married, have children, live independently, or develop a circle of friends. Disability in schizophrenia is essentially a functional death sentence.¹⁴

4. Incarceration and criminalization. So many of our patients with schizophrenia get arrested when they become psychotic and behave erratically due to delusions, hallucinations, or both. They typically are taken to jail instead of a hospital because almost all the state hospitals around the country have been closed. It is outrageous that a medical condition of the brain leads to criminalization of patients with schizophrenia.¹⁵ The only solution for this ongoing crisis of incarceration of our patients with schizophrenia is to prevent them from relapsing into psychosis. The so-called deinstitutionalization movement has mutated into trans-institutionalization, moving patients who are medically ill from state hospitals to more restrictive state prisons. Patients with schizophrenia should be surrounded by a mental health team, not by armed prison guards. The rate of recidivism among these individuals is extremely high because patients who are released often stop taking their medications and get re-arrested when their behavior deteriorates.

5. Suicide. The rate of suicide in the first year after FEP is astronomical. A recent study reported an unimaginably high suicide rate: 17,000% higher than that of the general population.¹⁶ Many patients with FEP commit suicide after they stop taking their antipsychotic medication, and often no antipsychotic medication is detected in their postmortem blood samples.

6. Homelessness. A disproportionate number of patients with schizophrenia become homeless.¹⁷ It started in the 1980s, when the shuttering of state hospitals began and patients with chronic illnesses were released into the community to fend for themselves. Many perished. Others became homeless, living on the streets of urban areas.

7. Early mortality. Schizophrenia has repeatedly been shown to be associated with early mortality, with a loss of approximately 25 potential years of life.¹⁷ This is attributed to lifestyle risk factors (eg, sedentary living, poor diet) and multiple medical comorbidities (eg, obesity, diabetes, hypertension). To make things worse, patients with schizophrenia do not receive basic medical care to protect them from cardiovascular morbidity, an appalling disparity of care.¹⁸ Interestingly, a recent 7-year follow-up study of patients with schizophrenia found that the lowest rate of mortality from all causes was among patients receiving a second-generation LAI.¹⁹ Relapse prevention with LAIs can reduce mortality! According to that study, the worst mortality rate was observed in patients with schizophrenia who were not receiving any antipsychotic medication.

Continue to: Posttraumatic stress disorder

8. Posttraumatic stress disorder (PTSD). Many studies report that psychosis triggers PTSD symptoms²⁰ because delusions and hallucinations can represent a life-threatening experience. The symptoms of PTSD get embedded within the positive and negative symptoms of schizophrenia, and every psychotic relapse serves as a “booster shot” for PTSD, leading to depression, anxiety, personality changes, aggressive behavior, and suicide.

9. Hopelessness, depression, and demoralization. The stigma of a severe psychiatric brain disorder such as schizophrenia, with multiple episodes, disability, incarceration, and homelessness, extends to the patients themselves, who become hopeless and demoralized by a chronic illness that marginalizes them into desperately ill individuals.²¹ The more psychotic episodes, the more intense the demoralization, hopelessness, and depression.

10. Family burden. The repercussions of psychotic relapses after FEP leads to significant financial and emotional stress on patients’ families.²² The heavy burden of caregiving among family members can be highly distressing, leading to depression and medical illness due to compromised immune functions.

Preventing relapse: It is not rocket science

It is obvious that the single most important therapeutic action for patients with schizophrenia is to prevent psychotic relapses. Even partial nonadherence must be prevented, because a drop of 25% in a patient’s serum antipsychotic level has been reported to lead to a psychotic relapse.²³ Preventing relapse after FEP is not rocket science: Switch the patient to an LAI before discharge from the hospital,²⁴ and provide the clinically necessary psychosocial treatments at every monthly follow-up visit (supportive psychotherapy, social skill training, vocational rehabilitation, and cognitive remediation). I have witnessed firsthand how stable and functional a patient who has had FEP can become when started on a second-generation LAI very soon after the onset of the illness.

I will finish with a simple question to my clinician readers: given the many devastating consequences of psychotic relapses, what would you do for your young patient with FEP? I hope you will treat them like a family member, and protect them from brain atrophy, disability, incarceration, homelessness, and suicide by starting them on an LAI antipsychotic before they leave the hospital. We must do no less for this highly vulnerable, young patient population.

It breaks my heart every time young patients with functional disability and a history of several psychotic episodes are referred to me. It makes me wonder why they weren’t protected from a lifetime of disability with the use of one of the FDA-approved long-acting injectable (LAI) antipsychotics right after discharge from their initial hospitalization for first-episode psychosis (FEP).

Two decades ago, psychiatric research discovered that psychotic episodes are neurotoxic and neurodegenerative, with grave consequences for the brain if they recur. Although many clinicians are aware of the high rate of nonadherence in patients with schizophrenia—which inevitably leads to a psychotic relapse—the vast majority (>99%, in my estimate) never prescribe an LAI after the FEP to guarantee full adherence and protect the patient’s brain from further atrophy due to relapses. The overall rate of LAI antipsychotic use is astonishingly low (approximately 10%), despite the neurologic malignancy of psychotic episodes. Further, LAIs are most often used after a patient has experienced multiple psychotic episodes, at which point the patient has already lost a significant amount of brain tissue and has already descended into a life of permanent disability.

Oral antipsychotics have the same efficacy as their LAI counterparts, and certainly should be used initially in the hospital during FEP to ascertain the absence of an allergic reaction after initial exposure, and to establish tolerability. Inpatient nurses are experts at making sure a reluctant patient actually swallows the pills and does not cheek them to spit them out later. So patients who have had FEP do improve with oral medications in the hospital, but all bets are off that those patients will regularly ingest tablets every day after discharge. Studies show patients have a high rate of nonadherence within days or weeks after leaving the hospital for FEP.¹ This leads to repetitive psychotic relapses and rehospitalizations, with dire consequences for young patients with schizophrenia—a very serious brain disorder that had been labeled “the worst disease of mankind”² in the era before studies showed LAI second-generation antipsychotics for FEP had remarkable rates of relapse prevention and recovery.^3,4

Psychiatrists should approach FEP the same way oncologists approach cancer when it is diagnosed as Stage 1. Oncologists immediately take action to prevent the recurrence of the patient’s cancer with chemotherapy and/or radiation therapy, and do not wait for the cancer to advance to Stage 4, with widespread metastasis, before administering these potentially life-saving therapies (despite their toxic adverse effects). In schizophrenia, functional disability is the equivalent of Stage 4 cancer and should be aggressively prevented by using LAIs at the time of initial diagnosis, which is Stage 1 schizophrenia. Knowing the grave consequences of psychotic relapses, there is no logical reason whatsoever not to switch patients who have had FEP to an LAI before they are discharged from the hospital. A well-known study by a UCLA research group that compared patients who had FEP and were assigned to oral vs LAI antipsychotics at the time of discharge reported a stunning difference at the end of 1 year: a 650% higher relapse rate among the oral medication group compared with the LAI group!⁵ In light of such a massive difference, wouldn’t psychiatrists want to treat their sons or daughters with an LAI antipsychotic right after FEP? I certainly would, and I have always believed in treating every patient like a family member.

Catastrophic consequences

This lack of early intervention with LAI antipsychotics following FEP is the main reason schizophrenia is associated with poor clinical and functional outcomes. Patients are prescribed pills that they often take erratically or not at all, and end up relapsing repeatedly, with multiple catastrophic consequences, such as:

1. Brain tissue loss. Until recently, psychiatry did not know that psychosis destroys gray and white matter in the brain and causes progressive brain atrophy with every psychotic relapse.^6,7 The neurotoxicity of psychosis is attributed to 2 destructive processes: neuro­inflammation^8,9 and free radicals.¹⁰ Approximately 11 cc of brain tissue is lost during FEP and with every subsequent relapse.⁶ Simple math shows that after 3 to 5 relapses, patients’ brains will shrink by 35 cc to 60 cc. No wonder recurrent psychoses lead to a life of permanent disability. As I have said in a past editorial,¹¹ just as cardiologists do everything they can to prevent a second myocardial infarction (“heart attack”), psychiatrists must do the same to prevent a second psychotic episode (“brain attack”).

2. Treatment resistance. With each psychotic episode, the low antipsychotic dose that worked well in FEP is no longer enough and must be increased. The neurodegenerative effects of psychosis implies that the brain structure changes with each episode. Higher and higher doses become necessary with every psychotic recurrence, and studies show that approximately 1 in 8 patients may stop responding altogether after a psychotic relapse.¹²

Continue to: Disability

3. Disability. Functional disability, both vocational and social, usually begins after the second psychotic episode, which is why it is so important to prevent the second episode.¹³ Patients usually must drop out of high school or college or quit the job they held before FEP. Most patients with multiple psychotic episodes will never be able to work, get married, have children, live independently, or develop a circle of friends. Disability in schizophrenia is essentially a functional death sentence.¹⁴

4. Incarceration and criminalization. So many of our patients with schizophrenia get arrested when they become psychotic and behave erratically due to delusions, hallucinations, or both. They typically are taken to jail instead of a hospital because almost all the state hospitals around the country have been closed. It is outrageous that a medical condition of the brain leads to criminalization of patients with schizophrenia.¹⁵ The only solution for this ongoing crisis of incarceration of our patients with schizophrenia is to prevent them from relapsing into psychosis. The so-called deinstitutionalization movement has mutated into trans-institutionalization, moving patients who are medically ill from state hospitals to more restrictive state prisons. Patients with schizophrenia should be surrounded by a mental health team, not by armed prison guards. The rate of recidivism among these individuals is extremely high because patients who are released often stop taking their medications and get re-arrested when their behavior deteriorates.

5. Suicide. The rate of suicide in the first year after FEP is astronomical. A recent study reported an unimaginably high suicide rate: 17,000% higher than that of the general population.¹⁶ Many patients with FEP commit suicide after they stop taking their antipsychotic medication, and often no antipsychotic medication is detected in their postmortem blood samples.

6. Homelessness. A disproportionate number of patients with schizophrenia become homeless.¹⁷ It started in the 1980s, when the shuttering of state hospitals began and patients with chronic illnesses were released into the community to fend for themselves. Many perished. Others became homeless, living on the streets of urban areas.

7. Early mortality. Schizophrenia has repeatedly been shown to be associated with early mortality, with a loss of approximately 25 potential years of life.¹⁷ This is attributed to lifestyle risk factors (eg, sedentary living, poor diet) and multiple medical comorbidities (eg, obesity, diabetes, hypertension). To make things worse, patients with schizophrenia do not receive basic medical care to protect them from cardiovascular morbidity, an appalling disparity of care.¹⁸ Interestingly, a recent 7-year follow-up study of patients with schizophrenia found that the lowest rate of mortality from all causes was among patients receiving a second-generation LAI.¹⁹ Relapse prevention with LAIs can reduce mortality! According to that study, the worst mortality rate was observed in patients with schizophrenia who were not receiving any antipsychotic medication.

Continue to: Posttraumatic stress disorder

8. Posttraumatic stress disorder (PTSD). Many studies report that psychosis triggers PTSD symptoms²⁰ because delusions and hallucinations can represent a life-threatening experience. The symptoms of PTSD get embedded within the positive and negative symptoms of schizophrenia, and every psychotic relapse serves as a “booster shot” for PTSD, leading to depression, anxiety, personality changes, aggressive behavior, and suicide.

9. Hopelessness, depression, and demoralization. The stigma of a severe psychiatric brain disorder such as schizophrenia, with multiple episodes, disability, incarceration, and homelessness, extends to the patients themselves, who become hopeless and demoralized by a chronic illness that marginalizes them into desperately ill individuals.²¹ The more psychotic episodes, the more intense the demoralization, hopelessness, and depression.

10. Family burden. The repercussions of psychotic relapses after FEP leads to significant financial and emotional stress on patients’ families.²² The heavy burden of caregiving among family members can be highly distressing, leading to depression and medical illness due to compromised immune functions.

Preventing relapse: It is not rocket science

It is obvious that the single most important therapeutic action for patients with schizophrenia is to prevent psychotic relapses. Even partial nonadherence must be prevented, because a drop of 25% in a patient’s serum antipsychotic level has been reported to lead to a psychotic relapse.²³ Preventing relapse after FEP is not rocket science: Switch the patient to an LAI before discharge from the hospital,²⁴ and provide the clinically necessary psychosocial treatments at every monthly follow-up visit (supportive psychotherapy, social skill training, vocational rehabilitation, and cognitive remediation). I have witnessed firsthand how stable and functional a patient who has had FEP can become when started on a second-generation LAI very soon after the onset of the illness.

I will finish with a simple question to my clinician readers: given the many devastating consequences of psychotic relapses, what would you do for your young patient with FEP? I hope you will treat them like a family member, and protect them from brain atrophy, disability, incarceration, homelessness, and suicide by starting them on an LAI antipsychotic before they leave the hospital. We must do no less for this highly vulnerable, young patient population.

Cognitive remediation (CR), a therapy that encompasses nonpharmacologic approaches to improving cognitive function for patients with severe mental illness, may lead to significant improvement for patients with schizophrenia, new research suggests.
 

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A systematic review of 130 worldwide studies that included almost 9,000 participants showed that CR significantly improved global cognition and global functioning. In addition, investigators identified key patient characteristics that flagged ideal candidates for the therapy.

“Because pharmacological treatment exerts limited effects on cognitive deficits, and clinical remission does not necessarily result in functional recovery, widespread implementation of CR could be a game-changer for achieving the patient’s personal recovery goals,” the researchers wrote.

“We hope that this systematic review could help clinicians understand how to make CR even more effective and even more personalized,” lead author Antonio Vita, MD, PhD, department of clinical and experimental sciences, University of Brescia, Italy, said in an interview.

Dr. Vita noted that he would also encourage clinicians to consider “proposing it for clinical practice.”

The findings were presented at the virtual congress of the Schizophrenia International Research Society (SIRS 2021) and were published simultaneously in JAMA Psychiatry.
 

Resistance continues

Cognition “should be a focus of treatment because most of the disability and functional consequences of the disease are related to ... neurocognitive impairment and impairment of social cognition,” Dr. Vita said.

He noted that treatments that focus on cognition are crucial for the recovery of patients with schizophrenia.

However, despite a “solid body of evidence” supporting the efficacy of CR and guideline recommendations that CR be included in psychiatric services, reluctance remains, the investigators noted.

The study’s goal was to determine optimal candidates for CR and to assess outcomes of the therapy and its four core elements:

• The presence of an active and trained therapist.
• Repeated practice of cognitive exercises.
• Structured development of cognitive strategies.
• Techniques to improve the transfer of cognitive gains to the real world, such as integrated psychosocial rehabilitation.

The investigators conducted a systematic literature search of the PubMed, Scopus, and PsychInfo databases to find relevant studies of CR published between January 2011 and February 2020. They also “hand-searched” meta-analyses, reviews, and reference lists.

Ultimately, the analysis included 130 randomized clinical trials comparing CR with a control condition in 8,851 patients with schizophrenia spectrum disorders.

Of these studies, 57 were conducted in Europe, 38 in the United States, 22 in Asia, 4 in Canada, 4 in Middle Eastern countries, 3 in Australia, and 2 in Brazil.

The mean age of the participants was 36.7 years, and 68% were men. The average age at the time of schizophrenia onset was 23.3 years, and the mean duration of illness was 13.8 years.

The average duration of CR treatment was 15.2 weeks. The four elements were well represented; each was offered to at least 71% of patients.

The comparator therapy was treatment as usual (TAU), in 34.3% of cases, or active TAU with multidisciplinary rehabilitation, in 15.2% of cases. The remaining interventions were either nonspecific (30.8%) or were devised specifically for the study (19.9%).

Results showed that CR had a significant, albeit moderate, effect on global cognition (Cohen’s d effect size, 0.29; P < .001) and global functioning (effect size, 0.22; P < .01).

Having an active and trained therapist had a significant impact on cognition and functioning (P = .04 for both), as did the structured development of cognitive strategies (P = .002 for cognition; P = .004 for functioning).

The integration of psychosocial rehabilitation also had a significant effect on functioning (P = .003).

Interventions that included all of the core elements had a “highly significant” association with global cognition (P = .02) and global functioning (P < .001), the investigators reported. Longer treatments were significantly associated with greater functional improvement (P = .006).

The investigators found that improvements were greater among patients who had fewer years of education (P = .03 for cognition; P = .02 for functioning), lower premorbid IQ scores (P = .04 for functioning), and more severe symptoms at baseline (P = .005 for cognition).

The researchers noted that CR should become more widely available because it has the “potential to be an element of standard care rather than an optional intervention targeting selected individuals.”
 

An overlooked treatment option

Commenting on the findings for this news organization, Alice Medalia, PhD, director of the Lieber Recovery Clinic at Columbia University Irving Medical Center, New York, noted that this study is the second large-scale analysis of the use of CR for patients with schizophrenia to come out this year. The other was published in Schizophrenia Bulletin.

“So this is a banner year for large reviews,” she said. “It’s great to have two studies like this [that] tell a very consistent story.”

Dr. Medalia, who was not involved with the research, said individuals “don’t really talk about cognition very much.”

CR, she added, is “one of an array of services that one should be providing, and the bigger picture is that every single person should have their cognitive health needs addressed.

“If someone is having problems, and it’s getting in the way of them being the kind of person they want to be and doing want they want to do, we need to intervene. How we intervene should always be in the least disruptive and intense way,” she said.

These measures could include examining sleep hygiene, adjusting medications, or introducing exercise.

“But there really does come a time for some people where cognitive remediation is going to be helpful, so it should be more available,” Dr. Medalia said.

Although increased availability is partially dependent on having enough trained therapists, the main reason CR is not more widely available is because “people just don’t think about cognition and they don’t know how to talk about it,” she noted. In addition, she said, even when it is available, clinicians don’t refer patients.

“That tells you something. The solution here is not to put a cognitive remediation program everywhere but ... to get people comfortable talking about cognition and identifying when an intervention is needed,” said Dr. Medalia.

One study author received grants from the National Institute for Health Research during the conduct of the study and is the creator of CIRCuiTs, a cognitive remediation software program. The other investigators and Dr. Medalia have reported no relevant financial relationships.

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

Cognitive remediation (CR), a therapy that encompasses nonpharmacologic approaches to improving cognitive function for patients with severe mental illness, may lead to significant improvement for patients with schizophrenia, new research suggests.
 

verbaska_studio/Getty Images

A systematic review of 130 worldwide studies that included almost 9,000 participants showed that CR significantly improved global cognition and global functioning. In addition, investigators identified key patient characteristics that flagged ideal candidates for the therapy.

“Because pharmacological treatment exerts limited effects on cognitive deficits, and clinical remission does not necessarily result in functional recovery, widespread implementation of CR could be a game-changer for achieving the patient’s personal recovery goals,” the researchers wrote.

“We hope that this systematic review could help clinicians understand how to make CR even more effective and even more personalized,” lead author Antonio Vita, MD, PhD, department of clinical and experimental sciences, University of Brescia, Italy, said in an interview.

Dr. Vita noted that he would also encourage clinicians to consider “proposing it for clinical practice.”

The findings were presented at the virtual congress of the Schizophrenia International Research Society (SIRS 2021) and were published simultaneously in JAMA Psychiatry.
 

Resistance continues

Cognition “should be a focus of treatment because most of the disability and functional consequences of the disease are related to ... neurocognitive impairment and impairment of social cognition,” Dr. Vita said.

He noted that treatments that focus on cognition are crucial for the recovery of patients with schizophrenia.

However, despite a “solid body of evidence” supporting the efficacy of CR and guideline recommendations that CR be included in psychiatric services, reluctance remains, the investigators noted.

The study’s goal was to determine optimal candidates for CR and to assess outcomes of the therapy and its four core elements:

• The presence of an active and trained therapist.
• Repeated practice of cognitive exercises.
• Structured development of cognitive strategies.
• Techniques to improve the transfer of cognitive gains to the real world, such as integrated psychosocial rehabilitation.

The investigators conducted a systematic literature search of the PubMed, Scopus, and PsychInfo databases to find relevant studies of CR published between January 2011 and February 2020. They also “hand-searched” meta-analyses, reviews, and reference lists.

Ultimately, the analysis included 130 randomized clinical trials comparing CR with a control condition in 8,851 patients with schizophrenia spectrum disorders.

Of these studies, 57 were conducted in Europe, 38 in the United States, 22 in Asia, 4 in Canada, 4 in Middle Eastern countries, 3 in Australia, and 2 in Brazil.

The mean age of the participants was 36.7 years, and 68% were men. The average age at the time of schizophrenia onset was 23.3 years, and the mean duration of illness was 13.8 years.

The average duration of CR treatment was 15.2 weeks. The four elements were well represented; each was offered to at least 71% of patients.

The comparator therapy was treatment as usual (TAU), in 34.3% of cases, or active TAU with multidisciplinary rehabilitation, in 15.2% of cases. The remaining interventions were either nonspecific (30.8%) or were devised specifically for the study (19.9%).

Results showed that CR had a significant, albeit moderate, effect on global cognition (Cohen’s d effect size, 0.29; P < .001) and global functioning (effect size, 0.22; P < .01).

Having an active and trained therapist had a significant impact on cognition and functioning (P = .04 for both), as did the structured development of cognitive strategies (P = .002 for cognition; P = .004 for functioning).

The integration of psychosocial rehabilitation also had a significant effect on functioning (P = .003).

Interventions that included all of the core elements had a “highly significant” association with global cognition (P = .02) and global functioning (P < .001), the investigators reported. Longer treatments were significantly associated with greater functional improvement (P = .006).

The investigators found that improvements were greater among patients who had fewer years of education (P = .03 for cognition; P = .02 for functioning), lower premorbid IQ scores (P = .04 for functioning), and more severe symptoms at baseline (P = .005 for cognition).

The researchers noted that CR should become more widely available because it has the “potential to be an element of standard care rather than an optional intervention targeting selected individuals.”
 

An overlooked treatment option

Commenting on the findings for this news organization, Alice Medalia, PhD, director of the Lieber Recovery Clinic at Columbia University Irving Medical Center, New York, noted that this study is the second large-scale analysis of the use of CR for patients with schizophrenia to come out this year. The other was published in Schizophrenia Bulletin.

“So this is a banner year for large reviews,” she said. “It’s great to have two studies like this [that] tell a very consistent story.”

Dr. Medalia, who was not involved with the research, said individuals “don’t really talk about cognition very much.”

CR, she added, is “one of an array of services that one should be providing, and the bigger picture is that every single person should have their cognitive health needs addressed.

“If someone is having problems, and it’s getting in the way of them being the kind of person they want to be and doing want they want to do, we need to intervene. How we intervene should always be in the least disruptive and intense way,” she said.

These measures could include examining sleep hygiene, adjusting medications, or introducing exercise.

“But there really does come a time for some people where cognitive remediation is going to be helpful, so it should be more available,” Dr. Medalia said.

Although increased availability is partially dependent on having enough trained therapists, the main reason CR is not more widely available is because “people just don’t think about cognition and they don’t know how to talk about it,” she noted. In addition, she said, even when it is available, clinicians don’t refer patients.

“That tells you something. The solution here is not to put a cognitive remediation program everywhere but ... to get people comfortable talking about cognition and identifying when an intervention is needed,” said Dr. Medalia.

One study author received grants from the National Institute for Health Research during the conduct of the study and is the creator of CIRCuiTs, a cognitive remediation software program. The other investigators and Dr. Medalia have reported no relevant financial relationships.

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

Cognitive remediation (CR), a therapy that encompasses nonpharmacologic approaches to improving cognitive function for patients with severe mental illness, may lead to significant improvement for patients with schizophrenia, new research suggests.
 

verbaska_studio/Getty Images

A systematic review of 130 worldwide studies that included almost 9,000 participants showed that CR significantly improved global cognition and global functioning. In addition, investigators identified key patient characteristics that flagged ideal candidates for the therapy.

“Because pharmacological treatment exerts limited effects on cognitive deficits, and clinical remission does not necessarily result in functional recovery, widespread implementation of CR could be a game-changer for achieving the patient’s personal recovery goals,” the researchers wrote.

“We hope that this systematic review could help clinicians understand how to make CR even more effective and even more personalized,” lead author Antonio Vita, MD, PhD, department of clinical and experimental sciences, University of Brescia, Italy, said in an interview.

Dr. Vita noted that he would also encourage clinicians to consider “proposing it for clinical practice.”

The findings were presented at the virtual congress of the Schizophrenia International Research Society (SIRS 2021) and were published simultaneously in JAMA Psychiatry.
 

Resistance continues

Cognition “should be a focus of treatment because most of the disability and functional consequences of the disease are related to ... neurocognitive impairment and impairment of social cognition,” Dr. Vita said.

He noted that treatments that focus on cognition are crucial for the recovery of patients with schizophrenia.

However, despite a “solid body of evidence” supporting the efficacy of CR and guideline recommendations that CR be included in psychiatric services, reluctance remains, the investigators noted.

The study’s goal was to determine optimal candidates for CR and to assess outcomes of the therapy and its four core elements:

• The presence of an active and trained therapist.
• Repeated practice of cognitive exercises.
• Structured development of cognitive strategies.
• Techniques to improve the transfer of cognitive gains to the real world, such as integrated psychosocial rehabilitation.

The investigators conducted a systematic literature search of the PubMed, Scopus, and PsychInfo databases to find relevant studies of CR published between January 2011 and February 2020. They also “hand-searched” meta-analyses, reviews, and reference lists.

Ultimately, the analysis included 130 randomized clinical trials comparing CR with a control condition in 8,851 patients with schizophrenia spectrum disorders.

Of these studies, 57 were conducted in Europe, 38 in the United States, 22 in Asia, 4 in Canada, 4 in Middle Eastern countries, 3 in Australia, and 2 in Brazil.

The mean age of the participants was 36.7 years, and 68% were men. The average age at the time of schizophrenia onset was 23.3 years, and the mean duration of illness was 13.8 years.

The average duration of CR treatment was 15.2 weeks. The four elements were well represented; each was offered to at least 71% of patients.

The comparator therapy was treatment as usual (TAU), in 34.3% of cases, or active TAU with multidisciplinary rehabilitation, in 15.2% of cases. The remaining interventions were either nonspecific (30.8%) or were devised specifically for the study (19.9%).

Results showed that CR had a significant, albeit moderate, effect on global cognition (Cohen’s d effect size, 0.29; P < .001) and global functioning (effect size, 0.22; P < .01).

Having an active and trained therapist had a significant impact on cognition and functioning (P = .04 for both), as did the structured development of cognitive strategies (P = .002 for cognition; P = .004 for functioning).

The integration of psychosocial rehabilitation also had a significant effect on functioning (P = .003).

Interventions that included all of the core elements had a “highly significant” association with global cognition (P = .02) and global functioning (P < .001), the investigators reported. Longer treatments were significantly associated with greater functional improvement (P = .006).

The investigators found that improvements were greater among patients who had fewer years of education (P = .03 for cognition; P = .02 for functioning), lower premorbid IQ scores (P = .04 for functioning), and more severe symptoms at baseline (P = .005 for cognition).

The researchers noted that CR should become more widely available because it has the “potential to be an element of standard care rather than an optional intervention targeting selected individuals.”
 

An overlooked treatment option

Commenting on the findings for this news organization, Alice Medalia, PhD, director of the Lieber Recovery Clinic at Columbia University Irving Medical Center, New York, noted that this study is the second large-scale analysis of the use of CR for patients with schizophrenia to come out this year. The other was published in Schizophrenia Bulletin.

“So this is a banner year for large reviews,” she said. “It’s great to have two studies like this [that] tell a very consistent story.”

Dr. Medalia, who was not involved with the research, said individuals “don’t really talk about cognition very much.”

CR, she added, is “one of an array of services that one should be providing, and the bigger picture is that every single person should have their cognitive health needs addressed.

“If someone is having problems, and it’s getting in the way of them being the kind of person they want to be and doing want they want to do, we need to intervene. How we intervene should always be in the least disruptive and intense way,” she said.

These measures could include examining sleep hygiene, adjusting medications, or introducing exercise.

“But there really does come a time for some people where cognitive remediation is going to be helpful, so it should be more available,” Dr. Medalia said.

Although increased availability is partially dependent on having enough trained therapists, the main reason CR is not more widely available is because “people just don’t think about cognition and they don’t know how to talk about it,” she noted. In addition, she said, even when it is available, clinicians don’t refer patients.

“That tells you something. The solution here is not to put a cognitive remediation program everywhere but ... to get people comfortable talking about cognition and identifying when an intervention is needed,” said Dr. Medalia.

One study author received grants from the National Institute for Health Research during the conduct of the study and is the creator of CIRCuiTs, a cognitive remediation software program. The other investigators and Dr. Medalia have reported no relevant financial relationships.

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

The novel antipsychotic agent SEP-363856 (Sunovion Pharmaceuticals) has a significant and ongoing effect on negative symptoms in patients with schizophrenia, new research shows.

Results of a phase 2, placebo-controlled trial show SEP-363856 significantly decreased total scores on the Brief Negative Symptom Scale (BNSS), and lowered subscale scores for such symptoms as alogia and asociality, compared with placebo.

The active-treatment group also showed significantly lower scores on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). During an open-label extension of the study, both BNSS total scores and PANSS negative symptom scores continued to decrease.

Overall, the results “provide further confirmation of the effectiveness of SEP-363856 in treating schizophrenia,” study investigator Kenneth Koblan, PhD, of Sunovion said in an interview.

He added that the compound also showed “a favorable safety and tolerability profile that is differentiated from first and second generation antipsychotics, and which is consistent with the absence of D2-receptor binding.”

The findings were presented at the 2021 annual congress of the Schizophrenia International Research Society.
 

FDA breakthrough designation

SEP-363856 has a completely different mechanism of action from currently available antipsychotics.

In May 2019, it was granted breakthrough therapy designation by the Food and Drug Administration as a novel treatment for patients with schizophrenia.

Phase 2 data published in the New England Journal of Medicine in 2020 showed it achieved significant and clinically meaningful improvements in PANSS total scores after 4 weeks in patients hospitalized with an acute exacerbation of schizophrenia. It also showed durable effects out to 26 weeks.

In the current analysis, the investigators focused on negative symptoms, both in the initial acute treatment phase and an open-label extension.

They analyzed data from the previous phase 2 trial using a validated Uncorrelated PANSS Score Matrix (UPSM) transformation of the PANSS to isolate the effects of the drug on apathy/avolition and deficit of expression. They also used the BNSS.

Patients aged 18-40 years with an acute exacerbation of schizophrenia were randomly assigned to receive either 50 mg or 75 mg of SEP-363856 per day (n = 120) or matching placebo (n = 125) for 4 weeks. Completers were eligible for enrollment in a 26-week phase 2 extension study of 25 mg, 50 mg, or 75 mg of SEP-363856 per day.

The mean age of the participants was 30 years, and 64% were men. The treatment groups were balanced in terms of demographics.

Significant improvement

The BNSS total score decreased significantly with SEP-363856 over placebo during the 4-week acute treatment period, at a mean reduction of 7.1 versus 2.7, or an effect size of 0.48 (P < .001).

Scores on the PANSS negative subscale also decreased significantly with the active drugs, with an effect size of 0.37 versus placebo (P < .05), as did scores on the UPSM apathy/avolition and deficit of expression subscales (effect size, 0.32; P < .05 for both).

In addition, there were significant reductions with SEP-363856 over placebo for the BNSS alogia, asociality, anhedonia, avolition, and blunted-affect subscales (P < .05 for all comparisons) but not for the distress subscale.

During the open-label extension, mean BNSS total scores continued to decrease for the SEP-363856 group, at an average reduction versus extension enrollment across the whole cohort of 11.3.

PANSS negative symptom scores also decreased by an average of 5.2 points, while UPSM apathy/volition scores decreased by 0.4 points on average. UPSM deficit expression scores decreased by 0.5 points.

When the researchers restricted the analysis to those who received SEP-363856 during the acute treatment phase and then continued using the drug during the open-label extension, they found BNSS total scores decreased by an additional 8 points.

Similarly, PANSS negative symptom scores decreased during the open-label extension by an average of 4 points. For UPSM apathy/avolition and deficit of expression, the additional decrease was 0.3 points on average.

In addition, an analysis of the drug’s safety and tolerability showed that, compared with the commonly prescribed antipsychotic lurasidone, it had a significantly lower risk of adverse effects. In addition, the drug was not associated with extrapyramidal symptoms and had no adverse cardiometabolic effects, Dr. Koblan reported.
 

Still in development

Commenting on the findings, René S. Kahn, MD, PhD, chair of the department of psychiatry, Icahn School of Medicine at Mount Sinai, New York, noted that, although the results showed that the drug had a “nice effect” on negative symptoms, it’s still in development.

Courtesy Mount Sinai Health System

Dr. Kahn, who was not involved in the research, said “we’ve all seen” drugs that were extremely promising in phase 2 trials that have then failed in phase 3 trials. “The proof of the pudding is phase 3, and we have to wait and see,” he added.

“Obviously I hope it’s going to work out, because we are in desperate need of new drugs, especially with a new mechanism of action and not ‘me too’ drugs. And this definitely not a ‘me too’ drug,” Dr. Kahn said. However, “we’ll have to wait.”

He noted that psychosis is often the primary focus of schizophrenia management. However, he added, cognitive and negative symptoms are also “very relevant” to the disorder.

“In fact, both of them may be more important in determining the long-term outcome of schizophrenia than psychosis, [and] most of the antipsychotics that we currently have are not very effective against negative symptoms,” he said.

“So it would really be a breakthrough if we have a drug that is really effective not only against positive psychotic symptoms, but also against negative and possibly cognitive, symptoms,” Dr. Kahn added.

Commenting on the drug’s safety, Dr. Kahn said there is a need for head-to-head studies of active drugs before any firm conclusions can be drawn.

However, he noted the exploratory analysis suggests it has a different side effect profile, compared with other medications on the market.

The study was supported by Sunovion Pharmaceuticals. Dr. Koblan and his coinvestigators are employees of Sunovion.

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

The novel antipsychotic agent SEP-363856 (Sunovion Pharmaceuticals) has a significant and ongoing effect on negative symptoms in patients with schizophrenia, new research shows.

Results of a phase 2, placebo-controlled trial show SEP-363856 significantly decreased total scores on the Brief Negative Symptom Scale (BNSS), and lowered subscale scores for such symptoms as alogia and asociality, compared with placebo.

The active-treatment group also showed significantly lower scores on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). During an open-label extension of the study, both BNSS total scores and PANSS negative symptom scores continued to decrease.

Overall, the results “provide further confirmation of the effectiveness of SEP-363856 in treating schizophrenia,” study investigator Kenneth Koblan, PhD, of Sunovion said in an interview.

He added that the compound also showed “a favorable safety and tolerability profile that is differentiated from first and second generation antipsychotics, and which is consistent with the absence of D2-receptor binding.”

The findings were presented at the 2021 annual congress of the Schizophrenia International Research Society.
 

FDA breakthrough designation

SEP-363856 has a completely different mechanism of action from currently available antipsychotics.

In May 2019, it was granted breakthrough therapy designation by the Food and Drug Administration as a novel treatment for patients with schizophrenia.

Phase 2 data published in the New England Journal of Medicine in 2020 showed it achieved significant and clinically meaningful improvements in PANSS total scores after 4 weeks in patients hospitalized with an acute exacerbation of schizophrenia. It also showed durable effects out to 26 weeks.

In the current analysis, the investigators focused on negative symptoms, both in the initial acute treatment phase and an open-label extension.

They analyzed data from the previous phase 2 trial using a validated Uncorrelated PANSS Score Matrix (UPSM) transformation of the PANSS to isolate the effects of the drug on apathy/avolition and deficit of expression. They also used the BNSS.

Patients aged 18-40 years with an acute exacerbation of schizophrenia were randomly assigned to receive either 50 mg or 75 mg of SEP-363856 per day (n = 120) or matching placebo (n = 125) for 4 weeks. Completers were eligible for enrollment in a 26-week phase 2 extension study of 25 mg, 50 mg, or 75 mg of SEP-363856 per day.

The mean age of the participants was 30 years, and 64% were men. The treatment groups were balanced in terms of demographics.

Significant improvement

The BNSS total score decreased significantly with SEP-363856 over placebo during the 4-week acute treatment period, at a mean reduction of 7.1 versus 2.7, or an effect size of 0.48 (P < .001).

Scores on the PANSS negative subscale also decreased significantly with the active drugs, with an effect size of 0.37 versus placebo (P < .05), as did scores on the UPSM apathy/avolition and deficit of expression subscales (effect size, 0.32; P < .05 for both).

In addition, there were significant reductions with SEP-363856 over placebo for the BNSS alogia, asociality, anhedonia, avolition, and blunted-affect subscales (P < .05 for all comparisons) but not for the distress subscale.

During the open-label extension, mean BNSS total scores continued to decrease for the SEP-363856 group, at an average reduction versus extension enrollment across the whole cohort of 11.3.

PANSS negative symptom scores also decreased by an average of 5.2 points, while UPSM apathy/volition scores decreased by 0.4 points on average. UPSM deficit expression scores decreased by 0.5 points.

When the researchers restricted the analysis to those who received SEP-363856 during the acute treatment phase and then continued using the drug during the open-label extension, they found BNSS total scores decreased by an additional 8 points.

Similarly, PANSS negative symptom scores decreased during the open-label extension by an average of 4 points. For UPSM apathy/avolition and deficit of expression, the additional decrease was 0.3 points on average.

In addition, an analysis of the drug’s safety and tolerability showed that, compared with the commonly prescribed antipsychotic lurasidone, it had a significantly lower risk of adverse effects. In addition, the drug was not associated with extrapyramidal symptoms and had no adverse cardiometabolic effects, Dr. Koblan reported.
 

Still in development

Commenting on the findings, René S. Kahn, MD, PhD, chair of the department of psychiatry, Icahn School of Medicine at Mount Sinai, New York, noted that, although the results showed that the drug had a “nice effect” on negative symptoms, it’s still in development.

Courtesy Mount Sinai Health System

Dr. Kahn, who was not involved in the research, said “we’ve all seen” drugs that were extremely promising in phase 2 trials that have then failed in phase 3 trials. “The proof of the pudding is phase 3, and we have to wait and see,” he added.

“Obviously I hope it’s going to work out, because we are in desperate need of new drugs, especially with a new mechanism of action and not ‘me too’ drugs. And this definitely not a ‘me too’ drug,” Dr. Kahn said. However, “we’ll have to wait.”

He noted that psychosis is often the primary focus of schizophrenia management. However, he added, cognitive and negative symptoms are also “very relevant” to the disorder.

“In fact, both of them may be more important in determining the long-term outcome of schizophrenia than psychosis, [and] most of the antipsychotics that we currently have are not very effective against negative symptoms,” he said.

“So it would really be a breakthrough if we have a drug that is really effective not only against positive psychotic symptoms, but also against negative and possibly cognitive, symptoms,” Dr. Kahn added.

Commenting on the drug’s safety, Dr. Kahn said there is a need for head-to-head studies of active drugs before any firm conclusions can be drawn.

However, he noted the exploratory analysis suggests it has a different side effect profile, compared with other medications on the market.

The study was supported by Sunovion Pharmaceuticals. Dr. Koblan and his coinvestigators are employees of Sunovion.

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

The novel antipsychotic agent SEP-363856 (Sunovion Pharmaceuticals) has a significant and ongoing effect on negative symptoms in patients with schizophrenia, new research shows.

Results of a phase 2, placebo-controlled trial show SEP-363856 significantly decreased total scores on the Brief Negative Symptom Scale (BNSS), and lowered subscale scores for such symptoms as alogia and asociality, compared with placebo.

The active-treatment group also showed significantly lower scores on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). During an open-label extension of the study, both BNSS total scores and PANSS negative symptom scores continued to decrease.

Overall, the results “provide further confirmation of the effectiveness of SEP-363856 in treating schizophrenia,” study investigator Kenneth Koblan, PhD, of Sunovion said in an interview.

He added that the compound also showed “a favorable safety and tolerability profile that is differentiated from first and second generation antipsychotics, and which is consistent with the absence of D2-receptor binding.”

The findings were presented at the 2021 annual congress of the Schizophrenia International Research Society.
 

FDA breakthrough designation

SEP-363856 has a completely different mechanism of action from currently available antipsychotics.

In May 2019, it was granted breakthrough therapy designation by the Food and Drug Administration as a novel treatment for patients with schizophrenia.

Phase 2 data published in the New England Journal of Medicine in 2020 showed it achieved significant and clinically meaningful improvements in PANSS total scores after 4 weeks in patients hospitalized with an acute exacerbation of schizophrenia. It also showed durable effects out to 26 weeks.

In the current analysis, the investigators focused on negative symptoms, both in the initial acute treatment phase and an open-label extension.

They analyzed data from the previous phase 2 trial using a validated Uncorrelated PANSS Score Matrix (UPSM) transformation of the PANSS to isolate the effects of the drug on apathy/avolition and deficit of expression. They also used the BNSS.

Patients aged 18-40 years with an acute exacerbation of schizophrenia were randomly assigned to receive either 50 mg or 75 mg of SEP-363856 per day (n = 120) or matching placebo (n = 125) for 4 weeks. Completers were eligible for enrollment in a 26-week phase 2 extension study of 25 mg, 50 mg, or 75 mg of SEP-363856 per day.

The mean age of the participants was 30 years, and 64% were men. The treatment groups were balanced in terms of demographics.

Significant improvement

The BNSS total score decreased significantly with SEP-363856 over placebo during the 4-week acute treatment period, at a mean reduction of 7.1 versus 2.7, or an effect size of 0.48 (P < .001).

Scores on the PANSS negative subscale also decreased significantly with the active drugs, with an effect size of 0.37 versus placebo (P < .05), as did scores on the UPSM apathy/avolition and deficit of expression subscales (effect size, 0.32; P < .05 for both).

In addition, there were significant reductions with SEP-363856 over placebo for the BNSS alogia, asociality, anhedonia, avolition, and blunted-affect subscales (P < .05 for all comparisons) but not for the distress subscale.

During the open-label extension, mean BNSS total scores continued to decrease for the SEP-363856 group, at an average reduction versus extension enrollment across the whole cohort of 11.3.

PANSS negative symptom scores also decreased by an average of 5.2 points, while UPSM apathy/volition scores decreased by 0.4 points on average. UPSM deficit expression scores decreased by 0.5 points.

When the researchers restricted the analysis to those who received SEP-363856 during the acute treatment phase and then continued using the drug during the open-label extension, they found BNSS total scores decreased by an additional 8 points.

Similarly, PANSS negative symptom scores decreased during the open-label extension by an average of 4 points. For UPSM apathy/avolition and deficit of expression, the additional decrease was 0.3 points on average.

In addition, an analysis of the drug’s safety and tolerability showed that, compared with the commonly prescribed antipsychotic lurasidone, it had a significantly lower risk of adverse effects. In addition, the drug was not associated with extrapyramidal symptoms and had no adverse cardiometabolic effects, Dr. Koblan reported.
 

Still in development

Commenting on the findings, René S. Kahn, MD, PhD, chair of the department of psychiatry, Icahn School of Medicine at Mount Sinai, New York, noted that, although the results showed that the drug had a “nice effect” on negative symptoms, it’s still in development.

Courtesy Mount Sinai Health System

Dr. Kahn, who was not involved in the research, said “we’ve all seen” drugs that were extremely promising in phase 2 trials that have then failed in phase 3 trials. “The proof of the pudding is phase 3, and we have to wait and see,” he added.

“Obviously I hope it’s going to work out, because we are in desperate need of new drugs, especially with a new mechanism of action and not ‘me too’ drugs. And this definitely not a ‘me too’ drug,” Dr. Kahn said. However, “we’ll have to wait.”

He noted that psychosis is often the primary focus of schizophrenia management. However, he added, cognitive and negative symptoms are also “very relevant” to the disorder.

“In fact, both of them may be more important in determining the long-term outcome of schizophrenia than psychosis, [and] most of the antipsychotics that we currently have are not very effective against negative symptoms,” he said.

“So it would really be a breakthrough if we have a drug that is really effective not only against positive psychotic symptoms, but also against negative and possibly cognitive, symptoms,” Dr. Kahn added.

Commenting on the drug’s safety, Dr. Kahn said there is a need for head-to-head studies of active drugs before any firm conclusions can be drawn.

However, he noted the exploratory analysis suggests it has a different side effect profile, compared with other medications on the market.

The study was supported by Sunovion Pharmaceuticals. Dr. Koblan and his coinvestigators are employees of Sunovion.

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