Current Psychiatry

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

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

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

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

Psychosis-proneness underlies functional psychoses

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

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

An evolutionary perspective

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

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

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

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

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

Obsessive-compulsive disorder⁵

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

Panic anxiety⁵

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

Social anxiety⁵

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

Atypical depression and bipolar I mania⁵

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

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

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

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

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

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

Our proposed 5 comorbidity subtypes are¹:

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

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

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

Box 1

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

Continue to: Bipolar 1 mania with delusions...

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

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

Recognizing affective trees in a psychotic forest

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

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

Diagnostic approaches

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

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

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

Continue to: Treatment by comorbidity subtype...

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

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

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

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

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

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

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

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

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

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

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

Box 2

Larger studies are needed

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

Bottom Line

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

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

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

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

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

Psychosis-proneness underlies functional psychoses

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

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

An evolutionary perspective

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

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

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

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

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

Obsessive-compulsive disorder⁵

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

Panic anxiety⁵

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

Social anxiety⁵

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

Atypical depression and bipolar I mania⁵

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

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

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

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

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

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

Our proposed 5 comorbidity subtypes are¹:

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

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

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

Box 1

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

Continue to: Bipolar 1 mania with delusions...

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

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

Recognizing affective trees in a psychotic forest

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

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

Diagnostic approaches

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

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

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

Continue to: Treatment by comorbidity subtype...

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

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

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

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

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

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

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

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

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

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

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

Box 2

Larger studies are needed

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

Bottom Line

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

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

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

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

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

Psychosis-proneness underlies functional psychoses

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

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

An evolutionary perspective

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

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

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

Five affective comorbidities evolved from primeval altruistic instincts

Melancholic depression⁵

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

Obsessive-compulsive disorder⁵

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

Panic anxiety⁵

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

Social anxiety⁵

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

Atypical depression and bipolar I mania⁵

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

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

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

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

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

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

Our proposed 5 comorbidity subtypes are¹:

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

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

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

Box 1

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

Continue to: Bipolar 1 mania with delusions...

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

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

Recognizing affective trees in a psychotic forest

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

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

Diagnostic approaches

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

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

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

Continue to: Treatment by comorbidity subtype...

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

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

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

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

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

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

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

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

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

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

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

Box 2

Larger studies are needed

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

Bottom Line

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

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

FIRST OF 2 PARTS

Autism spectrum disorder (ASD) is a complex, heterogenous neurodevelopmental disorder with genetic and environmental underpinnings, and an onset early in life.^1-9 It affects social communication, cognition, and sensory-motor domains, and manifests as deficits in social reciprocity, repetitive behavior, restricted range of interests, and sensory sensitivities.^6,10-14 In recent years, the prevalence of ASD has been increasing.^3,6,10 A large percentage of individuals with ASD experience significant social deficits in adulthood,¹⁰ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^15,16 Interventions in early childhood can result in significant and lasting changes in outcome and in functioning of individuals with ASD.

This article provides an update on various aspects of ASD diagnosis, with the goal of equipping clinicians with knowledge to help make an accurate ASD diagnosis at an early stage. Part 1 focuses on early detection and diagnosis, while Part 2 will describe treatment strategies.

Benefits of early detection

Substantial research has established that early intervention confers substantial benefits for outcomes among children with ASD.^{2,3,5,6,9,13,14,16-22} Earlier age of intervention correlates with greater developmental gain and symptom reduction.^21,23 The atypical neural development responsible for ASD likely occurs much earlier than the behavioral manifestations of this disorder, which implies that there is a crucial period to intervene before behavioral features emerge.¹ This necessitates early recognition of ASD,^9,17 and the need for further research to find novel ways to detect ASD earlier.

In the United States, children with ASD are diagnosed with the disorder on average between age 3 and 4 years.^6,24 However, evidence suggests there may be a prodromal phase for ASD during the first several months of life, wherein infants and toddlers exhibit developmentally inadequate communication and social skills and/or unusual behaviors.¹⁸ Behavioral signs suggestive of ASD may be evident as early as infancy, and commonly earlier than age 18 months.^1,17,19 Problems with sleeping and eating may be evident in early childhood.¹⁹ Deficits in joint attention may be evident as early as age 6 months to 8 months. Research suggests that a diagnosis of ASD by trained, expert professionals is likely to be accurate at the age of 2, and even as early as 18 months.^6,24

In a prospective study, Anderson et al²⁵ found that 9% of children who were diagnosed with ASD at age 2 no longer met the diagnostic criteria for ASD by adulthood.⁶ Those who no longer met ASD criteria were more likely to have received early intervention, had a verbal IQ ≥70, and had experienced a larger decrease in repetitive behaviors between ages 2 and 3, compared with other youth in this study who had a verbal IQ ≥70. One of the limitations of this study was a small sample size (85 participants); larger, randomized studies are needed to replicate these findings.²⁵

Continue to: Characteristics of ASD...

Characteristics of ASD

Table 1^{6,8,10,13,15,26-29} outlines various characteristics of ASD, which may manifest in varying degrees among children with the condition.

Speech/language. Speech helps to facilitate bonding between parents and an infant by offering a soothing, pleasurable, and reinforcing experience.³⁰ More than 50% of children with ASD have language delays or deficits that persist throughout adulthood.¹³ The extent of these language deficits varies; in general, the more severe the speech/language deficits, the more severe the long-term symptoms.¹³ Language deficits in young children with ASD tend to be of both the expressive and receptive type, with onset in infancy, which suggests that neural processes predate the emergence of behavioral symptoms of ASD, and also that early language deficits/delays could be a marker for or indicator of future risk of ASD.¹³ Individuals with ASD also have been noted to have limitations in orienting or attending to human voices.^13,30

Facial recognition. Evidence has linked ASD with deficits in facial recognition that emerge in the first few months of life.² Earlier studies have found that lack of attention to others’ faces was the strongest distinguishing factor between 1-year-olds with ASD and typically developing 1-year-olds.^2,31 A recent study that used EEG to compare facial emotion recognition in boys with ASD vs typically developing boys found that boys with ASD exhibited significantly lower sensitivity to angry and fearful faces.²⁷

Other features. A 2020 study (N = 37) found that compared with typically developing children, those with ASD show less “interactional synchrony’’ (a dynamic process in which the timing of children and caregivers’ behaviors [specifically, vocalizations and movements] become mutually coordinated) with both familiar and unfamiliar adults.³² These researchers concluded that impairment in interactional synchrony may be linked to social communication deficits in ASD.³²

A recent study (N = 98) evaluated “sluggish cognitive tempo” in 3 groups of children: children with attention-deficit/hyperactivity disorder (ADHD), children with ASD, and children with both ADHD and ASD.³³ It found that children with ASD exhibited sluggish cognitive tempo at levels similar to those of the other 2 groups, and indicated that sluggish cognitive tempo may be linked with “social and global impairment above and beyond” the impairment associated with ASD.³³ Executive function challenges are common in ASD, and are linked with poorer adaptive outcomes, regardless of IQ.⁶ Children with ASD commonly experience anxiety symptoms, depressive symptoms, obsessive-compulsive symptoms, sleep difficulties, and eating problems.⁶ Each of these symptom sets needs to be evaluated thoroughly to determine whether the symptoms are a part of ASD or if they constitute an independent condition. A longitudinal study (N = 421) found moderate and severe restricted, repetitive behavior in children with ASD was linked to a risk for increased anxiety in the future.³⁴

Understanding early aberrations in neurobiologic processes in ASD can help develop biomarkers for early recognition of ASD, as well as guide the development of targeted interventions and treatments (Box^{1-3,7-9,12,13,30,35-39}).

Box

The differential diagnosis of ASD warrants careful attention and consideration to rule out other developmental and psychiatric conditions.

Intellectual disability (ID). DSM-5 diagnostic criteria for ASD necessitate that disturbances are not better explained by ID or global developmental delay and that deficits should exceed impairment consistent with the level of intellectual disability.²⁸ Still, ASD is often overdiagnosed in children with ID.²⁸ Research suggests phenotypic and genetic overlap between ID and ASD.²⁸ Social functioning is often impaired in patients with ID; the greater the severity of ID, the greater the degree of social deficits.²⁸ In approximately 30% of cases, ASD and ID are comorbid.⁶ This overlap and comorbidity can pose a challenge, particularly due to the inherent complexities involved in assessment and differentiation.²⁸ When ID is present in ASD, there is a greater degree of social-communication deficits.⁶ It may be difficult to assess for ASD symptoms in children with severe ID.²⁸ Although there is no minimum age or developmental level below which ASD should not be diagnosed, some studies have started to use minimum criteria for diagnosis, such as a nonverbal mental age of 18 months.^28,40 Commonly used tests for ASD have much lower specificity when used for children with nonverbal age <15 months.²⁸ It would make sense, then, that the presence of ID might significantly affect the results of these diagnostic tests.²⁸

Other conditions that need to be ruled out include language disorders, hearing loss, rare genetic neurodevelopmental disorders (eg, Fragile X syndrome,³ Rett syndrome⁶), childhood-onset schizophrenia, obsessive-compulsive disorder, attachment disorders, and other conditions.¹⁸ ASD may be overdiagnosed in children with genetic disorders such as Angelman syndrome.⁴¹ In a systematic review, Moss and Howlin⁴² recommended caution when evaluating ASD-like behavioral symptoms in children with genetic syndromes and severe ID. On the other hand, some research has observed that individuals with Fragile X syndrome may exhibit symptoms that meet criteria for ASD.^6,43 McDuffie et al⁴³ used the Autism Diagnostic Interview-Revised (ADI-R) to compare boys with Fragile X syndrome who also met criteria for ASD with boys with nonsyndromic ASD. Those in the former group had lesser impairment in social smiling, offering, showing, and nonverbal gestures, but had more complex mannerisms, compared with boys in the latter group.⁴³

Milder manifestations of ASD may be more challenging to diagnose,¹ particularly in children age <3 and those with above-average cognition.⁶ Generally, in the case of a patient with ASD, parents find that the child did not have a period of typical development, or unusual behaviors were evident early on.¹⁷

ASD can be comorbid with ADHD. The presence of ADHD may mask or delay the diagnosis of ASD in children.⁶ In children with both ASD and ADHD, studies have found greater reduction in social and adaptive functioning compared with children with ADHD alone.⁴⁴

Table 2^{6,10,15,17,31,43} highlights some of the features that can be used to distinguish ASD from other conditions.

Continue to: Screening and diagnosis...

A medical workup is the first step to rule out other potential conditions that could be masquerading as ASD.¹⁷ Obtain a comprehensive history from parents/caregivers, particularly regarding social, behavioral, movement, sensory, and developmental aspects. In addition, audiologic testing is an essential step. Consider genetic testing, particularly if any dysmorphic features and/or ID are present, both of which confer additional risk for a genetic syndrome.⁶ A physical exam to detect any neurologic anomalies, organ dysfunction, and body dysmorphic features should be conducted.⁶

The Modified Checklist for Autism in Toddlers–Revised (MCHAT-R) is a commonly used, validated parental screening survey for ASD.^5,6 Research has shown that this survey has <50% specificity.⁵A recent American Academy of Pediatrics Clinical Report recommended universal screening for ASD at pediatric visits at age 18 months and at 24 months, in addition to developmental screening for all children at routine pediatric visits at age 9, 18, and 30 months.^6,19

Screening tools such as the Modified Checklist for Autism in Toddlers with Follow-Up (M-CHAT/F) can be integrated into routine primary health care. In a large (N = 25,999) study, Guthrie et al⁴⁵ used M-CHAT/F to conduct universal, primary care–based screening in young children. They found that the positive predictive value of M-CHAT/F was lower among girls, children of color, and those from lower-income households. There is a need for development of screening tools with higher accuracy and sensitivity for identifying young children with ASD regardless of their ethnic or socioeconomic background, and also for children older than 30 months.^5,6,45

Definitive diagnosis of ASD is ideally done by a multidisciplinary team⁴⁶ using established gold standard measures such as the ADOS (Autism Diagnostic Observation Schedule) and ADI-R.⁴⁷ Such multidisciplinary teams usually include a child psychiatrist, child psychologist, speech therapist, occupational therapist, school educator, and developmental pediatrician. However, because there are long wait times to receive this type of diagnosis in the United States,⁶ in the interest of not missing the critical window of early intervention, physicians who suspect a patient may have ASD should refer the child and family for appropriate educational and behavioral interventions as early as possible, rather than waiting for definitive testing.⁶

ADI-R has limitations in distinguishing ASD from other conditions, especially in very young children, and particularly in distinguishing ASD from childhood-onset schizophrenia.⁴⁷ Similarly, ADOS, which is a semi-structured, standardized, observation assessment tool, also has limitations, including generating false-positive results, which can make it difficult to distinguish children and adolescents with developmental disabilities from those with ASD.⁴⁷ However, in combination, these 2 tools are generally efficacious.⁴⁷ Further research is warranted to develop and fine-tune definitive diagnostic tools with greater sensitivity and specificity.

A newer measure—the Autism Parent Screen for Infants (APSI) questionnaire—has been shown to be effective in detecting early signs predictive of ASD in high-risk infants (eg, siblings of children with ASD), and has potential as an early screening tool.^48,49

Part 2 of this article will review nonpharmacologic and pharmacologic treatments for patients with ASD.

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

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

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

Metformin exerts its hypoglycemic effects by:

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

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

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

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

Metabolic benefits

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

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

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

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

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

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

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

Metformin exerts its hypoglycemic effects by:

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

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

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

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

Metabolic benefits

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

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

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

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

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

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

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

Metformin exerts its hypoglycemic effects by:

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

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

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

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

Metabolic benefits

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

Continue on to: Nonmetabolic benefits...

Nonmetabolic benefits

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

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

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

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

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

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

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

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

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

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

Continue on to: Case Continued...

CASE CONTINUED

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

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

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

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

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

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

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

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

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

Continue on to: Case Continued...

CASE CONTINUED

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

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

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

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

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

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

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

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

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

Continue on to: Case Continued...

CASE CONTINUED

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

Among patients with bipolar I or II disorder (BD I or II), major depressive episodes represent the predominant mood state when not euthymic, and are disproportionately associated with the functional disability of BD and its suicide risk.¹ Long-term naturalistic studies of weekly mood states in patients with BD I or II found that the proportion of time spent depressed greatly exceeded that spent in a mixed, hypomanic, or manic state during >12 years of follow-up (Figure 1²and Figure 2³). In the 20th century, traditional antidepressants represented the sole option for management of bipolar depression despite concerns of manic switching or lack of efficacy.^4,5 Efficacy concerns were subsequently confirmed by placebo-controlled studies, such as the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, which found limited effectiveness of adjunctive antidepressants for bipolar depression.⁶ Comprehensive reviews of randomized controlled trials and observational studies documented the risk of mood cycling and manic switching, especially in patients with BD I, even if antidepressants were used in the presence of mood-stabilizing medications.^7,8

Several newer antipsychotics have been FDA-approved for treating depressive episodes associated with BD (Table 1). Approval of olanzapine/fluoxetine combination (OFC) in December 2003 for depressive episodes associated with BD I established that mechanisms exist which can effectively treat acute depressive episodes in patients with BD without an inordinate risk of mood instability. Subsequent approval of quetia­pine in October 2006 for depression associated with BD I or II, lurasidone in June 2013, and cariprazine in May 2019 for major depression in BD I greatly expanded the options for management of acute bipolar depression. However, despite the array of molecules available, for certain patients these agents presented tolerability issues such as sedation, weight gain, akathisia, or parkinsonism that could hamper effective treatment.⁹ Safety and efficacy data in bipolar depression for adjunctive use with lithium or divalproex/valproate (VPA) also are lacking for quetiapine, OFC, and cariprazine.^10,11 Moreover, despite the fact that BD II is as prevalent as BD I, and that patients with BD II have comparable rates of comorbidity, chronicity, disability, and suicidality,¹² only quetiapine was approved for acute treatment of depression in patients with BD II. This omission is particularly problematic because the depressive episodes of BD II predominate over the time spent in hypomanic and cycling/mixed states (50.3% for depression vs 3.6% for hypomania/cycling/mixed combined), much more than is seen with BD I (31.9% for depression vs 14.8% for hypomania/cycling/mixed combined).^2,3 The paucity of data for the use of newer antipsychotics in BD II depression presents a problem when patients cannot tolerate or refuse to consider quetiapine. This prevents clinicians from engaging in evidence-based efficacy discussions of other options, even if it is assumed that the tolerability profile for BD II depression patients may be similar to that seen when these agents are used for BD I depression.

Continue to: Table 1...

Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).¹³ Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).^13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).¹⁵ At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,^13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.^13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.¹⁹ This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.¹³ There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.¹³

Continue to: Clinical implications...

Clinical implications

The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.²³

Efficacy in adults with BD I or II depression.

The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,¹⁷ and 1 study when used adjunctively to lithium or VPA.¹⁸ The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.¹⁷ Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.¹⁷

The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).

The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.¹⁸ Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.¹⁸ Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).

The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.¹⁸ As of this writing, a secondary analysis by BD subtype has not yet been presented.

A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.

Continue on to: Adverse reactions...

Adverse reactions

In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.¹⁷ The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).¹³ Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.¹³ Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.¹⁷ Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.

Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).¹³ Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.¹³ Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.¹⁸ Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.¹⁸

Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.¹³

Continue on to: Pharmacologic profile...

Pharmacologic profile

Lumateperone’s preclinical discovery program found an impact on markers associated with increased glutamatergic neurotransmission, properties that were predicted to yield antidepressant benefit.^14,15,24 This is hypothesized to be based on the complex pharmacology of lumateperone, including dopamine D1 agonism, modest SERT occupancy, and near saturation of the 5HT2A receptor.^15,22 Dopamine D2 affinity is modest (32 nM), and the D2 receptor occupancy at the 42 mg dose is low. These properties translate to rates of EPS in clinical studies of schizophrenia and BD that are close to that of placebo. Lumateperone has very high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), which also helps mitigate D2-related adverse effects and may be part of the therapeutic antidepressant mechanism. Underlying the tolerability profile is the low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).

Clinical considerations

Data from the lumateperone BD depression trials led to it being only the second agent approved for acute major depression in BD II patients, and the only agent which has approvals as monotherapy and adjunctive therapy for both BD subtypes. The monotherapy trial results substantiate that lumateperone was robustly effective regardless of BD subtype, with significant improvement in depressive symptoms experienced by patients with BD I (effect size 0.49, P < .0001) and those with BD II (effect size 0.81, P < .001). Effect sizes in acute BD depression studies are much larger in monotherapy trials than in adjunctive trials, as the latter group represents patients who have already failed pretreatment with a mood stabilizer.^25,26 In the lurasidone BD I depression trials, the effect size based on mean change in MADRS score over the course of 6 weeks was 0.51 in the monotherapy study compared to 0.34 when used adjunctively with lithium or VPA.^25,26 In the lumateperone adjunctive study, the effect size for the difference in mean MADRS total score from baseline for lumateperone 42 mg/d, was 0.27 (P < .05). Subgroup analyses by BD subtype are not yet available for adjunctive use, but the data presented to FDA were sufficient to permit an indication for adjunctive use across both diagnostic groups.

The absence of clinically significant EPS, the minimal impact on metabolic or endocrine parameters, and the lack of a need for titration are all appealing properties. At the present there is only 1 marketed dose (42 mg capsules), so the package insert includes cautionary language regarding situations when a patient might encounter less drug exposure (concurrent use of cytochrome P450 [CYP] 3A4 inducers), or greater drug exposure due to concurrent use of moderate or strong CYP3A4 inhibitors, as well as in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria (Child-Pugh B or C). These are not contraindications.

Unique properties of lumateperone include efficacy established as monotherapy for BD I and BD II patients, and efficacy for adjunctive use with lithium or VPA. Additionally, the extremely low rates of significant EPS and lack of clinically significant metabolic or endocrine adverse effects are unique properties of lumateperone.¹³

Why Rx? Reasons to prescribe lumateperone for adult BD depression patients include:

• data support efficacy for BD I and BD II patients, and for monotherapy or adjunctive use with lithium/VPA
• favorable tolerability profile, including no significant signal for EPS, endocrine or metabolic adverse effects, or QT prolongation
• no need for titration.

Dosing. There is only 1 dose available for lumateperone: 42 mg capsules (Table 3). As the dose cannot be modified, the package insert contains cautionary language regarding situations with less drug exposure (use of CYP3A4 inducers), or greater drug exposure (use with moderate or strong CYP3A4 inhibitors or in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria [Child-Pugh B or C]). These are not contraindications. Based on newer pharmacokinetic studies, lumateperone does not need to be dosed with food, and there is no clinically significant interaction with UGT1A4 inhibitors such as VPA.

Bottom Line

Data support the efficacy of lumateperone for treating depressive episodes in adults with bipolar I or bipolar II disorder, either as monotherapy or adjunctive to lithium or divalproex/valproate. Potential advantages of lumateperone for this indication include a favorable tolerability profile and no need for titration.

Among patients with bipolar I or II disorder (BD I or II), major depressive episodes represent the predominant mood state when not euthymic, and are disproportionately associated with the functional disability of BD and its suicide risk.¹ Long-term naturalistic studies of weekly mood states in patients with BD I or II found that the proportion of time spent depressed greatly exceeded that spent in a mixed, hypomanic, or manic state during >12 years of follow-up (Figure 1²and Figure 2³). In the 20th century, traditional antidepressants represented the sole option for management of bipolar depression despite concerns of manic switching or lack of efficacy.^4,5 Efficacy concerns were subsequently confirmed by placebo-controlled studies, such as the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, which found limited effectiveness of adjunctive antidepressants for bipolar depression.⁶ Comprehensive reviews of randomized controlled trials and observational studies documented the risk of mood cycling and manic switching, especially in patients with BD I, even if antidepressants were used in the presence of mood-stabilizing medications.^7,8

Several newer antipsychotics have been FDA-approved for treating depressive episodes associated with BD (Table 1). Approval of olanzapine/fluoxetine combination (OFC) in December 2003 for depressive episodes associated with BD I established that mechanisms exist which can effectively treat acute depressive episodes in patients with BD without an inordinate risk of mood instability. Subsequent approval of quetia­pine in October 2006 for depression associated with BD I or II, lurasidone in June 2013, and cariprazine in May 2019 for major depression in BD I greatly expanded the options for management of acute bipolar depression. However, despite the array of molecules available, for certain patients these agents presented tolerability issues such as sedation, weight gain, akathisia, or parkinsonism that could hamper effective treatment.⁹ Safety and efficacy data in bipolar depression for adjunctive use with lithium or divalproex/valproate (VPA) also are lacking for quetiapine, OFC, and cariprazine.^10,11 Moreover, despite the fact that BD II is as prevalent as BD I, and that patients with BD II have comparable rates of comorbidity, chronicity, disability, and suicidality,¹² only quetiapine was approved for acute treatment of depression in patients with BD II. This omission is particularly problematic because the depressive episodes of BD II predominate over the time spent in hypomanic and cycling/mixed states (50.3% for depression vs 3.6% for hypomania/cycling/mixed combined), much more than is seen with BD I (31.9% for depression vs 14.8% for hypomania/cycling/mixed combined).^2,3 The paucity of data for the use of newer antipsychotics in BD II depression presents a problem when patients cannot tolerate or refuse to consider quetiapine. This prevents clinicians from engaging in evidence-based efficacy discussions of other options, even if it is assumed that the tolerability profile for BD II depression patients may be similar to that seen when these agents are used for BD I depression.

Continue to: Table 1...

Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).¹³ Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).^13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).¹⁵ At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,^13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.^13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.¹⁹ This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.¹³ There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.¹³

Continue to: Clinical implications...

Clinical implications

The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.²³

Efficacy in adults with BD I or II depression.

The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,¹⁷ and 1 study when used adjunctively to lithium or VPA.¹⁸ The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.¹⁷ Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.¹⁷

The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).

The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.¹⁸ Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.¹⁸ Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).

The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.¹⁸ As of this writing, a secondary analysis by BD subtype has not yet been presented.

A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.

Continue on to: Adverse reactions...

Adverse reactions

In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.¹⁷ The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).¹³ Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.¹³ Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.¹⁷ Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.

Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).¹³ Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.¹³ Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.¹⁸ Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.¹⁸

Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.¹³

Continue on to: Pharmacologic profile...

Pharmacologic profile

Lumateperone’s preclinical discovery program found an impact on markers associated with increased glutamatergic neurotransmission, properties that were predicted to yield antidepressant benefit.^14,15,24 This is hypothesized to be based on the complex pharmacology of lumateperone, including dopamine D1 agonism, modest SERT occupancy, and near saturation of the 5HT2A receptor.^15,22 Dopamine D2 affinity is modest (32 nM), and the D2 receptor occupancy at the 42 mg dose is low. These properties translate to rates of EPS in clinical studies of schizophrenia and BD that are close to that of placebo. Lumateperone has very high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), which also helps mitigate D2-related adverse effects and may be part of the therapeutic antidepressant mechanism. Underlying the tolerability profile is the low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).

Clinical considerations

Data from the lumateperone BD depression trials led to it being only the second agent approved for acute major depression in BD II patients, and the only agent which has approvals as monotherapy and adjunctive therapy for both BD subtypes. The monotherapy trial results substantiate that lumateperone was robustly effective regardless of BD subtype, with significant improvement in depressive symptoms experienced by patients with BD I (effect size 0.49, P < .0001) and those with BD II (effect size 0.81, P < .001). Effect sizes in acute BD depression studies are much larger in monotherapy trials than in adjunctive trials, as the latter group represents patients who have already failed pretreatment with a mood stabilizer.^25,26 In the lurasidone BD I depression trials, the effect size based on mean change in MADRS score over the course of 6 weeks was 0.51 in the monotherapy study compared to 0.34 when used adjunctively with lithium or VPA.^25,26 In the lumateperone adjunctive study, the effect size for the difference in mean MADRS total score from baseline for lumateperone 42 mg/d, was 0.27 (P < .05). Subgroup analyses by BD subtype are not yet available for adjunctive use, but the data presented to FDA were sufficient to permit an indication for adjunctive use across both diagnostic groups.

The absence of clinically significant EPS, the minimal impact on metabolic or endocrine parameters, and the lack of a need for titration are all appealing properties. At the present there is only 1 marketed dose (42 mg capsules), so the package insert includes cautionary language regarding situations when a patient might encounter less drug exposure (concurrent use of cytochrome P450 [CYP] 3A4 inducers), or greater drug exposure due to concurrent use of moderate or strong CYP3A4 inhibitors, as well as in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria (Child-Pugh B or C). These are not contraindications.

Unique properties of lumateperone include efficacy established as monotherapy for BD I and BD II patients, and efficacy for adjunctive use with lithium or VPA. Additionally, the extremely low rates of significant EPS and lack of clinically significant metabolic or endocrine adverse effects are unique properties of lumateperone.¹³

Why Rx? Reasons to prescribe lumateperone for adult BD depression patients include:

• data support efficacy for BD I and BD II patients, and for monotherapy or adjunctive use with lithium/VPA
• favorable tolerability profile, including no significant signal for EPS, endocrine or metabolic adverse effects, or QT prolongation
• no need for titration.

Dosing. There is only 1 dose available for lumateperone: 42 mg capsules (Table 3). As the dose cannot be modified, the package insert contains cautionary language regarding situations with less drug exposure (use of CYP3A4 inducers), or greater drug exposure (use with moderate or strong CYP3A4 inhibitors or in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria [Child-Pugh B or C]). These are not contraindications. Based on newer pharmacokinetic studies, lumateperone does not need to be dosed with food, and there is no clinically significant interaction with UGT1A4 inhibitors such as VPA.

Bottom Line

Data support the efficacy of lumateperone for treating depressive episodes in adults with bipolar I or bipolar II disorder, either as monotherapy or adjunctive to lithium or divalproex/valproate. Potential advantages of lumateperone for this indication include a favorable tolerability profile and no need for titration.

Among patients with bipolar I or II disorder (BD I or II), major depressive episodes represent the predominant mood state when not euthymic, and are disproportionately associated with the functional disability of BD and its suicide risk.¹ Long-term naturalistic studies of weekly mood states in patients with BD I or II found that the proportion of time spent depressed greatly exceeded that spent in a mixed, hypomanic, or manic state during >12 years of follow-up (Figure 1²and Figure 2³). In the 20th century, traditional antidepressants represented the sole option for management of bipolar depression despite concerns of manic switching or lack of efficacy.^4,5 Efficacy concerns were subsequently confirmed by placebo-controlled studies, such as the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, which found limited effectiveness of adjunctive antidepressants for bipolar depression.⁶ Comprehensive reviews of randomized controlled trials and observational studies documented the risk of mood cycling and manic switching, especially in patients with BD I, even if antidepressants were used in the presence of mood-stabilizing medications.^7,8

Several newer antipsychotics have been FDA-approved for treating depressive episodes associated with BD (Table 1). Approval of olanzapine/fluoxetine combination (OFC) in December 2003 for depressive episodes associated with BD I established that mechanisms exist which can effectively treat acute depressive episodes in patients with BD without an inordinate risk of mood instability. Subsequent approval of quetia­pine in October 2006 for depression associated with BD I or II, lurasidone in June 2013, and cariprazine in May 2019 for major depression in BD I greatly expanded the options for management of acute bipolar depression. However, despite the array of molecules available, for certain patients these agents presented tolerability issues such as sedation, weight gain, akathisia, or parkinsonism that could hamper effective treatment.⁹ Safety and efficacy data in bipolar depression for adjunctive use with lithium or divalproex/valproate (VPA) also are lacking for quetiapine, OFC, and cariprazine.^10,11 Moreover, despite the fact that BD II is as prevalent as BD I, and that patients with BD II have comparable rates of comorbidity, chronicity, disability, and suicidality,¹² only quetiapine was approved for acute treatment of depression in patients with BD II. This omission is particularly problematic because the depressive episodes of BD II predominate over the time spent in hypomanic and cycling/mixed states (50.3% for depression vs 3.6% for hypomania/cycling/mixed combined), much more than is seen with BD I (31.9% for depression vs 14.8% for hypomania/cycling/mixed combined).^2,3 The paucity of data for the use of newer antipsychotics in BD II depression presents a problem when patients cannot tolerate or refuse to consider quetiapine. This prevents clinicians from engaging in evidence-based efficacy discussions of other options, even if it is assumed that the tolerability profile for BD II depression patients may be similar to that seen when these agents are used for BD I depression.

Continue to: Table 1...

Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).¹³ Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).^13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).¹⁵ At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,^13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.^13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.¹⁹ This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.¹³ There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.¹³

Continue to: Clinical implications...

Clinical implications

The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.²³

Efficacy in adults with BD I or II depression.

The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,¹⁷ and 1 study when used adjunctively to lithium or VPA.¹⁸ The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.¹⁷ Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.¹⁷

The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).

The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.¹⁸ Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.¹⁸ Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).

The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.¹⁸ As of this writing, a secondary analysis by BD subtype has not yet been presented.

A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.

Continue on to: Adverse reactions...

Adverse reactions

In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.¹⁷ The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).¹³ Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.¹³ Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.¹⁷ Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.

Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).¹³ Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.¹³ Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.¹⁸ Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.¹⁸

Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.¹³

Continue on to: Pharmacologic profile...

Pharmacologic profile

Lumateperone’s preclinical discovery program found an impact on markers associated with increased glutamatergic neurotransmission, properties that were predicted to yield antidepressant benefit.^14,15,24 This is hypothesized to be based on the complex pharmacology of lumateperone, including dopamine D1 agonism, modest SERT occupancy, and near saturation of the 5HT2A receptor.^15,22 Dopamine D2 affinity is modest (32 nM), and the D2 receptor occupancy at the 42 mg dose is low. These properties translate to rates of EPS in clinical studies of schizophrenia and BD that are close to that of placebo. Lumateperone has very high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), which also helps mitigate D2-related adverse effects and may be part of the therapeutic antidepressant mechanism. Underlying the tolerability profile is the low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).

Clinical considerations

Data from the lumateperone BD depression trials led to it being only the second agent approved for acute major depression in BD II patients, and the only agent which has approvals as monotherapy and adjunctive therapy for both BD subtypes. The monotherapy trial results substantiate that lumateperone was robustly effective regardless of BD subtype, with significant improvement in depressive symptoms experienced by patients with BD I (effect size 0.49, P < .0001) and those with BD II (effect size 0.81, P < .001). Effect sizes in acute BD depression studies are much larger in monotherapy trials than in adjunctive trials, as the latter group represents patients who have already failed pretreatment with a mood stabilizer.^25,26 In the lurasidone BD I depression trials, the effect size based on mean change in MADRS score over the course of 6 weeks was 0.51 in the monotherapy study compared to 0.34 when used adjunctively with lithium or VPA.^25,26 In the lumateperone adjunctive study, the effect size for the difference in mean MADRS total score from baseline for lumateperone 42 mg/d, was 0.27 (P < .05). Subgroup analyses by BD subtype are not yet available for adjunctive use, but the data presented to FDA were sufficient to permit an indication for adjunctive use across both diagnostic groups.

The absence of clinically significant EPS, the minimal impact on metabolic or endocrine parameters, and the lack of a need for titration are all appealing properties. At the present there is only 1 marketed dose (42 mg capsules), so the package insert includes cautionary language regarding situations when a patient might encounter less drug exposure (concurrent use of cytochrome P450 [CYP] 3A4 inducers), or greater drug exposure due to concurrent use of moderate or strong CYP3A4 inhibitors, as well as in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria (Child-Pugh B or C). These are not contraindications.

Unique properties of lumateperone include efficacy established as monotherapy for BD I and BD II patients, and efficacy for adjunctive use with lithium or VPA. Additionally, the extremely low rates of significant EPS and lack of clinically significant metabolic or endocrine adverse effects are unique properties of lumateperone.¹³

Why Rx? Reasons to prescribe lumateperone for adult BD depression patients include:

• data support efficacy for BD I and BD II patients, and for monotherapy or adjunctive use with lithium/VPA
• favorable tolerability profile, including no significant signal for EPS, endocrine or metabolic adverse effects, or QT prolongation
• no need for titration.

Dosing. There is only 1 dose available for lumateperone: 42 mg capsules (Table 3). As the dose cannot be modified, the package insert contains cautionary language regarding situations with less drug exposure (use of CYP3A4 inducers), or greater drug exposure (use with moderate or strong CYP3A4 inhibitors or in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria [Child-Pugh B or C]). These are not contraindications. Based on newer pharmacokinetic studies, lumateperone does not need to be dosed with food, and there is no clinically significant interaction with UGT1A4 inhibitors such as VPA.

Bottom Line

Data support the efficacy of lumateperone for treating depressive episodes in adults with bipolar I or bipolar II disorder, either as monotherapy or adjunctive to lithium or divalproex/valproate. Potential advantages of lumateperone for this indication include a favorable tolerability profile and no need for titration.

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

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

Differentiating SDC from schizophrenia

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

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

Differentiating SDC from ASD

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

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

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

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

Differentiating SDC from schizophrenia

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

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

Differentiating SDC from ASD

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

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

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

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

Differentiating SDC from schizophrenia

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

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

Differentiating SDC from ASD

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

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

Although we may want to say “yes” when our patients ask us for certain medications, work excuses, etc, often it is more appropriate to say “no” because the conditions do not support those requests. Saying no to a patient usually is not a comfortable experience, but we should not say yes to avoid hurting their feelings, damaging our rapport with them, or having them post potential negative reviews about us. For many of us, saying no is a skill that does not come naturally. For some, bluntly telling a patient no may work, but this approach is more likely to be ineffective. At the same time, saying no in an equivocal manner may weaken our patients’ confidence in us and could be displeasing for both our patients and us.^1,2

We should say no in an “effective, professional manner that fosters good patient care and preserves the therapeutic relationship, while supporting physician well-being.”¹ In this article, I provide practical tips for saying no to inappropriate patient requests in an emphatic manner so that we can feel more empowered and less uncomfortable.

Acknowledge and analyze your discomfort.

Before saying no, recognize that you are feeling uncomfortable with your patient’s inappropriate request. This uncomfortable feeling is a probable cue that there is likely no appropriate context for their request, ie, saying yes would be poor medical care, illegal, against policy, etc.^1,3 In most cases, you should be able to identify the reason(s) your patient’s request feels inappropriate and uncomfortable.

Gather information and provide an explanation.

Ask your patient for more information about their request so you can determine if there are any underlying factors and if any additional information is needed.³ Once you decide to say no, explain why. Your explanation should be brief, because lengthy explanations might create room for debate (which could be exhausting and/or time-consuming), lead to giving in to their inappropriate request, and/or lead them to become more frustrated and misunderstood.¹

Be empathetic, and re-establish rapport.

After declining a patient’s request, you may have to use empathy to re-establish rapport if it has been damaged. After being told no, your patient may feel frustrated or powerless. Acknowledge their feelings with statements such as “I know this is not want you wanted to hear” or “I can see you are irritated.”Accept your patient’s negative emotions, rather than minimizing them or trying to fix them.^1,3

Although we may want to say “yes” when our patients ask us for certain medications, work excuses, etc, often it is more appropriate to say “no” because the conditions do not support those requests. Saying no to a patient usually is not a comfortable experience, but we should not say yes to avoid hurting their feelings, damaging our rapport with them, or having them post potential negative reviews about us. For many of us, saying no is a skill that does not come naturally. For some, bluntly telling a patient no may work, but this approach is more likely to be ineffective. At the same time, saying no in an equivocal manner may weaken our patients’ confidence in us and could be displeasing for both our patients and us.^1,2

We should say no in an “effective, professional manner that fosters good patient care and preserves the therapeutic relationship, while supporting physician well-being.”¹ In this article, I provide practical tips for saying no to inappropriate patient requests in an emphatic manner so that we can feel more empowered and less uncomfortable.

Acknowledge and analyze your discomfort.

Before saying no, recognize that you are feeling uncomfortable with your patient’s inappropriate request. This uncomfortable feeling is a probable cue that there is likely no appropriate context for their request, ie, saying yes would be poor medical care, illegal, against policy, etc.^1,3 In most cases, you should be able to identify the reason(s) your patient’s request feels inappropriate and uncomfortable.

Gather information and provide an explanation.

Ask your patient for more information about their request so you can determine if there are any underlying factors and if any additional information is needed.³ Once you decide to say no, explain why. Your explanation should be brief, because lengthy explanations might create room for debate (which could be exhausting and/or time-consuming), lead to giving in to their inappropriate request, and/or lead them to become more frustrated and misunderstood.¹

Be empathetic, and re-establish rapport.

After declining a patient’s request, you may have to use empathy to re-establish rapport if it has been damaged. After being told no, your patient may feel frustrated or powerless. Acknowledge their feelings with statements such as “I know this is not want you wanted to hear” or “I can see you are irritated.”Accept your patient’s negative emotions, rather than minimizing them or trying to fix them.^1,3

Although we may want to say “yes” when our patients ask us for certain medications, work excuses, etc, often it is more appropriate to say “no” because the conditions do not support those requests. Saying no to a patient usually is not a comfortable experience, but we should not say yes to avoid hurting their feelings, damaging our rapport with them, or having them post potential negative reviews about us. For many of us, saying no is a skill that does not come naturally. For some, bluntly telling a patient no may work, but this approach is more likely to be ineffective. At the same time, saying no in an equivocal manner may weaken our patients’ confidence in us and could be displeasing for both our patients and us.^1,2

We should say no in an “effective, professional manner that fosters good patient care and preserves the therapeutic relationship, while supporting physician well-being.”¹ In this article, I provide practical tips for saying no to inappropriate patient requests in an emphatic manner so that we can feel more empowered and less uncomfortable.

Acknowledge and analyze your discomfort.

Before saying no, recognize that you are feeling uncomfortable with your patient’s inappropriate request. This uncomfortable feeling is a probable cue that there is likely no appropriate context for their request, ie, saying yes would be poor medical care, illegal, against policy, etc.^1,3 In most cases, you should be able to identify the reason(s) your patient’s request feels inappropriate and uncomfortable.

Gather information and provide an explanation.

Ask your patient for more information about their request so you can determine if there are any underlying factors and if any additional information is needed.³ Once you decide to say no, explain why. Your explanation should be brief, because lengthy explanations might create room for debate (which could be exhausting and/or time-consuming), lead to giving in to their inappropriate request, and/or lead them to become more frustrated and misunderstood.¹

Be empathetic, and re-establish rapport.

After declining a patient’s request, you may have to use empathy to re-establish rapport if it has been damaged. After being told no, your patient may feel frustrated or powerless. Acknowledge their feelings with statements such as “I know this is not want you wanted to hear” or “I can see you are irritated.”Accept your patient’s negative emotions, rather than minimizing them or trying to fix them.^1,3

Closing your practice can be a stressful experience, and it requires careful planning. The process requires numerous steps, such as informing your staff, notifying your patients, closing accounts with your vendors and suppliers, storing medical records, and following applicable federal and state laws for dissolving your practice.^1,2 Many of these steps may require consulting with an attorney, an accountant, and your malpractice insurance carrier.^1,2 Although the recommendations I provide in this article are not exhaustive, when faced with closing your practice, be sure to consider the following factors.

Notify staff and patients.

Select a date to close your practice that will allow you to stop taking new patients, provides adequate leeway for your staff to find new employment and for you to hire temporary staff if needed, ensures you meet your obligations to your staff, such as payroll, and gives you time to set up appropriate continuity of care for your patients. In addition to verbally notifying your patients of your practice’s closing, inform them in writing (whether hand-delivered or via certified mail with return receipt) of the date of the practice’s closure, reason for the closure, cancellation of scheduled appointments after the closure date, referral options, and how they can obtain a copy of their medical records.^1,2 Make sure your patients have an adequate supply of their medications before the closure.

Notify other parties.

Inform all suppliers, vendors, contracted service providers, insurance broker(s) for your practice, and payers (including Medicare and Medicaid, if applicable) of your intent to close your practice.^1,2 Provide payers with a forwarding address to send payments that resolve after your practice closes, and request final invoices from vendors and suppliers so you can close your accounts with them. If you don’t own the building in which your practice is located, notify the building management in accordance with the provisions of your lease.^1,2 Give cancellation notices to utilities and ancillary services (eg, labs, imaging facilities) to which you refer your patients, and notify facilities where you are credentialed and have admitting privileges.^1,2 Inform your state medical licensing board, your state’s controlled substance division, and the Drug Enforcement Administration, because these agencies have requirements regarding changing the status of your medical license (if you decide to retire), continuing or surrendering your state and federal controlled substance registration, and disposal of prescription medications and prescription pads.^1,2 Contact your local post office and delivery services with your change of address.

Address other considerations.

Set up a medical record retention and destruction plan in accordance with state and federal regulations, arrange for the safe storage for both paper and electronic medical records, and make sure storage facilities have experience handling confidential, Health Insurance Portability and Accountability Act (HIPAA)-sensitive patient information.^1,2 In addition, establish a process for permanently deleting all HIPAA-sensitive patient information from any equipment that you don’t intend to keep.^1,2

Closing your practice can be a stressful experience, and it requires careful planning. The process requires numerous steps, such as informing your staff, notifying your patients, closing accounts with your vendors and suppliers, storing medical records, and following applicable federal and state laws for dissolving your practice.^1,2 Many of these steps may require consulting with an attorney, an accountant, and your malpractice insurance carrier.^1,2 Although the recommendations I provide in this article are not exhaustive, when faced with closing your practice, be sure to consider the following factors.

Notify staff and patients.

Select a date to close your practice that will allow you to stop taking new patients, provides adequate leeway for your staff to find new employment and for you to hire temporary staff if needed, ensures you meet your obligations to your staff, such as payroll, and gives you time to set up appropriate continuity of care for your patients. In addition to verbally notifying your patients of your practice’s closing, inform them in writing (whether hand-delivered or via certified mail with return receipt) of the date of the practice’s closure, reason for the closure, cancellation of scheduled appointments after the closure date, referral options, and how they can obtain a copy of their medical records.^1,2 Make sure your patients have an adequate supply of their medications before the closure.

Notify other parties.

Inform all suppliers, vendors, contracted service providers, insurance broker(s) for your practice, and payers (including Medicare and Medicaid, if applicable) of your intent to close your practice.^1,2 Provide payers with a forwarding address to send payments that resolve after your practice closes, and request final invoices from vendors and suppliers so you can close your accounts with them. If you don’t own the building in which your practice is located, notify the building management in accordance with the provisions of your lease.^1,2 Give cancellation notices to utilities and ancillary services (eg, labs, imaging facilities) to which you refer your patients, and notify facilities where you are credentialed and have admitting privileges.^1,2 Inform your state medical licensing board, your state’s controlled substance division, and the Drug Enforcement Administration, because these agencies have requirements regarding changing the status of your medical license (if you decide to retire), continuing or surrendering your state and federal controlled substance registration, and disposal of prescription medications and prescription pads.^1,2 Contact your local post office and delivery services with your change of address.

Address other considerations.

Set up a medical record retention and destruction plan in accordance with state and federal regulations, arrange for the safe storage for both paper and electronic medical records, and make sure storage facilities have experience handling confidential, Health Insurance Portability and Accountability Act (HIPAA)-sensitive patient information.^1,2 In addition, establish a process for permanently deleting all HIPAA-sensitive patient information from any equipment that you don’t intend to keep.^1,2

Closing your practice can be a stressful experience, and it requires careful planning. The process requires numerous steps, such as informing your staff, notifying your patients, closing accounts with your vendors and suppliers, storing medical records, and following applicable federal and state laws for dissolving your practice.^1,2 Many of these steps may require consulting with an attorney, an accountant, and your malpractice insurance carrier.^1,2 Although the recommendations I provide in this article are not exhaustive, when faced with closing your practice, be sure to consider the following factors.

Notify staff and patients.

Select a date to close your practice that will allow you to stop taking new patients, provides adequate leeway for your staff to find new employment and for you to hire temporary staff if needed, ensures you meet your obligations to your staff, such as payroll, and gives you time to set up appropriate continuity of care for your patients. In addition to verbally notifying your patients of your practice’s closing, inform them in writing (whether hand-delivered or via certified mail with return receipt) of the date of the practice’s closure, reason for the closure, cancellation of scheduled appointments after the closure date, referral options, and how they can obtain a copy of their medical records.^1,2 Make sure your patients have an adequate supply of their medications before the closure.

Notify other parties.

Inform all suppliers, vendors, contracted service providers, insurance broker(s) for your practice, and payers (including Medicare and Medicaid, if applicable) of your intent to close your practice.^1,2 Provide payers with a forwarding address to send payments that resolve after your practice closes, and request final invoices from vendors and suppliers so you can close your accounts with them. If you don’t own the building in which your practice is located, notify the building management in accordance with the provisions of your lease.^1,2 Give cancellation notices to utilities and ancillary services (eg, labs, imaging facilities) to which you refer your patients, and notify facilities where you are credentialed and have admitting privileges.^1,2 Inform your state medical licensing board, your state’s controlled substance division, and the Drug Enforcement Administration, because these agencies have requirements regarding changing the status of your medical license (if you decide to retire), continuing or surrendering your state and federal controlled substance registration, and disposal of prescription medications and prescription pads.^1,2 Contact your local post office and delivery services with your change of address.

Address other considerations.

Set up a medical record retention and destruction plan in accordance with state and federal regulations, arrange for the safe storage for both paper and electronic medical records, and make sure storage facilities have experience handling confidential, Health Insurance Portability and Accountability Act (HIPAA)-sensitive patient information.^1,2 In addition, establish a process for permanently deleting all HIPAA-sensitive patient information from any equipment that you don’t intend to keep.^1,2