Schizophrenia & Other Psychotic Disorders

The human microbiota refers to the collection of bacteria, archaea, eukarya, and viruses that reside within the human body. The term gut microbiome indicates the composition of these microbes and genetic codes in the intestine.¹ Harkening back to the ancient Greek physician Galen, who treated gastrointestinal (GI) symptoms to relieve mental disturbances such as psychosis, the gut has been a therapeutic target in schizophrenia long before antipsychotics and the DSM.² In recent years, research into the gut microbiome has drastically increased, with genetic sequencing affording a more precise look into the specific bacteria that call the human intestines their home. This has led to the recognition that the gut microbiome may be severely disrupted in schizophrenia, a condition known as dysbiosis. Preliminary research suggests that gut bacteria are more helpful than many human genes in distinguishing individuals with schizophrenia from their healthy counterparts.^3,4 In this article, we discuss the potential role of the gut microbiome in schizophrenia, including new research correlating clinical symptoms of psychosis with dysbiosis. We also provide recommendations for promoting a healthy gut microbiome.

The enteric brain across life

The composition of our bodies is far more microbiota than human. Strikingly, microbiota cells in the gut outnumber human cells, and the distal gut alone hosts bacteria with 100 times the genetic content of the entire genome.⁵ The intricate meshwork of nerves in the gut is often called the enteric brain because the gut consists of 100 million neurons and synthesizes many neuroactive chemicals implicated in mood disorders and psychosis, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine.⁶ The variety of neuro­immunologic, hormonal, and metabolic paths by which the gutmicrobiome and the brain interact are collectively known as the gut-microbiota-brainaxis.⁷

How do we acquire our gut microbiome, and how does it come to influence ourbrain and behavior? On the first day of life, as babies pass through the birth canal, they are bathed in their mother’s vaginal microbiota. In the following weeks, the microbiome expands and colonizes the gut as bacteria are introduced from environmental sources such as skin-to-skin contact and breastmilk.⁸ The microbiome continues to evolve throughout early life. As children expand their diets and navigate new aspects of the physical world, additional bacteria join the unseen ecosystem growing inside.⁹ The development of the microbiome coincides with the development of the brain. From preclinical studies, we know the gut microbiome mediates important aspects of neurodevelopment such as the formation of the blood-brain barrier (BBB), synaptic pruning, glial activation, and myelination.¹⁰ Interestingly, many of the risk factors for schizophrenia are associated with gut dysbiosis, including obstetric complications, infections treated with antibiotics, and urbanization.^11-15

Throughout human life, the gut and brain remain in close communication. The gut microbiota continue to produce monoamines, along with other metabolites that are able to cross the BBB.⁶ The HPA axis, stimulation of the immune system, and the vagus nerve all provide highways of communication between the gut and the brain.⁷ The relationship between the enteric brain and cephalic brain continues through life, even up to a person’s final hour. One autopsy study that is often cited (but soberingly, cannot be found online) allegedly revealed that 92% of schizophrenia patients had developed colitis by the time of death.^16,17

First-episode psychosis and antipsychotic treatment

For patients with schizophrenia, first-episode psychosis (FEP) represents a cocktail of mounting genetic and environmental factors. Typically, by the time a patient receives psychiatric care, they present with characteristic psychotic symptoms—hallucinations, delusions, bizarre behavior, and unusual thought process—along with a unique gut microbiome profile.

This disrupted microbiome coincides with a marked state of inflammation in the intestines. Inflammation triggers increased endothelial barrier permeability, similar to the way immune signals increase capillary permeability to allow immune cells into the periphery of the blood. Specific gut bacteria play specific roles in maintaining the gut barrier.^18,19 Disruptions in the bacteria that maintain the gut barrier, combined with inflammation, contribute to a leaky gut. A leaky gut barrier allows bacterial and immune products to more easily enter the bloodstream and then the brain, which is a potential source of neuroinflammation in schizophrenia.²⁰ This increase in gut permeability (leaky gut syndrome) is likely one of several reasons low-grade inflammation is common in schizophrenia—numerous studies show higher serum levels of proinflammatory cytokines along with antibacterial immunoglobulins in patients with FEP.^21,22

Fortunately, antipsychotics, especially the second-generation agents, help restore a healthy gut microbiome and have substantial anti-inflammatory properties.^23,24 These medications interact heavily with the gut microbiome: they have been found to have antibiotic properties, even in doses lower than would normally reach the gut microbiome.²⁵ In humans, a randomized controlled trial of probiotic supplementation for schizophrenia patients taking antipsychotics showed a reduction in GI symptoms but no significant improvement in psychotic symptoms.²⁶

Dysbiosis in schizophrenia: cause or effect?

There is no consensus on what constitutes a healthy gut microbiome because the gut microbiome is highly variable, even among healthy individuals, and can change quickly. Those who adopt new diets, for example, see drastic shifts in the gut microbiome within a few days.²⁷ Despite this variation, the main separation between a healthy and dysbiotic gut comes from the diversity of bacteria present in the gut—a healthy gut microbiome is associated with increased diversity. Numerous disease states have been associated with decreased bacterial diversity, including Clostridium difficile infection, Parkinson disease, depression, Crohn disease, and schizophrenia spectrum disorders.^28,29

Although there are ethical limitations to studying causality in humans directly, animal models have provided a great deal of insight into the gut microbiome’s role in the development of schizophrenia. A recent study used fecal transplant to provide the gut microbiome from patients with schizophrenia to a group of germ-free mice and compared these animals to a group of mice that received a fecal transplant from individuals with a healthy gut microbiome. The mice receiving the schizophrenia microbiome showed an increased startle response and hyperactivity.³ This was consistent with mouse models of schizophrenia, although with obvious limitations.³⁰ In addition, the brains of these animals showed changes in glutamate, glutamine, and GABA in the hippocampus; these chemicals play a role in the neurophysiology of schizophrenia.^3,31 This study has not yet been replicated, and considerable variation remains within the schizophrenia biosignature.

Continue to: Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

• Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
• Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
• Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
• Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
• Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
• Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
• Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

• Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
• Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.

The human microbiota refers to the collection of bacteria, archaea, eukarya, and viruses that reside within the human body. The term gut microbiome indicates the composition of these microbes and genetic codes in the intestine.¹ Harkening back to the ancient Greek physician Galen, who treated gastrointestinal (GI) symptoms to relieve mental disturbances such as psychosis, the gut has been a therapeutic target in schizophrenia long before antipsychotics and the DSM.² In recent years, research into the gut microbiome has drastically increased, with genetic sequencing affording a more precise look into the specific bacteria that call the human intestines their home. This has led to the recognition that the gut microbiome may be severely disrupted in schizophrenia, a condition known as dysbiosis. Preliminary research suggests that gut bacteria are more helpful than many human genes in distinguishing individuals with schizophrenia from their healthy counterparts.^3,4 In this article, we discuss the potential role of the gut microbiome in schizophrenia, including new research correlating clinical symptoms of psychosis with dysbiosis. We also provide recommendations for promoting a healthy gut microbiome.

The enteric brain across life

The composition of our bodies is far more microbiota than human. Strikingly, microbiota cells in the gut outnumber human cells, and the distal gut alone hosts bacteria with 100 times the genetic content of the entire genome.⁵ The intricate meshwork of nerves in the gut is often called the enteric brain because the gut consists of 100 million neurons and synthesizes many neuroactive chemicals implicated in mood disorders and psychosis, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine.⁶ The variety of neuro­immunologic, hormonal, and metabolic paths by which the gutmicrobiome and the brain interact are collectively known as the gut-microbiota-brainaxis.⁷

How do we acquire our gut microbiome, and how does it come to influence ourbrain and behavior? On the first day of life, as babies pass through the birth canal, they are bathed in their mother’s vaginal microbiota. In the following weeks, the microbiome expands and colonizes the gut as bacteria are introduced from environmental sources such as skin-to-skin contact and breastmilk.⁸ The microbiome continues to evolve throughout early life. As children expand their diets and navigate new aspects of the physical world, additional bacteria join the unseen ecosystem growing inside.⁹ The development of the microbiome coincides with the development of the brain. From preclinical studies, we know the gut microbiome mediates important aspects of neurodevelopment such as the formation of the blood-brain barrier (BBB), synaptic pruning, glial activation, and myelination.¹⁰ Interestingly, many of the risk factors for schizophrenia are associated with gut dysbiosis, including obstetric complications, infections treated with antibiotics, and urbanization.^11-15

Throughout human life, the gut and brain remain in close communication. The gut microbiota continue to produce monoamines, along with other metabolites that are able to cross the BBB.⁶ The HPA axis, stimulation of the immune system, and the vagus nerve all provide highways of communication between the gut and the brain.⁷ The relationship between the enteric brain and cephalic brain continues through life, even up to a person’s final hour. One autopsy study that is often cited (but soberingly, cannot be found online) allegedly revealed that 92% of schizophrenia patients had developed colitis by the time of death.^16,17

First-episode psychosis and antipsychotic treatment

For patients with schizophrenia, first-episode psychosis (FEP) represents a cocktail of mounting genetic and environmental factors. Typically, by the time a patient receives psychiatric care, they present with characteristic psychotic symptoms—hallucinations, delusions, bizarre behavior, and unusual thought process—along with a unique gut microbiome profile.

This disrupted microbiome coincides with a marked state of inflammation in the intestines. Inflammation triggers increased endothelial barrier permeability, similar to the way immune signals increase capillary permeability to allow immune cells into the periphery of the blood. Specific gut bacteria play specific roles in maintaining the gut barrier.^18,19 Disruptions in the bacteria that maintain the gut barrier, combined with inflammation, contribute to a leaky gut. A leaky gut barrier allows bacterial and immune products to more easily enter the bloodstream and then the brain, which is a potential source of neuroinflammation in schizophrenia.²⁰ This increase in gut permeability (leaky gut syndrome) is likely one of several reasons low-grade inflammation is common in schizophrenia—numerous studies show higher serum levels of proinflammatory cytokines along with antibacterial immunoglobulins in patients with FEP.^21,22

Fortunately, antipsychotics, especially the second-generation agents, help restore a healthy gut microbiome and have substantial anti-inflammatory properties.^23,24 These medications interact heavily with the gut microbiome: they have been found to have antibiotic properties, even in doses lower than would normally reach the gut microbiome.²⁵ In humans, a randomized controlled trial of probiotic supplementation for schizophrenia patients taking antipsychotics showed a reduction in GI symptoms but no significant improvement in psychotic symptoms.²⁶

Dysbiosis in schizophrenia: cause or effect?

There is no consensus on what constitutes a healthy gut microbiome because the gut microbiome is highly variable, even among healthy individuals, and can change quickly. Those who adopt new diets, for example, see drastic shifts in the gut microbiome within a few days.²⁷ Despite this variation, the main separation between a healthy and dysbiotic gut comes from the diversity of bacteria present in the gut—a healthy gut microbiome is associated with increased diversity. Numerous disease states have been associated with decreased bacterial diversity, including Clostridium difficile infection, Parkinson disease, depression, Crohn disease, and schizophrenia spectrum disorders.^28,29

Although there are ethical limitations to studying causality in humans directly, animal models have provided a great deal of insight into the gut microbiome’s role in the development of schizophrenia. A recent study used fecal transplant to provide the gut microbiome from patients with schizophrenia to a group of germ-free mice and compared these animals to a group of mice that received a fecal transplant from individuals with a healthy gut microbiome. The mice receiving the schizophrenia microbiome showed an increased startle response and hyperactivity.³ This was consistent with mouse models of schizophrenia, although with obvious limitations.³⁰ In addition, the brains of these animals showed changes in glutamate, glutamine, and GABA in the hippocampus; these chemicals play a role in the neurophysiology of schizophrenia.^3,31 This study has not yet been replicated, and considerable variation remains within the schizophrenia biosignature.

Continue to: Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

• Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
• Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
• Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
• Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
• Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
• Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
• Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

• Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
• Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.

The human microbiota refers to the collection of bacteria, archaea, eukarya, and viruses that reside within the human body. The term gut microbiome indicates the composition of these microbes and genetic codes in the intestine.¹ Harkening back to the ancient Greek physician Galen, who treated gastrointestinal (GI) symptoms to relieve mental disturbances such as psychosis, the gut has been a therapeutic target in schizophrenia long before antipsychotics and the DSM.² In recent years, research into the gut microbiome has drastically increased, with genetic sequencing affording a more precise look into the specific bacteria that call the human intestines their home. This has led to the recognition that the gut microbiome may be severely disrupted in schizophrenia, a condition known as dysbiosis. Preliminary research suggests that gut bacteria are more helpful than many human genes in distinguishing individuals with schizophrenia from their healthy counterparts.^3,4 In this article, we discuss the potential role of the gut microbiome in schizophrenia, including new research correlating clinical symptoms of psychosis with dysbiosis. We also provide recommendations for promoting a healthy gut microbiome.

The enteric brain across life

The composition of our bodies is far more microbiota than human. Strikingly, microbiota cells in the gut outnumber human cells, and the distal gut alone hosts bacteria with 100 times the genetic content of the entire genome.⁵ The intricate meshwork of nerves in the gut is often called the enteric brain because the gut consists of 100 million neurons and synthesizes many neuroactive chemicals implicated in mood disorders and psychosis, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine.⁶ The variety of neuro­immunologic, hormonal, and metabolic paths by which the gutmicrobiome and the brain interact are collectively known as the gut-microbiota-brainaxis.⁷

How do we acquire our gut microbiome, and how does it come to influence ourbrain and behavior? On the first day of life, as babies pass through the birth canal, they are bathed in their mother’s vaginal microbiota. In the following weeks, the microbiome expands and colonizes the gut as bacteria are introduced from environmental sources such as skin-to-skin contact and breastmilk.⁸ The microbiome continues to evolve throughout early life. As children expand their diets and navigate new aspects of the physical world, additional bacteria join the unseen ecosystem growing inside.⁹ The development of the microbiome coincides with the development of the brain. From preclinical studies, we know the gut microbiome mediates important aspects of neurodevelopment such as the formation of the blood-brain barrier (BBB), synaptic pruning, glial activation, and myelination.¹⁰ Interestingly, many of the risk factors for schizophrenia are associated with gut dysbiosis, including obstetric complications, infections treated with antibiotics, and urbanization.^11-15

Throughout human life, the gut and brain remain in close communication. The gut microbiota continue to produce monoamines, along with other metabolites that are able to cross the BBB.⁶ The HPA axis, stimulation of the immune system, and the vagus nerve all provide highways of communication between the gut and the brain.⁷ The relationship between the enteric brain and cephalic brain continues through life, even up to a person’s final hour. One autopsy study that is often cited (but soberingly, cannot be found online) allegedly revealed that 92% of schizophrenia patients had developed colitis by the time of death.^16,17

First-episode psychosis and antipsychotic treatment

For patients with schizophrenia, first-episode psychosis (FEP) represents a cocktail of mounting genetic and environmental factors. Typically, by the time a patient receives psychiatric care, they present with characteristic psychotic symptoms—hallucinations, delusions, bizarre behavior, and unusual thought process—along with a unique gut microbiome profile.

This disrupted microbiome coincides with a marked state of inflammation in the intestines. Inflammation triggers increased endothelial barrier permeability, similar to the way immune signals increase capillary permeability to allow immune cells into the periphery of the blood. Specific gut bacteria play specific roles in maintaining the gut barrier.^18,19 Disruptions in the bacteria that maintain the gut barrier, combined with inflammation, contribute to a leaky gut. A leaky gut barrier allows bacterial and immune products to more easily enter the bloodstream and then the brain, which is a potential source of neuroinflammation in schizophrenia.²⁰ This increase in gut permeability (leaky gut syndrome) is likely one of several reasons low-grade inflammation is common in schizophrenia—numerous studies show higher serum levels of proinflammatory cytokines along with antibacterial immunoglobulins in patients with FEP.^21,22

Fortunately, antipsychotics, especially the second-generation agents, help restore a healthy gut microbiome and have substantial anti-inflammatory properties.^23,24 These medications interact heavily with the gut microbiome: they have been found to have antibiotic properties, even in doses lower than would normally reach the gut microbiome.²⁵ In humans, a randomized controlled trial of probiotic supplementation for schizophrenia patients taking antipsychotics showed a reduction in GI symptoms but no significant improvement in psychotic symptoms.²⁶

Dysbiosis in schizophrenia: cause or effect?

There is no consensus on what constitutes a healthy gut microbiome because the gut microbiome is highly variable, even among healthy individuals, and can change quickly. Those who adopt new diets, for example, see drastic shifts in the gut microbiome within a few days.²⁷ Despite this variation, the main separation between a healthy and dysbiotic gut comes from the diversity of bacteria present in the gut—a healthy gut microbiome is associated with increased diversity. Numerous disease states have been associated with decreased bacterial diversity, including Clostridium difficile infection, Parkinson disease, depression, Crohn disease, and schizophrenia spectrum disorders.^28,29

Although there are ethical limitations to studying causality in humans directly, animal models have provided a great deal of insight into the gut microbiome’s role in the development of schizophrenia. A recent study used fecal transplant to provide the gut microbiome from patients with schizophrenia to a group of germ-free mice and compared these animals to a group of mice that received a fecal transplant from individuals with a healthy gut microbiome. The mice receiving the schizophrenia microbiome showed an increased startle response and hyperactivity.³ This was consistent with mouse models of schizophrenia, although with obvious limitations.³⁰ In addition, the brains of these animals showed changes in glutamate, glutamine, and GABA in the hippocampus; these chemicals play a role in the neurophysiology of schizophrenia.^3,31 This study has not yet been replicated, and considerable variation remains within the schizophrenia biosignature.

Continue to: Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

• Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
• Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
• Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
• Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
• Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
• Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
• Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

• Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
• Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.

Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

• Highly genetic in etiology but with environmental influences and epigenetics
• Associated with childhood maltreatment, abuse, or neglect
• Disrupted neuroplasticity, especially shrinkage in hippocampal volume
• Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
• Extensive white matter pathology across interhemispheric and intrahemispheric bundles
• Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
• Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
• Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
• Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
• Elevated oxidative stress biomarkers, indicating an increase in free radicals
• Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
• Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
• Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

• Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
• Significantly elevated lifetime suicide risk
• Cognitive impairment (more severe in schizophrenia across several cognitive functions)
• Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
• Antidepressant medications im­-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
• Both have treatment-resistant subtypes that fail to respond to standard therapies
• Both are associated with comorbid generalized anxiety disorder
• Both are associated with comorbid obsessive-compulsive disorder
• Both are associated with serious alcohol and drug use
• Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
• Elevated risk of dementia with aging compared to the unaffected general population
• Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
• Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
• Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

• Glutamate N-methyl-D-aspar­tate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
• Muscarinic agonists improve psychosis but worsen depression
• High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
• Cortical thinning more severe in schizophrenia
• Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
• Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

• Auditory and visual hallucinations are more common in schizophrenia than in MDD
• Anosognosia is common in schizophrenia but not in MDD
• Implausible delusions are more common in schizophrenia than in MDD
• Mood-congruent delusions are more common in MDD than in schizophrenia
• Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
• Achieving full remission is more common in MDD than in schizophrenia
• Long-acting injectable medications are available for schizophrenia but not for MDD
• Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

• Highly genetic in etiology but with environmental influences and epigenetics
• Associated with childhood maltreatment, abuse, or neglect
• Disrupted neuroplasticity, especially shrinkage in hippocampal volume
• Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
• Extensive white matter pathology across interhemispheric and intrahemispheric bundles
• Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
• Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
• Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
• Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
• Elevated oxidative stress biomarkers, indicating an increase in free radicals
• Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
• Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
• Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

• Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
• Significantly elevated lifetime suicide risk
• Cognitive impairment (more severe in schizophrenia across several cognitive functions)
• Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
• Antidepressant medications im­-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
• Both have treatment-resistant subtypes that fail to respond to standard therapies
• Both are associated with comorbid generalized anxiety disorder
• Both are associated with comorbid obsessive-compulsive disorder
• Both are associated with serious alcohol and drug use
• Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
• Elevated risk of dementia with aging compared to the unaffected general population
• Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
• Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
• Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

• Glutamate N-methyl-D-aspar­tate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
• Muscarinic agonists improve psychosis but worsen depression
• High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
• Cortical thinning more severe in schizophrenia
• Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
• Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

• Auditory and visual hallucinations are more common in schizophrenia than in MDD
• Anosognosia is common in schizophrenia but not in MDD
• Implausible delusions are more common in schizophrenia than in MDD
• Mood-congruent delusions are more common in MDD than in schizophrenia
• Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
• Achieving full remission is more common in MDD than in schizophrenia
• Long-acting injectable medications are available for schizophrenia but not for MDD
• Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

• Highly genetic in etiology but with environmental influences and epigenetics
• Associated with childhood maltreatment, abuse, or neglect
• Disrupted neuroplasticity, especially shrinkage in hippocampal volume
• Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
• Extensive white matter pathology across interhemispheric and intrahemispheric bundles
• Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
• Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
• Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
• Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
• Elevated oxidative stress biomarkers, indicating an increase in free radicals
• Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
• Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
• Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

• Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
• Significantly elevated lifetime suicide risk
• Cognitive impairment (more severe in schizophrenia across several cognitive functions)
• Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
• Antidepressant medications im­-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
• Both have treatment-resistant subtypes that fail to respond to standard therapies
• Both are associated with comorbid generalized anxiety disorder
• Both are associated with comorbid obsessive-compulsive disorder
• Both are associated with serious alcohol and drug use
• Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
• Elevated risk of dementia with aging compared to the unaffected general population
• Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
• Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
• Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

• Glutamate N-methyl-D-aspar­tate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
• Muscarinic agonists improve psychosis but worsen depression
• High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
• Cortical thinning more severe in schizophrenia
• Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
• Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

• Auditory and visual hallucinations are more common in schizophrenia than in MDD
• Anosognosia is common in schizophrenia but not in MDD
• Implausible delusions are more common in schizophrenia than in MDD
• Mood-congruent delusions are more common in MDD than in schizophrenia
• Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
• Achieving full remission is more common in MDD than in schizophrenia
• Long-acting injectable medications are available for schizophrenia but not for MDD
• Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

There has been a substantial increase over the last 20 years in antipsychotic prescribing among children and adolescents in England – especially among those with autism, an analysis of primary care records from 7.2 million children and adolescents aged 3-18 years shows.

“This study demonstrates a concerning trend in antipsychotic prescribing in children and adolescents,” study investigator Matthias Pierce, PhD, senior research fellow at the University of Manchester (England) Center for Women’s Mental Health, who jointly led the study, said in a news release.

“We do not think the changes in prescribing necessarily relate to changes in clinical need; rather, it may be more likely to reflect changes in prescribing practice by clinicians,” Dr. Pierce said.

The study was published online in The Lancet Psychiatry.
 

Increase in long-term use

Between 2000 and 2019, prescriptions for antipsychotics nearly doubled from 0.06% to 0.11%.

The investigators note that the U.K.’s National Institute for Health and Care Excellence has approved the use of some antipsychotics in patients younger than age 18 with schizophrenia, bipolar disorder, and severely aggressive behavior attributable to conduct disorder.

However, these data suggest antipsychotics are being prescribed for an increasingly broad range of conditions, most commonly autism, but also for attention-deficit/ hyperactivity disorder, tic disorders like Tourrette syndrome, and learning difficulties.

“Broadening use of antipsychotics in developing young people begs questions about their safety over time and demands more research on this topic,” senior author Kathryn Abel, MBBS, PhD, from the University of Manchester said in the news release.

During the study period, antipsychotic prescribing in primary care increased by an average of 3.3% per year and the rate of first prescriptions increased by 2.2% per year.

The data also suggest that more children and adolescents are taking these powerful drugs for longer periods of time. The proportion receiving antipsychotics for at least 6 months after an initial prescription rose from 41.9% in 2000 to 62.8% in 2018.
 

Prescribing inequities

From 2009 onwards, more than 90% of prescriptions were for atypical antipsychotics.

Over time, risperidone dominated, with more than 60% of all prescriptions, followed by aripiprazole, quetiapine, olanzapine, and haloperidol as the most prescribed antipsychotics.

Boys and older children aged 15-18 years were most likely to receive an antipsychotic. However, the increasing trends were evident in all groups.

The data also point to inequities in prescribing as a result of deprivation levels, with typical antipsychotics prescribed more frequently in more deprived areas over time.

Dr. Pierce said he hopes this study will “help clinicians to evaluate the prescribing of antipsychotics to children more fully and will encourage them to consider better access to alternatives.”

Dr. Abel noted that antipsychotic medications “continue to have a valuable role in the treatment of serious mental illness. These findings represent a descriptive account of antipsychotic prescribing to children and adolescents in the U.K. today and provide a window onto current practice.”
 

Findings are no surprise

Emily Simonoff, MD, professor of child and adolescent psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, offered perspective on the study in a statement from the U.K. nonprofit Science Media Centre.

“To clinicians, it will not be surprising that the authors demonstrate an increase in rates of prescriptions over that time period, as there has been a steadily emerging evidence base for the benefits of this group of medication for a range of different indications, which has been further supported by new licensing indications and recommendations from NICE,” Dr. Simonoff said.

For example, “there is good evidence for their benefits for other conditions such as irritability in autism spectrum disorder.

“However, it should also be noted that NICE recommendations for their use in many conditions is as part of a multimodal treatment plan, for example including psychological or behavioral interventions. It’s unclear from the study whether such recommendations were being followed or medication was being used on its own,” she added.

Dr. Simonoff also said it’s “reassuring” that prescribing rates remain very low in the youngest children and notes that the authors “rightly highlight the need for high-quality, longer-term studies on efficacy and, most importantly, adverse effects. This should be a research priority.”

The study had no funding. The authors report no relevant financial relationships. Dr. Simonoff is a member of the NICE guideline development group for the management of autism and has published on the efficacy of antipsychotic medication for irritability in autism.

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

There has been a substantial increase over the last 20 years in antipsychotic prescribing among children and adolescents in England – especially among those with autism, an analysis of primary care records from 7.2 million children and adolescents aged 3-18 years shows.

“This study demonstrates a concerning trend in antipsychotic prescribing in children and adolescents,” study investigator Matthias Pierce, PhD, senior research fellow at the University of Manchester (England) Center for Women’s Mental Health, who jointly led the study, said in a news release.

“We do not think the changes in prescribing necessarily relate to changes in clinical need; rather, it may be more likely to reflect changes in prescribing practice by clinicians,” Dr. Pierce said.

The study was published online in The Lancet Psychiatry.
 

Increase in long-term use

Between 2000 and 2019, prescriptions for antipsychotics nearly doubled from 0.06% to 0.11%.

The investigators note that the U.K.’s National Institute for Health and Care Excellence has approved the use of some antipsychotics in patients younger than age 18 with schizophrenia, bipolar disorder, and severely aggressive behavior attributable to conduct disorder.

However, these data suggest antipsychotics are being prescribed for an increasingly broad range of conditions, most commonly autism, but also for attention-deficit/ hyperactivity disorder, tic disorders like Tourrette syndrome, and learning difficulties.

“Broadening use of antipsychotics in developing young people begs questions about their safety over time and demands more research on this topic,” senior author Kathryn Abel, MBBS, PhD, from the University of Manchester said in the news release.

During the study period, antipsychotic prescribing in primary care increased by an average of 3.3% per year and the rate of first prescriptions increased by 2.2% per year.

The data also suggest that more children and adolescents are taking these powerful drugs for longer periods of time. The proportion receiving antipsychotics for at least 6 months after an initial prescription rose from 41.9% in 2000 to 62.8% in 2018.
 

Prescribing inequities

From 2009 onwards, more than 90% of prescriptions were for atypical antipsychotics.

Over time, risperidone dominated, with more than 60% of all prescriptions, followed by aripiprazole, quetiapine, olanzapine, and haloperidol as the most prescribed antipsychotics.

Boys and older children aged 15-18 years were most likely to receive an antipsychotic. However, the increasing trends were evident in all groups.

The data also point to inequities in prescribing as a result of deprivation levels, with typical antipsychotics prescribed more frequently in more deprived areas over time.

Dr. Pierce said he hopes this study will “help clinicians to evaluate the prescribing of antipsychotics to children more fully and will encourage them to consider better access to alternatives.”

Dr. Abel noted that antipsychotic medications “continue to have a valuable role in the treatment of serious mental illness. These findings represent a descriptive account of antipsychotic prescribing to children and adolescents in the U.K. today and provide a window onto current practice.”
 

Findings are no surprise

Emily Simonoff, MD, professor of child and adolescent psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, offered perspective on the study in a statement from the U.K. nonprofit Science Media Centre.

“To clinicians, it will not be surprising that the authors demonstrate an increase in rates of prescriptions over that time period, as there has been a steadily emerging evidence base for the benefits of this group of medication for a range of different indications, which has been further supported by new licensing indications and recommendations from NICE,” Dr. Simonoff said.

For example, “there is good evidence for their benefits for other conditions such as irritability in autism spectrum disorder.

“However, it should also be noted that NICE recommendations for their use in many conditions is as part of a multimodal treatment plan, for example including psychological or behavioral interventions. It’s unclear from the study whether such recommendations were being followed or medication was being used on its own,” she added.

Dr. Simonoff also said it’s “reassuring” that prescribing rates remain very low in the youngest children and notes that the authors “rightly highlight the need for high-quality, longer-term studies on efficacy and, most importantly, adverse effects. This should be a research priority.”

The study had no funding. The authors report no relevant financial relationships. Dr. Simonoff is a member of the NICE guideline development group for the management of autism and has published on the efficacy of antipsychotic medication for irritability in autism.

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

There has been a substantial increase over the last 20 years in antipsychotic prescribing among children and adolescents in England – especially among those with autism, an analysis of primary care records from 7.2 million children and adolescents aged 3-18 years shows.

“This study demonstrates a concerning trend in antipsychotic prescribing in children and adolescents,” study investigator Matthias Pierce, PhD, senior research fellow at the University of Manchester (England) Center for Women’s Mental Health, who jointly led the study, said in a news release.

“We do not think the changes in prescribing necessarily relate to changes in clinical need; rather, it may be more likely to reflect changes in prescribing practice by clinicians,” Dr. Pierce said.

The study was published online in The Lancet Psychiatry.
 

Increase in long-term use

Between 2000 and 2019, prescriptions for antipsychotics nearly doubled from 0.06% to 0.11%.

The investigators note that the U.K.’s National Institute for Health and Care Excellence has approved the use of some antipsychotics in patients younger than age 18 with schizophrenia, bipolar disorder, and severely aggressive behavior attributable to conduct disorder.

However, these data suggest antipsychotics are being prescribed for an increasingly broad range of conditions, most commonly autism, but also for attention-deficit/ hyperactivity disorder, tic disorders like Tourrette syndrome, and learning difficulties.

“Broadening use of antipsychotics in developing young people begs questions about their safety over time and demands more research on this topic,” senior author Kathryn Abel, MBBS, PhD, from the University of Manchester said in the news release.

During the study period, antipsychotic prescribing in primary care increased by an average of 3.3% per year and the rate of first prescriptions increased by 2.2% per year.

The data also suggest that more children and adolescents are taking these powerful drugs for longer periods of time. The proportion receiving antipsychotics for at least 6 months after an initial prescription rose from 41.9% in 2000 to 62.8% in 2018.
 

Prescribing inequities

From 2009 onwards, more than 90% of prescriptions were for atypical antipsychotics.

Over time, risperidone dominated, with more than 60% of all prescriptions, followed by aripiprazole, quetiapine, olanzapine, and haloperidol as the most prescribed antipsychotics.

Boys and older children aged 15-18 years were most likely to receive an antipsychotic. However, the increasing trends were evident in all groups.

The data also point to inequities in prescribing as a result of deprivation levels, with typical antipsychotics prescribed more frequently in more deprived areas over time.

Dr. Pierce said he hopes this study will “help clinicians to evaluate the prescribing of antipsychotics to children more fully and will encourage them to consider better access to alternatives.”

Dr. Abel noted that antipsychotic medications “continue to have a valuable role in the treatment of serious mental illness. These findings represent a descriptive account of antipsychotic prescribing to children and adolescents in the U.K. today and provide a window onto current practice.”
 

Findings are no surprise

Emily Simonoff, MD, professor of child and adolescent psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, offered perspective on the study in a statement from the U.K. nonprofit Science Media Centre.

“To clinicians, it will not be surprising that the authors demonstrate an increase in rates of prescriptions over that time period, as there has been a steadily emerging evidence base for the benefits of this group of medication for a range of different indications, which has been further supported by new licensing indications and recommendations from NICE,” Dr. Simonoff said.

For example, “there is good evidence for their benefits for other conditions such as irritability in autism spectrum disorder.

“However, it should also be noted that NICE recommendations for their use in many conditions is as part of a multimodal treatment plan, for example including psychological or behavioral interventions. It’s unclear from the study whether such recommendations were being followed or medication was being used on its own,” she added.

Dr. Simonoff also said it’s “reassuring” that prescribing rates remain very low in the youngest children and notes that the authors “rightly highlight the need for high-quality, longer-term studies on efficacy and, most importantly, adverse effects. This should be a research priority.”

The study had no funding. The authors report no relevant financial relationships. Dr. Simonoff is a member of the NICE guideline development group for the management of autism and has published on the efficacy of antipsychotic medication for irritability in autism.

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

The experimental antipsychotic evenamide is associated with reduced severity of symptoms when added to an existing antipsychotic in treatment-resistant schizophrenia (TRS), new research suggests.

The topline results from an exploratory study, which were released by the developer Newron Pharmaceuticals, are “very encouraging,” Stephen R. Marder, MD, professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said in a company news release. 

“The magnitude of the improvements experienced by these TRS patients, not responding to their current antipsychotic, on evenamide was substantial, improved over time, and was likely to be clinically meaningful,” Dr. Marder said.
 

First 100 patients

The topline results are based on the first 100 patients enrolled in study 014 and randomly assigned to receive evenamide at 7.5 mg, 15 mg, or 30 mg twice daily, as well as patients in the extension arm (study 015) that have completed 30 weeks.

Key findings released by the company included statistically significant improvement over baseline at 30 weeks (P < .001) in Positive and Negative Syndrome Scale (PANSS) scores, with continued improvement over that seen at 6 weeks.

The proportion of patients with clinically meaningful PANSS improvement at 30 weeks more than doubled from 16.5% at 6 weeks.

In addition, results showed statistically significant improvement (P < .001) at week 30 compared with baseline in illness severity as measured by the Clinical Global Impression of Severity (CGI-S), with continued improvement over that seen at 6 weeks.

The proportion of patients whose illness improved by at least one level of severity was 60% at week 6 and increased approximately by an additional 20% at week 30.

The proportion of patients judged to have clinically meaningful improvement, defined as at least “much improved,” on the Clinical Global Impression of Change (CGI-C) was 27% at week 6 – and increased a further 10% at week 30.

Evenamide was also well tolerated, with few adverse effects reported, and 85 of 100 patients remained on treatment at 30 weeks.
 

New options ‘desperately needed’

Newron plans to present the full results from study 014 at the European Congress of Psychiatry, scheduled for March 25-28 in Paris.

The extension study 015 is ongoing and will provide results on evenamide treatment for up to 1 year by the second quarter of 2023.

The company reported it expects to launch a randomized, placebo-controlled study (study 003) of the drug in TRS this year.

If the current results are confirmed in the randomized controlled trial, “evenamide would be the first medication that could be added to an antipsychotic to improve symptoms in treatment-refractory schizophrenia,” Dr. Marder said.

New therapeutic options for TRS, which occurs in about one-third of patients, are “desperately needed,” Ravi Anand, MD, chief medical officer at Newron, said in the release.

The reported data, comparing the effect of evenamide at 6 weeks vs. 6 months, “suggest that not only was there sustained improvement in the key measures, but the proportion of patients achieving clinically meaningful improvement increased over time,” Dr. Anand added.

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

The experimental antipsychotic evenamide is associated with reduced severity of symptoms when added to an existing antipsychotic in treatment-resistant schizophrenia (TRS), new research suggests.

The topline results from an exploratory study, which were released by the developer Newron Pharmaceuticals, are “very encouraging,” Stephen R. Marder, MD, professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said in a company news release. 

“The magnitude of the improvements experienced by these TRS patients, not responding to their current antipsychotic, on evenamide was substantial, improved over time, and was likely to be clinically meaningful,” Dr. Marder said.
 

First 100 patients

The topline results are based on the first 100 patients enrolled in study 014 and randomly assigned to receive evenamide at 7.5 mg, 15 mg, or 30 mg twice daily, as well as patients in the extension arm (study 015) that have completed 30 weeks.

Key findings released by the company included statistically significant improvement over baseline at 30 weeks (P < .001) in Positive and Negative Syndrome Scale (PANSS) scores, with continued improvement over that seen at 6 weeks.

The proportion of patients with clinically meaningful PANSS improvement at 30 weeks more than doubled from 16.5% at 6 weeks.

In addition, results showed statistically significant improvement (P < .001) at week 30 compared with baseline in illness severity as measured by the Clinical Global Impression of Severity (CGI-S), with continued improvement over that seen at 6 weeks.

The proportion of patients whose illness improved by at least one level of severity was 60% at week 6 and increased approximately by an additional 20% at week 30.

The proportion of patients judged to have clinically meaningful improvement, defined as at least “much improved,” on the Clinical Global Impression of Change (CGI-C) was 27% at week 6 – and increased a further 10% at week 30.

Evenamide was also well tolerated, with few adverse effects reported, and 85 of 100 patients remained on treatment at 30 weeks.
 

New options ‘desperately needed’

Newron plans to present the full results from study 014 at the European Congress of Psychiatry, scheduled for March 25-28 in Paris.

The extension study 015 is ongoing and will provide results on evenamide treatment for up to 1 year by the second quarter of 2023.

The company reported it expects to launch a randomized, placebo-controlled study (study 003) of the drug in TRS this year.

If the current results are confirmed in the randomized controlled trial, “evenamide would be the first medication that could be added to an antipsychotic to improve symptoms in treatment-refractory schizophrenia,” Dr. Marder said.

New therapeutic options for TRS, which occurs in about one-third of patients, are “desperately needed,” Ravi Anand, MD, chief medical officer at Newron, said in the release.

The reported data, comparing the effect of evenamide at 6 weeks vs. 6 months, “suggest that not only was there sustained improvement in the key measures, but the proportion of patients achieving clinically meaningful improvement increased over time,” Dr. Anand added.

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

The experimental antipsychotic evenamide is associated with reduced severity of symptoms when added to an existing antipsychotic in treatment-resistant schizophrenia (TRS), new research suggests.

The topline results from an exploratory study, which were released by the developer Newron Pharmaceuticals, are “very encouraging,” Stephen R. Marder, MD, professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said in a company news release. 

“The magnitude of the improvements experienced by these TRS patients, not responding to their current antipsychotic, on evenamide was substantial, improved over time, and was likely to be clinically meaningful,” Dr. Marder said.
 

First 100 patients

The topline results are based on the first 100 patients enrolled in study 014 and randomly assigned to receive evenamide at 7.5 mg, 15 mg, or 30 mg twice daily, as well as patients in the extension arm (study 015) that have completed 30 weeks.

Key findings released by the company included statistically significant improvement over baseline at 30 weeks (P < .001) in Positive and Negative Syndrome Scale (PANSS) scores, with continued improvement over that seen at 6 weeks.

The proportion of patients with clinically meaningful PANSS improvement at 30 weeks more than doubled from 16.5% at 6 weeks.

In addition, results showed statistically significant improvement (P < .001) at week 30 compared with baseline in illness severity as measured by the Clinical Global Impression of Severity (CGI-S), with continued improvement over that seen at 6 weeks.

The proportion of patients whose illness improved by at least one level of severity was 60% at week 6 and increased approximately by an additional 20% at week 30.

The proportion of patients judged to have clinically meaningful improvement, defined as at least “much improved,” on the Clinical Global Impression of Change (CGI-C) was 27% at week 6 – and increased a further 10% at week 30.

Evenamide was also well tolerated, with few adverse effects reported, and 85 of 100 patients remained on treatment at 30 weeks.
 

New options ‘desperately needed’

Newron plans to present the full results from study 014 at the European Congress of Psychiatry, scheduled for March 25-28 in Paris.

The extension study 015 is ongoing and will provide results on evenamide treatment for up to 1 year by the second quarter of 2023.

The company reported it expects to launch a randomized, placebo-controlled study (study 003) of the drug in TRS this year.

If the current results are confirmed in the randomized controlled trial, “evenamide would be the first medication that could be added to an antipsychotic to improve symptoms in treatment-refractory schizophrenia,” Dr. Marder said.

New therapeutic options for TRS, which occurs in about one-third of patients, are “desperately needed,” Ravi Anand, MD, chief medical officer at Newron, said in the release.

The reported data, comparing the effect of evenamide at 6 weeks vs. 6 months, “suggest that not only was there sustained improvement in the key measures, but the proportion of patients achieving clinically meaningful improvement increased over time,” Dr. Anand added.

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

Individuals with schizophrenia showed larger discrepancies between actual and ideal positive affect, compared with healthy controls, in contrast to the investigators’ hypothesis in a study of 61 individuals.

Anhedonia is common in schizophrenia patients, but treatments have not been especially successful, possibly because of a lack of understanding the mechanisms behind anhedonia in these patients, Sydney H. James, a PhD candidate at the University of Georgia, Athens, and colleagues wrote.

Although many schizophrenia (SZ) patients exhibit anhedonia on diagnosis in a clinical interview setting, other recent research shows comparable response to pleasant stimuli between schizophrenic patients and healthy controls. The researchers proposed that anhedonia “reflects abnormalities in the valuation of desired affective states in individuals with SZ,” with differences between actual and ideal affect.

In a study published in the Journal of Psychiatric Research, the researchers identified 32 outpatients with schizophrenia and 29 healthy controls. The SZ participants were recruited from community outpatient mental health services in Georgia. All participants completed Structured Clinical Interview for DSM-5 Disorders and the SCID-5 Personality Disorders. Participants then completed the Affect Valuation Index and measures of negative symptom severity. Negative symptom severity was measured using the Negative Symptom Inventory-Self-Report, an 11-item questionnaire assessing three specific experiential and behavioral components (anhedonia, avolition, and asociality) over the past week.

The average age of the SZ patients and controls was approximately 40 years, and 10 SZ patients and 5 controls were male.

Overall, the researchers found a significant main effect of group, a significant main effect of arousal, and a significant group X arousal interaction for positive affect discrepancy scores. For negative affect discrepancy scores, they found a significant main effect on group, nonsignificant main effect of arousal, and significant group X arousal interaction.

Individuals with SZ showed greater positive and negative emotion discrepancy scores, compared with controls, in contrast to the researchers’ hypothesis. “Those diagnosed with SZ were more likely to want to feel less negative than they actually did,” they wrote. The negative affect discrepancy scores were positively associated with negative symptoms. The discrepancies between actual and ideal affect may be impacted by social interactions and the perceived expectations of others for levels of negative affect.

The study findings were limited by the small sample size and inability to test the relationship between ideal and actual affect as related to low-pleasure beliefs, which merits further study, the researchers noted. Other limitations include the focus on an outpatient population with mild to moderate SZ, and the use of a trait format to measure affect rather than experiential emotion knowledge.

However, the results have practical implications for treatment and suggest that, “given the positive associations between negative symptom and affect discrepancy scores, psychosocial treatments could target expectations for future positive and negative emotional experience,” and ecological momentary assessment could be used to track affect through a period of treatment and prompt conversations between SZ patients and therapists about discrepancies, they concluded.

The study participants were compensated by the National Institute of Mental Health through a grant to a corresponding author. Ms. James had no financial conflicts to disclose.

Individuals with schizophrenia showed larger discrepancies between actual and ideal positive affect, compared with healthy controls, in contrast to the investigators’ hypothesis in a study of 61 individuals.

Anhedonia is common in schizophrenia patients, but treatments have not been especially successful, possibly because of a lack of understanding the mechanisms behind anhedonia in these patients, Sydney H. James, a PhD candidate at the University of Georgia, Athens, and colleagues wrote.

Although many schizophrenia (SZ) patients exhibit anhedonia on diagnosis in a clinical interview setting, other recent research shows comparable response to pleasant stimuli between schizophrenic patients and healthy controls. The researchers proposed that anhedonia “reflects abnormalities in the valuation of desired affective states in individuals with SZ,” with differences between actual and ideal affect.

In a study published in the Journal of Psychiatric Research, the researchers identified 32 outpatients with schizophrenia and 29 healthy controls. The SZ participants were recruited from community outpatient mental health services in Georgia. All participants completed Structured Clinical Interview for DSM-5 Disorders and the SCID-5 Personality Disorders. Participants then completed the Affect Valuation Index and measures of negative symptom severity. Negative symptom severity was measured using the Negative Symptom Inventory-Self-Report, an 11-item questionnaire assessing three specific experiential and behavioral components (anhedonia, avolition, and asociality) over the past week.

The average age of the SZ patients and controls was approximately 40 years, and 10 SZ patients and 5 controls were male.

Overall, the researchers found a significant main effect of group, a significant main effect of arousal, and a significant group X arousal interaction for positive affect discrepancy scores. For negative affect discrepancy scores, they found a significant main effect on group, nonsignificant main effect of arousal, and significant group X arousal interaction.

Individuals with SZ showed greater positive and negative emotion discrepancy scores, compared with controls, in contrast to the researchers’ hypothesis. “Those diagnosed with SZ were more likely to want to feel less negative than they actually did,” they wrote. The negative affect discrepancy scores were positively associated with negative symptoms. The discrepancies between actual and ideal affect may be impacted by social interactions and the perceived expectations of others for levels of negative affect.

The study findings were limited by the small sample size and inability to test the relationship between ideal and actual affect as related to low-pleasure beliefs, which merits further study, the researchers noted. Other limitations include the focus on an outpatient population with mild to moderate SZ, and the use of a trait format to measure affect rather than experiential emotion knowledge.

However, the results have practical implications for treatment and suggest that, “given the positive associations between negative symptom and affect discrepancy scores, psychosocial treatments could target expectations for future positive and negative emotional experience,” and ecological momentary assessment could be used to track affect through a period of treatment and prompt conversations between SZ patients and therapists about discrepancies, they concluded.

The study participants were compensated by the National Institute of Mental Health through a grant to a corresponding author. Ms. James had no financial conflicts to disclose.

Individuals with schizophrenia showed larger discrepancies between actual and ideal positive affect, compared with healthy controls, in contrast to the investigators’ hypothesis in a study of 61 individuals.

Anhedonia is common in schizophrenia patients, but treatments have not been especially successful, possibly because of a lack of understanding the mechanisms behind anhedonia in these patients, Sydney H. James, a PhD candidate at the University of Georgia, Athens, and colleagues wrote.

Although many schizophrenia (SZ) patients exhibit anhedonia on diagnosis in a clinical interview setting, other recent research shows comparable response to pleasant stimuli between schizophrenic patients and healthy controls. The researchers proposed that anhedonia “reflects abnormalities in the valuation of desired affective states in individuals with SZ,” with differences between actual and ideal affect.

In a study published in the Journal of Psychiatric Research, the researchers identified 32 outpatients with schizophrenia and 29 healthy controls. The SZ participants were recruited from community outpatient mental health services in Georgia. All participants completed Structured Clinical Interview for DSM-5 Disorders and the SCID-5 Personality Disorders. Participants then completed the Affect Valuation Index and measures of negative symptom severity. Negative symptom severity was measured using the Negative Symptom Inventory-Self-Report, an 11-item questionnaire assessing three specific experiential and behavioral components (anhedonia, avolition, and asociality) over the past week.

The average age of the SZ patients and controls was approximately 40 years, and 10 SZ patients and 5 controls were male.

Overall, the researchers found a significant main effect of group, a significant main effect of arousal, and a significant group X arousal interaction for positive affect discrepancy scores. For negative affect discrepancy scores, they found a significant main effect on group, nonsignificant main effect of arousal, and significant group X arousal interaction.

Individuals with SZ showed greater positive and negative emotion discrepancy scores, compared with controls, in contrast to the researchers’ hypothesis. “Those diagnosed with SZ were more likely to want to feel less negative than they actually did,” they wrote. The negative affect discrepancy scores were positively associated with negative symptoms. The discrepancies between actual and ideal affect may be impacted by social interactions and the perceived expectations of others for levels of negative affect.

The study findings were limited by the small sample size and inability to test the relationship between ideal and actual affect as related to low-pleasure beliefs, which merits further study, the researchers noted. Other limitations include the focus on an outpatient population with mild to moderate SZ, and the use of a trait format to measure affect rather than experiential emotion knowledge.

However, the results have practical implications for treatment and suggest that, “given the positive associations between negative symptom and affect discrepancy scores, psychosocial treatments could target expectations for future positive and negative emotional experience,” and ecological momentary assessment could be used to track affect through a period of treatment and prompt conversations between SZ patients and therapists about discrepancies, they concluded.

The study participants were compensated by the National Institute of Mental Health through a grant to a corresponding author. Ms. James had no financial conflicts to disclose.

More than a quarter of cardiologists in an international survey reported experiencing mental health conditions ranging from anxiety or anger issues to major depression or other psychiatric disorders.  

Such conditions varied in prevalence by cardiology subspecialty and years in the field, were more common in women than in men, and were closely linked to enduring hostile work environments and other strains of professional life.

The survey, conducted only months before the COVID-19 pandemic and with its share of limitations, still paints a picture that’s not pretty.

For example, mental health concerns were reported by about 42% of respondents who cited a hostile work environment, defined as workplace experience of discrimination based on age, sex, religion, race or ethnicity, or emotional or sexual harassment. Conversely, the prevalence of these concerns reached only 17% among those without such workplace conditions.

The study shows substantial overlap between cardiologists reporting hostility at work and those with mental health concerns, “and that was a significant finding,” Garima Sharma, MD, Johns Hopkins University, Baltimore, said in an interview.

Still, only 31% of male and 42% of female cardiologists (P < .001) reporting mental health concerns also said they had sought professional help either within or outside their own institutions.

That means “there is a lot of silent suffering” in the field, said Dr. Sharma, who is lead author on the study, published in the Journal of the American College of Cardiology.
 

Bringing back the conversation

The survey findings, she added, point to at least two potential ways the cardiology community can strive to diminish what may be a major underlying cause of the mental health concerns and their consequences.

“If you work towards reducing hostility at work and making mental health a priority for your workforce, then those experiencing these types of egregious conditions based on age, gender, race, ethnicity, or sexual orientation are less likely to be harmed.”

Mental health concerns among cardiologists are seldom openly discussed, so the current study can be “a way to bring them back into the conversation,” Dr. Sharma said. Clinician mental health “is extremely important because it directly impacts patient care and productivity.”

The survey’s reported mental health conditions “are an issue across the board in medicine, and amongst our medical students as well,” senior author Laxmi S. Mehta, MD, professor of internal medicine at Ohio State University, Columbus, said in an interview. The current study provides new details about their prevalence and predictors in cardiology and, she hopes, may improve the field’s awareness of and efforts to address the problem.

“We need to support those who have underlying mental health conditions, as well as improve the work environment to reduce contributory factors to mental illnesses. And we also need to work on reducing the stigma associated with seeking treatment and on reducing the barriers to receiving treatment,” said Dr. Mehta, who chairs the Workgroup on Clinician Well-Being of the ACC, which conducted the survey in 2019.
 

A global perspective

Cardiologists in Africa, the Americas, Asia, Europe, the Middle East, and Oceania – 5,890 in all – responded to mental health questions on the survey, which was novel for its global reach and insights across continents and cultures.

Respondents in South America and Central America reported the highest prevalences of mental health concerns, outliers at about 39% and 33%, respectively. Rates for most other geographic regions ranged narrowly from about 20% to 26%, the lowest reported in Asia and the Middle East.

Dr. Sharma acknowledged that the countries probably varied widely in social and cultural factors likely to influence survey responses, such as interpretation of the questionnaire’s mental health terminology or the degree to which the disorders are stigmatized.

“I think it’s hard to say how people may or may not respond culturally to a certain word or metric,” she said. But on the survey results, “whether you’re practicing in rural America, in rural India, or in the United Arab Emirates, Oceania, or Eastern Europe, there is a level of consistency, across the board, in what people are recognizing as mental health conditions.”
 

Junior vs. senior physicians

The global perspective “is a nice positive of the study, and the high rates in Central America and South America I think were something the field was not aware of and are an important contribution,” Srijan Sen, MD, PhD, said in an interview.

The psychological toll of hostile work environments is an issue throughout medicine, “but it seems greater in certain specialties, and cardiology may be one where it’s more of a problem,” observed Dr. Sen, who studies physician mental health at the University of Michigan, Ann Arbor, and wasn’t associated with the survey.

Mental health concerns in the survey were significantly more common among women than men (33.7% vs 26.3%), and for younger cardiologists, compared with older cardiologists (32.2% for those < 40 vs. 22.1% and 16.8% for those 55-69 and 70 or older, respectively).

Those findings seem to make sense, Dr. Sen observed. “Generally, cardiology and medicine broadly are hierarchical, so being more junior can be stressful.” And if there’s more hostility in the workplace, “it might fall on junior people.”

In other studies, moreover, “a high level of work-family conflict has been a real driver of depression and burnout, and that likely is affecting younger physicians, particularly young women physicians,” who may have smaller children and a greater burden of childcare than their seniors.

He pointed to the survey’s low response rate as an important limitation of the study. Of the 71,022 cardiologists invited to participate, only 5,890 (8.3%) responded and answered the queries on mental health.

With a response rate that low, a survey “can be biased in ways that we can’t predict,” Dr. Sen noted. Also, anyone concerned about the toxicity of their own workplace might be “more likely to respond to the survey than if they worked in a more pleasant place. That would provide a skewed sense of the overall experience of cardiologists.”

Those issues might not be a concern with the current survey, however, “because the results are consistent with other studies with higher response rates.”
 

‘Sobering report’

An accompanying editorial said Dr. Sharm and colleagues have provided “a sobering report on the global prevalence and potential contributors to mental health concerns” in the surveyed population.

Based on its lessons, Andrew J. Sauer, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., proposed several potential “interventions” the field could enact.

It could “selectively promote leaders who strive to mitigate implicit bias, discrimination, and harassment while advancing diversity, equity, and inclusion within the broad ranks of cardiologists.”

Also, he continued, “we must eliminate the stigmatization of mental illness among physicians. We need to handle mental health concerns with compassion and without blaming, like how we strive to treat our veterans who suffer from posttraumatic stress disorder.”

Lastly, Dr. Sauer wrote, “mentorship programs should be formalized to assist the cardiologist in transition zones from early to mid-career, with particular attention to women and those experiencing a simultaneously increased load of family burdens that compound existing workplace contributors to burnout and psychological distress.”
 

Years in practice

Of the cardiologists who responded to the survey’s mental health questions, 28% reported they have experienced mental health issues that could include alcohol/drug use disorder, suicidal tendencies, psychological distress (including anxiety, irritability, or anger), “other psychiatric disorders” (such as panic disorder, posttraumatic stress, or eating disorders) or major psychiatric disorders such as major depression, bipolar disorder, or schizophrenia.

Cardiologists with 5-10 years of practice post-training were more likely than cardiologists practicing for at least 20 years to have mental health concerns (31.9% vs. 22.6%, P < .001).

Mental health concerns were cited by 42% of respondents who cited “any type of discrimination” based on age, sex, race or ethnicity, or sexual orientation, the report noted.

Among those reporting any mental health concern, 2.7% considered suicide within the past year and 2.9% considered suicide more than 12 months previously. Women were more likely than men to consider suicide within the past year (3.8% vs. 2.3%) but were also more likely to seek help (42.3% vs. 31.1%; P < .001 for both differences), the authors wrote.

In multivariate analysis, predictors of mental health concerns included emotional harassment, 2.81 (odds ratio, 2.81; 95% confidence interval, 2.46-3.20), any discrimination (OR, 1.85; 95% CI, 1.61-2.12), being divorced (OR, 1.73; 95% CI, 1.26-2.36, age less than 55 years (OR, 1.43; 95% CI, 1.24-1.66), and being mid-career versus late (OR, 1.36; 95% CI, 1.14-1.62).

Because the survey was conducted from September to October 2019, before the pandemic’s traumatic effects unfolded on health care nearly everywhere, “I think there needs to be a follow-up at some point when everything has leveled out,” Dr. Sharma said. The current study is “a baseline, and not a healthy baseline,” for the field’s state of mental health that has likely grown worse during the pandemic.

But even without such a follow-up, the current study “is actionable enough that it forces us to do something about it right now.”

Dr. Sharma, Dr. Mehta, their coauthors, Dr. Sen, and Dr. Sauer reported no relevant disclosures.

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

More than a quarter of cardiologists in an international survey reported experiencing mental health conditions ranging from anxiety or anger issues to major depression or other psychiatric disorders.  

Such conditions varied in prevalence by cardiology subspecialty and years in the field, were more common in women than in men, and were closely linked to enduring hostile work environments and other strains of professional life.

The survey, conducted only months before the COVID-19 pandemic and with its share of limitations, still paints a picture that’s not pretty.

For example, mental health concerns were reported by about 42% of respondents who cited a hostile work environment, defined as workplace experience of discrimination based on age, sex, religion, race or ethnicity, or emotional or sexual harassment. Conversely, the prevalence of these concerns reached only 17% among those without such workplace conditions.

The study shows substantial overlap between cardiologists reporting hostility at work and those with mental health concerns, “and that was a significant finding,” Garima Sharma, MD, Johns Hopkins University, Baltimore, said in an interview.

Still, only 31% of male and 42% of female cardiologists (P < .001) reporting mental health concerns also said they had sought professional help either within or outside their own institutions.

That means “there is a lot of silent suffering” in the field, said Dr. Sharma, who is lead author on the study, published in the Journal of the American College of Cardiology.
 

Bringing back the conversation

The survey findings, she added, point to at least two potential ways the cardiology community can strive to diminish what may be a major underlying cause of the mental health concerns and their consequences.

“If you work towards reducing hostility at work and making mental health a priority for your workforce, then those experiencing these types of egregious conditions based on age, gender, race, ethnicity, or sexual orientation are less likely to be harmed.”

Mental health concerns among cardiologists are seldom openly discussed, so the current study can be “a way to bring them back into the conversation,” Dr. Sharma said. Clinician mental health “is extremely important because it directly impacts patient care and productivity.”

The survey’s reported mental health conditions “are an issue across the board in medicine, and amongst our medical students as well,” senior author Laxmi S. Mehta, MD, professor of internal medicine at Ohio State University, Columbus, said in an interview. The current study provides new details about their prevalence and predictors in cardiology and, she hopes, may improve the field’s awareness of and efforts to address the problem.

“We need to support those who have underlying mental health conditions, as well as improve the work environment to reduce contributory factors to mental illnesses. And we also need to work on reducing the stigma associated with seeking treatment and on reducing the barriers to receiving treatment,” said Dr. Mehta, who chairs the Workgroup on Clinician Well-Being of the ACC, which conducted the survey in 2019.
 

A global perspective

Cardiologists in Africa, the Americas, Asia, Europe, the Middle East, and Oceania – 5,890 in all – responded to mental health questions on the survey, which was novel for its global reach and insights across continents and cultures.

Respondents in South America and Central America reported the highest prevalences of mental health concerns, outliers at about 39% and 33%, respectively. Rates for most other geographic regions ranged narrowly from about 20% to 26%, the lowest reported in Asia and the Middle East.

Dr. Sharma acknowledged that the countries probably varied widely in social and cultural factors likely to influence survey responses, such as interpretation of the questionnaire’s mental health terminology or the degree to which the disorders are stigmatized.

“I think it’s hard to say how people may or may not respond culturally to a certain word or metric,” she said. But on the survey results, “whether you’re practicing in rural America, in rural India, or in the United Arab Emirates, Oceania, or Eastern Europe, there is a level of consistency, across the board, in what people are recognizing as mental health conditions.”
 

Junior vs. senior physicians

The global perspective “is a nice positive of the study, and the high rates in Central America and South America I think were something the field was not aware of and are an important contribution,” Srijan Sen, MD, PhD, said in an interview.

The psychological toll of hostile work environments is an issue throughout medicine, “but it seems greater in certain specialties, and cardiology may be one where it’s more of a problem,” observed Dr. Sen, who studies physician mental health at the University of Michigan, Ann Arbor, and wasn’t associated with the survey.

Mental health concerns in the survey were significantly more common among women than men (33.7% vs 26.3%), and for younger cardiologists, compared with older cardiologists (32.2% for those < 40 vs. 22.1% and 16.8% for those 55-69 and 70 or older, respectively).

Those findings seem to make sense, Dr. Sen observed. “Generally, cardiology and medicine broadly are hierarchical, so being more junior can be stressful.” And if there’s more hostility in the workplace, “it might fall on junior people.”

In other studies, moreover, “a high level of work-family conflict has been a real driver of depression and burnout, and that likely is affecting younger physicians, particularly young women physicians,” who may have smaller children and a greater burden of childcare than their seniors.

He pointed to the survey’s low response rate as an important limitation of the study. Of the 71,022 cardiologists invited to participate, only 5,890 (8.3%) responded and answered the queries on mental health.

With a response rate that low, a survey “can be biased in ways that we can’t predict,” Dr. Sen noted. Also, anyone concerned about the toxicity of their own workplace might be “more likely to respond to the survey than if they worked in a more pleasant place. That would provide a skewed sense of the overall experience of cardiologists.”

Those issues might not be a concern with the current survey, however, “because the results are consistent with other studies with higher response rates.”
 

‘Sobering report’

An accompanying editorial said Dr. Sharm and colleagues have provided “a sobering report on the global prevalence and potential contributors to mental health concerns” in the surveyed population.

Based on its lessons, Andrew J. Sauer, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., proposed several potential “interventions” the field could enact.

It could “selectively promote leaders who strive to mitigate implicit bias, discrimination, and harassment while advancing diversity, equity, and inclusion within the broad ranks of cardiologists.”

Also, he continued, “we must eliminate the stigmatization of mental illness among physicians. We need to handle mental health concerns with compassion and without blaming, like how we strive to treat our veterans who suffer from posttraumatic stress disorder.”

Lastly, Dr. Sauer wrote, “mentorship programs should be formalized to assist the cardiologist in transition zones from early to mid-career, with particular attention to women and those experiencing a simultaneously increased load of family burdens that compound existing workplace contributors to burnout and psychological distress.”
 

Years in practice

Of the cardiologists who responded to the survey’s mental health questions, 28% reported they have experienced mental health issues that could include alcohol/drug use disorder, suicidal tendencies, psychological distress (including anxiety, irritability, or anger), “other psychiatric disorders” (such as panic disorder, posttraumatic stress, or eating disorders) or major psychiatric disorders such as major depression, bipolar disorder, or schizophrenia.

Cardiologists with 5-10 years of practice post-training were more likely than cardiologists practicing for at least 20 years to have mental health concerns (31.9% vs. 22.6%, P < .001).

Mental health concerns were cited by 42% of respondents who cited “any type of discrimination” based on age, sex, race or ethnicity, or sexual orientation, the report noted.

Among those reporting any mental health concern, 2.7% considered suicide within the past year and 2.9% considered suicide more than 12 months previously. Women were more likely than men to consider suicide within the past year (3.8% vs. 2.3%) but were also more likely to seek help (42.3% vs. 31.1%; P < .001 for both differences), the authors wrote.

In multivariate analysis, predictors of mental health concerns included emotional harassment, 2.81 (odds ratio, 2.81; 95% confidence interval, 2.46-3.20), any discrimination (OR, 1.85; 95% CI, 1.61-2.12), being divorced (OR, 1.73; 95% CI, 1.26-2.36, age less than 55 years (OR, 1.43; 95% CI, 1.24-1.66), and being mid-career versus late (OR, 1.36; 95% CI, 1.14-1.62).

Because the survey was conducted from September to October 2019, before the pandemic’s traumatic effects unfolded on health care nearly everywhere, “I think there needs to be a follow-up at some point when everything has leveled out,” Dr. Sharma said. The current study is “a baseline, and not a healthy baseline,” for the field’s state of mental health that has likely grown worse during the pandemic.

But even without such a follow-up, the current study “is actionable enough that it forces us to do something about it right now.”

Dr. Sharma, Dr. Mehta, their coauthors, Dr. Sen, and Dr. Sauer reported no relevant disclosures.

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

More than a quarter of cardiologists in an international survey reported experiencing mental health conditions ranging from anxiety or anger issues to major depression or other psychiatric disorders.  

Such conditions varied in prevalence by cardiology subspecialty and years in the field, were more common in women than in men, and were closely linked to enduring hostile work environments and other strains of professional life.

The survey, conducted only months before the COVID-19 pandemic and with its share of limitations, still paints a picture that’s not pretty.

For example, mental health concerns were reported by about 42% of respondents who cited a hostile work environment, defined as workplace experience of discrimination based on age, sex, religion, race or ethnicity, or emotional or sexual harassment. Conversely, the prevalence of these concerns reached only 17% among those without such workplace conditions.

The study shows substantial overlap between cardiologists reporting hostility at work and those with mental health concerns, “and that was a significant finding,” Garima Sharma, MD, Johns Hopkins University, Baltimore, said in an interview.

Still, only 31% of male and 42% of female cardiologists (P < .001) reporting mental health concerns also said they had sought professional help either within or outside their own institutions.

That means “there is a lot of silent suffering” in the field, said Dr. Sharma, who is lead author on the study, published in the Journal of the American College of Cardiology.
 

Bringing back the conversation

The survey findings, she added, point to at least two potential ways the cardiology community can strive to diminish what may be a major underlying cause of the mental health concerns and their consequences.

“If you work towards reducing hostility at work and making mental health a priority for your workforce, then those experiencing these types of egregious conditions based on age, gender, race, ethnicity, or sexual orientation are less likely to be harmed.”

Mental health concerns among cardiologists are seldom openly discussed, so the current study can be “a way to bring them back into the conversation,” Dr. Sharma said. Clinician mental health “is extremely important because it directly impacts patient care and productivity.”

The survey’s reported mental health conditions “are an issue across the board in medicine, and amongst our medical students as well,” senior author Laxmi S. Mehta, MD, professor of internal medicine at Ohio State University, Columbus, said in an interview. The current study provides new details about their prevalence and predictors in cardiology and, she hopes, may improve the field’s awareness of and efforts to address the problem.

“We need to support those who have underlying mental health conditions, as well as improve the work environment to reduce contributory factors to mental illnesses. And we also need to work on reducing the stigma associated with seeking treatment and on reducing the barriers to receiving treatment,” said Dr. Mehta, who chairs the Workgroup on Clinician Well-Being of the ACC, which conducted the survey in 2019.
 

A global perspective

Cardiologists in Africa, the Americas, Asia, Europe, the Middle East, and Oceania – 5,890 in all – responded to mental health questions on the survey, which was novel for its global reach and insights across continents and cultures.

Respondents in South America and Central America reported the highest prevalences of mental health concerns, outliers at about 39% and 33%, respectively. Rates for most other geographic regions ranged narrowly from about 20% to 26%, the lowest reported in Asia and the Middle East.

Dr. Sharma acknowledged that the countries probably varied widely in social and cultural factors likely to influence survey responses, such as interpretation of the questionnaire’s mental health terminology or the degree to which the disorders are stigmatized.

“I think it’s hard to say how people may or may not respond culturally to a certain word or metric,” she said. But on the survey results, “whether you’re practicing in rural America, in rural India, or in the United Arab Emirates, Oceania, or Eastern Europe, there is a level of consistency, across the board, in what people are recognizing as mental health conditions.”
 

Junior vs. senior physicians

The global perspective “is a nice positive of the study, and the high rates in Central America and South America I think were something the field was not aware of and are an important contribution,” Srijan Sen, MD, PhD, said in an interview.

The psychological toll of hostile work environments is an issue throughout medicine, “but it seems greater in certain specialties, and cardiology may be one where it’s more of a problem,” observed Dr. Sen, who studies physician mental health at the University of Michigan, Ann Arbor, and wasn’t associated with the survey.

Mental health concerns in the survey were significantly more common among women than men (33.7% vs 26.3%), and for younger cardiologists, compared with older cardiologists (32.2% for those < 40 vs. 22.1% and 16.8% for those 55-69 and 70 or older, respectively).

Those findings seem to make sense, Dr. Sen observed. “Generally, cardiology and medicine broadly are hierarchical, so being more junior can be stressful.” And if there’s more hostility in the workplace, “it might fall on junior people.”

In other studies, moreover, “a high level of work-family conflict has been a real driver of depression and burnout, and that likely is affecting younger physicians, particularly young women physicians,” who may have smaller children and a greater burden of childcare than their seniors.

He pointed to the survey’s low response rate as an important limitation of the study. Of the 71,022 cardiologists invited to participate, only 5,890 (8.3%) responded and answered the queries on mental health.

With a response rate that low, a survey “can be biased in ways that we can’t predict,” Dr. Sen noted. Also, anyone concerned about the toxicity of their own workplace might be “more likely to respond to the survey than if they worked in a more pleasant place. That would provide a skewed sense of the overall experience of cardiologists.”

Those issues might not be a concern with the current survey, however, “because the results are consistent with other studies with higher response rates.”
 

‘Sobering report’

An accompanying editorial said Dr. Sharm and colleagues have provided “a sobering report on the global prevalence and potential contributors to mental health concerns” in the surveyed population.

Based on its lessons, Andrew J. Sauer, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., proposed several potential “interventions” the field could enact.

It could “selectively promote leaders who strive to mitigate implicit bias, discrimination, and harassment while advancing diversity, equity, and inclusion within the broad ranks of cardiologists.”

Also, he continued, “we must eliminate the stigmatization of mental illness among physicians. We need to handle mental health concerns with compassion and without blaming, like how we strive to treat our veterans who suffer from posttraumatic stress disorder.”

Lastly, Dr. Sauer wrote, “mentorship programs should be formalized to assist the cardiologist in transition zones from early to mid-career, with particular attention to women and those experiencing a simultaneously increased load of family burdens that compound existing workplace contributors to burnout and psychological distress.”
 

Years in practice

Of the cardiologists who responded to the survey’s mental health questions, 28% reported they have experienced mental health issues that could include alcohol/drug use disorder, suicidal tendencies, psychological distress (including anxiety, irritability, or anger), “other psychiatric disorders” (such as panic disorder, posttraumatic stress, or eating disorders) or major psychiatric disorders such as major depression, bipolar disorder, or schizophrenia.

Cardiologists with 5-10 years of practice post-training were more likely than cardiologists practicing for at least 20 years to have mental health concerns (31.9% vs. 22.6%, P < .001).

Mental health concerns were cited by 42% of respondents who cited “any type of discrimination” based on age, sex, race or ethnicity, or sexual orientation, the report noted.

Among those reporting any mental health concern, 2.7% considered suicide within the past year and 2.9% considered suicide more than 12 months previously. Women were more likely than men to consider suicide within the past year (3.8% vs. 2.3%) but were also more likely to seek help (42.3% vs. 31.1%; P < .001 for both differences), the authors wrote.

In multivariate analysis, predictors of mental health concerns included emotional harassment, 2.81 (odds ratio, 2.81; 95% confidence interval, 2.46-3.20), any discrimination (OR, 1.85; 95% CI, 1.61-2.12), being divorced (OR, 1.73; 95% CI, 1.26-2.36, age less than 55 years (OR, 1.43; 95% CI, 1.24-1.66), and being mid-career versus late (OR, 1.36; 95% CI, 1.14-1.62).

Because the survey was conducted from September to October 2019, before the pandemic’s traumatic effects unfolded on health care nearly everywhere, “I think there needs to be a follow-up at some point when everything has leveled out,” Dr. Sharma said. The current study is “a baseline, and not a healthy baseline,” for the field’s state of mental health that has likely grown worse during the pandemic.

But even without such a follow-up, the current study “is actionable enough that it forces us to do something about it right now.”

Dr. Sharma, Dr. Mehta, their coauthors, Dr. Sen, and Dr. Sauer reported no relevant disclosures.

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

Editor’s note: This article was adapted with permission from a version originally published in the Ohio Psychiatric Physician Association’s newsletter, Insight Matters, Fall 2022.

Acknowledging and analyzing strengths, weaknesses, opportunities, and threats (SWOT) is an important tactic many organizations use to develop a strategic plan to grow, move forward, and thrive. A SWOT analysis can provide a “big picture” view of the status and the desired future directions not only for companies but for medical disciplines such as psychiatry. So here are my perspectives on psychiatry’s strengths, weaknesses, opportunities, and threats. It is a work in progress, and I welcome (and encourage) you to send additional items or comments to me at [email protected].

Strengths

• The American Psychiatric Association (APA) is the oldest medical professional organization, established in 1844 (3 years before the American Medical Association)¹
• Strong organizational structure and governance, and a “big tent” with several tiers of membership
• Effective, member-driven District Branches
• The medical identity at the core of psychiatry—we are psychiatric physicians²
• Escalating number of senior medical students choosing psychiatry as a career, far more than a decade ago
• High demand for psychiatrists in all settings around the country
• Increased compensation for psychiatrists (market forces of supply and demand)
• Psychiatry is continuously evolving and reinventing itself: seismic shifts in etiopathogenesis, disease conceptualization, terminology, and therapies (4 major shifts over the past century)³
• An abundant body of evidence supporting that all psychiatric disorders are brain disorders and transdiagnostic in nature⁴
• Many vibrant subspecialty societies
• Substantial number of Tier 1, evidence-based treatments
• Novel mechanisms of action and treatment strategies are being introduced on a regular basis for psychotic and mood disorders^5,6
• Advances in neuromodulation techniques to treat a wide spectrum of psychiatric disorders, including electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, transcranial direct current stimulation, deep brain stimulation, cranial electric stimulation, epidural cortical stimulation, focused ultrasound, low field magnetic stimulation, magnetic seizure therapy, and near infrared light therapy, with mechanisms that are electric, ultrasound, magnetic, or optical^7,8
• Psychiatric physicians develop wisdom by practicing psychiatry (ie, they become more empathic, tolerant of ambiguity, prosocial, introspective, aware of one’s strengths and limitations). Neuroplasticity in the frontal cortex is triggered by conducting psychotherapy⁹

Weaknesses

• Shrinking workforce due to a static number of residency training slots for 40 years¹⁰
• High rate of retirement by aging psychiatrists
• Persistent stigma around mental disorders despite massive scientific and medical advances¹¹
• Still no real parity! We need succinct laws with “teeth”¹²
• Demedicalization in the public sector, referring to psychiatric physicians as “providers” and labeling patients as “clients”²
• Not enough graduating residents choosing to do subspecialty fellowships (especially geriatric, addiction, psychosomatic psychiatry) to meet escalating societal needs
• Very low presence in rural areas (both psychiatrists and psychiatric hospitals)
• Persistent APA member apathy: only 10% to 15% vote in the APA national elections or volunteer to serve on committees
• Widespread member dissatisfaction with maintenance of certification
• Neuroscience advances are not being translated fast enough for practical clinical applications
• Many in the public at large do not realize psychiatric symptoms are generated from anomalous brain circuits or that psychiatric disorders are highly genetic but also have environmental and epigenetic etiologies
• The DSM diagnostic system needs a paradigm shift: it is still based on a menu of clinical signs and symptoms and is devoid of objective diagnostic measures such as biomarkers⁴
• Neuroscience literacy among busy psychiatric practitioners is insufficient at a time of explosive growth in basic and clinical neuroscience¹³
• No effective treatment for alcohol or substance use disorders despite their very high morbidity and mortality
• Major psychiatric disorders are still associated with significant disability (schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, eating disorders, substance use disorders)
• Suicide rate (other than opioid deaths) has continued to rise in the past 3 decades¹⁴

Opportunities

• Potentially momentous clinical applications of the neuroscience breakthroughs
• Collaborative care with primary care physicians and increasing colocalization
• Dramatic increase in public awareness about the importance of mental health due to the COVID-19 pandemic¹⁵
• Powerful new data management tools, including machine learning, artificial intelligence, super computers, big data, deep learning, nanotechnology, and metabolomics, all of which are expediting neurobiological discoveries¹⁶
• The potential of reclassifying psychiatric disorders as neurological disorders, which will improve reimbursement for patient health care and reduce stigma¹⁷
• Emergence of new mechanisms of action of disease etiology, such as microbiota, mitochondrial dysfunction, permeable blood-brain barrier, and neuroimmune dysregulation^18,19
• The advent and growth of “precision psychiatry”²⁰
• The tremendous potential of molecular genetics and gene therapy for psychiatric disorders, most of which are genetic in etiology
• Expanding applications of neuroimaging techniques, including morphological, spectroscopic, functional, diffusion tensor imaging, and receptor imaging²¹
• Epigenetic advances in neuropsychiatric disorders
• Remarkably powerful research methods, such as pluripotent cells (producing neurons from skin cells), optogenetics (activating genes with light), gene-wide association studies, CRISPR (clustered regularly interspaced short palindromic repeats, which serve as genetic scissors to remove and replace abnormal genes), and brain connectomics²²
• Psychiatry should develop and promote an “annual mental health checkup” for all age groups, similar to an annual physical exam²³
• Focus on the social determinants of health
• Address the unmet mental health needs of individuals who are members of minority groups
• Lobby ferociously for a much larger budget for the National Institute of Mental Health to advance funding for research of serious psychiatric brain disorders
• Remind Congress continuously that the cost of mental illness is $700 billion annually and costs can only be reduced by funding neurobiological research¹
• Partner with the pharmaceutical industry instead of demonizing them. They are the only entity that develops medication for psychiatry, where 80% of disorders have no FDA-approved drugs.²⁴ Without the pharmaceutical industry and the help of medications, many psychiatric patients would still be institutionalized and unable to lead a normal life. We must recognize the contributions of pharmaceutical companies to the health of our patients, similar to the warp speed development of vaccines for the deadly coronavirus
• Psychiatric clinicians must refer patients to clinical trials because without patients enrolling in FDA studies, no drug developments can take place
• Many “out-of-the-box” therapies are being developed, such as antiapoptotic therapy, microglia inhibition, mitochondrial repair, white matter fiber remyelination, neuroprotection, and reversing N-methyl-d-aspartate receptor hypofunction²⁵
• The emerging evidence that psychotherapy is in fact a biological treatment that induces brain changes (neuroplasticity) and can modulate the immune system²⁶
• Druggable genes, providing innovative new medications²⁷
• Reposition psychedelics as revolutionary new treatments²⁸
• Emphasize measurement-based care (rating scales), which can upgrade patient care²⁹
• Because psychosis is associated with brain tissue loss, just like heart attacks are associated with myocardium destruction, psychiatrists must act like cardiologists³⁰ and treat psychotic episodes urgently, like a stroke,³¹ to reduce the duration of untreated psychosis and improve patient outcomes

Threats

• Antipsychiatry cults continue to disparage and attack psychiatry³²
• Health delivery systems are replacing psychiatric physicians with nurse practitioners to lower costs, regardless of quality and experience, and they inappropriately lump them together as “providers”²
• Psychologists continue to seek prescribing privileges with absurdly sketchy, predominantly online training supervised by other psychologists³³
• Many legislators and policymakers, as well as the public, still don’t understand the difference between psychiatrists and psychologists, and the extensively disparate medical training in quality and quantity
• A dearth of psychiatric physician-scientists because very few residents are pursuing research fellowships after training³⁴
• Disproportionate emphasis on clinical care and generating clinical revenue (relative value units) in academic institutions, with fewer tenure-track faculty members having protected time to write grants for federal or foundation grants to support their salaries and research operations³⁵
• Meager financial support for teaching in psychiatry departments
• Many seriously psychiatrically ill persons do not have access to psychiatric medical care (and often to primary care as well)
• Many in the public falsely believe psychiatric disorders are hopeless and untreatable, which perpetuates stigma
• Long-acting injectable antipsychotic formulations are not used early enough in patients with psychosis, who are known to have a high nonadherence rate with oral medications following discharge from their first hospitalization. This leads to many recurrences with multiple devastating consequences, including progressive brain tissue loss, treatment resistance, disability, incarceration, and suicide³⁶
• Many clinicians do not have full-text access to all studies indexed in PubMed, which is vital for lifelong learning in a rapidly growing medical discipline such as psychiatry
• Psychiatrists are often unable to prescribe medications shortly after they are approved by the FDA due to the insurance companies’ outrageous preauthorization racket that enforces a fail-first policy with cheaper generics, even if generic medications are associated with safety and tolerability problems³⁷
• The continued use of decades-old first-generation antipsychotic medications despite 32 published studies reporting their neurotoxicity and the death of brain cells³⁸

Using this analysis to benefit our patients

Despite its strengths, psychiatry must overcome its weaknesses, fend off its threats, and exploit its many opportunities. The only way to do that is for psychiatrists to unify and for the APA to provide inspired leadership to achieve the aspirational goals of our field. However, we must adopt “moonshot thinking”³⁹ to magnify the Ss, diminish the Ws, exploit the Os, and stave off the Ts of our SWOT, thereby attaining all our cherished and lofty goals. Ultimately, the greatest beneficiaries will be our patients.

Editor’s note: This article was adapted with permission from a version originally published in the Ohio Psychiatric Physician Association’s newsletter, Insight Matters, Fall 2022.

Acknowledging and analyzing strengths, weaknesses, opportunities, and threats (SWOT) is an important tactic many organizations use to develop a strategic plan to grow, move forward, and thrive. A SWOT analysis can provide a “big picture” view of the status and the desired future directions not only for companies but for medical disciplines such as psychiatry. So here are my perspectives on psychiatry’s strengths, weaknesses, opportunities, and threats. It is a work in progress, and I welcome (and encourage) you to send additional items or comments to me at [email protected].

Strengths

• The American Psychiatric Association (APA) is the oldest medical professional organization, established in 1844 (3 years before the American Medical Association)¹
• Strong organizational structure and governance, and a “big tent” with several tiers of membership
• Effective, member-driven District Branches
• The medical identity at the core of psychiatry—we are psychiatric physicians²
• Escalating number of senior medical students choosing psychiatry as a career, far more than a decade ago
• High demand for psychiatrists in all settings around the country
• Increased compensation for psychiatrists (market forces of supply and demand)
• Psychiatry is continuously evolving and reinventing itself: seismic shifts in etiopathogenesis, disease conceptualization, terminology, and therapies (4 major shifts over the past century)³
• An abundant body of evidence supporting that all psychiatric disorders are brain disorders and transdiagnostic in nature⁴
• Many vibrant subspecialty societies
• Substantial number of Tier 1, evidence-based treatments
• Novel mechanisms of action and treatment strategies are being introduced on a regular basis for psychotic and mood disorders^5,6
• Advances in neuromodulation techniques to treat a wide spectrum of psychiatric disorders, including electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, transcranial direct current stimulation, deep brain stimulation, cranial electric stimulation, epidural cortical stimulation, focused ultrasound, low field magnetic stimulation, magnetic seizure therapy, and near infrared light therapy, with mechanisms that are electric, ultrasound, magnetic, or optical^7,8
• Psychiatric physicians develop wisdom by practicing psychiatry (ie, they become more empathic, tolerant of ambiguity, prosocial, introspective, aware of one’s strengths and limitations). Neuroplasticity in the frontal cortex is triggered by conducting psychotherapy⁹

Weaknesses

• Shrinking workforce due to a static number of residency training slots for 40 years¹⁰
• High rate of retirement by aging psychiatrists
• Persistent stigma around mental disorders despite massive scientific and medical advances¹¹
• Still no real parity! We need succinct laws with “teeth”¹²
• Demedicalization in the public sector, referring to psychiatric physicians as “providers” and labeling patients as “clients”²
• Not enough graduating residents choosing to do subspecialty fellowships (especially geriatric, addiction, psychosomatic psychiatry) to meet escalating societal needs
• Very low presence in rural areas (both psychiatrists and psychiatric hospitals)
• Persistent APA member apathy: only 10% to 15% vote in the APA national elections or volunteer to serve on committees
• Widespread member dissatisfaction with maintenance of certification
• Neuroscience advances are not being translated fast enough for practical clinical applications
• Many in the public at large do not realize psychiatric symptoms are generated from anomalous brain circuits or that psychiatric disorders are highly genetic but also have environmental and epigenetic etiologies
• The DSM diagnostic system needs a paradigm shift: it is still based on a menu of clinical signs and symptoms and is devoid of objective diagnostic measures such as biomarkers⁴
• Neuroscience literacy among busy psychiatric practitioners is insufficient at a time of explosive growth in basic and clinical neuroscience¹³
• No effective treatment for alcohol or substance use disorders despite their very high morbidity and mortality
• Major psychiatric disorders are still associated with significant disability (schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, eating disorders, substance use disorders)
• Suicide rate (other than opioid deaths) has continued to rise in the past 3 decades¹⁴

Opportunities

• Potentially momentous clinical applications of the neuroscience breakthroughs
• Collaborative care with primary care physicians and increasing colocalization
• Dramatic increase in public awareness about the importance of mental health due to the COVID-19 pandemic¹⁵
• Powerful new data management tools, including machine learning, artificial intelligence, super computers, big data, deep learning, nanotechnology, and metabolomics, all of which are expediting neurobiological discoveries¹⁶
• The potential of reclassifying psychiatric disorders as neurological disorders, which will improve reimbursement for patient health care and reduce stigma¹⁷
• Emergence of new mechanisms of action of disease etiology, such as microbiota, mitochondrial dysfunction, permeable blood-brain barrier, and neuroimmune dysregulation^18,19
• The advent and growth of “precision psychiatry”²⁰
• The tremendous potential of molecular genetics and gene therapy for psychiatric disorders, most of which are genetic in etiology
• Expanding applications of neuroimaging techniques, including morphological, spectroscopic, functional, diffusion tensor imaging, and receptor imaging²¹
• Epigenetic advances in neuropsychiatric disorders
• Remarkably powerful research methods, such as pluripotent cells (producing neurons from skin cells), optogenetics (activating genes with light), gene-wide association studies, CRISPR (clustered regularly interspaced short palindromic repeats, which serve as genetic scissors to remove and replace abnormal genes), and brain connectomics²²
• Psychiatry should develop and promote an “annual mental health checkup” for all age groups, similar to an annual physical exam²³
• Focus on the social determinants of health
• Address the unmet mental health needs of individuals who are members of minority groups
• Lobby ferociously for a much larger budget for the National Institute of Mental Health to advance funding for research of serious psychiatric brain disorders
• Remind Congress continuously that the cost of mental illness is $700 billion annually and costs can only be reduced by funding neurobiological research¹
• Partner with the pharmaceutical industry instead of demonizing them. They are the only entity that develops medication for psychiatry, where 80% of disorders have no FDA-approved drugs.²⁴ Without the pharmaceutical industry and the help of medications, many psychiatric patients would still be institutionalized and unable to lead a normal life. We must recognize the contributions of pharmaceutical companies to the health of our patients, similar to the warp speed development of vaccines for the deadly coronavirus
• Psychiatric clinicians must refer patients to clinical trials because without patients enrolling in FDA studies, no drug developments can take place
• Many “out-of-the-box” therapies are being developed, such as antiapoptotic therapy, microglia inhibition, mitochondrial repair, white matter fiber remyelination, neuroprotection, and reversing N-methyl-d-aspartate receptor hypofunction²⁵
• The emerging evidence that psychotherapy is in fact a biological treatment that induces brain changes (neuroplasticity) and can modulate the immune system²⁶
• Druggable genes, providing innovative new medications²⁷
• Reposition psychedelics as revolutionary new treatments²⁸
• Emphasize measurement-based care (rating scales), which can upgrade patient care²⁹
• Because psychosis is associated with brain tissue loss, just like heart attacks are associated with myocardium destruction, psychiatrists must act like cardiologists³⁰ and treat psychotic episodes urgently, like a stroke,³¹ to reduce the duration of untreated psychosis and improve patient outcomes

Threats

• Antipsychiatry cults continue to disparage and attack psychiatry³²
• Health delivery systems are replacing psychiatric physicians with nurse practitioners to lower costs, regardless of quality and experience, and they inappropriately lump them together as “providers”²
• Psychologists continue to seek prescribing privileges with absurdly sketchy, predominantly online training supervised by other psychologists³³
• Many legislators and policymakers, as well as the public, still don’t understand the difference between psychiatrists and psychologists, and the extensively disparate medical training in quality and quantity
• A dearth of psychiatric physician-scientists because very few residents are pursuing research fellowships after training³⁴
• Disproportionate emphasis on clinical care and generating clinical revenue (relative value units) in academic institutions, with fewer tenure-track faculty members having protected time to write grants for federal or foundation grants to support their salaries and research operations³⁵
• Meager financial support for teaching in psychiatry departments
• Many seriously psychiatrically ill persons do not have access to psychiatric medical care (and often to primary care as well)
• Many in the public falsely believe psychiatric disorders are hopeless and untreatable, which perpetuates stigma
• Long-acting injectable antipsychotic formulations are not used early enough in patients with psychosis, who are known to have a high nonadherence rate with oral medications following discharge from their first hospitalization. This leads to many recurrences with multiple devastating consequences, including progressive brain tissue loss, treatment resistance, disability, incarceration, and suicide³⁶
• Many clinicians do not have full-text access to all studies indexed in PubMed, which is vital for lifelong learning in a rapidly growing medical discipline such as psychiatry
• Psychiatrists are often unable to prescribe medications shortly after they are approved by the FDA due to the insurance companies’ outrageous preauthorization racket that enforces a fail-first policy with cheaper generics, even if generic medications are associated with safety and tolerability problems³⁷
• The continued use of decades-old first-generation antipsychotic medications despite 32 published studies reporting their neurotoxicity and the death of brain cells³⁸

Using this analysis to benefit our patients

Despite its strengths, psychiatry must overcome its weaknesses, fend off its threats, and exploit its many opportunities. The only way to do that is for psychiatrists to unify and for the APA to provide inspired leadership to achieve the aspirational goals of our field. However, we must adopt “moonshot thinking”³⁹ to magnify the Ss, diminish the Ws, exploit the Os, and stave off the Ts of our SWOT, thereby attaining all our cherished and lofty goals. Ultimately, the greatest beneficiaries will be our patients.

Editor’s note: This article was adapted with permission from a version originally published in the Ohio Psychiatric Physician Association’s newsletter, Insight Matters, Fall 2022.

Acknowledging and analyzing strengths, weaknesses, opportunities, and threats (SWOT) is an important tactic many organizations use to develop a strategic plan to grow, move forward, and thrive. A SWOT analysis can provide a “big picture” view of the status and the desired future directions not only for companies but for medical disciplines such as psychiatry. So here are my perspectives on psychiatry’s strengths, weaknesses, opportunities, and threats. It is a work in progress, and I welcome (and encourage) you to send additional items or comments to me at [email protected].

Strengths

• The American Psychiatric Association (APA) is the oldest medical professional organization, established in 1844 (3 years before the American Medical Association)¹
• Strong organizational structure and governance, and a “big tent” with several tiers of membership
• Effective, member-driven District Branches
• The medical identity at the core of psychiatry—we are psychiatric physicians²
• Escalating number of senior medical students choosing psychiatry as a career, far more than a decade ago
• High demand for psychiatrists in all settings around the country
• Increased compensation for psychiatrists (market forces of supply and demand)
• Psychiatry is continuously evolving and reinventing itself: seismic shifts in etiopathogenesis, disease conceptualization, terminology, and therapies (4 major shifts over the past century)³
• An abundant body of evidence supporting that all psychiatric disorders are brain disorders and transdiagnostic in nature⁴
• Many vibrant subspecialty societies
• Substantial number of Tier 1, evidence-based treatments
• Novel mechanisms of action and treatment strategies are being introduced on a regular basis for psychotic and mood disorders^5,6
• Advances in neuromodulation techniques to treat a wide spectrum of psychiatric disorders, including electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, transcranial direct current stimulation, deep brain stimulation, cranial electric stimulation, epidural cortical stimulation, focused ultrasound, low field magnetic stimulation, magnetic seizure therapy, and near infrared light therapy, with mechanisms that are electric, ultrasound, magnetic, or optical^7,8
• Psychiatric physicians develop wisdom by practicing psychiatry (ie, they become more empathic, tolerant of ambiguity, prosocial, introspective, aware of one’s strengths and limitations). Neuroplasticity in the frontal cortex is triggered by conducting psychotherapy⁹

Weaknesses

• Shrinking workforce due to a static number of residency training slots for 40 years¹⁰
• High rate of retirement by aging psychiatrists
• Persistent stigma around mental disorders despite massive scientific and medical advances¹¹
• Still no real parity! We need succinct laws with “teeth”¹²
• Demedicalization in the public sector, referring to psychiatric physicians as “providers” and labeling patients as “clients”²
• Not enough graduating residents choosing to do subspecialty fellowships (especially geriatric, addiction, psychosomatic psychiatry) to meet escalating societal needs
• Very low presence in rural areas (both psychiatrists and psychiatric hospitals)
• Persistent APA member apathy: only 10% to 15% vote in the APA national elections or volunteer to serve on committees
• Widespread member dissatisfaction with maintenance of certification
• Neuroscience advances are not being translated fast enough for practical clinical applications
• Many in the public at large do not realize psychiatric symptoms are generated from anomalous brain circuits or that psychiatric disorders are highly genetic but also have environmental and epigenetic etiologies
• The DSM diagnostic system needs a paradigm shift: it is still based on a menu of clinical signs and symptoms and is devoid of objective diagnostic measures such as biomarkers⁴
• Neuroscience literacy among busy psychiatric practitioners is insufficient at a time of explosive growth in basic and clinical neuroscience¹³
• No effective treatment for alcohol or substance use disorders despite their very high morbidity and mortality
• Major psychiatric disorders are still associated with significant disability (schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, eating disorders, substance use disorders)
• Suicide rate (other than opioid deaths) has continued to rise in the past 3 decades¹⁴

Opportunities

• Potentially momentous clinical applications of the neuroscience breakthroughs
• Collaborative care with primary care physicians and increasing colocalization
• Dramatic increase in public awareness about the importance of mental health due to the COVID-19 pandemic¹⁵
• Powerful new data management tools, including machine learning, artificial intelligence, super computers, big data, deep learning, nanotechnology, and metabolomics, all of which are expediting neurobiological discoveries¹⁶
• The potential of reclassifying psychiatric disorders as neurological disorders, which will improve reimbursement for patient health care and reduce stigma¹⁷
• Emergence of new mechanisms of action of disease etiology, such as microbiota, mitochondrial dysfunction, permeable blood-brain barrier, and neuroimmune dysregulation^18,19
• The advent and growth of “precision psychiatry”²⁰
• The tremendous potential of molecular genetics and gene therapy for psychiatric disorders, most of which are genetic in etiology
• Expanding applications of neuroimaging techniques, including morphological, spectroscopic, functional, diffusion tensor imaging, and receptor imaging²¹
• Epigenetic advances in neuropsychiatric disorders
• Remarkably powerful research methods, such as pluripotent cells (producing neurons from skin cells), optogenetics (activating genes with light), gene-wide association studies, CRISPR (clustered regularly interspaced short palindromic repeats, which serve as genetic scissors to remove and replace abnormal genes), and brain connectomics²²
• Psychiatry should develop and promote an “annual mental health checkup” for all age groups, similar to an annual physical exam²³
• Focus on the social determinants of health
• Address the unmet mental health needs of individuals who are members of minority groups
• Lobby ferociously for a much larger budget for the National Institute of Mental Health to advance funding for research of serious psychiatric brain disorders
• Remind Congress continuously that the cost of mental illness is $700 billion annually and costs can only be reduced by funding neurobiological research¹
• Partner with the pharmaceutical industry instead of demonizing them. They are the only entity that develops medication for psychiatry, where 80% of disorders have no FDA-approved drugs.²⁴ Without the pharmaceutical industry and the help of medications, many psychiatric patients would still be institutionalized and unable to lead a normal life. We must recognize the contributions of pharmaceutical companies to the health of our patients, similar to the warp speed development of vaccines for the deadly coronavirus
• Psychiatric clinicians must refer patients to clinical trials because without patients enrolling in FDA studies, no drug developments can take place
• Many “out-of-the-box” therapies are being developed, such as antiapoptotic therapy, microglia inhibition, mitochondrial repair, white matter fiber remyelination, neuroprotection, and reversing N-methyl-d-aspartate receptor hypofunction²⁵
• The emerging evidence that psychotherapy is in fact a biological treatment that induces brain changes (neuroplasticity) and can modulate the immune system²⁶
• Druggable genes, providing innovative new medications²⁷
• Reposition psychedelics as revolutionary new treatments²⁸
• Emphasize measurement-based care (rating scales), which can upgrade patient care²⁹
• Because psychosis is associated with brain tissue loss, just like heart attacks are associated with myocardium destruction, psychiatrists must act like cardiologists³⁰ and treat psychotic episodes urgently, like a stroke,³¹ to reduce the duration of untreated psychosis and improve patient outcomes

Threats

• Antipsychiatry cults continue to disparage and attack psychiatry³²
• Health delivery systems are replacing psychiatric physicians with nurse practitioners to lower costs, regardless of quality and experience, and they inappropriately lump them together as “providers”²
• Psychologists continue to seek prescribing privileges with absurdly sketchy, predominantly online training supervised by other psychologists³³
• Many legislators and policymakers, as well as the public, still don’t understand the difference between psychiatrists and psychologists, and the extensively disparate medical training in quality and quantity
• A dearth of psychiatric physician-scientists because very few residents are pursuing research fellowships after training³⁴
• Disproportionate emphasis on clinical care and generating clinical revenue (relative value units) in academic institutions, with fewer tenure-track faculty members having protected time to write grants for federal or foundation grants to support their salaries and research operations³⁵
• Meager financial support for teaching in psychiatry departments
• Many seriously psychiatrically ill persons do not have access to psychiatric medical care (and often to primary care as well)
• Many in the public falsely believe psychiatric disorders are hopeless and untreatable, which perpetuates stigma
• Long-acting injectable antipsychotic formulations are not used early enough in patients with psychosis, who are known to have a high nonadherence rate with oral medications following discharge from their first hospitalization. This leads to many recurrences with multiple devastating consequences, including progressive brain tissue loss, treatment resistance, disability, incarceration, and suicide³⁶
• Many clinicians do not have full-text access to all studies indexed in PubMed, which is vital for lifelong learning in a rapidly growing medical discipline such as psychiatry
• Psychiatrists are often unable to prescribe medications shortly after they are approved by the FDA due to the insurance companies’ outrageous preauthorization racket that enforces a fail-first policy with cheaper generics, even if generic medications are associated with safety and tolerability problems³⁷
• The continued use of decades-old first-generation antipsychotic medications despite 32 published studies reporting their neurotoxicity and the death of brain cells³⁸

Using this analysis to benefit our patients

Despite its strengths, psychiatry must overcome its weaknesses, fend off its threats, and exploit its many opportunities. The only way to do that is for psychiatrists to unify and for the APA to provide inspired leadership to achieve the aspirational goals of our field. However, we must adopt “moonshot thinking”³⁹ to magnify the Ss, diminish the Ws, exploit the Os, and stave off the Ts of our SWOT, thereby attaining all our cherished and lofty goals. Ultimately, the greatest beneficiaries will be our patients.

Groupthink is hazardous, especially when perfused with religious fervor. It can lead to adopting irrational thinking¹ and aversion to new ideas or facts. Tenaciously clinging to 1 ideology as “the absolute truth” precludes an open-minded, constructive debate with any other point of view.

Three historical examples come to mind:

• The discovery of chlorpromazine in 1952 was a scientifically and clinically seismic and transformational event for the treatment of psychosis, which for centuries had been dogmatically deemed irreversible. Jean Delay, MD, the French psychiatrist and co-discoverer of chlorpromazine, was the first physician to witness the magical and dazzling dissolution of delusions and hallucinations in chronically institutionalized patients with psychosis.² He published his landmark clinical observations and then traveled to the United States to share the great news and present his findings at a large psychiatric conference, hoping to enthrall American psychiatrists with the historic breakthrough in treating psychosis. This was an era in which psychoanalysis dominated American psychiatry (despite its dearth of empirical evidence). Dr. Delay was shocked when the audience of psycho­analysts booed him for saying that psychosis can be treated with a medication instead of with psychoanalysis (which, in the most intense groupthink in the history of psychiatry, they all believed was the only therapy for psychosis). Deeply disheartened, Dr. Delay returned to France and never returned to the United States. This groupthink was a prime example of intellectual constipation. Since then, not surprisingly, psychopharmacology grew meteorically while psychoanalysis declined precipitously.
• The monoamine hypothesis of depression, first propagated 60 years ago, became a groupthink dogma among psychiatric researchers for the next several decades, stultifying broader antidepressant medication development by focusing only on monoamines (eg, serotonin, norepinephrine, and dopamine). More recently, researchers have become more open-minded, and the monoamine hypothesis has taken a backseat to innovative new models of antidepressant therapy based on advances in the pathophysiology of depression, such as glutamatergic, opioid, and sigma pathways as well as neuroplasticity models.³ The consequence of groupthink in antidepressant research was a half-century delay in the development of effective alternative treatments that could have helped millions of patients recover from a life-threatening brain disorder such as major depressive disorder.
• Peptic ulcer and its serious gastritis were long believed to be due to stress and increased stomach acidity. So the groupthink gastroenterologists mocked 2 Australian researchers, Barry Marshall and Robin Warren, when they proposed that peptic ulcer may be due to an infection with a bacterium called Helicobacter pylori, and published their data demonstrating it.⁴ Marshall and Warren had the last laugh when they were awarded the 2005 Nobel Prize in Medicine and Physiology. It is ironic that even gastro­enterologists are not immune to the affliction of intellectual constipation!

Intellectual constipation’s effects on youth

The principle of a civilized debate of contrarian ideas must be inculcated early, especially during college years. Youth should be mentored about not cowering into an ideological cocoon and shun listening to different or opposing points of view.⁵ Institutions of higher learning are incubators of future leaders. They must provide their young students with a wide diversity of ideas and philosophies and encourage them to critique those ideas, not “shelter” or isolate them from any ideas. Youth need to recognize that the complex societies in which we all live and work are not placid or unidimensional but a hotbed of clashing ideas and perspectives. An open-minded approach to education will inoculate young minds from developing intellectual constipation in adulthood.

Avoiding or insulating oneself from the ideas of others—no matter how disagreeable—leads to cognitive cowardice and behavioral intolerance. Healthy and vibrant debate is necessary as an inoculation against extremism, hate, paranoia, and, ultimately, violence. Psychiatrists help patients to self-reflect, gain insight, and consider changing their view of themselves and the world to help them grow into mature and resilient individuals. But for the millions of people with intellectual constipation, a potent cerebral enema comprised of a salubrious concoction of insight, common sense, and compromise may be the prescription to forestall lethal intellectual ileus.

Groupthink is hazardous, especially when perfused with religious fervor. It can lead to adopting irrational thinking¹ and aversion to new ideas or facts. Tenaciously clinging to 1 ideology as “the absolute truth” precludes an open-minded, constructive debate with any other point of view.

Three historical examples come to mind:

• The discovery of chlorpromazine in 1952 was a scientifically and clinically seismic and transformational event for the treatment of psychosis, which for centuries had been dogmatically deemed irreversible. Jean Delay, MD, the French psychiatrist and co-discoverer of chlorpromazine, was the first physician to witness the magical and dazzling dissolution of delusions and hallucinations in chronically institutionalized patients with psychosis.² He published his landmark clinical observations and then traveled to the United States to share the great news and present his findings at a large psychiatric conference, hoping to enthrall American psychiatrists with the historic breakthrough in treating psychosis. This was an era in which psychoanalysis dominated American psychiatry (despite its dearth of empirical evidence). Dr. Delay was shocked when the audience of psycho­analysts booed him for saying that psychosis can be treated with a medication instead of with psychoanalysis (which, in the most intense groupthink in the history of psychiatry, they all believed was the only therapy for psychosis). Deeply disheartened, Dr. Delay returned to France and never returned to the United States. This groupthink was a prime example of intellectual constipation. Since then, not surprisingly, psychopharmacology grew meteorically while psychoanalysis declined precipitously.
• The monoamine hypothesis of depression, first propagated 60 years ago, became a groupthink dogma among psychiatric researchers for the next several decades, stultifying broader antidepressant medication development by focusing only on monoamines (eg, serotonin, norepinephrine, and dopamine). More recently, researchers have become more open-minded, and the monoamine hypothesis has taken a backseat to innovative new models of antidepressant therapy based on advances in the pathophysiology of depression, such as glutamatergic, opioid, and sigma pathways as well as neuroplasticity models.³ The consequence of groupthink in antidepressant research was a half-century delay in the development of effective alternative treatments that could have helped millions of patients recover from a life-threatening brain disorder such as major depressive disorder.
• Peptic ulcer and its serious gastritis were long believed to be due to stress and increased stomach acidity. So the groupthink gastroenterologists mocked 2 Australian researchers, Barry Marshall and Robin Warren, when they proposed that peptic ulcer may be due to an infection with a bacterium called Helicobacter pylori, and published their data demonstrating it.⁴ Marshall and Warren had the last laugh when they were awarded the 2005 Nobel Prize in Medicine and Physiology. It is ironic that even gastro­enterologists are not immune to the affliction of intellectual constipation!

Intellectual constipation’s effects on youth

The principle of a civilized debate of contrarian ideas must be inculcated early, especially during college years. Youth should be mentored about not cowering into an ideological cocoon and shun listening to different or opposing points of view.⁵ Institutions of higher learning are incubators of future leaders. They must provide their young students with a wide diversity of ideas and philosophies and encourage them to critique those ideas, not “shelter” or isolate them from any ideas. Youth need to recognize that the complex societies in which we all live and work are not placid or unidimensional but a hotbed of clashing ideas and perspectives. An open-minded approach to education will inoculate young minds from developing intellectual constipation in adulthood.

Avoiding or insulating oneself from the ideas of others—no matter how disagreeable—leads to cognitive cowardice and behavioral intolerance. Healthy and vibrant debate is necessary as an inoculation against extremism, hate, paranoia, and, ultimately, violence. Psychiatrists help patients to self-reflect, gain insight, and consider changing their view of themselves and the world to help them grow into mature and resilient individuals. But for the millions of people with intellectual constipation, a potent cerebral enema comprised of a salubrious concoction of insight, common sense, and compromise may be the prescription to forestall lethal intellectual ileus.

Groupthink is hazardous, especially when perfused with religious fervor. It can lead to adopting irrational thinking¹ and aversion to new ideas or facts. Tenaciously clinging to 1 ideology as “the absolute truth” precludes an open-minded, constructive debate with any other point of view.

Three historical examples come to mind:

• The discovery of chlorpromazine in 1952 was a scientifically and clinically seismic and transformational event for the treatment of psychosis, which for centuries had been dogmatically deemed irreversible. Jean Delay, MD, the French psychiatrist and co-discoverer of chlorpromazine, was the first physician to witness the magical and dazzling dissolution of delusions and hallucinations in chronically institutionalized patients with psychosis.² He published his landmark clinical observations and then traveled to the United States to share the great news and present his findings at a large psychiatric conference, hoping to enthrall American psychiatrists with the historic breakthrough in treating psychosis. This was an era in which psychoanalysis dominated American psychiatry (despite its dearth of empirical evidence). Dr. Delay was shocked when the audience of psycho­analysts booed him for saying that psychosis can be treated with a medication instead of with psychoanalysis (which, in the most intense groupthink in the history of psychiatry, they all believed was the only therapy for psychosis). Deeply disheartened, Dr. Delay returned to France and never returned to the United States. This groupthink was a prime example of intellectual constipation. Since then, not surprisingly, psychopharmacology grew meteorically while psychoanalysis declined precipitously.
• The monoamine hypothesis of depression, first propagated 60 years ago, became a groupthink dogma among psychiatric researchers for the next several decades, stultifying broader antidepressant medication development by focusing only on monoamines (eg, serotonin, norepinephrine, and dopamine). More recently, researchers have become more open-minded, and the monoamine hypothesis has taken a backseat to innovative new models of antidepressant therapy based on advances in the pathophysiology of depression, such as glutamatergic, opioid, and sigma pathways as well as neuroplasticity models.³ The consequence of groupthink in antidepressant research was a half-century delay in the development of effective alternative treatments that could have helped millions of patients recover from a life-threatening brain disorder such as major depressive disorder.
• Peptic ulcer and its serious gastritis were long believed to be due to stress and increased stomach acidity. So the groupthink gastroenterologists mocked 2 Australian researchers, Barry Marshall and Robin Warren, when they proposed that peptic ulcer may be due to an infection with a bacterium called Helicobacter pylori, and published their data demonstrating it.⁴ Marshall and Warren had the last laugh when they were awarded the 2005 Nobel Prize in Medicine and Physiology. It is ironic that even gastro­enterologists are not immune to the affliction of intellectual constipation!

Intellectual constipation’s effects on youth

The principle of a civilized debate of contrarian ideas must be inculcated early, especially during college years. Youth should be mentored about not cowering into an ideological cocoon and shun listening to different or opposing points of view.⁵ Institutions of higher learning are incubators of future leaders. They must provide their young students with a wide diversity of ideas and philosophies and encourage them to critique those ideas, not “shelter” or isolate them from any ideas. Youth need to recognize that the complex societies in which we all live and work are not placid or unidimensional but a hotbed of clashing ideas and perspectives. An open-minded approach to education will inoculate young minds from developing intellectual constipation in adulthood.

Avoiding or insulating oneself from the ideas of others—no matter how disagreeable—leads to cognitive cowardice and behavioral intolerance. Healthy and vibrant debate is necessary as an inoculation against extremism, hate, paranoia, and, ultimately, violence. Psychiatrists help patients to self-reflect, gain insight, and consider changing their view of themselves and the world to help them grow into mature and resilient individuals. But for the millions of people with intellectual constipation, a potent cerebral enema comprised of a salubrious concoction of insight, common sense, and compromise may be the prescription to forestall lethal intellectual ileus.

Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,¹ resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.² In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.

Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of under­utilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”

Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.³ Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.

What are GLP-1 agonists?

GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.

Routes of administration and FDA indications

Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m²) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m²) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.

Data in weight loss

Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.⁴

Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.⁵ Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.

Continue to: In studies of semaglutide...

In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.⁶ A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).⁷ Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.⁸ A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.⁹

In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).¹⁰ An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.¹⁰ As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes¹¹ found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.

Tolerability

Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)^5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.

Initial evidence prompts additional questions

GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:

• When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
• How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
• When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
• When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?

Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.

Bottom Line

The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.

Related Resources

• Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
• Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0

Drug Brand Names

Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran

Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,¹ resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.² In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.

Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of under­utilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”

Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.³ Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.

What are GLP-1 agonists?

GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.

Routes of administration and FDA indications

Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m²) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m²) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.

Data in weight loss

Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.⁴

Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.⁵ Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.

Continue to: In studies of semaglutide...

In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.⁶ A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).⁷ Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.⁸ A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.⁹

In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).¹⁰ An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.¹⁰ As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes¹¹ found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.

Tolerability

Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)^5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.

Initial evidence prompts additional questions

GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:

• When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
• How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
• When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
• When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?

Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.

Bottom Line

The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.

Related Resources

• Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
• Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0

Drug Brand Names

Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran

Obesity and overweight, with or without metabolic dysregulation, pose vexing problems for many patients with mood, anxiety, or psychotic disorders. More than one-half of individuals with severe mental illnesses are obese or overweight,¹ resulting from multiple factors that may include psychiatric symptoms (eg, anergia and hyperphagia), poor dietary choices, sedentary lifestyle, underlying inflammatory processes, medical comorbidities, and iatrogenic consequences of certain medications. Unfortunately, numerous psychotropic medications can increase weight and appetite due to a variety of mechanisms, including antihistaminergic effects, direct appetite-stimulating effects, and proclivities to cause insulin resistance. While individual agents can vary, a recent review identified an overall 2-fold increased risk for rapid, significant weight gain during treatment with antipsychotics as a class.² In addition to lifestyle modifications (diet and exercise), many pharmacologic strategies have been proposed to counter iatrogenic weight gain, including appetite suppressants (eg, pro-dopaminergic agents such as phentermine, stimulants, and amantadine), pro-anorectant anticonvulsants (eg, topiramate or zonisamide), opioid receptor antagonists (eg, olanzapine/samidorphan or naltrexone) and oral hypoglycemics such as metformin. However, the magnitude of impact for most of these agents to reverse iatrogenic weight gain tends to be modest, particularly once significant weight gain (ie, ≥7% of initial body weight) has already occurred.

Pharmacologic strategies to modulate or enhance the effects of insulin hold particular importance for combatting psychotropic-associated weight gain. Insulin transports glucose from the intravascular space to end organs for fuel consumption; to varying degrees, second-generation antipsychotics (SGAs) and some other psychotropic medications can cause insulin resistance. This in turn leads to excessive storage of under­utilized glucose in the liver (glycogenesis), the potential for developing fatty liver (ie, nonalcoholic steatohepatitis), and conversion of excess carbohydrates to fatty acids and triglycerides, with subsequent storage in adipose tissue. Medications that can enhance the activity of insulin (so-called incretin mimetics) can help to overcome insulin resistance caused by SGAs (and potentially by other psychotropic medications) and essentially lead to weight loss through enhanced “fuel efficiency.”

Metformin, typically dosed up to 1,000 mg twice daily with meals, has increasingly become recognized as a first-line strategy to attenuate weight gain and glycemic dysregulation from SGAs via its ability to reduce insulin resistance. Yet meta-analyses have shown that although results are significantly better than placebo, overall long-term weight loss from metformin alone tends to be rather modest (<4 kg) and associated with a reduction in body mass index (BMI) of only approximately 1 point.³ Psychiatrists (and other clinicians who prescribe psychotropic medications that can cause weight gain or metabolic dysregulation) therefore need to become familiar with alternative or adjunctive weight loss options. The use of a relatively new class of incretin mimetics called glucagon-like peptide 1 (GLP-1) agonists (Table) has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation.

What are GLP-1 agonists?

GLP-1 is a hormone secreted by L cells in the intestinal mucosa in response to food. GLP-1 agonists reduce blood sugar by increasing insulin secretion, decreasing glucagon release (thus downregulating further increases in blood sugar), and reducing insulin resistance. GLP-1 agonists also reduce appetite by directly stimulating the satiety center and slowing gastric emptying and GI motility. In addition to GLP-1 agonism, some medications in this family (notably tirzepatide) also agonize a second hormone, glucose-dependent insulinotropic polypeptide, which can further induce insulin secretion as well as decrease stomach acid secretion, potentially delivering an even more substantial reduction in appetite and weight.

Routes of administration and FDA indications

Due to limited bioavailability, most GLP-1 agonists require subcutaneous (SC) injections (the sole exception is the Rybelsus brand of semaglutide, which comes in a daily pill form). Most are FDA-approved not specifically for weight loss but for patients with type 2 diabetes (defined as a hemoglobin A1C ≥6.5% or a fasting blood glucose level ≥126 mg/dL). Weight loss represents a secondary outcome for GLP-1 agonists FDA-approved for glycemic control in patients with type 2 diabetes. The 2 current exceptions to this classification are the Wegovy brand of semaglutide (ie, dosing of 2.4 mg) and the Saxenda brand of liraglutide, both of which carry FDA indications for chronic weight management alone (when paired with dietary and lifestyle modification) in individuals who are obese (BMI >30 kg/m²) regardless of the presence or absence of diabetes, or for persons who are overweight (BMI >27 kg/m²) and have ≥1 weight-related comorbid condition (eg, hypertension, type 2 diabetes, or dyslipidemia). Although patients at risk for diabetes (ie, prediabetes, defined as a hemoglobin A1C 5.7% to 6.4% or a fasting blood glucose level 100 to 125 mg/dL) were included in FDA registration trials of Saxenda or Wegovy, prediabetes is not an FDA indication for any GLP-1 agonist.

Data in weight loss

Most of the existing empirical data on weight loss with GLP-1 agonists come from studies of individuals who are overweight or obese, with or without type 2 diabetes, rather than from studies using these agents to counteract iatrogenic weight gain. In a retrospective cohort study of patients with type 2 diabetes, coadministration with serotonergic antidepressants (eg, citalopram/escitalopram) was associated with attenuation of the weight loss effects of GLP-1 agonists.⁴

Liraglutide currently is the sole GLP-1 agonist studied for treating SGA-associated weight gain. A 16-week randomized trial compared once-daily SC injected liraglutide vs placebo in patients with schizophrenia who incurred weight gain and prediabetes after taking olanzapine or clozapine.⁵ Significantly more patients taking liraglutide than placebo developed normal glucose tolerance (64% vs 16%), and body weight decreased by a mean of 5.3 kg.

Continue to: In studies of semaglutide...

In studies of semaglutide for overweight/obese patients with type 2 diabetes or prediabetes, clinical trials of oral semaglutide (Rybelsus) found a mean weight loss over 26 weeks of -1.0 kg with dosing at 7 mg/d and -2.6 kg with dosing at 14 mg/d.⁶ A 68-week placebo-controlled trial of semaglutide (dosed at 2.4 mg SC weekly) for overweight/obese adults who did not have diabetes yielded a -15.3 kg weight loss (vs -2.6 kg with placebo); one-half of those who received semaglutide lost 15% of their initial body weight (Figure 1A and Figure 1B).⁷ Similar findings with semaglutide 2.4 mg SC weekly (Wegovy) were observed in overweight/obese adolescents, with 73% of participants losing ≥5% of their baseline weight.⁸ A comparative randomized trial in patients with type 2 diabetes also found modestly but significantly greater weight loss with oral semaglutide than with SC liraglutide.⁹

In a 72-week study of tirzepatide specifically for weight loss in nondiabetic patients who were overweight or obese, findings were especially dramatic (Figure 2A and Figure 2B).¹⁰ An overall 15% decrease in body weight was observed with 5 mg/week dosing alongside a 19.5% decrease in body weight with 10 mg/week dosing and a 20.9% weight reduction with 15 mg/week dosing.¹⁰ As noted in Figure 2B, the observed pattern of weight loss occurred along an exponential decay curve. Notably, a comparative study of tirzepatide vs once-weekly semaglutide (1 mg) in patients with type 2 diabetes¹¹ found significantly greater dose-dependent weight loss with tirzepatide than semaglutide (-1.9 kg at 5 mg, -3.6 kg at 10 mg, and -5.5 kg at 15 mg)—although the somewhat low dosing of semaglutide may have limited its optimal possible weight loss benefit.

Tolerability

Adverse effects with GLP-1 agonists are mainly gastrointestinal (eg, nausea, vomiting, abdominal pain, diarrhea, or constipation)^5-11 and generally transient. SC administration is performed in fatty tissue of the abdomen, thigh, or upper arm; site rotation is recommended to minimize injection site pain. All GLP-1 agonists carry manufacturers’ warning and precaution statements identifying the rare potential for acute pancreatitis, acute gall bladder disease, acute kidney injury, and hypoglycemia. Animal studies also have suggested an increased, dose-dependent risk for thyroid C-cell tumors with GLP-1 agonists; this has not been observed in human trials, although postmarketing pharmacovigilance reports have identified cases of medullary thyroid carcinoma in patients who took liraglutide. A manufacturer’s boxed warning indicates that a personal or family history of medullary carcinoma of the thyroid poses a contraindication for taking semaglutide, liraglutide, or tirzepatide.

Initial evidence prompts additional questions

GLP-1 agonists represent an emerging class of novel agents that can modulate glycemic dysregulation and overweight/obesity, often with dramatic results whose magnitude rivals the efficacy of bariatric surgery. Once-weekly formulations of semaglutide (Wegovy) and daily liraglutide (Saxenda) are FDA-approved for weight loss in patients who are overweight or obese while other existing formulations are approved solely for patients with type 2 diabetes, although it is likely that broader indications for weight loss (regardless of glycemic status) are forthcoming. Targeted use of GLP-1 agonists to counteract SGA-associated weight gain is supported by a handful of preliminary reports, with additional studies likely to come. Unanswered questions include:

• When should GLP-1 agonists be considered within a treatment algorithm for iatrogenic weight gain relative to other antidote strategies such as metformin or appetite-suppressing anticonvulsants?
• How effective might GLP-1 agonists be for iatrogenic weight gain from non-SGA psychotropic medications, such as serotonergic antidepressants?
• When and how can GLP-1 agonists be safely coprescribed with other nonincretin mimetic weight loss medications?
• When should psychiatrists prescribe GLP-1 agonists, or do so collaboratively with primary care physicians or endocrinologists, particularly in patients with metabolic syndrome?

Followers of the rapidly emerging literature in this area will likely find themselves best positioned to address these and other questions about optimal management of psychotropic-induced weight gain for the patients they treat.

Bottom Line

The use of glucagon-like peptide 1 (GLP-1) agonists, a relatively new class of incretin mimetics, has been associated with profound and often dramatic weight loss and improvement of glycemic parameters in patients with obesity and glycemic dysregulation. Preliminary reports support the potential targeted use of GLP-1 agonists to counteract weight gain associated with second-generation antipsychotics.

Related Resources

• Singh F, Allen A, Ianni A. Managing metabolic syndrome in patients with schizophrenia. Current Psychiatry. 2020;19(12):20-24,26. doi:10.12788/cp.0064
• Ard J, Fitch A, Fruh S, et al. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv Ther. 2021;38(6):2821- 2839. doi:10.1007/s12325-021-01710-0

Drug Brand Names

Amantadine • Gocovri
Citalopram • Celexa
Clozapine • Clozaril
Escitalopram • Lexapro
Liraglutide • Victoza, Saxenda
Metformin • Glucophage
Naltrexone • ReVia
Olanzapine • Zyprexa
Olanzapine/samidorphan • Lybalvi
Phentermine • Ionamin
Semaglutide • Rybelsus, Ozempic, Wegovy
Tirzepatide • Mounjaro
Topiramate • Topamax
Zonisamide • Zonegran