Schizophrenia & Other Psychotic Disorders

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.

The American Psychiatric Association’s DSM-5-TR (Text Revision) which is not a full revision, only includes one new condition, prolonged grief disorder.

It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.

The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.

“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.

For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.

However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
 

Money maker?

Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”

Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”

The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.

Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”  
 

Prolonged grief: Timely or overkill?

Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020. 

Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.

The diagnostic criteria for PCBD include:

• The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
• Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
• The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
• The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.

Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”

DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.

The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.

However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”

“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.

The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.

“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.

Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
 

Changes to gender terminology

The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.

Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.

“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.

“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.

However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.

Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.

“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.

That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”

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

Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.

The American Psychiatric Association’s DSM-5-TR (Text Revision) which is not a full revision, only includes one new condition, prolonged grief disorder.

It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.

The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.

“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.

For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.

However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
 

Money maker?

Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”

Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”

The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.

Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”  
 

Prolonged grief: Timely or overkill?

Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020. 

Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.

The diagnostic criteria for PCBD include:

• The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
• Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
• The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
• The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.

Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”

DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.

The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.

However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”

“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.

The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.

“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.

Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
 

Changes to gender terminology

The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.

Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.

“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.

“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.

However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.

Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.

“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.

That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”

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

Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.

The American Psychiatric Association’s DSM-5-TR (Text Revision) which is not a full revision, only includes one new condition, prolonged grief disorder.

It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.

The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.

“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.

For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.

However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
 

Money maker?

Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”

Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”

The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.

Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”  
 

Prolonged grief: Timely or overkill?

Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020. 

Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.

The diagnostic criteria for PCBD include:

• The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
• Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
• The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
• The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
• The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.

Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”

DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.

The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.

However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”

“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.

The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.

“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.

Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
 

Changes to gender terminology

The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.

Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.

“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.

“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.

However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.

Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.

“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.

That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”

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

How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.

Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.

This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.

Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,¹ we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.

Psychosis-proneness underlies functional psychoses

Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.^2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”⁴ It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,⁵ each corresponding to a specific anxiety or depressive subtype.

The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.^6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).^5-7

An evolutionary perspective

One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.⁵

More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.⁵ In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counter­intuitive approach may improve our ability to help patients.⁸

Continue to: Five affective comorbidities evolved from primeval altruistic instincts...

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.

Obsessive-compulsive disorder⁵

Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.

Panic anxiety⁵

Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.

Social anxiety⁵

Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.

Atypical depression and bipolar I mania⁵

Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.⁹

Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.⁵

Continue to: Five comorbidity psychoses from 5 primeval instincts.....

The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.^1,10

One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.¹⁰ At least 85% met criteria for ≥1 of the 5 subtypes.¹⁰ Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.¹

Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.^11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.^11,12

Our proposed 5 comorbidity subtypes are¹:

Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.

Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.

Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.¹³ These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.¹⁴ That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.

Box 1

Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).¹⁶ Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.¹⁷ Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.¹⁸

Continue to: Bipolar 1 mania with delusions...

Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.

Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.

Recognizing affective trees in a psychotic forest

Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.^11-13

Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.^11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.

Diagnostic approaches

Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).

Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.¹

Structured interview tools can assist diagnosis. The PaSI (Box 1,¹⁵) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.

Continue to: Treatment by comorbidity subtype...

Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.

The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.^1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.

Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.

Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (consider long-acting injectable formulation for increased compliance). Aripiprazole also may enhance the benefit of fluoxetine for comorbid OCD. Carefully titrate, as tolerated, to optimal dose of fluoxetine (40 to 80 mg/d; the long half-life of fluoxetine and its metabolite norfluoxetine also improves compliance), while watching for activation and other adverse effects.^21,22 Limited clinical experience suggests that lower-dose clonazepam every 12 hours may reduce the adverse effects of fluoxetine.

Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.²³ Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).¹⁴ Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.

Persecutory delusional disorder. Anti­psychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.

Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.

Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).²⁴

Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.²⁵ Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.²⁵ However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.

Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.

To illustrate this new approach to psychosis diagnosis and treatment, our book¹ includes detailed case studies on each of the 5 psychosis subtypes. The brief fictional case we present in Box 2 describes a patient who had both premorbid social anxiety and panic anxiety, and then developed a mixed psychosis that reflected both of those contributing anxiety disorders.

Box 2

Larger studies are needed

Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.

Bottom Line

New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.

How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.

Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.

This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.

Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,¹ we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.

Psychosis-proneness underlies functional psychoses

Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.^2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”⁴ It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,⁵ each corresponding to a specific anxiety or depressive subtype.

The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.^6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).^5-7

An evolutionary perspective

One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.⁵

More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.⁵ In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counter­intuitive approach may improve our ability to help patients.⁸

Continue to: Five affective comorbidities evolved from primeval altruistic instincts...

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.

Obsessive-compulsive disorder⁵

Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.

Panic anxiety⁵

Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.

Social anxiety⁵

Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.

Atypical depression and bipolar I mania⁵

Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.⁹

Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.⁵

Continue to: Five comorbidity psychoses from 5 primeval instincts.....

The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.^1,10

One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.¹⁰ At least 85% met criteria for ≥1 of the 5 subtypes.¹⁰ Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.¹

Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.^11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.^11,12

Our proposed 5 comorbidity subtypes are¹:

Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.

Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.

Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.¹³ These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.¹⁴ That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.

Box 1

Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).¹⁶ Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.¹⁷ Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.¹⁸

Continue to: Bipolar 1 mania with delusions...

Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.

Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.

Recognizing affective trees in a psychotic forest

Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.^11-13

Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.^11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.

Diagnostic approaches

Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).

Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.¹

Structured interview tools can assist diagnosis. The PaSI (Box 1,¹⁵) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.

Continue to: Treatment by comorbidity subtype...

Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.

The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.^1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.

Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.

Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (consider long-acting injectable formulation for increased compliance). Aripiprazole also may enhance the benefit of fluoxetine for comorbid OCD. Carefully titrate, as tolerated, to optimal dose of fluoxetine (40 to 80 mg/d; the long half-life of fluoxetine and its metabolite norfluoxetine also improves compliance), while watching for activation and other adverse effects.^21,22 Limited clinical experience suggests that lower-dose clonazepam every 12 hours may reduce the adverse effects of fluoxetine.

Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.²³ Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).¹⁴ Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.

Persecutory delusional disorder. Anti­psychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.

Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.

Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).²⁴

Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.²⁵ Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.²⁵ However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.

Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.

To illustrate this new approach to psychosis diagnosis and treatment, our book¹ includes detailed case studies on each of the 5 psychosis subtypes. The brief fictional case we present in Box 2 describes a patient who had both premorbid social anxiety and panic anxiety, and then developed a mixed psychosis that reflected both of those contributing anxiety disorders.

Box 2

Larger studies are needed

Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.

Bottom Line

New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.

How can we treat psychosis if we don’t know what we are treating? Over the years, attempts at defining psychosis subtypes have met with dead ends. However, recent research supports a new approach that offers a rational classification model organized according to 5 specific comorbid anxiety and depressive disorder diagnoses.

Anxiety and depressive symptoms are not just the result of psychotic despair. They are specific diagnoses, they precede psychosis onset, they help define psychotic syndromes, and they can point to much more effective treatment approaches. Most of the psychotic diagnoses in this schema are already recognized or posited. And, just as patients who do not have psychotic illness can have more than 1 anxiety or depressive disorder, patients with psychosis can present with a mixed picture that reflects more than 1 contributing comorbidity. Research further suggests that each of the 5 psychosis comorbidity diagnoses may involve some similar underlying factors that facilitate the formation of psychosis.

This article describes the basics of 5 psychosis subtypes, and provides initial guidelines to diagnosis, symptomatology, and treatment. Though clinical experience and existing research support the clinical presence and treatment value of this classification model, further verification will require considerably more controlled studies. An eventual validation of this approach could largely supplant ill-defined diagnoses of “schizophrenia” and other functional psychoses.

Recognizing the comorbidities in the context of their corresponding psychoses entails learning new interviewing skills and devoting more time to both initial and subsequent diagnosis and treatment. In our recently published book,¹ we provide extensive details on the approach we describe in this article, including case examples, new interview tools to simplify the diagnostic journey, and novel treatment approaches.

Psychosis-proneness underlies functional psychoses

Functional (idiopathic) schizophrenia and psychotic disorders have long been difficult to separate, and many categorizations have been discarded. Despite clinical dissimilarities, today we too often casually lump psychoses together as schizophrenia.^2,3 Eugen Bleuler first suggested the existence of a “group of schizophrenias.”⁴ It is possible that his group encompasses our 5 psychoses from 5 inbuilt emotional instincts,⁵ each corresponding to a specific anxiety or depressive subtype.

The 5 anxiety and depressive subtypes noted in this article are common, but psychosis is not. Considerable research suggests that certain global “psychotogenic” factors create susceptibility to all psychoses.^6,7 While many genetic, neuroanatomical, experiential, and other factors have been reported, the most important may be “hypofrontality” (genetically reduced frontal lobe function, size, or neuronal activity) and dopaminergic hyperfunction (genetically increased dopamine activity).^5-7

An evolutionary perspective

One evolutionary theory of psychopathology starts with the subtypes of depression and anxiety. For example, major depressive disorder and generalized anxiety disorder may encompass 5 commonplace and more specific anxiety and depressive subtypes. Consideration of the emotional, cognitive, and functional aspects of those subtypes suggests that they may have once been advantageous for primeval human herds. Those primeval altruistic instincts may have helped survival, reproduction, and preservation of kin group DNA.⁵

More than any other species, humans can draw upon consciousness and culture to rationally overcome the influences of unconscious instincts. But those instincts can then emerge from the deep, and painfully encourage obedience to their guidance. In nonpsychotic anxiety and depressive disorders, the specific messages are experienced as specific anxiety and depressive symptoms.⁵ In psychotic disorders, the messages can emerge as unreasoned and frightful fears, perceptions, beliefs, and behaviors. With newer research, clinical observation, and an evolutionary perspective, a novel and counter­intuitive approach may improve our ability to help patients.⁸

Continue to: Five affective comorbidities evolved from primeval altruistic instincts...

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

Melancholic depression is often triggered by serious illness, group exclusion, pronounced loss, or purposelessness. We hear patients talk painfully about illness, guilt, and death. Indeed, some increased risk of death, especially from infectious disease, may result from hypercortisolemia (documented by the dexamethasone suppression test). Hypercortisolemic death also occurs in salmon after spawning, and in male marsupial mice after mating. The tragic passing of an individual saves scarce resources for the remainder of the herd.

Obsessive-compulsive disorder⁵

Factor-analytic studies suggest 4 main obsessive-compulsive disorder (OCD) subtypes: cleanliness, hoarding, intrusive thoughts, and organizing. Obsessive-compulsive traits can help maintain a safe and efficient environment in humans and other species, but OCD is dysfunctional.

Panic anxiety⁵

Panic anxiety is triggered by real, symbolic, or emotional separation from home and family. In toddlers, separation anxiety can reduce the odds of getting lost and hurt.

Social anxiety⁵

Social anxiety includes fear of self-embarrassment, exposure as a pretender to higher social rank, and thus often a reluctant avoidance of increased social rank. While consciousness and cultural encouragement can overcome that hesitation and thus lead to greater success, social anxiety activation can still cause painful anxiety. The social hierarchies of many species include comparable biological influences, and help preserve group DNA by reducing hierarchical infighting.

Atypical depression and bipolar I mania⁵

Atypical depression includes increased rejection sensitivity, resulting in inoffensive behavior to avoid social rejection. This reduces risk of isolation from the group, and improves group harmony. Unlike the 4 other syndromes, atypical depression and bipolar I mania may reflect 2 separate seasonal mood phases. Atypical depression (including seasonal affective disorder) often worsens with shortened winter daylight hours, akin to hibernation. Initial bipolar I mania is more common with springtime daylight, with symptoms not unlike exaggerated hibernation awakening.⁹

Primeval biological altruism has great evolutionary value in many species, and even somewhat in modern humans. But it is quite different from modern rational altruism. Although we sometimes override our instincts, they respond with messages experienced as emotional pain—they still tell us to follow instructions for primeval herd survival. In an earlier book, I (JPK) provide a lengthier description of the evidence for this evolutionary psychopathology theory, including interplay of the 5 instincts with psychotogenic factors.⁵

Continue to: Five comorbidity psychoses from 5 primeval instincts.....

The 5 affective comorbidities described above contribute to the presence, subtype, and treatment approaches of 5 corresponding psychoses. Ordinary panic attacks might occur when feeling trapped or separated from home, so people want to flee to safety. Nonhuman species with limited consciousness and language are unlikely to think “time to head for safety.” Instead, instincts encourage flight from danger through internally generated perceptions of threat. Likewise, people with psychosis and panic, without sufficient conscious modulation, may experience sensory perceptions of actual danger when feeling symbolically trapped.^1,10

One pilot study carefully examined the prevalence of these 5 comorbidities in an unselected group of psychotic patients.¹⁰ At least 85% met criteria for ≥1 of the 5 subtypes.¹⁰ Moreover, organic psychoses related to physical illness, substances, and iatrogenesis may also predict future episodes of functional psychoses.¹

Using statistical analysis of psychosis rating scales, 2 studies took a “transdiagnostic” look at psychoses, and each found 5 psychosis subtypes and a generalized psychosis susceptibility factor.^11,12 Replication of that transdiagnostic approach, newly including psychosis symptoms and our 5 specific comorbidities, might well find that the 5 subtype models resemble each other.^11,12

Our proposed 5 comorbidity subtypes are¹:

Delusional depression (melancholic depression). Most common in geriatric patients, this psychosis can also occur at younger ages. Prodromal melancholic depression can include guilt and hopelessness, and is acute, rather than the chronic course of our other 4 syndromes. Subsequent delusional depression includes delusions of bodily decay, illness, or death, as well as overwhelming guilt, shame, and remorse. The classic vegetative symptoms of depression continue. In addition to infectious disease issues, high suicide risk makes hospitalization imperative.

Obsessive-compulsive schizophrenia. Just as OCD has an early age of onset, obsessive-compulsive schizophrenia begins earlier than other psychoses. Despite preserved cognition, some nonpsychotic patients with OCD have diminished symptom insight. OCD may be comorbid with schizophrenia in 12% of cases, typically preceding psychosis onset. Obsessive-compulsive schizophrenia symptoms may include highly exaggerated doubt or ambivalence; contamination concerns; eccentric, ritualistic, motor stereotypy, checking, disorganized, and other behaviors; and paranoia.

Schizophrenia with voices (panic anxiety). Classic paranoid schizophrenia with voices appears to be the most similar to a “panic psychosis.” Patients with nonpsychotic panic anxiety have increased paranoid ideation and ideas of reference as measured on the Symptom Checklist-90. Schizophrenia is highly comorbid with panic anxiety, estimated at 45% in the Epidemiologic Catchment Area study.¹³ These are likely underestimates: cognitive impairment hinders reporting, and psychotic panic is masked as auditory hallucinations. A pilot study of schizophrenia with voices using a carbon dioxide panic induction challenge found that 100% had panic anxiety.¹⁴ That study and another found that virtually all participants reported voices concurrent with panic using our Panic and Schizophrenia Interview (PaSI) (Box 1). Panic onset precedes schizophrenia onset, and panic may reappear if antipsychotic medications sufficiently control voices: “voices without the voices,” say some.

Box 1

Persecutory delusional disorder (social anxiety). Some “schizophrenia” without voices may be misdiagnosis of persecutory (paranoid) delusional disorder (PDD). Therefore, the reported population prevalence (0.02%) may be underestimated. Social anxiety is highly comorbid with “schizophrenia” (15%).¹⁶ Case reports and clinical experience suggest that PDD is commonly preceded by social anxiety.¹⁷ Some nonpsychotic social anxiety symptoms closely resemble the PDD psychotic ideas of reference (a perception that low social rank attracts critical scrutiny by authorities). Patients with PDD may remain relatively functional, with few negative symptoms, despite pronounced paranoia. Outward manifestation of paranoia may be limited, unless quite intense. The typical age of onset (40 years) is later than that of schizophrenia, and symptoms can last a long time.¹⁸

Continue to: Bipolar 1 mania with delusions...

Bipolar I mania with delusions (atypical depression). Atypical depression is the most common depression in bipolar I disorder. Often more pronounced in winter, it may intensify at any time of year. Long ago, hypersomnia, lethargy, inactivity, inoffensiveness, and craving high-calorie food may have been conducive to hibernation.

Bipolar I mania includes delusions of special accomplishments or abilities, energetically focused on a grandiose mission to help everyone. These intense symptoms may be related to reduced frontal lobe modulation. In some milder form, bipolar I mania may once have encouraged hibernation awakening. Indeed, initial bipolar I mania episodes are more common in spring, as is the spring cleaning that helps us prepare for summer.

Recognizing affective trees in a psychotic forest

Though long observed, comorbid affective symptoms have generally been considered a hodgepodge of distress caused by painful psychotic illness. But the affective symptoms precede psychosis onset, can be masked during acute psychosis, and will revert to ordinary form if psychosis abates.^11-13

Rather than affective symptoms being a consequence of psychosis, it may well be the other way around. Affective disorders could be important causal and differentiating components of psychotic disorders.^11-13 Research and clinical experience suggest that adjunctive treatment of the comorbidities with correct medication can greatly enhance outcome.

Diagnostic approaches

Because interviews of patients with psychosis are often complicated by confusion, irritability, paranoid evasiveness, cognitive impairment, and medication, nuanced diagnosis is difficult. Interviews should explore psychotic syndromes and subtypes that correlate with comorbidity psychoses, including pre-psychotic anxiety and depressive diagnoses that are chronic (though unlike our 4 other diagnoses, melancholic depression is not chronic).

Establishing pre-psychotic diagnosis of chronic syndromes suggests that they are still present, even if they are difficult to assess during psychosis. Re-interview after some improvement allows for a significantly better diagnosis. Just as in nonpsychotic affective disorders, multiple comorbidities are common, and can lead to a mixed psychotic diagnosis and treatment plan.¹

Structured interview tools can assist diagnosis. The PaSI (Box 1,¹⁵) elicits past, present, and detailed history of DSM panic, and has been validated in a small pilot randomized controlled trial. The PaSI focuses patient attention on paroxysmal onset voices, and then evaluates the presence of concurrent DSM panic symptoms. If voices are mostly psychotic panic, they may well be a proxy for panic. Ultimately, diagnosis of 5 comorbidities and associated psychotic symptoms may allow simpler categorization into 1 (or more) of the 5 psychosis subtypes.

Continue to: Treatment by comorbidity subtype...

Treatment of psychosis generally begins with antipsychotics. Nominal psychotherapy (presence of a professionally detached, compassionate clinician) improves compliance and leads to supportive therapy. Cognitive-behavioral therapy and dialectical behavior therapy may help later, with limited interpersonal approaches further on for some patients.

The suggested approaches to pharmacotherapy noted here draw on research and clinical experience.^1,14,19-21 All medications used to treat comorbidities noted here are approved or generally accepted for that diagnosis. Estimated doses are similar to those for comorbidities when patients are nonpsychotic, and vary among patients. Doses, dosing schedules, and titration are extremely important for full benefit. Always consider compliance issues, suicidality, possible adverse effects, and potential drug/drug interactions. Although the medications we suggest using to treat the comorbidities may appear to also benefit psychosis, only antipsychotics are approved for psychosis per se.

Delusional depression. Antipsychotic + antidepressant. Tricyclic antidepressants are possibly most effective, but increase the risk of overdose and dangerous falls among fragile patients. Electroconvulsive therapy is sometimes used.

Obsessive-compulsive schizophrenia. Antipsychotic + selective serotonin reuptake inhibitor (SSRI). Consider aripiprazole (consider long-acting injectable formulation for increased compliance). Aripiprazole also may enhance the benefit of fluoxetine for comorbid OCD. Carefully titrate, as tolerated, to optimal dose of fluoxetine (40 to 80 mg/d; the long half-life of fluoxetine and its metabolite norfluoxetine also improves compliance), while watching for activation and other adverse effects.^21,22 Limited clinical experience suggests that lower-dose clonazepam every 12 hours may reduce the adverse effects of fluoxetine.

Schizophrenia with voices. Antipsychotic + clonazepam. Concurrent usage may stabilize psychosis more rapidly, and with a lower antipsychotic dose.²³ Titrate a fixed dose of clonazepam every 12 hours (avoid as-needed doses), starting low (ie, 0.5 mg) to limit initial drowsiness (which typically diminishes in 3 to 10 days). Titrate to full voice and panic cessation (1 to 2.5 mg every 12 hours).¹⁴ Exercise caution about excessive drowsiness, as well as outpatient compliance and abuse. Besides alprazolam, other antipanic medications have little incidental benefit for psychosis.

Persecutory delusional disorder. Anti­psychotic + SSRI. Aripiprazole (consider long-acting injectable for compliance) also enhances the benefits of fluoxetine for social anxiety. Long half-life fluoxetine (20 mg/d) improves compliance and near-term outcomes.

Bipolar I mania: mania with delusions. Consider olanzapine for acute phase, then add other antimanic medication (commonly lithium or valproic acid), check blood level, and then taper olanzapine some weeks later. Importantly, lamotrigine is not effective for bipolar I mania. Consider suicide risk, medical conditions, and outpatient compliance. Comorbid panic anxiety is also common in bipolar I mania, often presenting as nonthreatening voices.

Seasonality: Following research that bipolar I mania is more common in spring and summer, studies have shown beneficial clinical augmentation from dark therapy as provided by reduced light exposure, blue-blocking glasses, and exogenous melatonin (a darkness-signaling hormone).²⁴

Bipolar I mania atypical depression (significant current or historical symptoms). SSRI + booster medication. An SSRI (ie, escitalopram, 10 mg/d) is best started several weeks after full bipolar I mania resolution, while also continuing long-term antimanic medication. Booster medications (ie, buspirone 15 mg every 12 hours; lithium 300 mg/d; or trazodone 50 mg every 12 hours) can enhance SSRI benefits. Meta-analysis suggests SSRIs may have limited risk of inducing bipolar I mania.²⁵ Although not yet specifically tested for atypical depression, lamotrigine may be effective, and may be safer still.²⁵ However, lamotrigine requires very gradual dose titration to prevent a potentially dangerous rash, including after periods of outpatient noncompliance.

Seasonality: Atypical depression is often worse in winter (seasonal affective disorder). Light therapy can produce some clinically helpful benefits year-round.

To illustrate this new approach to psychosis diagnosis and treatment, our book¹ includes detailed case studies on each of the 5 psychosis subtypes. The brief fictional case we present in Box 2 describes a patient who had both premorbid social anxiety and panic anxiety, and then developed a mixed psychosis that reflected both of those contributing anxiety disorders.

Box 2

Larger studies are needed

Current research supports the concept of a 5-diagnosis classification of psychoses, which may correlate with our comorbid anxiety and depression model. Larger diagnostic and treatment studies would invaluably examine existing research and clinical experience, and potentially encourage more clinically useful diagnoses, specific treatments, and improved outcomes.

Bottom Line

New insights from evolutionary psychopathology, clinical research and observation, psychotogenesis, genetics, and epidemiology suggest that most functional psychoses may fall into 1 of 5 comorbidity-defined subtypes, for which specific treatments can lead to much improved outcomes.

Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.

Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.

T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.¹ This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.

Metformin exerts its hypoglycemic effects by:

• decreasing glucose production from the liver
• increasing insulin receptors’ sensitivity in various body tissues
• increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.

In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.² In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.

The adverse effects of metformin are dose-related and mostly gastro­intestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.

The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.

Metabolic benefits

• Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.³
• Decreasing weight, body mass index, and waist circumference with the use of clozapine.⁴
• Decreasing triglycerides and total cholesterol.⁵
• Mitigating clozapine-induced obesity, especially if used prophylactically.⁶
• Lowering antipsychotic-induced weight gain.⁷

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

• Lowering elevated serum prolactin levels to avert sexual dysfunction.^8-10
• Increasing the production of neurons by inducing neurogenesis.^11,12
• Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.¹³
• Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.¹⁴
• Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.¹⁵
• Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.¹⁶
• Exerting multiple anti-aging effects (Table¹⁷). Metformin reduces several hallmarks of aging and may increase longevity.¹⁷
• Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes¹⁸ due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
• Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.¹⁹

Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.²⁰ So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”

Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.

Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.

T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.¹ This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.

Metformin exerts its hypoglycemic effects by:

• decreasing glucose production from the liver
• increasing insulin receptors’ sensitivity in various body tissues
• increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.

In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.² In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.

The adverse effects of metformin are dose-related and mostly gastro­intestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.

The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.

Metabolic benefits

• Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.³
• Decreasing weight, body mass index, and waist circumference with the use of clozapine.⁴
• Decreasing triglycerides and total cholesterol.⁵
• Mitigating clozapine-induced obesity, especially if used prophylactically.⁶
• Lowering antipsychotic-induced weight gain.⁷

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

• Lowering elevated serum prolactin levels to avert sexual dysfunction.^8-10
• Increasing the production of neurons by inducing neurogenesis.^11,12
• Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.¹³
• Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.¹⁴
• Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.¹⁵
• Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.¹⁶
• Exerting multiple anti-aging effects (Table¹⁷). Metformin reduces several hallmarks of aging and may increase longevity.¹⁷
• Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes¹⁸ due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
• Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.¹⁹

Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.²⁰ So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”

Metabolic dysregulation is quite common among psychiatric patients, especially those with psychotic or mood disorders. Obesity, diabetes, and dyslipidemia can be present at the onset of the illness, or as an iatrogenic complication. This often leads to premature mortality due to elevated cardiovascular and cerebrovascular risks.

Enter metformin. It is the most widely used hypoglycemic agent for type 2 diabetes (T2D), and it is frequently used by psychiatric clinicians. Discovered in 1922 and developed in France in the 1950s, metformin was approved for use in the United States in 1995, 3 decades after its launch in Europe. Its original trade name in the United States was Glucophage, and it is currently available from several companies in generic form. It is included on the World Health Organization list of essential medications.

T2D is currently an epidemic across the general populations globally, especially in the United States, where approximately 95% of the 37 million individuals with diabetes have been diagnosed with T2D.¹ This is 300% higher than the prevalence in the 1970s. No wonder metformin is one of the most often-used drugs in all of medicine, and a staple in primary care and psychiatry. It has helped countless patients avoid the multisystem hazards of insulin resistance, which is the root cause of T2D.

Metformin exerts its hypoglycemic effects by:

• decreasing glucose production from the liver
• increasing insulin receptors’ sensitivity in various body tissues
• increasing secretion of growth differentiating factor, which reduces appetite and calorie intake.

In 2017, the American College of Physicians updated its guidelines to adopt metformin as the first-line treatment for T2D, especially because the class of sulfonylureas were associated with a more than 5-fold higher risk of severe low blood sugar events compared with metformin.² In addition, metformin causes weight loss, while sulfonylureas are associated with weight gain. Metformin is particularly useful in gestational diabetes, where babies are born with less visceral fat and are less prone to insulin resistance later in life as adults.

The adverse effects of metformin are dose-related and mostly gastro­intestinal (GI), including nausea, vomiting, cramps, diarrhea, and flatulence. Gradual titration or using the extended-release formulation can lower or avert GI discomfort. Metformin should not be used in patients with severe kidney or liver disease. With long-term use, metformin can cause malabsorption and eventual deficiency of vitamin B12.

The metabolic benefits of metformin listed below are why psychiatrists use it in clinical practice. However, this medication has several benefits that go beyond metabolic disorders. Clinicians should be aware of all of the following salutary physical and mental effects of metformin.

Metabolic benefits

• Decreasing glucose dysregulation with the use of clozapine and other antipsychotics.³
• Decreasing weight, body mass index, and waist circumference with the use of clozapine.⁴
• Decreasing triglycerides and total cholesterol.⁵
• Mitigating clozapine-induced obesity, especially if used prophylactically.⁶
• Lowering antipsychotic-induced weight gain.⁷

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

• Lowering elevated serum prolactin levels to avert sexual dysfunction.^8-10
• Increasing the production of neurons by inducing neurogenesis.^11,12
• Activating the cerebral cortex to blunt the adverse effects of clozapine (such as deterioration of motivation, attention, cognition, and behavior) and increasing the activity of the dopamine D1 receptor, which is believed to be involved with cognition in schizophrenia.¹³
• Reducing the symptoms of anxiety and depression by increasing serotonin activity and hippocampal concentration of serotonin.¹⁴
• Decreasing the depressive symptoms known to be associated with uncontrolled diabetes.¹⁵
• Improving insulin resistance associated with polycystic ovary syndrome and helping with infertility.¹⁶
• Exerting multiple anti-aging effects (Table¹⁷). Metformin reduces several hallmarks of aging and may increase longevity.¹⁷
• Lowering the risks of cancer, dementia, and mortality in patients with and without diabetes¹⁸ due to its anti-aging effects. Scientists are actively studying metformin’s anti-aging effects and trying to develop drugs with similar effects.
• Counteracting inflammatory bowel disease, osteoporosis, neurodegeneration, inflammation, frailty, and senescence.¹⁹

Metformin may sound like a wonder drug or panacea, but most of its multiple beneficial effects have been reported and replicated. Its therapeutic effects on obesity, diabetes, and dyslipidemia can prevent early mortality, but its anti-aging effects are also important and may help reduce premature mortality, which is common in psychiatric patients.²⁰ So, the question arises: At some point, will metformin be used for persons not afflicted by diabetes or metabolic syndrome? For now, psychiatrists should continue to use it on label, but in the future, our patients may benefit from its “fringe benefits.”

Ms. A, age 45, is hospitalized for abdominal pain. She is noted to have hiccups, the onset of which she reports was >1 month ago and did not have a clear precipitant. Abdominal and head imaging return no acute findings, and data from a serum electrolyte test, hepatic function test, and thyroid function test are within normal limits. The medical team notices that Ms. A’s speech is pressured, she hardly sleeps, and she appears animated, full of ideas and energy.

Ms. A has a history of bipolar I disorder, hypertension, hyperlipidemia, gastroesophageal reflux disease, and hypothyroidism. Her present medications include hydrochlorothiazide 25 mg/d; levothyroxine 25 mcg/d; omeprazole 20 mg/d; and lovastatin 20 mg/d. She states that she was remotely treated for bipolar disorder, but she was cured by a shamanic healer, and therefore no longer needs treatment.

Approximately 35% of adults in the United States age 60 to 79 reported taking ≥5 prescription medications in 2016, compared to 15% of adults age 40 to 59.¹ In a study of 372 patients with advanced, life-limiting illness, Schenker et al² found that those who took multiple medications (mean: 11.6 medications) had a lower quality of life and worse symptoms. Optimizing medications to patients’ specific needs and diagnoses in order to reduce pill burden can be a favorable intervention. In addition, some patients—approximately 30% of those with schizophrenia and 20% of those with bipolar disorder—may not have insight into their mental illness as they do with their medical conditions, and may be more accepting of treatment for the latter.³ Dual-indication prescribing may be a useful way to decrease polypharmacy, reduce potential drug-drug interactions (DDIs), increase patient acceptance and adherence, and improve a patient’s overall health.

Continue on for: Multiple uses for antidepressants and antipsychotics...

One of the first medications discovered to have antidepressant effects was iproniazid, a monoamine oxidase inhibitor (MAOI) initially used to treat tuberculosis.⁴ Since then, numerous classes of antidepressant medications have been developed that capitalize on monoamine reuptake through several different mechanisms of action. These drugs can be grouped into subclasses that include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, MAOIs, and others. True to their roots in iproniazid, these medications can have a myriad of effects not limited to mental health and can therefore be beneficial for a variety of comorbid conditions.

As was the case with antidepressants, the first medication approved in the antipsychotic class, chlorpromazine, was serendipitously discovered to treat psychosis and agitation after being approved and used to treat presurgical apprehension.⁵ The term “antipsychotic” is almost a misnomer given these agents’ broad pharmacology profiles and impact on various mental illnesses, including bipolar disorder, depressive disorders, anxiety disorders, and many other mental conditions. First-generation antipsychotics (FGAs) were the first to enter the market; they work primarily by blocking dopamine-2 (D2) receptors. Second-generation antipsychotics have less movement-based adverse effects than FGAs by having higher affinity for serotonin 5-HT2A receptors than for D2 receptors. However, they tend to carry a higher risk for weight gain and metabolic syndrome.

Antidepressants and antipsychotics are widely utilized in psychiatry. Many have been found to have additional uses beyond their original FDA-approved indication and can therefore be beneficial for a variety of comorbid conditions.

One limitation of using psychiatric medications for nonpsychiatric indications is that different doses of antidepressants and antipsychotics are typically targeted for different indications based on receptor binding affinity. A common example of this is trazodone, where doses below 100 mg are used as needed for insomnia, but higher doses ranging from 200 to 600 mg/d are used for depression. Another important consideration is DDIs. For example, the possibility of adding an agent such as fluoxetine to a complex pain regimen for fibromyalgia could impact the clearance of other agents that are cytochrome P450 (CYP) 2D6 substrates due to fluoxetine’s potent inhibition of the enzyme.^6,7 Table 1^6-51, Table 2^52-68, Table 3^69-107, and Table 4^108-123 provide information on select antidepressants, while Table 5^124-140 and Table 6^141-171 provide information on select antipsychotics. Each table lists psychiatric and nonpsychiatric indications for the respective medications, including both FDA-approved (where applicable) and common off-label uses. Most of the indications listed are for adult use only, unless otherwise noted.

Continue on to: Case Continued...

CASE CONTINUED

After reviewing Ms. A’s medical history, the treatment team initiates chlorpromazine, 25 mg 3 times a day, for intractable hiccups, and increases the dosage to 50 mg 3 times a day after 3 days. Chlorpromazine is FDA-approved for treating bipolar mania, and also for treating intractable hiccups. Shortly thereafter, Ms. A’s hiccups subside, she sleeps for longer periods, and her manic symptoms resolve.

Ms. A, age 45, is hospitalized for abdominal pain. She is noted to have hiccups, the onset of which she reports was >1 month ago and did not have a clear precipitant. Abdominal and head imaging return no acute findings, and data from a serum electrolyte test, hepatic function test, and thyroid function test are within normal limits. The medical team notices that Ms. A’s speech is pressured, she hardly sleeps, and she appears animated, full of ideas and energy.

Ms. A has a history of bipolar I disorder, hypertension, hyperlipidemia, gastroesophageal reflux disease, and hypothyroidism. Her present medications include hydrochlorothiazide 25 mg/d; levothyroxine 25 mcg/d; omeprazole 20 mg/d; and lovastatin 20 mg/d. She states that she was remotely treated for bipolar disorder, but she was cured by a shamanic healer, and therefore no longer needs treatment.

Approximately 35% of adults in the United States age 60 to 79 reported taking ≥5 prescription medications in 2016, compared to 15% of adults age 40 to 59.¹ In a study of 372 patients with advanced, life-limiting illness, Schenker et al² found that those who took multiple medications (mean: 11.6 medications) had a lower quality of life and worse symptoms. Optimizing medications to patients’ specific needs and diagnoses in order to reduce pill burden can be a favorable intervention. In addition, some patients—approximately 30% of those with schizophrenia and 20% of those with bipolar disorder—may not have insight into their mental illness as they do with their medical conditions, and may be more accepting of treatment for the latter.³ Dual-indication prescribing may be a useful way to decrease polypharmacy, reduce potential drug-drug interactions (DDIs), increase patient acceptance and adherence, and improve a patient’s overall health.

Continue on for: Multiple uses for antidepressants and antipsychotics...

One of the first medications discovered to have antidepressant effects was iproniazid, a monoamine oxidase inhibitor (MAOI) initially used to treat tuberculosis.⁴ Since then, numerous classes of antidepressant medications have been developed that capitalize on monoamine reuptake through several different mechanisms of action. These drugs can be grouped into subclasses that include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, MAOIs, and others. True to their roots in iproniazid, these medications can have a myriad of effects not limited to mental health and can therefore be beneficial for a variety of comorbid conditions.

As was the case with antidepressants, the first medication approved in the antipsychotic class, chlorpromazine, was serendipitously discovered to treat psychosis and agitation after being approved and used to treat presurgical apprehension.⁵ The term “antipsychotic” is almost a misnomer given these agents’ broad pharmacology profiles and impact on various mental illnesses, including bipolar disorder, depressive disorders, anxiety disorders, and many other mental conditions. First-generation antipsychotics (FGAs) were the first to enter the market; they work primarily by blocking dopamine-2 (D2) receptors. Second-generation antipsychotics have less movement-based adverse effects than FGAs by having higher affinity for serotonin 5-HT2A receptors than for D2 receptors. However, they tend to carry a higher risk for weight gain and metabolic syndrome.

Antidepressants and antipsychotics are widely utilized in psychiatry. Many have been found to have additional uses beyond their original FDA-approved indication and can therefore be beneficial for a variety of comorbid conditions.

One limitation of using psychiatric medications for nonpsychiatric indications is that different doses of antidepressants and antipsychotics are typically targeted for different indications based on receptor binding affinity. A common example of this is trazodone, where doses below 100 mg are used as needed for insomnia, but higher doses ranging from 200 to 600 mg/d are used for depression. Another important consideration is DDIs. For example, the possibility of adding an agent such as fluoxetine to a complex pain regimen for fibromyalgia could impact the clearance of other agents that are cytochrome P450 (CYP) 2D6 substrates due to fluoxetine’s potent inhibition of the enzyme.^6,7 Table 1^6-51, Table 2^52-68, Table 3^69-107, and Table 4^108-123 provide information on select antidepressants, while Table 5^124-140 and Table 6^141-171 provide information on select antipsychotics. Each table lists psychiatric and nonpsychiatric indications for the respective medications, including both FDA-approved (where applicable) and common off-label uses. Most of the indications listed are for adult use only, unless otherwise noted.

Continue on to: Case Continued...

CASE CONTINUED

After reviewing Ms. A’s medical history, the treatment team initiates chlorpromazine, 25 mg 3 times a day, for intractable hiccups, and increases the dosage to 50 mg 3 times a day after 3 days. Chlorpromazine is FDA-approved for treating bipolar mania, and also for treating intractable hiccups. Shortly thereafter, Ms. A’s hiccups subside, she sleeps for longer periods, and her manic symptoms resolve.

Ms. A, age 45, is hospitalized for abdominal pain. She is noted to have hiccups, the onset of which she reports was >1 month ago and did not have a clear precipitant. Abdominal and head imaging return no acute findings, and data from a serum electrolyte test, hepatic function test, and thyroid function test are within normal limits. The medical team notices that Ms. A’s speech is pressured, she hardly sleeps, and she appears animated, full of ideas and energy.

Ms. A has a history of bipolar I disorder, hypertension, hyperlipidemia, gastroesophageal reflux disease, and hypothyroidism. Her present medications include hydrochlorothiazide 25 mg/d; levothyroxine 25 mcg/d; omeprazole 20 mg/d; and lovastatin 20 mg/d. She states that she was remotely treated for bipolar disorder, but she was cured by a shamanic healer, and therefore no longer needs treatment.

Approximately 35% of adults in the United States age 60 to 79 reported taking ≥5 prescription medications in 2016, compared to 15% of adults age 40 to 59.¹ In a study of 372 patients with advanced, life-limiting illness, Schenker et al² found that those who took multiple medications (mean: 11.6 medications) had a lower quality of life and worse symptoms. Optimizing medications to patients’ specific needs and diagnoses in order to reduce pill burden can be a favorable intervention. In addition, some patients—approximately 30% of those with schizophrenia and 20% of those with bipolar disorder—may not have insight into their mental illness as they do with their medical conditions, and may be more accepting of treatment for the latter.³ Dual-indication prescribing may be a useful way to decrease polypharmacy, reduce potential drug-drug interactions (DDIs), increase patient acceptance and adherence, and improve a patient’s overall health.

Continue on for: Multiple uses for antidepressants and antipsychotics...

One of the first medications discovered to have antidepressant effects was iproniazid, a monoamine oxidase inhibitor (MAOI) initially used to treat tuberculosis.⁴ Since then, numerous classes of antidepressant medications have been developed that capitalize on monoamine reuptake through several different mechanisms of action. These drugs can be grouped into subclasses that include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, MAOIs, and others. True to their roots in iproniazid, these medications can have a myriad of effects not limited to mental health and can therefore be beneficial for a variety of comorbid conditions.

As was the case with antidepressants, the first medication approved in the antipsychotic class, chlorpromazine, was serendipitously discovered to treat psychosis and agitation after being approved and used to treat presurgical apprehension.⁵ The term “antipsychotic” is almost a misnomer given these agents’ broad pharmacology profiles and impact on various mental illnesses, including bipolar disorder, depressive disorders, anxiety disorders, and many other mental conditions. First-generation antipsychotics (FGAs) were the first to enter the market; they work primarily by blocking dopamine-2 (D2) receptors. Second-generation antipsychotics have less movement-based adverse effects than FGAs by having higher affinity for serotonin 5-HT2A receptors than for D2 receptors. However, they tend to carry a higher risk for weight gain and metabolic syndrome.

Antidepressants and antipsychotics are widely utilized in psychiatry. Many have been found to have additional uses beyond their original FDA-approved indication and can therefore be beneficial for a variety of comorbid conditions.

One limitation of using psychiatric medications for nonpsychiatric indications is that different doses of antidepressants and antipsychotics are typically targeted for different indications based on receptor binding affinity. A common example of this is trazodone, where doses below 100 mg are used as needed for insomnia, but higher doses ranging from 200 to 600 mg/d are used for depression. Another important consideration is DDIs. For example, the possibility of adding an agent such as fluoxetine to a complex pain regimen for fibromyalgia could impact the clearance of other agents that are cytochrome P450 (CYP) 2D6 substrates due to fluoxetine’s potent inhibition of the enzyme.^6,7 Table 1^6-51, Table 2^52-68, Table 3^69-107, and Table 4^108-123 provide information on select antidepressants, while Table 5^124-140 and Table 6^141-171 provide information on select antipsychotics. Each table lists psychiatric and nonpsychiatric indications for the respective medications, including both FDA-approved (where applicable) and common off-label uses. Most of the indications listed are for adult use only, unless otherwise noted.

Continue on to: Case Continued...

CASE CONTINUED

After reviewing Ms. A’s medical history, the treatment team initiates chlorpromazine, 25 mg 3 times a day, for intractable hiccups, and increases the dosage to 50 mg 3 times a day after 3 days. Chlorpromazine is FDA-approved for treating bipolar mania, and also for treating intractable hiccups. Shortly thereafter, Ms. A’s hiccups subside, she sleeps for longer periods, and her manic symptoms resolve.

Schizotypal disorder is a complex condition that is characterized by cognitive-perceptual impairments, oddness, disorganization, and interpersonal difficulties. It often is unrecognized or underdiagnosed. In DSM-5, schizotypal disorder is categorized a personality disorder, but it is also considered part of the schizophrenia spectrum disorders.¹ The diagnostic criteria for schizotypal disorder are outlined in the Table.^1,2

Although schizotypal disorder has a lifetime prevalence of approximately 4% in the general population of the United States,² it can present during childhood or adolescence and may be overlooked in the differential diagnosis for psychotic symptoms in pediatric patients.³ Schizotypal disorder of childhood (SDC) can present with significant overlap with several pediatric diagnoses, including schizophrenia spectrum disorders and autism spectrum disorder (ASD), all of which may include psychotic symptoms and difficulties in interpersonal relationships. This overlap, combined with the lack of awareness of schizotypal disorder, can pose a diagnostic challenge. Better recognition of SDC could result in earlier and more effective treatment. In this article, we provide tips for differentiating SDC from childhood-onset schizophrenia and from ASD.

Differentiating SDC from schizophrenia

SDC may be mistaken for childhood-onset schizophrenia due to its perceptual disturbances (which may be interpreted as visual or auditory hallucinations), bizarre fantasies (which may be mistaken for overt delusions), paranoia, and odd behavior. Two ways to distinguish SDC from childhood schizophrenia are by clinical course and by severity of negative psychotic symptoms.

SDC tends to have an overall stable clinical course,⁴ with patients experiencing periods of time when they exhibit a more normal mental status complemented by fluctuations in symptom severity, which are exacerbated by stressors and followed by a return to baseline.³ SDC psychotic symptoms are predominantly positive, and patients typically do not demonstrate negative features beyond social difficulties. Childhood-onset schizophrenia is typically progressive and disabling, with worsening severity over time, and is much more likely to incorporate prominent negative symptoms.³

Differentiating SDC from ASD

SDC also demonstrates considerable diagnostic overlap with ASD, especially with regards to inappropriate affect; odd thinking, behavior, and speech; and social difficulties. Further complicating the diagnosis, ASD and SDC are comorbid in approximately 40% of ASD cases.^3,5 The Melbourne Assessment of Schizotypy in Kids demonstrates validity in diagnosing schizotypal disorder in patients with comorbid ASD.^5,6 For clinicians without easy access to advanced testing, 2 ways to distinguish SDC from ASD are the content of the odd behavior and thoughts, and the patient’s reaction to social deficits.

In SDC, odd behavior and thoughts most often revolve around daydreaming and a focus on “elaborate inner fantasies.”^3,6 Unlike in ASD, in patients with SDC, behaviors don’t typically involve stereotyped mannerisms, the patient is unlikely to have rigid interests (apart from their fantasies), and there is not a particular focus on detail in the external world.^3,6 Notably, imaginary companions are common in SDC; children with ASD are less likely to have an imaginary companion compared with children with SDC or those with no psychiatric diagnosis.⁶ Patients with SDC have social difficulties (often due to social anxiety stemming from their paranoia) but usually seek out interaction and are bothered by alienation, while patients with ASD may have less interest in social engagement.⁶

Schizotypal disorder is a complex condition that is characterized by cognitive-perceptual impairments, oddness, disorganization, and interpersonal difficulties. It often is unrecognized or underdiagnosed. In DSM-5, schizotypal disorder is categorized a personality disorder, but it is also considered part of the schizophrenia spectrum disorders.¹ The diagnostic criteria for schizotypal disorder are outlined in the Table.^1,2

Although schizotypal disorder has a lifetime prevalence of approximately 4% in the general population of the United States,² it can present during childhood or adolescence and may be overlooked in the differential diagnosis for psychotic symptoms in pediatric patients.³ Schizotypal disorder of childhood (SDC) can present with significant overlap with several pediatric diagnoses, including schizophrenia spectrum disorders and autism spectrum disorder (ASD), all of which may include psychotic symptoms and difficulties in interpersonal relationships. This overlap, combined with the lack of awareness of schizotypal disorder, can pose a diagnostic challenge. Better recognition of SDC could result in earlier and more effective treatment. In this article, we provide tips for differentiating SDC from childhood-onset schizophrenia and from ASD.

Differentiating SDC from schizophrenia

SDC may be mistaken for childhood-onset schizophrenia due to its perceptual disturbances (which may be interpreted as visual or auditory hallucinations), bizarre fantasies (which may be mistaken for overt delusions), paranoia, and odd behavior. Two ways to distinguish SDC from childhood schizophrenia are by clinical course and by severity of negative psychotic symptoms.

SDC tends to have an overall stable clinical course,⁴ with patients experiencing periods of time when they exhibit a more normal mental status complemented by fluctuations in symptom severity, which are exacerbated by stressors and followed by a return to baseline.³ SDC psychotic symptoms are predominantly positive, and patients typically do not demonstrate negative features beyond social difficulties. Childhood-onset schizophrenia is typically progressive and disabling, with worsening severity over time, and is much more likely to incorporate prominent negative symptoms.³

Differentiating SDC from ASD

SDC also demonstrates considerable diagnostic overlap with ASD, especially with regards to inappropriate affect; odd thinking, behavior, and speech; and social difficulties. Further complicating the diagnosis, ASD and SDC are comorbid in approximately 40% of ASD cases.^3,5 The Melbourne Assessment of Schizotypy in Kids demonstrates validity in diagnosing schizotypal disorder in patients with comorbid ASD.^5,6 For clinicians without easy access to advanced testing, 2 ways to distinguish SDC from ASD are the content of the odd behavior and thoughts, and the patient’s reaction to social deficits.

In SDC, odd behavior and thoughts most often revolve around daydreaming and a focus on “elaborate inner fantasies.”^3,6 Unlike in ASD, in patients with SDC, behaviors don’t typically involve stereotyped mannerisms, the patient is unlikely to have rigid interests (apart from their fantasies), and there is not a particular focus on detail in the external world.^3,6 Notably, imaginary companions are common in SDC; children with ASD are less likely to have an imaginary companion compared with children with SDC or those with no psychiatric diagnosis.⁶ Patients with SDC have social difficulties (often due to social anxiety stemming from their paranoia) but usually seek out interaction and are bothered by alienation, while patients with ASD may have less interest in social engagement.⁶

Schizotypal disorder is a complex condition that is characterized by cognitive-perceptual impairments, oddness, disorganization, and interpersonal difficulties. It often is unrecognized or underdiagnosed. In DSM-5, schizotypal disorder is categorized a personality disorder, but it is also considered part of the schizophrenia spectrum disorders.¹ The diagnostic criteria for schizotypal disorder are outlined in the Table.^1,2

Although schizotypal disorder has a lifetime prevalence of approximately 4% in the general population of the United States,² it can present during childhood or adolescence and may be overlooked in the differential diagnosis for psychotic symptoms in pediatric patients.³ Schizotypal disorder of childhood (SDC) can present with significant overlap with several pediatric diagnoses, including schizophrenia spectrum disorders and autism spectrum disorder (ASD), all of which may include psychotic symptoms and difficulties in interpersonal relationships. This overlap, combined with the lack of awareness of schizotypal disorder, can pose a diagnostic challenge. Better recognition of SDC could result in earlier and more effective treatment. In this article, we provide tips for differentiating SDC from childhood-onset schizophrenia and from ASD.

Differentiating SDC from schizophrenia

SDC may be mistaken for childhood-onset schizophrenia due to its perceptual disturbances (which may be interpreted as visual or auditory hallucinations), bizarre fantasies (which may be mistaken for overt delusions), paranoia, and odd behavior. Two ways to distinguish SDC from childhood schizophrenia are by clinical course and by severity of negative psychotic symptoms.

SDC tends to have an overall stable clinical course,⁴ with patients experiencing periods of time when they exhibit a more normal mental status complemented by fluctuations in symptom severity, which are exacerbated by stressors and followed by a return to baseline.³ SDC psychotic symptoms are predominantly positive, and patients typically do not demonstrate negative features beyond social difficulties. Childhood-onset schizophrenia is typically progressive and disabling, with worsening severity over time, and is much more likely to incorporate prominent negative symptoms.³

Differentiating SDC from ASD

SDC also demonstrates considerable diagnostic overlap with ASD, especially with regards to inappropriate affect; odd thinking, behavior, and speech; and social difficulties. Further complicating the diagnosis, ASD and SDC are comorbid in approximately 40% of ASD cases.^3,5 The Melbourne Assessment of Schizotypy in Kids demonstrates validity in diagnosing schizotypal disorder in patients with comorbid ASD.^5,6 For clinicians without easy access to advanced testing, 2 ways to distinguish SDC from ASD are the content of the odd behavior and thoughts, and the patient’s reaction to social deficits.

In SDC, odd behavior and thoughts most often revolve around daydreaming and a focus on “elaborate inner fantasies.”^3,6 Unlike in ASD, in patients with SDC, behaviors don’t typically involve stereotyped mannerisms, the patient is unlikely to have rigid interests (apart from their fantasies), and there is not a particular focus on detail in the external world.^3,6 Notably, imaginary companions are common in SDC; children with ASD are less likely to have an imaginary companion compared with children with SDC or those with no psychiatric diagnosis.⁶ Patients with SDC have social difficulties (often due to social anxiety stemming from their paranoia) but usually seek out interaction and are bothered by alienation, while patients with ASD may have less interest in social engagement.⁶

LAS VEGAS – How do you know when a patient is a candidate for electroconvulsive therapy (ECT)?

In the opinion of Mark S. George, MD, it depends on the level of treatment resistance, other treatments the person may be receiving for severe depression or bipolar disorder, and the level of acuity.

“Acute ECT is also useful for catatonia that does not resolve with benzodiazepines, and it also works well for acute suicidality,” Dr. George, distinguished professor of psychiatry, radiology, and neurology at the Medical University of South Carolina, Charleston, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “The other reason you would go straight to ECT would be if someone has had good prior ECT response.”

ECT is the oldest biological psychiatry therapy, a treatment that he characterized as “our most effective treatment for depression. It is lifesaving. Some studies suggests that ECT is effective in Parkinson’s disease and schizophrenia. Antidepressant effects generally take 2-3 weeks, but quicker responses are sometimes seen, especially in patients with bipolar depression.”

In the past 20 years of research studies involving ECT, investigators have discovered that a generalized seizure of adequate duration is necessary for adequate antidepressant effects; reduced therapeutic effects are seen with parietal placement, meaning that proper scalp placement matters; a dose titration over the 12 treatments improves efficacy, and smaller pulse widths are more effective and may result in fewer toxic side effects. “ECT is still relatively spatially crude compared with the other brain stimulation treatments,” said Dr. George, editor-in-chief of Brain Stimulation. “It’s also invasive, requiring repeated anesthesia, and sometimes has possible side effects including impacts on short-term memory.”

An emerging adjunct to ECT is cervical invasive vagus nerve stimulation (VNS) therapy, in which mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain. “Surgeons wrap a wire around the vagus nerve and connect the wire to a generator which is embedded in the chest wall,” Dr. George explained. “The generator sends out a signal through the vagus nerve intermittently. You can program how it does that.”

A device from LivaNova known as the VNS Pulse Model 102 Generator was granted clearance for depression based on a comparative study, but in the absence of class I evidence. The generator is about the size of a quarter, is embedded under the skin, and its battery lasts for 8-10 years. “Patients are given a static magnet to use to turn the device off if they’re having side effects, as a safety precaution,” said Dr. George, a staff physician at the Ralph H. Johnson VA Medical Center in Charleston. “The side effects are mainly stimulation-based and typically decrease over time. There is a low rate of treatment discontinuation and no signal for treatment-related emergence of suicidal ideation/behavior. Sometimes you can get emergent mania or hypermania, but it’s rare. It’s pretty safe, but the insurance companies have been very slow to pay. You only get about 30% remission, this takes several months to years to achieve, and there’s no way to tell who’s going to respond before you place the device.”

However, results from a 5-year observational study of patients with treatment-resistant depression who were treated at 61 sites with VNS or treatment as usual found that the antidepressant effects built over time compared with treatment as usual (Am J Psychiatry 2017;174[7]:640-8). “There is remarkable durability but it’s not very fast,” he said. “It’s three months before you start seeing any differences.”

According to Dr. George, data from an informal registry of Medicare patients who received VNS treatment “did so much better” than untreated patients. “They didn’t need as much ECT and didn’t require as many hospitalizations,” he said. “They weren’t changing medications nearly as much. They found that VNS was saving money and saving people’s lives.” As a result, in September of 2019 LivaNova launched a prospective, multicenter, randomized, controlled, blinded trial of subjects implanted with VNS therapy, called RECOVER. Active treatment and no stimulation control are randomized at least 2 weeks after implantation and observed for 12 months. The study is ongoing with results expected in 2022 or 2023.

Dr. George disclosed that he is a paid consultant for Neurolief, Microtransponder, and Sooma and that he has been a paid consultant for GSK, Cyberonics, NeuroPace, and Jazz. He is an unpaid consultant to Brainsway, Neuronetics, Neostim, Neosync, and Magnus Medical.

LAS VEGAS – How do you know when a patient is a candidate for electroconvulsive therapy (ECT)?

In the opinion of Mark S. George, MD, it depends on the level of treatment resistance, other treatments the person may be receiving for severe depression or bipolar disorder, and the level of acuity.

“Acute ECT is also useful for catatonia that does not resolve with benzodiazepines, and it also works well for acute suicidality,” Dr. George, distinguished professor of psychiatry, radiology, and neurology at the Medical University of South Carolina, Charleston, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “The other reason you would go straight to ECT would be if someone has had good prior ECT response.”

ECT is the oldest biological psychiatry therapy, a treatment that he characterized as “our most effective treatment for depression. It is lifesaving. Some studies suggests that ECT is effective in Parkinson’s disease and schizophrenia. Antidepressant effects generally take 2-3 weeks, but quicker responses are sometimes seen, especially in patients with bipolar depression.”

In the past 20 years of research studies involving ECT, investigators have discovered that a generalized seizure of adequate duration is necessary for adequate antidepressant effects; reduced therapeutic effects are seen with parietal placement, meaning that proper scalp placement matters; a dose titration over the 12 treatments improves efficacy, and smaller pulse widths are more effective and may result in fewer toxic side effects. “ECT is still relatively spatially crude compared with the other brain stimulation treatments,” said Dr. George, editor-in-chief of Brain Stimulation. “It’s also invasive, requiring repeated anesthesia, and sometimes has possible side effects including impacts on short-term memory.”

An emerging adjunct to ECT is cervical invasive vagus nerve stimulation (VNS) therapy, in which mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain. “Surgeons wrap a wire around the vagus nerve and connect the wire to a generator which is embedded in the chest wall,” Dr. George explained. “The generator sends out a signal through the vagus nerve intermittently. You can program how it does that.”

A device from LivaNova known as the VNS Pulse Model 102 Generator was granted clearance for depression based on a comparative study, but in the absence of class I evidence. The generator is about the size of a quarter, is embedded under the skin, and its battery lasts for 8-10 years. “Patients are given a static magnet to use to turn the device off if they’re having side effects, as a safety precaution,” said Dr. George, a staff physician at the Ralph H. Johnson VA Medical Center in Charleston. “The side effects are mainly stimulation-based and typically decrease over time. There is a low rate of treatment discontinuation and no signal for treatment-related emergence of suicidal ideation/behavior. Sometimes you can get emergent mania or hypermania, but it’s rare. It’s pretty safe, but the insurance companies have been very slow to pay. You only get about 30% remission, this takes several months to years to achieve, and there’s no way to tell who’s going to respond before you place the device.”

However, results from a 5-year observational study of patients with treatment-resistant depression who were treated at 61 sites with VNS or treatment as usual found that the antidepressant effects built over time compared with treatment as usual (Am J Psychiatry 2017;174[7]:640-8). “There is remarkable durability but it’s not very fast,” he said. “It’s three months before you start seeing any differences.”

According to Dr. George, data from an informal registry of Medicare patients who received VNS treatment “did so much better” than untreated patients. “They didn’t need as much ECT and didn’t require as many hospitalizations,” he said. “They weren’t changing medications nearly as much. They found that VNS was saving money and saving people’s lives.” As a result, in September of 2019 LivaNova launched a prospective, multicenter, randomized, controlled, blinded trial of subjects implanted with VNS therapy, called RECOVER. Active treatment and no stimulation control are randomized at least 2 weeks after implantation and observed for 12 months. The study is ongoing with results expected in 2022 or 2023.

Dr. George disclosed that he is a paid consultant for Neurolief, Microtransponder, and Sooma and that he has been a paid consultant for GSK, Cyberonics, NeuroPace, and Jazz. He is an unpaid consultant to Brainsway, Neuronetics, Neostim, Neosync, and Magnus Medical.

LAS VEGAS – How do you know when a patient is a candidate for electroconvulsive therapy (ECT)?

In the opinion of Mark S. George, MD, it depends on the level of treatment resistance, other treatments the person may be receiving for severe depression or bipolar disorder, and the level of acuity.

“Acute ECT is also useful for catatonia that does not resolve with benzodiazepines, and it also works well for acute suicidality,” Dr. George, distinguished professor of psychiatry, radiology, and neurology at the Medical University of South Carolina, Charleston, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “The other reason you would go straight to ECT would be if someone has had good prior ECT response.”

ECT is the oldest biological psychiatry therapy, a treatment that he characterized as “our most effective treatment for depression. It is lifesaving. Some studies suggests that ECT is effective in Parkinson’s disease and schizophrenia. Antidepressant effects generally take 2-3 weeks, but quicker responses are sometimes seen, especially in patients with bipolar depression.”

In the past 20 years of research studies involving ECT, investigators have discovered that a generalized seizure of adequate duration is necessary for adequate antidepressant effects; reduced therapeutic effects are seen with parietal placement, meaning that proper scalp placement matters; a dose titration over the 12 treatments improves efficacy, and smaller pulse widths are more effective and may result in fewer toxic side effects. “ECT is still relatively spatially crude compared with the other brain stimulation treatments,” said Dr. George, editor-in-chief of Brain Stimulation. “It’s also invasive, requiring repeated anesthesia, and sometimes has possible side effects including impacts on short-term memory.”

An emerging adjunct to ECT is cervical invasive vagus nerve stimulation (VNS) therapy, in which mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain. “Surgeons wrap a wire around the vagus nerve and connect the wire to a generator which is embedded in the chest wall,” Dr. George explained. “The generator sends out a signal through the vagus nerve intermittently. You can program how it does that.”

A device from LivaNova known as the VNS Pulse Model 102 Generator was granted clearance for depression based on a comparative study, but in the absence of class I evidence. The generator is about the size of a quarter, is embedded under the skin, and its battery lasts for 8-10 years. “Patients are given a static magnet to use to turn the device off if they’re having side effects, as a safety precaution,” said Dr. George, a staff physician at the Ralph H. Johnson VA Medical Center in Charleston. “The side effects are mainly stimulation-based and typically decrease over time. There is a low rate of treatment discontinuation and no signal for treatment-related emergence of suicidal ideation/behavior. Sometimes you can get emergent mania or hypermania, but it’s rare. It’s pretty safe, but the insurance companies have been very slow to pay. You only get about 30% remission, this takes several months to years to achieve, and there’s no way to tell who’s going to respond before you place the device.”

However, results from a 5-year observational study of patients with treatment-resistant depression who were treated at 61 sites with VNS or treatment as usual found that the antidepressant effects built over time compared with treatment as usual (Am J Psychiatry 2017;174[7]:640-8). “There is remarkable durability but it’s not very fast,” he said. “It’s three months before you start seeing any differences.”

According to Dr. George, data from an informal registry of Medicare patients who received VNS treatment “did so much better” than untreated patients. “They didn’t need as much ECT and didn’t require as many hospitalizations,” he said. “They weren’t changing medications nearly as much. They found that VNS was saving money and saving people’s lives.” As a result, in September of 2019 LivaNova launched a prospective, multicenter, randomized, controlled, blinded trial of subjects implanted with VNS therapy, called RECOVER. Active treatment and no stimulation control are randomized at least 2 weeks after implantation and observed for 12 months. The study is ongoing with results expected in 2022 or 2023.

Dr. George disclosed that he is a paid consultant for Neurolief, Microtransponder, and Sooma and that he has been a paid consultant for GSK, Cyberonics, NeuroPace, and Jazz. He is an unpaid consultant to Brainsway, Neuronetics, Neostim, Neosync, and Magnus Medical.

LAS VEGAS – In the opinion of Christoph U. Correll, MD, tardive dyskinesia (TD) “has been somewhat forgotten” by psychiatrists because the risk of patients developing the condition is considered to be significantly lower with second-generation antipsychotics compared with first-generation antipsychotics.

“But this does not seem to always be the case, because there is still a risk of TD, and we need to monitor for it,” Dr. Correll, professor of psychiatry and molecular medicine at The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “It is important to minimize the risk of TD by educating patients and caregivers about the risks of and alternatives to antipsychotic medication and early signs of TD.”

First described in 1957, TD is characterized by involuntary repetitive but irregular movements, mostly in the oral, lingual, and buccal regions – such as tongue protruding, puckering, chewing, and grimacing. Less often, there are movements in the hands, legs, feet, and torso. Symptoms can include mannerisms, stereotypies, tics, myoclonus, dystonias, tremor, and akathisia. “TD can be severe, persistent, and have medical and psychosocial consequences,” Dr. Correll said. “It can occur in untreated patients, but treatment with dopamine blocking agents – antipsychotics and metoclopramide – increases risk for TD.”

Differential diagnoses to consider include morbus Huntington, benign familial Chorea, and Sydenham’s Chorea. Less frequent causes of TD include metabolic conditions such as uremia, hyponatremia, hypernatremia, hypoparathyroidism, and hyperparathyroidism. “Those would need to be ruled out during the physical exam,” he said. There can also be inflammatory causes of TD such as herpes simplex virus, varicella, measles, mumps, and rubella.

A standard measure for TD diagnosis is the Abnormal Involuntary Movement Scale (AIMS), an observer-rated 12-item anchored scale that takes 5-10 minutes to administer. However, the AIMS on its own does not diagnose TD. In 1982, researchers developed three diagnostic criteria for TD: At least 3 months of cumulative antipsychotic drug exposure; presence of at least moderate abnormal involuntary movements in one or more body area(s) or mild movements in two or more body areas, and absence of other conditions that might produce involuntary movements (Arch Gen Psychiatry 1982;39:486-7).

The impact of TD on everyday functioning depends on anatomic location as well as severity, Dr. Correll continued. The condition can cause impairments to speech, verbal communication, dentition, temporomandibular joint pain/myalgia, swallowing difficulties, and fine motor skills including instrumental activities of daily living and written communication. Truncal and lower extremity TD can affect gait, posture and postural stability, strength, power flexibility, physical capacity, and one’s ability to exercise. “There are also psychological impairments,” he said. “Patients can develop different awareness so they become self-conscious; there can be cognitive abnormalities, and they can become more anxious or [have an] increased sense of paranoia, isolation, stigma, social and/or educational/vocational impairment.”

According to research by Dr. Correll and colleagues, unmodifiable patient-related risk factors for TD include older age, female sex, and being of white or African descent (J Neurol Sci 2018 June 15; 389:21-7). Unmodifiable illness-related risk factors include longer duration of illness, intellectual disability and brain damage, negative symptoms in schizophrenia, mood disorders, cognitive symptoms in mood disorders, and gene polymorphisms involving antipsychotic metabolism and dopamine functioning. Modifiable comorbidity-related factors include diabetes, smoking, and alcohol/substance abuse, while modifiable treatment-related factors include dopamine receptor blockers, higher cumulative and current antipsychotic dose or plasma levels, early parkinsonian side effects, treatment-emergent akathisia, and anticholinergic co-treatment. In a meta-analysis of 41 studies that aimed to determine the prevalence of TD, the mean age of the 11,493 patients was 43, 66% were male, and 77% had schizophrenia spectrum disorders (J Clin Psychiatry. 2017 Mar;78[3]:e264-78). The global mean TD prevalence was 25%, but the rates were lower with patients on current treatment with second-generation antipsychotics compared with those on first-generation antipsychotics (21% vs. 30%, respectively).

According to Dr. Correll, strategies for preventing TD include confirming and documenting the indication for dopamine antagonist antipsychotic medications, using conservative maintenance doses, and considering the use of SGAs, especially in those at high risk for EPS (extrapyramidal symptoms). “Don’t go too high [with the dose],” he said. “Stay below the EPS threshold. Inform patients and caregivers of the risk of TD and assess for incipient signs regularly using the AIMS.”

Treatment options include discontinuing antipsychotics, adjusting their dose, or switching patients from a first-generation antipsychotic to a second-generation antipsychotic. Supplementation with antioxidants/radical scavengers such as vitamin E, vitamin B₆, ginkgo biloba, and fish oil “can be tried, but have limited evidence, as is the case for melatonin.” Other options include clonazepam, amantadine, donepezil, and tetrabenazine, a reversible and specific inhibitor of vesicular monoamine transporter-2 (VMAT-2), a transporter that packages neurotransmitters (preferentially dopamine) into vesicles for release into the synapse and was approved in 2008 as an orphan drug for the treatment of choreiform movements associated with Huntington’s disease. “Neurologists have using tetrabenazine off-label for TD, but in schizophrenia and other psychiatric care, we rarely use it because it has to be given three times a day and it has a black box warning for depression and suicidality,” he said.

Dr. Correll noted that the Food and Drug Administration approval of two more recent VMAT-2 inhibitors – deutetrabenazine (Austedo) and valbenazine (Ingrezza) – provides an evidence-based care option for the effective management of TD. Deutetrabenazine requires titration over several weeks and twice-daily dosing, while valbenazine can reach the maximum dose by the beginning of week 2 and is dosed once daily. Deutetrabenazine should be taken with food, which is not required valbenazine.

“Both VMAT-2 inhibitors are generally well tolerated and have a positive benefit-risk ratio,” he said. “Both are recommended by the APA guidelines as the preferred and only evidence-based treatment for TD.”

Dr. Correll reported that he has received honoraria from and has been an advisory board member for numerous pharmaceutical companies. He has also received grant support from Janssen, the National Institute of Mental Health, the Patient Centered Outcomes Research Institute, Takeda, and the Thrasher Foundation.

LAS VEGAS – In the opinion of Christoph U. Correll, MD, tardive dyskinesia (TD) “has been somewhat forgotten” by psychiatrists because the risk of patients developing the condition is considered to be significantly lower with second-generation antipsychotics compared with first-generation antipsychotics.

“But this does not seem to always be the case, because there is still a risk of TD, and we need to monitor for it,” Dr. Correll, professor of psychiatry and molecular medicine at The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “It is important to minimize the risk of TD by educating patients and caregivers about the risks of and alternatives to antipsychotic medication and early signs of TD.”

First described in 1957, TD is characterized by involuntary repetitive but irregular movements, mostly in the oral, lingual, and buccal regions – such as tongue protruding, puckering, chewing, and grimacing. Less often, there are movements in the hands, legs, feet, and torso. Symptoms can include mannerisms, stereotypies, tics, myoclonus, dystonias, tremor, and akathisia. “TD can be severe, persistent, and have medical and psychosocial consequences,” Dr. Correll said. “It can occur in untreated patients, but treatment with dopamine blocking agents – antipsychotics and metoclopramide – increases risk for TD.”

Differential diagnoses to consider include morbus Huntington, benign familial Chorea, and Sydenham’s Chorea. Less frequent causes of TD include metabolic conditions such as uremia, hyponatremia, hypernatremia, hypoparathyroidism, and hyperparathyroidism. “Those would need to be ruled out during the physical exam,” he said. There can also be inflammatory causes of TD such as herpes simplex virus, varicella, measles, mumps, and rubella.

A standard measure for TD diagnosis is the Abnormal Involuntary Movement Scale (AIMS), an observer-rated 12-item anchored scale that takes 5-10 minutes to administer. However, the AIMS on its own does not diagnose TD. In 1982, researchers developed three diagnostic criteria for TD: At least 3 months of cumulative antipsychotic drug exposure; presence of at least moderate abnormal involuntary movements in one or more body area(s) or mild movements in two or more body areas, and absence of other conditions that might produce involuntary movements (Arch Gen Psychiatry 1982;39:486-7).

The impact of TD on everyday functioning depends on anatomic location as well as severity, Dr. Correll continued. The condition can cause impairments to speech, verbal communication, dentition, temporomandibular joint pain/myalgia, swallowing difficulties, and fine motor skills including instrumental activities of daily living and written communication. Truncal and lower extremity TD can affect gait, posture and postural stability, strength, power flexibility, physical capacity, and one’s ability to exercise. “There are also psychological impairments,” he said. “Patients can develop different awareness so they become self-conscious; there can be cognitive abnormalities, and they can become more anxious or [have an] increased sense of paranoia, isolation, stigma, social and/or educational/vocational impairment.”

According to research by Dr. Correll and colleagues, unmodifiable patient-related risk factors for TD include older age, female sex, and being of white or African descent (J Neurol Sci 2018 June 15; 389:21-7). Unmodifiable illness-related risk factors include longer duration of illness, intellectual disability and brain damage, negative symptoms in schizophrenia, mood disorders, cognitive symptoms in mood disorders, and gene polymorphisms involving antipsychotic metabolism and dopamine functioning. Modifiable comorbidity-related factors include diabetes, smoking, and alcohol/substance abuse, while modifiable treatment-related factors include dopamine receptor blockers, higher cumulative and current antipsychotic dose or plasma levels, early parkinsonian side effects, treatment-emergent akathisia, and anticholinergic co-treatment. In a meta-analysis of 41 studies that aimed to determine the prevalence of TD, the mean age of the 11,493 patients was 43, 66% were male, and 77% had schizophrenia spectrum disorders (J Clin Psychiatry. 2017 Mar;78[3]:e264-78). The global mean TD prevalence was 25%, but the rates were lower with patients on current treatment with second-generation antipsychotics compared with those on first-generation antipsychotics (21% vs. 30%, respectively).

According to Dr. Correll, strategies for preventing TD include confirming and documenting the indication for dopamine antagonist antipsychotic medications, using conservative maintenance doses, and considering the use of SGAs, especially in those at high risk for EPS (extrapyramidal symptoms). “Don’t go too high [with the dose],” he said. “Stay below the EPS threshold. Inform patients and caregivers of the risk of TD and assess for incipient signs regularly using the AIMS.”

Treatment options include discontinuing antipsychotics, adjusting their dose, or switching patients from a first-generation antipsychotic to a second-generation antipsychotic. Supplementation with antioxidants/radical scavengers such as vitamin E, vitamin B₆, ginkgo biloba, and fish oil “can be tried, but have limited evidence, as is the case for melatonin.” Other options include clonazepam, amantadine, donepezil, and tetrabenazine, a reversible and specific inhibitor of vesicular monoamine transporter-2 (VMAT-2), a transporter that packages neurotransmitters (preferentially dopamine) into vesicles for release into the synapse and was approved in 2008 as an orphan drug for the treatment of choreiform movements associated with Huntington’s disease. “Neurologists have using tetrabenazine off-label for TD, but in schizophrenia and other psychiatric care, we rarely use it because it has to be given three times a day and it has a black box warning for depression and suicidality,” he said.

Dr. Correll noted that the Food and Drug Administration approval of two more recent VMAT-2 inhibitors – deutetrabenazine (Austedo) and valbenazine (Ingrezza) – provides an evidence-based care option for the effective management of TD. Deutetrabenazine requires titration over several weeks and twice-daily dosing, while valbenazine can reach the maximum dose by the beginning of week 2 and is dosed once daily. Deutetrabenazine should be taken with food, which is not required valbenazine.

“Both VMAT-2 inhibitors are generally well tolerated and have a positive benefit-risk ratio,” he said. “Both are recommended by the APA guidelines as the preferred and only evidence-based treatment for TD.”

Dr. Correll reported that he has received honoraria from and has been an advisory board member for numerous pharmaceutical companies. He has also received grant support from Janssen, the National Institute of Mental Health, the Patient Centered Outcomes Research Institute, Takeda, and the Thrasher Foundation.

LAS VEGAS – In the opinion of Christoph U. Correll, MD, tardive dyskinesia (TD) “has been somewhat forgotten” by psychiatrists because the risk of patients developing the condition is considered to be significantly lower with second-generation antipsychotics compared with first-generation antipsychotics.

“But this does not seem to always be the case, because there is still a risk of TD, and we need to monitor for it,” Dr. Correll, professor of psychiatry and molecular medicine at The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “It is important to minimize the risk of TD by educating patients and caregivers about the risks of and alternatives to antipsychotic medication and early signs of TD.”

First described in 1957, TD is characterized by involuntary repetitive but irregular movements, mostly in the oral, lingual, and buccal regions – such as tongue protruding, puckering, chewing, and grimacing. Less often, there are movements in the hands, legs, feet, and torso. Symptoms can include mannerisms, stereotypies, tics, myoclonus, dystonias, tremor, and akathisia. “TD can be severe, persistent, and have medical and psychosocial consequences,” Dr. Correll said. “It can occur in untreated patients, but treatment with dopamine blocking agents – antipsychotics and metoclopramide – increases risk for TD.”

Differential diagnoses to consider include morbus Huntington, benign familial Chorea, and Sydenham’s Chorea. Less frequent causes of TD include metabolic conditions such as uremia, hyponatremia, hypernatremia, hypoparathyroidism, and hyperparathyroidism. “Those would need to be ruled out during the physical exam,” he said. There can also be inflammatory causes of TD such as herpes simplex virus, varicella, measles, mumps, and rubella.

A standard measure for TD diagnosis is the Abnormal Involuntary Movement Scale (AIMS), an observer-rated 12-item anchored scale that takes 5-10 minutes to administer. However, the AIMS on its own does not diagnose TD. In 1982, researchers developed three diagnostic criteria for TD: At least 3 months of cumulative antipsychotic drug exposure; presence of at least moderate abnormal involuntary movements in one or more body area(s) or mild movements in two or more body areas, and absence of other conditions that might produce involuntary movements (Arch Gen Psychiatry 1982;39:486-7).

The impact of TD on everyday functioning depends on anatomic location as well as severity, Dr. Correll continued. The condition can cause impairments to speech, verbal communication, dentition, temporomandibular joint pain/myalgia, swallowing difficulties, and fine motor skills including instrumental activities of daily living and written communication. Truncal and lower extremity TD can affect gait, posture and postural stability, strength, power flexibility, physical capacity, and one’s ability to exercise. “There are also psychological impairments,” he said. “Patients can develop different awareness so they become self-conscious; there can be cognitive abnormalities, and they can become more anxious or [have an] increased sense of paranoia, isolation, stigma, social and/or educational/vocational impairment.”

According to research by Dr. Correll and colleagues, unmodifiable patient-related risk factors for TD include older age, female sex, and being of white or African descent (J Neurol Sci 2018 June 15; 389:21-7). Unmodifiable illness-related risk factors include longer duration of illness, intellectual disability and brain damage, negative symptoms in schizophrenia, mood disorders, cognitive symptoms in mood disorders, and gene polymorphisms involving antipsychotic metabolism and dopamine functioning. Modifiable comorbidity-related factors include diabetes, smoking, and alcohol/substance abuse, while modifiable treatment-related factors include dopamine receptor blockers, higher cumulative and current antipsychotic dose or plasma levels, early parkinsonian side effects, treatment-emergent akathisia, and anticholinergic co-treatment. In a meta-analysis of 41 studies that aimed to determine the prevalence of TD, the mean age of the 11,493 patients was 43, 66% were male, and 77% had schizophrenia spectrum disorders (J Clin Psychiatry. 2017 Mar;78[3]:e264-78). The global mean TD prevalence was 25%, but the rates were lower with patients on current treatment with second-generation antipsychotics compared with those on first-generation antipsychotics (21% vs. 30%, respectively).

According to Dr. Correll, strategies for preventing TD include confirming and documenting the indication for dopamine antagonist antipsychotic medications, using conservative maintenance doses, and considering the use of SGAs, especially in those at high risk for EPS (extrapyramidal symptoms). “Don’t go too high [with the dose],” he said. “Stay below the EPS threshold. Inform patients and caregivers of the risk of TD and assess for incipient signs regularly using the AIMS.”

Treatment options include discontinuing antipsychotics, adjusting their dose, or switching patients from a first-generation antipsychotic to a second-generation antipsychotic. Supplementation with antioxidants/radical scavengers such as vitamin E, vitamin B₆, ginkgo biloba, and fish oil “can be tried, but have limited evidence, as is the case for melatonin.” Other options include clonazepam, amantadine, donepezil, and tetrabenazine, a reversible and specific inhibitor of vesicular monoamine transporter-2 (VMAT-2), a transporter that packages neurotransmitters (preferentially dopamine) into vesicles for release into the synapse and was approved in 2008 as an orphan drug for the treatment of choreiform movements associated with Huntington’s disease. “Neurologists have using tetrabenazine off-label for TD, but in schizophrenia and other psychiatric care, we rarely use it because it has to be given three times a day and it has a black box warning for depression and suicidality,” he said.

Dr. Correll noted that the Food and Drug Administration approval of two more recent VMAT-2 inhibitors – deutetrabenazine (Austedo) and valbenazine (Ingrezza) – provides an evidence-based care option for the effective management of TD. Deutetrabenazine requires titration over several weeks and twice-daily dosing, while valbenazine can reach the maximum dose by the beginning of week 2 and is dosed once daily. Deutetrabenazine should be taken with food, which is not required valbenazine.

“Both VMAT-2 inhibitors are generally well tolerated and have a positive benefit-risk ratio,” he said. “Both are recommended by the APA guidelines as the preferred and only evidence-based treatment for TD.”

Dr. Correll reported that he has received honoraria from and has been an advisory board member for numerous pharmaceutical companies. He has also received grant support from Janssen, the National Institute of Mental Health, the Patient Centered Outcomes Research Institute, Takeda, and the Thrasher Foundation.

Psychiatric partial hospitalization programs (PHPs), previously known as “day hospitals,” serve to bridge the gap between inpatient and outpatient facilities by providing intensive, highly structured outpatient behavioral health services (typically several hours of psychotherapy each weekday for most days of the week). The concept of PHPs has existed since at least the 1950s, but such programs started to become more common in the United States as the result of legislation passed in 1963 (Box^1-3). In this article, I provide a brief introductory review of PHPs, while acknowledging that most research on PHPs was conducted years ago and is rather limited.

Box

PHPs: What they are, and how they work

The term “partial hospitalization” is fraught with confusion because initially it was used to contrast such services from full hospitalization. Historically, it was used to describe services for patients who had been discharged home from a state hospital and attended a program on the hospital grounds during the day as outpatients. In reality, today’s PHPs are “day treatment” programs, but the terminology has stuck.

PHPs are neither an inpatient service nor a strict outpatient service, but rather a midground along the continuum of treatment intensity between the 2 traditional types of psychiatric services for patients with a range of mental illness of varying severity. The Association for Ambulatory Behavioral Healthcare, which has set standards and guidelines for PHPs, defines a PHP as “an ambulatory treatment program that includes the major diagnostic, medical, psychiatric, psychosocial, and prevocational treatment modalities designed for patients with serious mental disorders who require coordinated intensive, comprehensive, and multidisciplinary treatment not provided in an outpatient clinical setting.”⁴ PHPs can render acute care as an alternative to inpatient treatment, provide transitional stabilization treatment between an inpatient stay and traditional outpatient treatment (once a week or less frequent), and function as a supplement to traditional outpatient treatment.

Medicare has established criteria that PHPs must meet to qualify for reimbursement⁵; these criteria are now widely accepted as standards of care by the insurance industry. To meet the Medicare criteria, PHP treatment must be active and structured to provide an individualized treatment plan that incorporates coordination of services to meet the particular needs of the patient.⁵ It must include a multidisciplinary team approach to patient care under the direction of a physician, and the treatment goals must be measurable, functional, time-framed, medically necessary, and directly related to the reason for admission.⁵ The physician must certify the medical necessity for admission by documenting that the patient has a diagnosis of an acute Axis I mental disorder, a level of functioning that includes severe impairments in multiple areas of daily life, and a “reasonable expectation” that the disorder and level of functioning will improve as a result of the treatment.⁵

The Joint Commission (formerly JCAHO) lumps day treatment, intensive outpatient, partial hospitalization, and adult day care services into a single category of an ambulatory health care environment offering an organized day or night program of assessment, treatment, care, services, habilitation, or rehabilitation for individuals who do not require 24-hour care.⁶ For behavioral health, this may be a structured, ongoing program that typically meets 2 to 5 times a week for 2 to 5 hours per day.⁶

Most PHPs for adult patients provide services during the day 5 days per week and average 5 to 6 hours of programming per day. Night or evening programming may be a good option for patients who work during the day. Typically, treatment is provided in a group therapy format, with individual therapy at least once a week. Group therapy may include cognitive-behavioral therapy, coping with grief and loss, trauma recovery, conflict resolution, stress management, anger control, and behavioral modification. Family therapy is provided as needed, but usually is mandatory for children and adolescents. Many PHPs offer intensive outpatient programs (IOPs) as a step down to further facilitate a patient’s adjustment to psychosocial and family functioning while returning to work on a part-time basis. IOPs typically provide 3 to 4 hours of service per day 3 days per week. While not evidence-based, the typical duration of PHP treatment is 4 to 6 weeks, followed by an additional 2 to 4 weeks of IOP.

Continue to: Advantages and disadvantages...

Based on a qualitative literature review, Neffinger¹ outlined potential advantages and disadvantages of PHPs vs inpatient hospitalization (Table¹). While these have not been empirically studied, they may be useful to consider when determining if a PHP would be beneficial for a specific patient.

Which factors are most therapeutic?

Research on which factors of PHPs are of therapeutic value is quite limited and primarily consists of surveys of small numbers of participants. Hoge et al⁷ explored the active therapeutic factors responsible for change in the Connecticut Mental Health Center PHP by comparing responses of 20 patients with those of their clinicians. Ninety-five percent of patients rated structure as the top therapeutic factor, followed by interpersonal contact, medication, and altruism. Other factors that were rated as important by 40% or fewer participants were catharsis, learning, mobilization of family support, connection to community, universality, patient autonomy, successful completion, security, feedback on behavior, and practice at home. In a British study⁸ that used a similar method, patients reported that counseling was the most helpful aspect of treatment, followed by medical treatment, while staff picked groups followed by a planned approach.

Evidence supports PHPs’ effectiveness

Some research has suggested that PHPs can be effective, both clinically and in terms of cost. Marshall et al⁹ conducted a systematic review of the effectiveness of an acute day hospital vs inpatient admission vs outpatient care that included 9 trials. They concluded that psychiatric inpatient admissions could be reduced by at least 23% if patients were diverted to an acute day hospital. They also found some evidence that day treatment programs may be superior to outpatient care in improving symptoms in nonpsychotic patients who are refractory to outpatient treatment. In a systematic review of 18 studies, high rates of satisfaction with PHP services suggested PHPs have an advantage over inpatient treatment within 1 year of discharge; patients and families were more satisfied with PHPs.¹⁰ In a study of 197 urban, socioeconomically disadvantaged, severely ill patients, Sledge et al¹¹ compared the clinical outcomes of those who participated in day hospital programs with those of patients who received inpatient care. They found that while overall the 2 approaches produced similar outcomes, there were slightly more positive effects for day hospital programs in measures of symptoms, overall functioning, and social functioning. In terms of cost effectiveness, a 1978 study found that even after correcting for differences in treatment days between inpatient and PHP services, there was a significant financial advantage with PHP (costs were one-third less), primarily because of lower costs per day.¹² In another study, PHP cost savings were 20%, and potential savings were higher for nonpsychotic patients.¹³

Are PHPs appropriate for children and adolescents?

Studies of PHPs for adolescents found that patients made gains in peer relationships, behavioral and academic performance, and control of their emotions.^14,15 A review of PHPs’ effectiveness for children suggested that 66% to 99% of treated patients demonstrated improvement and successful return to community-based schools, and family functioning was a major factor in improvement.¹⁴ In a follow-up study that surveyed patients via telephone >1 year after discharge from a PHP, almost 80% of the children and adolescents were either “doing OK” or were “well-adjusted.”¹⁴ Only 22.5% required inpatient or residential treatment; the majority were doing well in school, with only 7% failing.¹⁴ In addition, 60% of parents reported satisfaction with treatment, and 85% reported functional improvement in their children.¹⁴

Factors that predict PHP success or failure

In an analysis of a day treatment program that provided 4 months of intensive psychodynamic, group-oriented milieu treatment for patients with long-standing personality disorders, Rosie et al¹⁶ found 3 factors that contributed to the success of the PHP:

• optimal treatment-patient matching
• judicious use of authority in milieu therapy
• maintaining close relationships with referral sources.

In a study that compared 58 patients who completed an Ottawa hospital PHP and 44 who did not complete the program, psychological mindedness and chronicity of psychiatric illness were found to predict completion.¹⁷ However, a study of 59 females with anorexia nervosa who were transferred from inpatient care to an eating disorder day hospital program found that a longer duration of illness, amenorrhea, and a lower body mass index were associated with PHP treatment failure and inpatient rehospitalization.¹⁸ One study found that for individuals who were referred to a PHP from inpatient care, suicidal ideation and greater psychotic symptoms were associated with acute inpatient rehospitalization.¹⁹ Other factors associated with PHP nonattendance and treatment failure include limited personal and economic resources, high rates of substance abuse disorders, multiple admissions, and disability.²⁰ In a study of 103 alcohol-dependent patients who completed IOP treatment, 64% were abstinent at 6 months follow-up; relapse was associated with a longer duration of alcohol dependence and a higher number of prior treatments, while favorable outcomes were associated with a lower degree of depression, anxiety, and craving.²¹ Patients with cocaine dependence who completed an IOP showed significant improvements in addiction scores and had more favorable outcomes in employment status and psychological problems if they stayed longer in treatment.²²

Bottom Line

Psychiatric partial hospitalization programs (PHPs) provide a transition from inpatient hospitalization to outpatient treatment for patients who need further stabilization, or serve as an alternative to inpatient treatment for patients who don’t need or want inpatient hospitalization. PHPs can be as effective as inpatient treatment for all but the most seriously ill patients, and are more cost-effective than inpatient treatment.

Psychiatric partial hospitalization programs (PHPs), previously known as “day hospitals,” serve to bridge the gap between inpatient and outpatient facilities by providing intensive, highly structured outpatient behavioral health services (typically several hours of psychotherapy each weekday for most days of the week). The concept of PHPs has existed since at least the 1950s, but such programs started to become more common in the United States as the result of legislation passed in 1963 (Box^1-3). In this article, I provide a brief introductory review of PHPs, while acknowledging that most research on PHPs was conducted years ago and is rather limited.

Box

PHPs: What they are, and how they work

The term “partial hospitalization” is fraught with confusion because initially it was used to contrast such services from full hospitalization. Historically, it was used to describe services for patients who had been discharged home from a state hospital and attended a program on the hospital grounds during the day as outpatients. In reality, today’s PHPs are “day treatment” programs, but the terminology has stuck.

PHPs are neither an inpatient service nor a strict outpatient service, but rather a midground along the continuum of treatment intensity between the 2 traditional types of psychiatric services for patients with a range of mental illness of varying severity. The Association for Ambulatory Behavioral Healthcare, which has set standards and guidelines for PHPs, defines a PHP as “an ambulatory treatment program that includes the major diagnostic, medical, psychiatric, psychosocial, and prevocational treatment modalities designed for patients with serious mental disorders who require coordinated intensive, comprehensive, and multidisciplinary treatment not provided in an outpatient clinical setting.”⁴ PHPs can render acute care as an alternative to inpatient treatment, provide transitional stabilization treatment between an inpatient stay and traditional outpatient treatment (once a week or less frequent), and function as a supplement to traditional outpatient treatment.

Medicare has established criteria that PHPs must meet to qualify for reimbursement⁵; these criteria are now widely accepted as standards of care by the insurance industry. To meet the Medicare criteria, PHP treatment must be active and structured to provide an individualized treatment plan that incorporates coordination of services to meet the particular needs of the patient.⁵ It must include a multidisciplinary team approach to patient care under the direction of a physician, and the treatment goals must be measurable, functional, time-framed, medically necessary, and directly related to the reason for admission.⁵ The physician must certify the medical necessity for admission by documenting that the patient has a diagnosis of an acute Axis I mental disorder, a level of functioning that includes severe impairments in multiple areas of daily life, and a “reasonable expectation” that the disorder and level of functioning will improve as a result of the treatment.⁵

The Joint Commission (formerly JCAHO) lumps day treatment, intensive outpatient, partial hospitalization, and adult day care services into a single category of an ambulatory health care environment offering an organized day or night program of assessment, treatment, care, services, habilitation, or rehabilitation for individuals who do not require 24-hour care.⁶ For behavioral health, this may be a structured, ongoing program that typically meets 2 to 5 times a week for 2 to 5 hours per day.⁶

Most PHPs for adult patients provide services during the day 5 days per week and average 5 to 6 hours of programming per day. Night or evening programming may be a good option for patients who work during the day. Typically, treatment is provided in a group therapy format, with individual therapy at least once a week. Group therapy may include cognitive-behavioral therapy, coping with grief and loss, trauma recovery, conflict resolution, stress management, anger control, and behavioral modification. Family therapy is provided as needed, but usually is mandatory for children and adolescents. Many PHPs offer intensive outpatient programs (IOPs) as a step down to further facilitate a patient’s adjustment to psychosocial and family functioning while returning to work on a part-time basis. IOPs typically provide 3 to 4 hours of service per day 3 days per week. While not evidence-based, the typical duration of PHP treatment is 4 to 6 weeks, followed by an additional 2 to 4 weeks of IOP.

Continue to: Advantages and disadvantages...

Based on a qualitative literature review, Neffinger¹ outlined potential advantages and disadvantages of PHPs vs inpatient hospitalization (Table¹). While these have not been empirically studied, they may be useful to consider when determining if a PHP would be beneficial for a specific patient.

Which factors are most therapeutic?

Research on which factors of PHPs are of therapeutic value is quite limited and primarily consists of surveys of small numbers of participants. Hoge et al⁷ explored the active therapeutic factors responsible for change in the Connecticut Mental Health Center PHP by comparing responses of 20 patients with those of their clinicians. Ninety-five percent of patients rated structure as the top therapeutic factor, followed by interpersonal contact, medication, and altruism. Other factors that were rated as important by 40% or fewer participants were catharsis, learning, mobilization of family support, connection to community, universality, patient autonomy, successful completion, security, feedback on behavior, and practice at home. In a British study⁸ that used a similar method, patients reported that counseling was the most helpful aspect of treatment, followed by medical treatment, while staff picked groups followed by a planned approach.

Evidence supports PHPs’ effectiveness

Some research has suggested that PHPs can be effective, both clinically and in terms of cost. Marshall et al⁹ conducted a systematic review of the effectiveness of an acute day hospital vs inpatient admission vs outpatient care that included 9 trials. They concluded that psychiatric inpatient admissions could be reduced by at least 23% if patients were diverted to an acute day hospital. They also found some evidence that day treatment programs may be superior to outpatient care in improving symptoms in nonpsychotic patients who are refractory to outpatient treatment. In a systematic review of 18 studies, high rates of satisfaction with PHP services suggested PHPs have an advantage over inpatient treatment within 1 year of discharge; patients and families were more satisfied with PHPs.¹⁰ In a study of 197 urban, socioeconomically disadvantaged, severely ill patients, Sledge et al¹¹ compared the clinical outcomes of those who participated in day hospital programs with those of patients who received inpatient care. They found that while overall the 2 approaches produced similar outcomes, there were slightly more positive effects for day hospital programs in measures of symptoms, overall functioning, and social functioning. In terms of cost effectiveness, a 1978 study found that even after correcting for differences in treatment days between inpatient and PHP services, there was a significant financial advantage with PHP (costs were one-third less), primarily because of lower costs per day.¹² In another study, PHP cost savings were 20%, and potential savings were higher for nonpsychotic patients.¹³

Are PHPs appropriate for children and adolescents?

Studies of PHPs for adolescents found that patients made gains in peer relationships, behavioral and academic performance, and control of their emotions.^14,15 A review of PHPs’ effectiveness for children suggested that 66% to 99% of treated patients demonstrated improvement and successful return to community-based schools, and family functioning was a major factor in improvement.¹⁴ In a follow-up study that surveyed patients via telephone >1 year after discharge from a PHP, almost 80% of the children and adolescents were either “doing OK” or were “well-adjusted.”¹⁴ Only 22.5% required inpatient or residential treatment; the majority were doing well in school, with only 7% failing.¹⁴ In addition, 60% of parents reported satisfaction with treatment, and 85% reported functional improvement in their children.¹⁴

Factors that predict PHP success or failure

In an analysis of a day treatment program that provided 4 months of intensive psychodynamic, group-oriented milieu treatment for patients with long-standing personality disorders, Rosie et al¹⁶ found 3 factors that contributed to the success of the PHP:

• optimal treatment-patient matching
• judicious use of authority in milieu therapy
• maintaining close relationships with referral sources.

In a study that compared 58 patients who completed an Ottawa hospital PHP and 44 who did not complete the program, psychological mindedness and chronicity of psychiatric illness were found to predict completion.¹⁷ However, a study of 59 females with anorexia nervosa who were transferred from inpatient care to an eating disorder day hospital program found that a longer duration of illness, amenorrhea, and a lower body mass index were associated with PHP treatment failure and inpatient rehospitalization.¹⁸ One study found that for individuals who were referred to a PHP from inpatient care, suicidal ideation and greater psychotic symptoms were associated with acute inpatient rehospitalization.¹⁹ Other factors associated with PHP nonattendance and treatment failure include limited personal and economic resources, high rates of substance abuse disorders, multiple admissions, and disability.²⁰ In a study of 103 alcohol-dependent patients who completed IOP treatment, 64% were abstinent at 6 months follow-up; relapse was associated with a longer duration of alcohol dependence and a higher number of prior treatments, while favorable outcomes were associated with a lower degree of depression, anxiety, and craving.²¹ Patients with cocaine dependence who completed an IOP showed significant improvements in addiction scores and had more favorable outcomes in employment status and psychological problems if they stayed longer in treatment.²²

Bottom Line

Psychiatric partial hospitalization programs (PHPs) provide a transition from inpatient hospitalization to outpatient treatment for patients who need further stabilization, or serve as an alternative to inpatient treatment for patients who don’t need or want inpatient hospitalization. PHPs can be as effective as inpatient treatment for all but the most seriously ill patients, and are more cost-effective than inpatient treatment.

Psychiatric partial hospitalization programs (PHPs), previously known as “day hospitals,” serve to bridge the gap between inpatient and outpatient facilities by providing intensive, highly structured outpatient behavioral health services (typically several hours of psychotherapy each weekday for most days of the week). The concept of PHPs has existed since at least the 1950s, but such programs started to become more common in the United States as the result of legislation passed in 1963 (Box^1-3). In this article, I provide a brief introductory review of PHPs, while acknowledging that most research on PHPs was conducted years ago and is rather limited.

Box

PHPs: What they are, and how they work

The term “partial hospitalization” is fraught with confusion because initially it was used to contrast such services from full hospitalization. Historically, it was used to describe services for patients who had been discharged home from a state hospital and attended a program on the hospital grounds during the day as outpatients. In reality, today’s PHPs are “day treatment” programs, but the terminology has stuck.

PHPs are neither an inpatient service nor a strict outpatient service, but rather a midground along the continuum of treatment intensity between the 2 traditional types of psychiatric services for patients with a range of mental illness of varying severity. The Association for Ambulatory Behavioral Healthcare, which has set standards and guidelines for PHPs, defines a PHP as “an ambulatory treatment program that includes the major diagnostic, medical, psychiatric, psychosocial, and prevocational treatment modalities designed for patients with serious mental disorders who require coordinated intensive, comprehensive, and multidisciplinary treatment not provided in an outpatient clinical setting.”⁴ PHPs can render acute care as an alternative to inpatient treatment, provide transitional stabilization treatment between an inpatient stay and traditional outpatient treatment (once a week or less frequent), and function as a supplement to traditional outpatient treatment.

Medicare has established criteria that PHPs must meet to qualify for reimbursement⁵; these criteria are now widely accepted as standards of care by the insurance industry. To meet the Medicare criteria, PHP treatment must be active and structured to provide an individualized treatment plan that incorporates coordination of services to meet the particular needs of the patient.⁵ It must include a multidisciplinary team approach to patient care under the direction of a physician, and the treatment goals must be measurable, functional, time-framed, medically necessary, and directly related to the reason for admission.⁵ The physician must certify the medical necessity for admission by documenting that the patient has a diagnosis of an acute Axis I mental disorder, a level of functioning that includes severe impairments in multiple areas of daily life, and a “reasonable expectation” that the disorder and level of functioning will improve as a result of the treatment.⁵

The Joint Commission (formerly JCAHO) lumps day treatment, intensive outpatient, partial hospitalization, and adult day care services into a single category of an ambulatory health care environment offering an organized day or night program of assessment, treatment, care, services, habilitation, or rehabilitation for individuals who do not require 24-hour care.⁶ For behavioral health, this may be a structured, ongoing program that typically meets 2 to 5 times a week for 2 to 5 hours per day.⁶

Most PHPs for adult patients provide services during the day 5 days per week and average 5 to 6 hours of programming per day. Night or evening programming may be a good option for patients who work during the day. Typically, treatment is provided in a group therapy format, with individual therapy at least once a week. Group therapy may include cognitive-behavioral therapy, coping with grief and loss, trauma recovery, conflict resolution, stress management, anger control, and behavioral modification. Family therapy is provided as needed, but usually is mandatory for children and adolescents. Many PHPs offer intensive outpatient programs (IOPs) as a step down to further facilitate a patient’s adjustment to psychosocial and family functioning while returning to work on a part-time basis. IOPs typically provide 3 to 4 hours of service per day 3 days per week. While not evidence-based, the typical duration of PHP treatment is 4 to 6 weeks, followed by an additional 2 to 4 weeks of IOP.

Continue to: Advantages and disadvantages...

Based on a qualitative literature review, Neffinger¹ outlined potential advantages and disadvantages of PHPs vs inpatient hospitalization (Table¹). While these have not been empirically studied, they may be useful to consider when determining if a PHP would be beneficial for a specific patient.

Which factors are most therapeutic?

Research on which factors of PHPs are of therapeutic value is quite limited and primarily consists of surveys of small numbers of participants. Hoge et al⁷ explored the active therapeutic factors responsible for change in the Connecticut Mental Health Center PHP by comparing responses of 20 patients with those of their clinicians. Ninety-five percent of patients rated structure as the top therapeutic factor, followed by interpersonal contact, medication, and altruism. Other factors that were rated as important by 40% or fewer participants were catharsis, learning, mobilization of family support, connection to community, universality, patient autonomy, successful completion, security, feedback on behavior, and practice at home. In a British study⁸ that used a similar method, patients reported that counseling was the most helpful aspect of treatment, followed by medical treatment, while staff picked groups followed by a planned approach.

Evidence supports PHPs’ effectiveness

Some research has suggested that PHPs can be effective, both clinically and in terms of cost. Marshall et al⁹ conducted a systematic review of the effectiveness of an acute day hospital vs inpatient admission vs outpatient care that included 9 trials. They concluded that psychiatric inpatient admissions could be reduced by at least 23% if patients were diverted to an acute day hospital. They also found some evidence that day treatment programs may be superior to outpatient care in improving symptoms in nonpsychotic patients who are refractory to outpatient treatment. In a systematic review of 18 studies, high rates of satisfaction with PHP services suggested PHPs have an advantage over inpatient treatment within 1 year of discharge; patients and families were more satisfied with PHPs.¹⁰ In a study of 197 urban, socioeconomically disadvantaged, severely ill patients, Sledge et al¹¹ compared the clinical outcomes of those who participated in day hospital programs with those of patients who received inpatient care. They found that while overall the 2 approaches produced similar outcomes, there were slightly more positive effects for day hospital programs in measures of symptoms, overall functioning, and social functioning. In terms of cost effectiveness, a 1978 study found that even after correcting for differences in treatment days between inpatient and PHP services, there was a significant financial advantage with PHP (costs were one-third less), primarily because of lower costs per day.¹² In another study, PHP cost savings were 20%, and potential savings were higher for nonpsychotic patients.¹³

Are PHPs appropriate for children and adolescents?

Studies of PHPs for adolescents found that patients made gains in peer relationships, behavioral and academic performance, and control of their emotions.^14,15 A review of PHPs’ effectiveness for children suggested that 66% to 99% of treated patients demonstrated improvement and successful return to community-based schools, and family functioning was a major factor in improvement.¹⁴ In a follow-up study that surveyed patients via telephone >1 year after discharge from a PHP, almost 80% of the children and adolescents were either “doing OK” or were “well-adjusted.”¹⁴ Only 22.5% required inpatient or residential treatment; the majority were doing well in school, with only 7% failing.¹⁴ In addition, 60% of parents reported satisfaction with treatment, and 85% reported functional improvement in their children.¹⁴

Factors that predict PHP success or failure

In an analysis of a day treatment program that provided 4 months of intensive psychodynamic, group-oriented milieu treatment for patients with long-standing personality disorders, Rosie et al¹⁶ found 3 factors that contributed to the success of the PHP:

• optimal treatment-patient matching
• judicious use of authority in milieu therapy
• maintaining close relationships with referral sources.

In a study that compared 58 patients who completed an Ottawa hospital PHP and 44 who did not complete the program, psychological mindedness and chronicity of psychiatric illness were found to predict completion.¹⁷ However, a study of 59 females with anorexia nervosa who were transferred from inpatient care to an eating disorder day hospital program found that a longer duration of illness, amenorrhea, and a lower body mass index were associated with PHP treatment failure and inpatient rehospitalization.¹⁸ One study found that for individuals who were referred to a PHP from inpatient care, suicidal ideation and greater psychotic symptoms were associated with acute inpatient rehospitalization.¹⁹ Other factors associated with PHP nonattendance and treatment failure include limited personal and economic resources, high rates of substance abuse disorders, multiple admissions, and disability.²⁰ In a study of 103 alcohol-dependent patients who completed IOP treatment, 64% were abstinent at 6 months follow-up; relapse was associated with a longer duration of alcohol dependence and a higher number of prior treatments, while favorable outcomes were associated with a lower degree of depression, anxiety, and craving.²¹ Patients with cocaine dependence who completed an IOP showed significant improvements in addiction scores and had more favorable outcomes in employment status and psychological problems if they stayed longer in treatment.²²

Bottom Line

Psychiatric partial hospitalization programs (PHPs) provide a transition from inpatient hospitalization to outpatient treatment for patients who need further stabilization, or serve as an alternative to inpatient treatment for patients who don’t need or want inpatient hospitalization. PHPs can be as effective as inpatient treatment for all but the most seriously ill patients, and are more cost-effective than inpatient treatment.

Mr. J, age 35, is brought to the hospital from prison due to priapism that does not improve with treatment. He says he has had priapism 5 times previously, with the first incidence occurring “years ago” due to trazodone.

Recently, he has been receiving risperidone, which the treatment team believes is the cause of his current priapism. His medical history includes asthma, schizophrenia, hypertension, seizures, and sickle cell trait. Mr. J is experiencing auditory hallucinations, which he describes as “continuous, neutral voices that are annoying.” He would like relief from his auditory hallucinations and is willing to change his antipsychotic, but does not want additional treatment for his priapism. His present medications include risperidone, 1 mg twice a day, escitalopram, 10 mg/d, benztropine, 1 mg twice a day, and phenytoin, 500 mg/d at bedtime.

Priapism is a prolonged, persistent, and often painful erection that occurs without sexual stimulation. Although relatively rare, it can result in potentially serious long-term complications, including impotence and gangrene, and requires immediate evaluation and management.

There are 2 types of priapism: nonischemic, or “high-flow,” priapism, and ischemic, or “low-flow,” priapism (Table 1). While nonischemic priapism is typically caused by penile or perineal trauma, ischemic priapism can occur as a result of medications, including antipsychotics, antidepressants, anxiolytics, and antihypertensives, or hematological conditions such as sickle cell disease.¹ Other risk factors associated with priapism include substance abuse, hyperprolactinemia, diabetes, and liver disease.⁴

Antipsychotic-induced priapism

Medication-induced priapism is a rare adverse drug reaction (ADR). Of the medication classes associated with priapism, antipsychotics have the highest incidence and account for approximately 20% of all cases.¹

The mechanism of priapism associated with antipsychotics is thought to be related to alpha-1 blockade in the corpora cavernosa of the penis. Although antipsychotics within each class share common characteristics, each agent has a unique profile of receptor affinities. As such, antipsychotics have varying affinities for the alpha-adrenergic receptor (Table 2). Agents such as ziprasidone, chlorpromazine, and risperidone—which have the highest affinity for the alpha-1 adrenoceptors—may be more likely to cause priapism compared with agents with lower affinity, such as olanzapine. Priapism may occur at any time during antipsychotic treatment, and does not appear to be dose-related.

Continue to: Antipsychotic drug interactions and priapism...

Patients who are receiving multiple medications as treatment for chronic medical or psychiatric conditions have an increased likelihood of experiencing drug-drug interactions (DDIs) that lead to adverse effects.

Various case reports have described priapism as a result of DDIs related to antipsychotic agents combined with other psychotropic or nonpsychotropic medications.³ Most of these DDIs have been attributed to the cytochrome P450 (CYP) family of enzymes, including CYP2D6, CYP1A2, and CYP3A4/5, which are major enzymes implicated in the metabolism of antipsychotics (Table 3).

Mitigating the risk of priapism

Although there are associated risk factors for priapism, there are no concrete indicators to predict the onset or development of the condition. The best predictor may be a history of prolonged and painless erections.³

As such, when choosing an antipsychotic, it is critical to screen the patient for the previously mentioned risk factors, including the presence of medications with strong alpha-1 receptor affinity and CYP interactions, especially to minimize the risk of recurrence of priapism in those with prior or similar episodes. Management of patients with priapism due to antipsychotics has involved reducing the dose of the offending agent and/or changing the medication to one with a lower alpha-adrenergic affinity (Table 2²).

Similar to most situations, management is patient-specific and depends on several factors, including the severity of the patient’s psychiatric disease, history/severity of priapism and treatment, concurrent medication list, etc. For example, although clozapine is considered to have relatively high affinity for the alpha-1 receptor, it is also the agent of choice for treatment-refractory schizophrenia. Risks and benefits must be weighed on a individualized basis. Case reports have described symptom improvement via lowering the dose of clozapine and adding on or switching to an antipsychotic agent with minimal alpha-1 receptor affinity.⁴

After considering Mr. J’s history, risk factors, and preferences, the treatment team discontinues risperidone and initiates haloperidol, 5 mg twice a day. Soon after, Mr. J no longer experiences priapism.

Mr. J, age 35, is brought to the hospital from prison due to priapism that does not improve with treatment. He says he has had priapism 5 times previously, with the first incidence occurring “years ago” due to trazodone.

Recently, he has been receiving risperidone, which the treatment team believes is the cause of his current priapism. His medical history includes asthma, schizophrenia, hypertension, seizures, and sickle cell trait. Mr. J is experiencing auditory hallucinations, which he describes as “continuous, neutral voices that are annoying.” He would like relief from his auditory hallucinations and is willing to change his antipsychotic, but does not want additional treatment for his priapism. His present medications include risperidone, 1 mg twice a day, escitalopram, 10 mg/d, benztropine, 1 mg twice a day, and phenytoin, 500 mg/d at bedtime.

Priapism is a prolonged, persistent, and often painful erection that occurs without sexual stimulation. Although relatively rare, it can result in potentially serious long-term complications, including impotence and gangrene, and requires immediate evaluation and management.

There are 2 types of priapism: nonischemic, or “high-flow,” priapism, and ischemic, or “low-flow,” priapism (Table 1). While nonischemic priapism is typically caused by penile or perineal trauma, ischemic priapism can occur as a result of medications, including antipsychotics, antidepressants, anxiolytics, and antihypertensives, or hematological conditions such as sickle cell disease.¹ Other risk factors associated with priapism include substance abuse, hyperprolactinemia, diabetes, and liver disease.⁴

Antipsychotic-induced priapism

Medication-induced priapism is a rare adverse drug reaction (ADR). Of the medication classes associated with priapism, antipsychotics have the highest incidence and account for approximately 20% of all cases.¹

The mechanism of priapism associated with antipsychotics is thought to be related to alpha-1 blockade in the corpora cavernosa of the penis. Although antipsychotics within each class share common characteristics, each agent has a unique profile of receptor affinities. As such, antipsychotics have varying affinities for the alpha-adrenergic receptor (Table 2). Agents such as ziprasidone, chlorpromazine, and risperidone—which have the highest affinity for the alpha-1 adrenoceptors—may be more likely to cause priapism compared with agents with lower affinity, such as olanzapine. Priapism may occur at any time during antipsychotic treatment, and does not appear to be dose-related.

Continue to: Antipsychotic drug interactions and priapism...

Patients who are receiving multiple medications as treatment for chronic medical or psychiatric conditions have an increased likelihood of experiencing drug-drug interactions (DDIs) that lead to adverse effects.

Various case reports have described priapism as a result of DDIs related to antipsychotic agents combined with other psychotropic or nonpsychotropic medications.³ Most of these DDIs have been attributed to the cytochrome P450 (CYP) family of enzymes, including CYP2D6, CYP1A2, and CYP3A4/5, which are major enzymes implicated in the metabolism of antipsychotics (Table 3).

Mitigating the risk of priapism

Although there are associated risk factors for priapism, there are no concrete indicators to predict the onset or development of the condition. The best predictor may be a history of prolonged and painless erections.³

As such, when choosing an antipsychotic, it is critical to screen the patient for the previously mentioned risk factors, including the presence of medications with strong alpha-1 receptor affinity and CYP interactions, especially to minimize the risk of recurrence of priapism in those with prior or similar episodes. Management of patients with priapism due to antipsychotics has involved reducing the dose of the offending agent and/or changing the medication to one with a lower alpha-adrenergic affinity (Table 2²).

Similar to most situations, management is patient-specific and depends on several factors, including the severity of the patient’s psychiatric disease, history/severity of priapism and treatment, concurrent medication list, etc. For example, although clozapine is considered to have relatively high affinity for the alpha-1 receptor, it is also the agent of choice for treatment-refractory schizophrenia. Risks and benefits must be weighed on a individualized basis. Case reports have described symptom improvement via lowering the dose of clozapine and adding on or switching to an antipsychotic agent with minimal alpha-1 receptor affinity.⁴

After considering Mr. J’s history, risk factors, and preferences, the treatment team discontinues risperidone and initiates haloperidol, 5 mg twice a day. Soon after, Mr. J no longer experiences priapism.

Mr. J, age 35, is brought to the hospital from prison due to priapism that does not improve with treatment. He says he has had priapism 5 times previously, with the first incidence occurring “years ago” due to trazodone.

Recently, he has been receiving risperidone, which the treatment team believes is the cause of his current priapism. His medical history includes asthma, schizophrenia, hypertension, seizures, and sickle cell trait. Mr. J is experiencing auditory hallucinations, which he describes as “continuous, neutral voices that are annoying.” He would like relief from his auditory hallucinations and is willing to change his antipsychotic, but does not want additional treatment for his priapism. His present medications include risperidone, 1 mg twice a day, escitalopram, 10 mg/d, benztropine, 1 mg twice a day, and phenytoin, 500 mg/d at bedtime.

Priapism is a prolonged, persistent, and often painful erection that occurs without sexual stimulation. Although relatively rare, it can result in potentially serious long-term complications, including impotence and gangrene, and requires immediate evaluation and management.

There are 2 types of priapism: nonischemic, or “high-flow,” priapism, and ischemic, or “low-flow,” priapism (Table 1). While nonischemic priapism is typically caused by penile or perineal trauma, ischemic priapism can occur as a result of medications, including antipsychotics, antidepressants, anxiolytics, and antihypertensives, or hematological conditions such as sickle cell disease.¹ Other risk factors associated with priapism include substance abuse, hyperprolactinemia, diabetes, and liver disease.⁴

Antipsychotic-induced priapism

Medication-induced priapism is a rare adverse drug reaction (ADR). Of the medication classes associated with priapism, antipsychotics have the highest incidence and account for approximately 20% of all cases.¹

The mechanism of priapism associated with antipsychotics is thought to be related to alpha-1 blockade in the corpora cavernosa of the penis. Although antipsychotics within each class share common characteristics, each agent has a unique profile of receptor affinities. As such, antipsychotics have varying affinities for the alpha-adrenergic receptor (Table 2). Agents such as ziprasidone, chlorpromazine, and risperidone—which have the highest affinity for the alpha-1 adrenoceptors—may be more likely to cause priapism compared with agents with lower affinity, such as olanzapine. Priapism may occur at any time during antipsychotic treatment, and does not appear to be dose-related.

Continue to: Antipsychotic drug interactions and priapism...

Patients who are receiving multiple medications as treatment for chronic medical or psychiatric conditions have an increased likelihood of experiencing drug-drug interactions (DDIs) that lead to adverse effects.

Various case reports have described priapism as a result of DDIs related to antipsychotic agents combined with other psychotropic or nonpsychotropic medications.³ Most of these DDIs have been attributed to the cytochrome P450 (CYP) family of enzymes, including CYP2D6, CYP1A2, and CYP3A4/5, which are major enzymes implicated in the metabolism of antipsychotics (Table 3).

Mitigating the risk of priapism

Although there are associated risk factors for priapism, there are no concrete indicators to predict the onset or development of the condition. The best predictor may be a history of prolonged and painless erections.³

As such, when choosing an antipsychotic, it is critical to screen the patient for the previously mentioned risk factors, including the presence of medications with strong alpha-1 receptor affinity and CYP interactions, especially to minimize the risk of recurrence of priapism in those with prior or similar episodes. Management of patients with priapism due to antipsychotics has involved reducing the dose of the offending agent and/or changing the medication to one with a lower alpha-adrenergic affinity (Table 2²).

Similar to most situations, management is patient-specific and depends on several factors, including the severity of the patient’s psychiatric disease, history/severity of priapism and treatment, concurrent medication list, etc. For example, although clozapine is considered to have relatively high affinity for the alpha-1 receptor, it is also the agent of choice for treatment-refractory schizophrenia. Risks and benefits must be weighed on a individualized basis. Case reports have described symptom improvement via lowering the dose of clozapine and adding on or switching to an antipsychotic agent with minimal alpha-1 receptor affinity.⁴

After considering Mr. J’s history, risk factors, and preferences, the treatment team discontinues risperidone and initiates haloperidol, 5 mg twice a day. Soon after, Mr. J no longer experiences priapism.