Henry A. Nasrallah, MD

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

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

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

Psilocybin’s therapeutic effects

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

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

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

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

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

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

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

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

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

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

Psilocybin’s therapeutic effects

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

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

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

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

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

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

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

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

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

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

Psilocybin’s therapeutic effects

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

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

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

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

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

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

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

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Schizophrenia is arguably the most serious psychiatric brain syndrome. It disables teens and young adults and robs them of their potential and life dreams. It is widely regarded as a hopeless illness.

But it does not have to be. The reason most patients with schizophrenia do not return to their baseline is because obsolete clinical management approaches, a carryover from the last century, continue to be used.

Approximately 20 years ago, psychiatric researchers made a major discovery: psychosis is a neurotoxic state, and each psychotic episode is associated with significant brain damage in both gray and white matter.¹ Based on that discovery, a more rational management of schizophrenia has emerged, focused on protecting patients from experiencing psychotic recurrence after the first-episode psychosis (FEP). In the past century, this strategy did not exist because psychiatrists were in a state of scientific ignorance, completely unaware that the malignant component of schizophrenia that leads to disability is psychotic relapses, the primary cause of which is very poor medication adherence after hospital discharge following the FEP.

Based on the emerging scientific evidence, here are 3 essential principles to halt the deterioration and bend the curve of outcomes in schizophrenia:

1. Minimize the duration of untreated psychosis (DUP)

Numerous studies have shown that the longer the DUP, the worse the outcome in schizophrenia.^2,3 It is therefore vital to shorten the DUP spanning the emergence of psychotic symptoms at home, prior to the first hospital admission.⁴ The DUP is often prolonged from weeks to months by a combination of anosognosia by the patient, who fails to recognize how pathological their hallucinations and delusions are, plus the stigma of mental illness, which leads parents to delay bringing their son or daughter for psychiatric evaluation and treatment.

Another reason for a prolonged DUP is the legal system’s governing of the initiation of antipsychotic medications for an acutely psychotic patient who does not believe he/she is sick, and who adamantly refuses to receive medications. Laws passed decades ago have not kept up with scientific advances about brain damage during the DUP. Instead of delegating the rapid administration of an antipsychotic medication to the psychiatric physician who evaluated and diagnosed a patient with acute psychosis, the legal system further prolongs the DUP by requiring the psychiatrist to go to court and have a judge order the administration of antipsychotic medications. Such a legal requirement that delays urgently needed treatment has never been imposed on neurologists when administering medication to an obtunded stroke patient. Yet psychosis damages brain tissue and must be treated as urgently as stroke.⁵

Perhaps the most common reason for a long DUP is the recurrent relapses of psychosis, almost always caused by the high nonadherence rate among patients with schizophrenia due to multiple factors related to the illness itself.⁶ Ensuring uninterrupted delivery of an antipsychotic to a patient’s brain is as important to maintaining remission in schizophrenia as uninterrupted insulin treatment is for an individual with diabetes. The only way to guarantee ongoing daily pharmacotherapy in schizophrenia and avoid a longer DUP and more brain damage is to use long-acting injectable (LAI) formulations of antipsychotic medications, which are infrequently used despite making eminent sense to protect patients from the tragic consequences of psychotic relapse.⁷

Continue to: Start very early use of LAIs

2. Start very early use of LAIs

There is no doubt that switching from an oral to an LAI antipsychotic immediately after hospital discharge for the FEP is the single most important medical decision psychiatrists can make for patients with schizophrenia.⁸ This is because disability in schizophrenia begins after the second episode, not the first.^9-11 Therefore, psychiatrists must behave like cardiologists,¹² who strive to prevent a second destructive myocardial infarction. Regrettably, 99.9% of psychiatric practitioners never start an LAI after the FEP, and usually wait until the patient experiences multiple relapses, after extensive gray matter atrophy and white matter disintegration have occurred due to the neuro­inflammation and oxidative stress (free radicals) that occur with every psychotic episode.^13,14 This clearly does not make clinical sense, but remains the standard current practice.

In oncology, chemotherapy is far more effective in Stage 1 cancer, immediately after the diagnosis is made, rather than in Stage 4, when the prognosis is very poor. Similarly, LAIs are best used in Stage 1 schizophrenia, which is the first episode (schizophrenia researchers now regard the illness as having stages).¹⁵ Unfortunately, it is now rare for patients with schizophrenia to be switched to LAI pharmacotherapy right after recovery from the FEP. Instead, LAIs are more commonly used in Stage 3 or Stage 4, when the brains of patients with chronic schizophrenia have been already structurally damaged, and functional disability had set in. Bending the cure of outcome in schizophrenia is only possible when LAIs are used very early to prevent the second episode.

The prevention of relapse by using LAIs in FEP is truly remarkable. Subotnik et al¹⁶ reported that only 5% of FEP patients who received an LAI antipsychotic relapsed, compared to 33% of those who received an oral formulation of the same antipsychotic (a 650% difference). It is frankly inexplicable why psychiatrists do not exploit the relapse-preventing properties of LAIs at the time of discharge after the FEP, and instead continue to perpetuate the use of prescribing oral tablets to patients who are incapable of full adherence and doomed to “self-destruct.” This was the practice model in the previous century, when there was total ignorance about the brain-damaging effects of psychosis, and no sense of urgency about preventing psychotic relapses and DUP. Psychiatrists regarded LAIs as a last resort instead of a life-saving first resort.

In addition to relapse prevention,¹⁷ the benefits of second-generation LAIs include neuroprotection¹⁸ and lower all-cause mortality,¹⁹ a remarkable triad of benefits for patients with schizophrenia.²⁰

3. Implement comprehensive psychosocial treatment

Most patients with schizophrenia do not have access to the array of psychosocial treatments that have been shown to be vital for rehabilitation following the FEP, just as physical rehabilitation is indispensable after the first stroke. Studies such as RAISE,²¹ which was funded by the National Institute of Mental Health, have demonstrated the value of psychosocial therapies (Table^21-23). Collaborative care with primary care physicians is also essential due to the high prevalence of metabolic disorders (obesity, diabetics, dyslipidemia, hypertension), which tend to be undertreated in patients with schizophrenia.²⁴

Finally, when patients continue to experience delusions and hallucinations despite full adherence (with LAIs), clozapine must be used. Like LAIs, clozapine is woefully under­utilized²⁵ despite having been shown to restore mental health and full recovery to many (but not all) patients written off as hopeless due to persistent and refractory psychotic symptoms.²⁶

If clinicians who treat schizophrenia implement these 3 steps in their FEP patients, they will be gratified to witness a more benign trajectory of schizophrenia, which I have personally seen. The curve can indeed be bent in favor of better outcomes. By using the 3 evidence-based steps described here, clinicians will realize that schizophrenia does not have to carry the label of “the worst disease affecting mankind,” as an editorial in a top-tier journal pessimistically stated over 3 decades ago.²⁷

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

As a regular viewer of Jeopardy! I find it both interesting and educational. But the psychiatric neuroscientist in me marvels at the splendid cerebral attributes embedded in the brains of Jeopardy! champions.

Back in my college days, I participated in what were then called “general knowledge contests” and won a couple of trophies, the most gratifying of which was when our team of medical students beat the faculty team! Later, when my wife and I had children, Trivial Pursuit was a game frequently played in our household. So it is no wonder I have often thought of the remarkable, sometimes stunning intellectual performances of Jeopardy! champions.

What does it take to excel at Jeopardy!?

Watching contestants successfully answer a bewildering array of questions across an extensive spectrum of topics is simply dazzling and prompts me to ask: Which neurologic structures play a central role in the brains of Jeopardy! champions? So I channeled my inner neurobiologist and came up with the following prerequisites to excel at Jeopardy!:

• A hippocampus on steroids! Memory is obviously a core ingredient for responding to Jeopardy! questions. Unlike ordinary mortals, Jeopardy! champions appear to retain and instantaneously, accurately recall everything they have read, saw, or heard.
• A sublime network of dendritic spines, where learning is immediately transduced to biological memories, thanks to the wonders of experiential neuroplasticity in homo sapiens.
• A superlative frontal lobe, which provides the champion with an ultra-rapid abstraction ability in the dorsolateral prefrontal cortex, along with razor-sharp concentration and attention.
• An extremely well-myelinated network of the 137,000 miles of white mat­ter fibers in the human brain. This is what leads to fabulous processing speed. Rapid neurotransmission is impossible without very well-myelinated axons and dendrites. It is not enough for a Jeopardy! champion to know the answer and retrieve it from the hippocampus—they also must transmit the answer at lightning speed to the speech area, and then activate the motor area to enunciate the answer. Processing speed is the foundation of overall cognitive functioning.
• A first-rate Broca’s area, referred to as “the brain’s scriptwriter,” which shapes human speech. It receives the flow of sensory information from the temporal cortex, devises a plan for speaking, and passes that plan seamlessly to the motor cortex, which controls the movements of the mouth.
• Blistering speed reflexes to click the handheld response buzzer within a fraction of a millisecond after the host finishes reading the clue (not before, or a penalty is incurred). Jeopardy! champions always click the buzzer faster than their competitors, who may know the answer but have ordinary motor reflexes (also related to the degree of myelination and a motoric component of processing speed).
• A thick corpus callosum, the largest interhemispheric commissure, a bundle of 200 million white matter fibers connecting analogous regions in the right and left hemispheres, is vital for the rapid bidirectional transfer of bits of information from the intuitive/nonverbal right hemisphere to the mathematical/verbal left hemisphere, when the answer requires right hemispheric input.
• A bright occipital cortex and exceptional optic nerve and retina, so that champions can recognize faces or locations and read the questions before the host finishes reading them, which gives them an awesome edge on other contestants.

Obviously, the brains of Jeopardy! champions are a breed of their own, with exceptional performances by multiple regions converging to produce a winning performance. But during their childhood and youthful years, such brains also generate motivation, curiosity, and interest in a wide range of topics, from cultures, regions, music genres, and word games to history, geography, sports, science, medicine, astronomy, and Greek mythology.

Jeopardy! champions may appear to have regular jobs and ordinary lives, but they have resplendent “renaissance” brains. I wonder how they spent their childhood, who mentored them, what type of family lives they had, and what they dream of accomplishing other than winning on Jeopardy!. Will their awe-inspiring performance in Jeopardy! translate to overall success in life? That’s a story that remains to be told.

As a regular viewer of Jeopardy! I find it both interesting and educational. But the psychiatric neuroscientist in me marvels at the splendid cerebral attributes embedded in the brains of Jeopardy! champions.

Back in my college days, I participated in what were then called “general knowledge contests” and won a couple of trophies, the most gratifying of which was when our team of medical students beat the faculty team! Later, when my wife and I had children, Trivial Pursuit was a game frequently played in our household. So it is no wonder I have often thought of the remarkable, sometimes stunning intellectual performances of Jeopardy! champions.

What does it take to excel at Jeopardy!?

Watching contestants successfully answer a bewildering array of questions across an extensive spectrum of topics is simply dazzling and prompts me to ask: Which neurologic structures play a central role in the brains of Jeopardy! champions? So I channeled my inner neurobiologist and came up with the following prerequisites to excel at Jeopardy!:

• A hippocampus on steroids! Memory is obviously a core ingredient for responding to Jeopardy! questions. Unlike ordinary mortals, Jeopardy! champions appear to retain and instantaneously, accurately recall everything they have read, saw, or heard.
• A sublime network of dendritic spines, where learning is immediately transduced to biological memories, thanks to the wonders of experiential neuroplasticity in homo sapiens.
• A superlative frontal lobe, which provides the champion with an ultra-rapid abstraction ability in the dorsolateral prefrontal cortex, along with razor-sharp concentration and attention.
• An extremely well-myelinated network of the 137,000 miles of white mat­ter fibers in the human brain. This is what leads to fabulous processing speed. Rapid neurotransmission is impossible without very well-myelinated axons and dendrites. It is not enough for a Jeopardy! champion to know the answer and retrieve it from the hippocampus—they also must transmit the answer at lightning speed to the speech area, and then activate the motor area to enunciate the answer. Processing speed is the foundation of overall cognitive functioning.
• A first-rate Broca’s area, referred to as “the brain’s scriptwriter,” which shapes human speech. It receives the flow of sensory information from the temporal cortex, devises a plan for speaking, and passes that plan seamlessly to the motor cortex, which controls the movements of the mouth.
• Blistering speed reflexes to click the handheld response buzzer within a fraction of a millisecond after the host finishes reading the clue (not before, or a penalty is incurred). Jeopardy! champions always click the buzzer faster than their competitors, who may know the answer but have ordinary motor reflexes (also related to the degree of myelination and a motoric component of processing speed).
• A thick corpus callosum, the largest interhemispheric commissure, a bundle of 200 million white matter fibers connecting analogous regions in the right and left hemispheres, is vital for the rapid bidirectional transfer of bits of information from the intuitive/nonverbal right hemisphere to the mathematical/verbal left hemisphere, when the answer requires right hemispheric input.
• A bright occipital cortex and exceptional optic nerve and retina, so that champions can recognize faces or locations and read the questions before the host finishes reading them, which gives them an awesome edge on other contestants.

Obviously, the brains of Jeopardy! champions are a breed of their own, with exceptional performances by multiple regions converging to produce a winning performance. But during their childhood and youthful years, such brains also generate motivation, curiosity, and interest in a wide range of topics, from cultures, regions, music genres, and word games to history, geography, sports, science, medicine, astronomy, and Greek mythology.

Jeopardy! champions may appear to have regular jobs and ordinary lives, but they have resplendent “renaissance” brains. I wonder how they spent their childhood, who mentored them, what type of family lives they had, and what they dream of accomplishing other than winning on Jeopardy!. Will their awe-inspiring performance in Jeopardy! translate to overall success in life? That’s a story that remains to be told.

As a regular viewer of Jeopardy! I find it both interesting and educational. But the psychiatric neuroscientist in me marvels at the splendid cerebral attributes embedded in the brains of Jeopardy! champions.

Back in my college days, I participated in what were then called “general knowledge contests” and won a couple of trophies, the most gratifying of which was when our team of medical students beat the faculty team! Later, when my wife and I had children, Trivial Pursuit was a game frequently played in our household. So it is no wonder I have often thought of the remarkable, sometimes stunning intellectual performances of Jeopardy! champions.

What does it take to excel at Jeopardy!?

Watching contestants successfully answer a bewildering array of questions across an extensive spectrum of topics is simply dazzling and prompts me to ask: Which neurologic structures play a central role in the brains of Jeopardy! champions? So I channeled my inner neurobiologist and came up with the following prerequisites to excel at Jeopardy!:

• A hippocampus on steroids! Memory is obviously a core ingredient for responding to Jeopardy! questions. Unlike ordinary mortals, Jeopardy! champions appear to retain and instantaneously, accurately recall everything they have read, saw, or heard.
• A sublime network of dendritic spines, where learning is immediately transduced to biological memories, thanks to the wonders of experiential neuroplasticity in homo sapiens.
• A superlative frontal lobe, which provides the champion with an ultra-rapid abstraction ability in the dorsolateral prefrontal cortex, along with razor-sharp concentration and attention.
• An extremely well-myelinated network of the 137,000 miles of white mat­ter fibers in the human brain. This is what leads to fabulous processing speed. Rapid neurotransmission is impossible without very well-myelinated axons and dendrites. It is not enough for a Jeopardy! champion to know the answer and retrieve it from the hippocampus—they also must transmit the answer at lightning speed to the speech area, and then activate the motor area to enunciate the answer. Processing speed is the foundation of overall cognitive functioning.
• A first-rate Broca’s area, referred to as “the brain’s scriptwriter,” which shapes human speech. It receives the flow of sensory information from the temporal cortex, devises a plan for speaking, and passes that plan seamlessly to the motor cortex, which controls the movements of the mouth.
• Blistering speed reflexes to click the handheld response buzzer within a fraction of a millisecond after the host finishes reading the clue (not before, or a penalty is incurred). Jeopardy! champions always click the buzzer faster than their competitors, who may know the answer but have ordinary motor reflexes (also related to the degree of myelination and a motoric component of processing speed).
• A thick corpus callosum, the largest interhemispheric commissure, a bundle of 200 million white matter fibers connecting analogous regions in the right and left hemispheres, is vital for the rapid bidirectional transfer of bits of information from the intuitive/nonverbal right hemisphere to the mathematical/verbal left hemisphere, when the answer requires right hemispheric input.
• A bright occipital cortex and exceptional optic nerve and retina, so that champions can recognize faces or locations and read the questions before the host finishes reading them, which gives them an awesome edge on other contestants.

Obviously, the brains of Jeopardy! champions are a breed of their own, with exceptional performances by multiple regions converging to produce a winning performance. But during their childhood and youthful years, such brains also generate motivation, curiosity, and interest in a wide range of topics, from cultures, regions, music genres, and word games to history, geography, sports, science, medicine, astronomy, and Greek mythology.

Jeopardy! champions may appear to have regular jobs and ordinary lives, but they have resplendent “renaissance” brains. I wonder how they spent their childhood, who mentored them, what type of family lives they had, and what they dream of accomplishing other than winning on Jeopardy!. Will their awe-inspiring performance in Jeopardy! translate to overall success in life? That’s a story that remains to be told.

Evidence is strong that sexual partners transmit microbiota (bacteria, viruses, fungi, protozoa, and archaea) to each other. While microbial flora are abundant in the gastrointestinal tract, they are also present in the vagina, penis, urethra, mouth, and skin.¹ For better or worse, sexual contact of all types means that participants will acquire each other’s microbiota.

The 39 trillion microbiota in the body (which exceed the 30 trillion cells in the body) are commensal and influence both the larger brain in the skull and the smaller enteric brain in the gut. The microbiota and their microbiome genes (1,000 times larger than the human genome) have been linked to depression, anxiety, psychosis, and autism.^2-4 They produce 90% of the body’s serotonin, as well as catecholamines (norepinephrine, epinephrine, dopamine), make hormones (eg, cortisol), and modulate the immune system. Microbiota have several important functions, including food digestion, synthesis of vitamins, autoimmunity, hypothalamic-pituitary-adrenal axis regulation, and CNS modulation.

Consequences of dysbiosis

Everyone should be concerned about maintaining a healthy diversity of microbiota in their body, with a predominance of beneficial bacteria such as Lactobacillus and Bacteroides, and avoiding acquiring pathogenic bacteria such as Gardnerella, Prevotella, and Atopobium. Sexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis, defined as a reduction in microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria.

Dysbiosis is associated with multiple symptoms, including⁵:

• brain “fog,” irritability, mood changes, and anxiety
• bloating, loss of intestinal permeability, and insufficient reclamation of nutrients
• congestion of certain organs, such as the liver, gallbladder, and pancreas
• production of antigen-antibody complexes in response to chemicals in partially digested food
• aggravation of inflammatory disorders such as migraine, arthritis, and autoimmune disorders.

Apart from intimate sexual contact, simply sharing a household with someone leads to sharing of gut microflora. Persons who live together, whether genetically related or not, have similar microbiota. Compared with people living in separate households, cohabiting human pairs, dog pairs, and human-dog pairs share most of their microbiota (especially in the skin).

A consequence of acquiring pathogenic microbiota in the vagina is bacterial vaginosis (BV), which is not an infection but an ecologic imbalance in the composition of the vaginal microbiota. BV is caused by a significant decline in the beneficial vaginal Lactobacillus and a marked increase in the non-Lactobacillus taxa (especially Gardnerella and Atopobium).⁶ It can last for a least 1 week after sexual intercourse. BV is rare or absent among virgins. For a male partner, penile microbiota changes significantly after unprotected sex.⁶

Pathogenic bacteria can be cultivated from the glans, the coronal sulcus, and the prepuce, as well as from the penile skin, semen, urethra, and urine.⁶ Diverse bacteria exist in human semen, regardless if the male is fertile or infertile.⁷Anaerococcus is a biomarker for low sperm quality. Many of the semen bacteria are also found in the vagina of women with BV.⁷ Semen is a medium for the transmission of bacteria and viruses between men and women, and can contribute to sexually transmitted diseases.⁸

There are approximately 21 million cases of BV in the United States each year, and BV can also increase the risk of HIV and poor obstetric outcomes.⁹ The microbiota in the penile skin and urethra in males who have monogamous relationships with females are very similar to the vaginal microbiota of their female partner.

Consequences of BV include:

• decrease in hydrogen peroxide–producing bacilli
• prevalence of anaerobic bacteria (Prevotella, Gardnerella, and Atopobium)
• alkalinization, fishy odor, and gray-white vaginal discharge
• increase in the rate of pelvic inflammatory disease, ectopic pregnancy, endometriosis, preterm birth, and tubal factor infertility.⁹

Circumcision decreases the risk of BV. There is an increased rate of BV bacterial taxa in men with extramarital affairs and in women with multiple partners. Both oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiota. Gingivitis has also been reported after oral sex.¹⁰

A link to psychiatric disorders

Given that all forms of sexual contact (vaginal, oral, anal, or skin) can transmit microbiota bidirectionally between partners, it is vital to practice safe sex and consider a monogamous relationship rather than indiscriminate promiscuity. Unfortunately, certain psychiatric disorders, such as bipolar disorder, are associated with hypersexuality and multiple partners, which may disrupt the microbiota. This can further disrupt the diversity of an individual’s microbiome and may put them at risk for mood, anxiety, and other psychiatric disorders. Another problem is sexually transmitted infections such as gonorrhea or syphilis require antibiotic therapy. It is well established that antibiotics kill both the bad pathogenic and the good nonpathogenic microbiota, further exacerbating dysbiosis and leading to disruptions in the microbiota-gut-brain (MGB) axis, which then results in psychiatric disorders.

The MGB axis modulates neurological processes via the vagus nerve, the major “highway” connecting the gut and brain for bidirectional traffic. The MGB axis produces microbial metabolites and immune factors that can lead to changes in brain neurotransmitters as well as neuroinflammation and psychiatric symptoms such as depression and anxiety.⁵

Many researchers are focusing on how to exploit the microbiome to develop novel therapeutic strategies, and encouraging advances are emerging.⁵ But the exact mechanisms by which the gut microbiome can impact mental health is still a work in progress. It is highly likely that dysbiosis is associated with mood and anxiety symptoms.

The bottom line: Sexual activity—whether it is heavy kissing, vaginal intercourse, oral sex, anal sex, or extensive skin contact—can lead to the exchange of microbiota. If an individual has dysbiosis, that could impact the mental health of their sexual partner(s). This raises the question of whether counseling patients about avoiding indiscriminate sex and practicing safe sex is as important for mental health as diet and exercise counseling is for physical health.

Evidence is strong that sexual partners transmit microbiota (bacteria, viruses, fungi, protozoa, and archaea) to each other. While microbial flora are abundant in the gastrointestinal tract, they are also present in the vagina, penis, urethra, mouth, and skin.¹ For better or worse, sexual contact of all types means that participants will acquire each other’s microbiota.

The 39 trillion microbiota in the body (which exceed the 30 trillion cells in the body) are commensal and influence both the larger brain in the skull and the smaller enteric brain in the gut. The microbiota and their microbiome genes (1,000 times larger than the human genome) have been linked to depression, anxiety, psychosis, and autism.^2-4 They produce 90% of the body’s serotonin, as well as catecholamines (norepinephrine, epinephrine, dopamine), make hormones (eg, cortisol), and modulate the immune system. Microbiota have several important functions, including food digestion, synthesis of vitamins, autoimmunity, hypothalamic-pituitary-adrenal axis regulation, and CNS modulation.

Consequences of dysbiosis

Everyone should be concerned about maintaining a healthy diversity of microbiota in their body, with a predominance of beneficial bacteria such as Lactobacillus and Bacteroides, and avoiding acquiring pathogenic bacteria such as Gardnerella, Prevotella, and Atopobium. Sexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis, defined as a reduction in microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria.

Dysbiosis is associated with multiple symptoms, including⁵:

• brain “fog,” irritability, mood changes, and anxiety
• bloating, loss of intestinal permeability, and insufficient reclamation of nutrients
• congestion of certain organs, such as the liver, gallbladder, and pancreas
• production of antigen-antibody complexes in response to chemicals in partially digested food
• aggravation of inflammatory disorders such as migraine, arthritis, and autoimmune disorders.

Apart from intimate sexual contact, simply sharing a household with someone leads to sharing of gut microflora. Persons who live together, whether genetically related or not, have similar microbiota. Compared with people living in separate households, cohabiting human pairs, dog pairs, and human-dog pairs share most of their microbiota (especially in the skin).

A consequence of acquiring pathogenic microbiota in the vagina is bacterial vaginosis (BV), which is not an infection but an ecologic imbalance in the composition of the vaginal microbiota. BV is caused by a significant decline in the beneficial vaginal Lactobacillus and a marked increase in the non-Lactobacillus taxa (especially Gardnerella and Atopobium).⁶ It can last for a least 1 week after sexual intercourse. BV is rare or absent among virgins. For a male partner, penile microbiota changes significantly after unprotected sex.⁶

Pathogenic bacteria can be cultivated from the glans, the coronal sulcus, and the prepuce, as well as from the penile skin, semen, urethra, and urine.⁶ Diverse bacteria exist in human semen, regardless if the male is fertile or infertile.⁷Anaerococcus is a biomarker for low sperm quality. Many of the semen bacteria are also found in the vagina of women with BV.⁷ Semen is a medium for the transmission of bacteria and viruses between men and women, and can contribute to sexually transmitted diseases.⁸

There are approximately 21 million cases of BV in the United States each year, and BV can also increase the risk of HIV and poor obstetric outcomes.⁹ The microbiota in the penile skin and urethra in males who have monogamous relationships with females are very similar to the vaginal microbiota of their female partner.

Consequences of BV include:

• decrease in hydrogen peroxide–producing bacilli
• prevalence of anaerobic bacteria (Prevotella, Gardnerella, and Atopobium)
• alkalinization, fishy odor, and gray-white vaginal discharge
• increase in the rate of pelvic inflammatory disease, ectopic pregnancy, endometriosis, preterm birth, and tubal factor infertility.⁹

Circumcision decreases the risk of BV. There is an increased rate of BV bacterial taxa in men with extramarital affairs and in women with multiple partners. Both oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiota. Gingivitis has also been reported after oral sex.¹⁰

A link to psychiatric disorders

Given that all forms of sexual contact (vaginal, oral, anal, or skin) can transmit microbiota bidirectionally between partners, it is vital to practice safe sex and consider a monogamous relationship rather than indiscriminate promiscuity. Unfortunately, certain psychiatric disorders, such as bipolar disorder, are associated with hypersexuality and multiple partners, which may disrupt the microbiota. This can further disrupt the diversity of an individual’s microbiome and may put them at risk for mood, anxiety, and other psychiatric disorders. Another problem is sexually transmitted infections such as gonorrhea or syphilis require antibiotic therapy. It is well established that antibiotics kill both the bad pathogenic and the good nonpathogenic microbiota, further exacerbating dysbiosis and leading to disruptions in the microbiota-gut-brain (MGB) axis, which then results in psychiatric disorders.

The MGB axis modulates neurological processes via the vagus nerve, the major “highway” connecting the gut and brain for bidirectional traffic. The MGB axis produces microbial metabolites and immune factors that can lead to changes in brain neurotransmitters as well as neuroinflammation and psychiatric symptoms such as depression and anxiety.⁵

Many researchers are focusing on how to exploit the microbiome to develop novel therapeutic strategies, and encouraging advances are emerging.⁵ But the exact mechanisms by which the gut microbiome can impact mental health is still a work in progress. It is highly likely that dysbiosis is associated with mood and anxiety symptoms.

The bottom line: Sexual activity—whether it is heavy kissing, vaginal intercourse, oral sex, anal sex, or extensive skin contact—can lead to the exchange of microbiota. If an individual has dysbiosis, that could impact the mental health of their sexual partner(s). This raises the question of whether counseling patients about avoiding indiscriminate sex and practicing safe sex is as important for mental health as diet and exercise counseling is for physical health.

Evidence is strong that sexual partners transmit microbiota (bacteria, viruses, fungi, protozoa, and archaea) to each other. While microbial flora are abundant in the gastrointestinal tract, they are also present in the vagina, penis, urethra, mouth, and skin.¹ For better or worse, sexual contact of all types means that participants will acquire each other’s microbiota.

The 39 trillion microbiota in the body (which exceed the 30 trillion cells in the body) are commensal and influence both the larger brain in the skull and the smaller enteric brain in the gut. The microbiota and their microbiome genes (1,000 times larger than the human genome) have been linked to depression, anxiety, psychosis, and autism.^2-4 They produce 90% of the body’s serotonin, as well as catecholamines (norepinephrine, epinephrine, dopamine), make hormones (eg, cortisol), and modulate the immune system. Microbiota have several important functions, including food digestion, synthesis of vitamins, autoimmunity, hypothalamic-pituitary-adrenal axis regulation, and CNS modulation.

Consequences of dysbiosis

Everyone should be concerned about maintaining a healthy diversity of microbiota in their body, with a predominance of beneficial bacteria such as Lactobacillus and Bacteroides, and avoiding acquiring pathogenic bacteria such as Gardnerella, Prevotella, and Atopobium. Sexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis, defined as a reduction in microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria.

Dysbiosis is associated with multiple symptoms, including⁵:

• brain “fog,” irritability, mood changes, and anxiety
• bloating, loss of intestinal permeability, and insufficient reclamation of nutrients
• congestion of certain organs, such as the liver, gallbladder, and pancreas
• production of antigen-antibody complexes in response to chemicals in partially digested food
• aggravation of inflammatory disorders such as migraine, arthritis, and autoimmune disorders.

Apart from intimate sexual contact, simply sharing a household with someone leads to sharing of gut microflora. Persons who live together, whether genetically related or not, have similar microbiota. Compared with people living in separate households, cohabiting human pairs, dog pairs, and human-dog pairs share most of their microbiota (especially in the skin).

A consequence of acquiring pathogenic microbiota in the vagina is bacterial vaginosis (BV), which is not an infection but an ecologic imbalance in the composition of the vaginal microbiota. BV is caused by a significant decline in the beneficial vaginal Lactobacillus and a marked increase in the non-Lactobacillus taxa (especially Gardnerella and Atopobium).⁶ It can last for a least 1 week after sexual intercourse. BV is rare or absent among virgins. For a male partner, penile microbiota changes significantly after unprotected sex.⁶

Pathogenic bacteria can be cultivated from the glans, the coronal sulcus, and the prepuce, as well as from the penile skin, semen, urethra, and urine.⁶ Diverse bacteria exist in human semen, regardless if the male is fertile or infertile.⁷Anaerococcus is a biomarker for low sperm quality. Many of the semen bacteria are also found in the vagina of women with BV.⁷ Semen is a medium for the transmission of bacteria and viruses between men and women, and can contribute to sexually transmitted diseases.⁸

There are approximately 21 million cases of BV in the United States each year, and BV can also increase the risk of HIV and poor obstetric outcomes.⁹ The microbiota in the penile skin and urethra in males who have monogamous relationships with females are very similar to the vaginal microbiota of their female partner.

Consequences of BV include:

• decrease in hydrogen peroxide–producing bacilli
• prevalence of anaerobic bacteria (Prevotella, Gardnerella, and Atopobium)
• alkalinization, fishy odor, and gray-white vaginal discharge
• increase in the rate of pelvic inflammatory disease, ectopic pregnancy, endometriosis, preterm birth, and tubal factor infertility.⁹

Circumcision decreases the risk of BV. There is an increased rate of BV bacterial taxa in men with extramarital affairs and in women with multiple partners. Both oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiota. Gingivitis has also been reported after oral sex.¹⁰

A link to psychiatric disorders

Given that all forms of sexual contact (vaginal, oral, anal, or skin) can transmit microbiota bidirectionally between partners, it is vital to practice safe sex and consider a monogamous relationship rather than indiscriminate promiscuity. Unfortunately, certain psychiatric disorders, such as bipolar disorder, are associated with hypersexuality and multiple partners, which may disrupt the microbiota. This can further disrupt the diversity of an individual’s microbiome and may put them at risk for mood, anxiety, and other psychiatric disorders. Another problem is sexually transmitted infections such as gonorrhea or syphilis require antibiotic therapy. It is well established that antibiotics kill both the bad pathogenic and the good nonpathogenic microbiota, further exacerbating dysbiosis and leading to disruptions in the microbiota-gut-brain (MGB) axis, which then results in psychiatric disorders.

The MGB axis modulates neurological processes via the vagus nerve, the major “highway” connecting the gut and brain for bidirectional traffic. The MGB axis produces microbial metabolites and immune factors that can lead to changes in brain neurotransmitters as well as neuroinflammation and psychiatric symptoms such as depression and anxiety.⁵

Many researchers are focusing on how to exploit the microbiome to develop novel therapeutic strategies, and encouraging advances are emerging.⁵ But the exact mechanisms by which the gut microbiome can impact mental health is still a work in progress. It is highly likely that dysbiosis is associated with mood and anxiety symptoms.

The bottom line: Sexual activity—whether it is heavy kissing, vaginal intercourse, oral sex, anal sex, or extensive skin contact—can lead to the exchange of microbiota. If an individual has dysbiosis, that could impact the mental health of their sexual partner(s). This raises the question of whether counseling patients about avoiding indiscriminate sex and practicing safe sex is as important for mental health as diet and exercise counseling is for physical health.

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.”

“I believe that this nation should commit itself to achieving the goal, before the decade is out, of landing a man on the Moon and returning him safely to Earth.”

President John F. Kennedy, May 25, 1961

Despite significant progress, there remain many unmet needs in psychiatry. These include a granular understanding of the neurobiology of various psychopathologies, an objective and valid diagnostic schema, and disease-modifying treatments for chronic and disabling psychiatric disorders. Several moonshots are needed to address those festering needs.

A “moonshot” is an extremely ambitious, dramatic, imaginative, and inspiring goal. Landing on the Moon was generally believed to be impossible when President Kennedy boldly set that as a goal for the United States in 1961. Yet, 8 short years later, on July 20, 1969, Neil Armstrong stepped off the lunar module ladder onto the Moon’s surface, a feat that captured the imagination of the nation and the world. I distinctly remember watching it on television with amazement as a young boy. It was a surreal experience. That’s what achieving a moonshot feels like.

Successful organizations should always have 1 or more moonshots (American Psychiatric Association and National Institute of Mental Health [NIMH], are you listening?). Setting lofty goals that require monumental determination and effort to accomplish will have a transformative, long-lasting impact. The construction of the Panama Canal to connect 2 oceans and the Manhattan Project to develop the first nuclear bomb, which ended World War II, are examples of moonshots that continue to reverberate. A more recent moonshot is the driverless car, which in the past was a laughable idea but is now a reality that will change society and the world in many ways. Innovative billionaire moguls now speak loudly about colonizing Mars, which sounds improbable and highly risky, but it’s a moonshot that may be achieved within a few years. Establishing world peace is a moonshot that requires collective Kennedy-esque vision and motivation among world leaders, which currently is sadly lacking.

So, for contemporary psychiatry, what is the equivalent of landing on the Moon? Here is the list that pops in my brain’s mind (let us know which of these would be your top 3 moonshots by taking our survey at https://bit.ly/3qkKqTa):

• A cure for schizophrenia (across positive, negative, and cognitive symptom domains)
• A cure for mood disorders, unipolar and bipolar (including suicide)
• A cure for anxiety disorders
• A cure for obsessive-compulsive disorder
• A cure for posttraumatic stress disorder
• A cure for alcoholism/addiction
• A cure for autism
• A cure for Alzheimer’s disease and other dementias
• A cure for personality disorders, especially antisocial and borderline
• A cure for the visceral hatred across political parties that permeates our society (obviously not a psychiatric category, but perhaps it should be added to DSM because it is so destructive).

Those moonshots may be regarded as absurd, and totally unachievable, but so was landing on the Moon, until it was accomplished. Psychiatry must stop thinking small and being content with tiny advances (which is like changing the chairs to more comfortable sofas on the deck of the Titanic and calling it “progress…”). Psychiatry needs to be unified under the flag of “moonshot thinking” by several visionary and transformative leaders to start believing in a miraculously better future for our patients. But to pave the way for moonshots in psychiatry, the leading organizations must collaborate closely to open the door for unprecedented scientific and medical breakthroughs of a moonshot by:

1. Lobbying effectively to secure massive funding for research from federal, state, corporate, and foundation sources (perhaps convincing the Gates Foundation that schizophrenia is as devastating worldwide as malaria may bring a few badly needed billions into psychiatric brain research).
2. Reminding members of Congress that in the United States, costs associated with psychiatric brain disorders total an estimated $700 billion annually,¹ and that this must be addressed by boosting the meager NIMH budget by at least an order of magnitude. The NIMH should disproportionately invest its resources on severe brain disorders such as schizophrenia because breakthrough advances in its neurobiology will provide unprecedented insights to the pathophysiology of other severe psychiatric brain disorders.
3. Partnering intimately with the pharmaceutical industry in a powerful public-private coalition to exploit the extensive research infrastructure of this industry.
4. Creating the necessary army of researchers (physician-scientists) by providing huge incentives to medical students and psychiatric residents to pursue careers in neuroscience research. Incentives can include paying for an individual’s entire medical education and research training, and providing generous salaries that match or exceed the income of a very successful clinical practice.
5. Convincing all psychiatric clinicians to support research by referring patients to research projects. Clinical psychiatrists are badly needed to care for the population, but they must be reminded that every treatment they are using today was a research project in the past, and that the research of today will evolve into the treatments (or cures) of tomorrow.

Pursuing lofty moonshots via innovative research is very likely to enhance serendipity and lead to unexpected discoveries along the way. As Louis Pasteur said, “chance only favors the prepared mind.”² Moonshot thinking in psychiatry today is more feasible than ever before because of the many advances in research methods (neuroimaging, pluripotent cells, optogenetics, CRISPR, etc) and complex data management technologies (big data, machine learning, artificial intelligence), each of which qualifies as a preparatory moonshot in its own right.

Given the tragic consequences of psychiatric brain disorders, it is imperative that we “think big.” Humanity expects us to do that. We must envision the future of psychiatry as dramatically different from the present. Moonshot thinking is the indispensable vehicle to take us there.

“I believe that this nation should commit itself to achieving the goal, before the decade is out, of landing a man on the Moon and returning him safely to Earth.”

President John F. Kennedy, May 25, 1961

Despite significant progress, there remain many unmet needs in psychiatry. These include a granular understanding of the neurobiology of various psychopathologies, an objective and valid diagnostic schema, and disease-modifying treatments for chronic and disabling psychiatric disorders. Several moonshots are needed to address those festering needs.

A “moonshot” is an extremely ambitious, dramatic, imaginative, and inspiring goal. Landing on the Moon was generally believed to be impossible when President Kennedy boldly set that as a goal for the United States in 1961. Yet, 8 short years later, on July 20, 1969, Neil Armstrong stepped off the lunar module ladder onto the Moon’s surface, a feat that captured the imagination of the nation and the world. I distinctly remember watching it on television with amazement as a young boy. It was a surreal experience. That’s what achieving a moonshot feels like.

Successful organizations should always have 1 or more moonshots (American Psychiatric Association and National Institute of Mental Health [NIMH], are you listening?). Setting lofty goals that require monumental determination and effort to accomplish will have a transformative, long-lasting impact. The construction of the Panama Canal to connect 2 oceans and the Manhattan Project to develop the first nuclear bomb, which ended World War II, are examples of moonshots that continue to reverberate. A more recent moonshot is the driverless car, which in the past was a laughable idea but is now a reality that will change society and the world in many ways. Innovative billionaire moguls now speak loudly about colonizing Mars, which sounds improbable and highly risky, but it’s a moonshot that may be achieved within a few years. Establishing world peace is a moonshot that requires collective Kennedy-esque vision and motivation among world leaders, which currently is sadly lacking.

So, for contemporary psychiatry, what is the equivalent of landing on the Moon? Here is the list that pops in my brain’s mind (let us know which of these would be your top 3 moonshots by taking our survey at https://bit.ly/3qkKqTa):

• A cure for schizophrenia (across positive, negative, and cognitive symptom domains)
• A cure for mood disorders, unipolar and bipolar (including suicide)
• A cure for anxiety disorders
• A cure for obsessive-compulsive disorder
• A cure for posttraumatic stress disorder
• A cure for alcoholism/addiction
• A cure for autism
• A cure for Alzheimer’s disease and other dementias
• A cure for personality disorders, especially antisocial and borderline
• A cure for the visceral hatred across political parties that permeates our society (obviously not a psychiatric category, but perhaps it should be added to DSM because it is so destructive).

Those moonshots may be regarded as absurd, and totally unachievable, but so was landing on the Moon, until it was accomplished. Psychiatry must stop thinking small and being content with tiny advances (which is like changing the chairs to more comfortable sofas on the deck of the Titanic and calling it “progress…”). Psychiatry needs to be unified under the flag of “moonshot thinking” by several visionary and transformative leaders to start believing in a miraculously better future for our patients. But to pave the way for moonshots in psychiatry, the leading organizations must collaborate closely to open the door for unprecedented scientific and medical breakthroughs of a moonshot by:

1. Lobbying effectively to secure massive funding for research from federal, state, corporate, and foundation sources (perhaps convincing the Gates Foundation that schizophrenia is as devastating worldwide as malaria may bring a few badly needed billions into psychiatric brain research).
2. Reminding members of Congress that in the United States, costs associated with psychiatric brain disorders total an estimated $700 billion annually,¹ and that this must be addressed by boosting the meager NIMH budget by at least an order of magnitude. The NIMH should disproportionately invest its resources on severe brain disorders such as schizophrenia because breakthrough advances in its neurobiology will provide unprecedented insights to the pathophysiology of other severe psychiatric brain disorders.
3. Partnering intimately with the pharmaceutical industry in a powerful public-private coalition to exploit the extensive research infrastructure of this industry.
4. Creating the necessary army of researchers (physician-scientists) by providing huge incentives to medical students and psychiatric residents to pursue careers in neuroscience research. Incentives can include paying for an individual’s entire medical education and research training, and providing generous salaries that match or exceed the income of a very successful clinical practice.
5. Convincing all psychiatric clinicians to support research by referring patients to research projects. Clinical psychiatrists are badly needed to care for the population, but they must be reminded that every treatment they are using today was a research project in the past, and that the research of today will evolve into the treatments (or cures) of tomorrow.

Pursuing lofty moonshots via innovative research is very likely to enhance serendipity and lead to unexpected discoveries along the way. As Louis Pasteur said, “chance only favors the prepared mind.”² Moonshot thinking in psychiatry today is more feasible than ever before because of the many advances in research methods (neuroimaging, pluripotent cells, optogenetics, CRISPR, etc) and complex data management technologies (big data, machine learning, artificial intelligence), each of which qualifies as a preparatory moonshot in its own right.

Given the tragic consequences of psychiatric brain disorders, it is imperative that we “think big.” Humanity expects us to do that. We must envision the future of psychiatry as dramatically different from the present. Moonshot thinking is the indispensable vehicle to take us there.

“I believe that this nation should commit itself to achieving the goal, before the decade is out, of landing a man on the Moon and returning him safely to Earth.”

President John F. Kennedy, May 25, 1961

Despite significant progress, there remain many unmet needs in psychiatry. These include a granular understanding of the neurobiology of various psychopathologies, an objective and valid diagnostic schema, and disease-modifying treatments for chronic and disabling psychiatric disorders. Several moonshots are needed to address those festering needs.

A “moonshot” is an extremely ambitious, dramatic, imaginative, and inspiring goal. Landing on the Moon was generally believed to be impossible when President Kennedy boldly set that as a goal for the United States in 1961. Yet, 8 short years later, on July 20, 1969, Neil Armstrong stepped off the lunar module ladder onto the Moon’s surface, a feat that captured the imagination of the nation and the world. I distinctly remember watching it on television with amazement as a young boy. It was a surreal experience. That’s what achieving a moonshot feels like.

Successful organizations should always have 1 or more moonshots (American Psychiatric Association and National Institute of Mental Health [NIMH], are you listening?). Setting lofty goals that require monumental determination and effort to accomplish will have a transformative, long-lasting impact. The construction of the Panama Canal to connect 2 oceans and the Manhattan Project to develop the first nuclear bomb, which ended World War II, are examples of moonshots that continue to reverberate. A more recent moonshot is the driverless car, which in the past was a laughable idea but is now a reality that will change society and the world in many ways. Innovative billionaire moguls now speak loudly about colonizing Mars, which sounds improbable and highly risky, but it’s a moonshot that may be achieved within a few years. Establishing world peace is a moonshot that requires collective Kennedy-esque vision and motivation among world leaders, which currently is sadly lacking.

So, for contemporary psychiatry, what is the equivalent of landing on the Moon? Here is the list that pops in my brain’s mind (let us know which of these would be your top 3 moonshots by taking our survey at https://bit.ly/3qkKqTa):

• A cure for schizophrenia (across positive, negative, and cognitive symptom domains)
• A cure for mood disorders, unipolar and bipolar (including suicide)
• A cure for anxiety disorders
• A cure for obsessive-compulsive disorder
• A cure for posttraumatic stress disorder
• A cure for alcoholism/addiction
• A cure for autism
• A cure for Alzheimer’s disease and other dementias
• A cure for personality disorders, especially antisocial and borderline
• A cure for the visceral hatred across political parties that permeates our society (obviously not a psychiatric category, but perhaps it should be added to DSM because it is so destructive).

Those moonshots may be regarded as absurd, and totally unachievable, but so was landing on the Moon, until it was accomplished. Psychiatry must stop thinking small and being content with tiny advances (which is like changing the chairs to more comfortable sofas on the deck of the Titanic and calling it “progress…”). Psychiatry needs to be unified under the flag of “moonshot thinking” by several visionary and transformative leaders to start believing in a miraculously better future for our patients. But to pave the way for moonshots in psychiatry, the leading organizations must collaborate closely to open the door for unprecedented scientific and medical breakthroughs of a moonshot by:

1. Lobbying effectively to secure massive funding for research from federal, state, corporate, and foundation sources (perhaps convincing the Gates Foundation that schizophrenia is as devastating worldwide as malaria may bring a few badly needed billions into psychiatric brain research).
2. Reminding members of Congress that in the United States, costs associated with psychiatric brain disorders total an estimated $700 billion annually,¹ and that this must be addressed by boosting the meager NIMH budget by at least an order of magnitude. The NIMH should disproportionately invest its resources on severe brain disorders such as schizophrenia because breakthrough advances in its neurobiology will provide unprecedented insights to the pathophysiology of other severe psychiatric brain disorders.
3. Partnering intimately with the pharmaceutical industry in a powerful public-private coalition to exploit the extensive research infrastructure of this industry.
4. Creating the necessary army of researchers (physician-scientists) by providing huge incentives to medical students and psychiatric residents to pursue careers in neuroscience research. Incentives can include paying for an individual’s entire medical education and research training, and providing generous salaries that match or exceed the income of a very successful clinical practice.
5. Convincing all psychiatric clinicians to support research by referring patients to research projects. Clinical psychiatrists are badly needed to care for the population, but they must be reminded that every treatment they are using today was a research project in the past, and that the research of today will evolve into the treatments (or cures) of tomorrow.

Pursuing lofty moonshots via innovative research is very likely to enhance serendipity and lead to unexpected discoveries along the way. As Louis Pasteur said, “chance only favors the prepared mind.”² Moonshot thinking in psychiatry today is more feasible than ever before because of the many advances in research methods (neuroimaging, pluripotent cells, optogenetics, CRISPR, etc) and complex data management technologies (big data, machine learning, artificial intelligence), each of which qualifies as a preparatory moonshot in its own right.

Given the tragic consequences of psychiatric brain disorders, it is imperative that we “think big.” Humanity expects us to do that. We must envision the future of psychiatry as dramatically different from the present. Moonshot thinking is the indispensable vehicle to take us there.

Anosognosia is the lack of awareness of a disabling physical or mental illness. The term was coined by Joseph Babinski in 1914 following his observations that patients with left-side paralysis due to right hemisphere stroke do not recognize their hemiplegia and strongly deny that there is anything physically wrong with their body, or that they need treatment or rehabilitation.

Psychiatrists have long observed anosognosia in patients with acute psychoses such as schizophrenia or mania who vehemently deny that there is anything wrong with them, despite experiencing hallucinations, delusions, and/or bizarre behavior. They adamantly refuse medical care and often have to be involuntarily hospitalized to receive urgently needed medications they don’t believe they need.

So is anosognosia in schizophrenia a fixed false belief (delusion), a negative symptom, or a cognitive deficit? Arguments can be made for any of those 3 options, but the evidence suggests that anosognosia is a disorder of consciousness, a “meta-cognitive” deficit, or, as I referred to it in a previous publication, the loss of self-proprioception.¹

Anosognosia in neurologic brain disorders

Although right hemispheric stroke is the most common disease state associated with anosognosia,² other neurologic disorders can be associated with anosognosia, including Anton’s syndrome of cortical blindness,³ traumatic brain injury,⁴ Wernicke’s aphasia,⁵ mild cognitive impairment,⁶ and Alzheimer’s disease.⁷ In addition to anosognosia, those disorders can be accompanied by indifference to the deficit, which is referred to as “anosodiaphoria.”

The neuroanatomy of anosognosia generally implicates right hemisphere deficits, especially the frontal cortex, the right parietal lobe, the temporoparietal cortex, and the thalamus. It can be conceptualized as a disturbance of “body schema” because all motor and sensory functions of the body have a “representation” in brain structure.

Anosognosia in psychiatric brain disorders

Although schizophrenia is most frequently associated with anosognosia, other psychiatric disorders also exhibit this absence of insight. They include delusional disorder,⁸ bipolar disorder,⁹ intellectual disability,¹⁰ and personality disorders.¹¹ In all those psychiatric disorders, there is a lack of self-reflection (metacognition). At the neuroanatomical level, most studies have focused on schizophrenia, and abnormalities have been described in the frontal and parietal regions. Significant pathology in the inferior parietal lobe has been identified in schizophrenia.¹² However, the right insula, which is connected to multiple neural circuits,¹³ appears to be intimately associated with anosognosia when impaired. The insula also regulates interoception and a “sense of self.”¹⁴ The loss of cortical gray matter in schizophrenia is most pronounced in the insula bilaterally. Another neurologic mechanism associated with anosognosia in schizophrenia is the default mode network (DMN). The DMN, which usually is overactive at rest and is deactivated during a focused activity, is involved in both insight and social cognition.¹⁵

Measurement of anosognosia

Several rating scales are used to measure the severity of anosognosia and the loss of insight. They include:

• The Insight and Treatment Attitude Questionnaire¹⁶
• The Scale to Assess Unawareness of Mental Disorder¹⁷
• The Beck Cognitive Insight Scale,¹⁸ the only self-administered scale that measures a patient’s ability to evaluate their psychiatric beliefs and possibly modify them
• The Positive and Negative Syndrome Scale,¹⁹ which is the gold standard for measuring the overall severity of schizophrenia, has only 1 item related to insight within the 16-item General Subscale (G12: Lack of judgement and insight).

Continue to: Consequences of anosognosia...

Consequences of anosognosia

Patients with anosognosia neglect themselves both mentally and physically and fail to seek or accept medical attention. Thus, schizophrenia is associated with many serious and damaging consequences due to the lack of self-monitoring or appraising their health needs. The Table summarizes the multiple consequences of anosognosia.

Is anosognosia treatable or irreversible?

Schizophrenia is well established to be a heterogeneous syndrome with hundreds of biotypes that share a similar phenotype of positive, negative, cognitive, mood, and neuromotor symptoms of variable severities.²⁰ This includes anosognosia, which has been reported in 57% to 98% of patients in various studies.^21,22

So what happens to anosognosia with antipsychotic therapy? In the first study that used a long-acting injectable (LAI) second-generation antipsychotic (SGA) in first-episode psychosis to ensure full adherence, Emsley et al²³ reported a 64% remission rate after 2 years of treatment, and observed that many patients regained their insight after several months of uninterrupted antipsychotic pharmacotherapy. This suggests that avoiding psychotic relapse with uninterrupted antipsychotic therapy with LAIs may help restore insight. I have personally witnessed reversal of anosognosia in patients with first-episode schizophrenia whom I treated with LAI SGAs continuously for several years; these patients not only regained insight into their illness but were able to return to college or to work.

There is also evidence that stroke patients with left-side hemiplegia, or patients with cortical blindness (due to calcarine cortex damage secondary to posterior cerebral artery infarct), who paradoxically deny being blind due to anosognosia, do regain their insight after several months. Cognitive-behavioral therapy (CBT) and adherence therapy, as well as psychoeducation, can help in reversing anosognosia. Bilateral electroconvulsive therapy has been reported to improve insight in schizophrenia. Transcranial magnetic stimulation over the posterior parietal cortex has been reported to restore insight in patients with visuospatial neglect due to a stroke. However, more research targeting anosognosia along with psychotic symptoms is needed. It should be noted that patients with bipolar disorder who have anosognosia during the manic phase of their illness do have insight when they switch to a depressed phase,⁹ which suggests that anosognosia is reversible in bipolar disorder and is phase-dependent (ie, a state, not a trait, variable).
 

A symptom of impaired consciousness

A large body of evidence links lesions in the right hemisphere to delusion and to anosognosia.²⁴ Gazzaniga and Miller²⁵ published a book chapter with the provocative title “the left hemisphere does not miss the right hemisphere.” Such right-hemisphere lesions can lead to a disruption of consciousness, leading to anosognosia. Schizophrenia is a pervasive brain syndrome involving multiple brain regions and a wide range of clinical symptoms ranging across psychotic as well as negative and cognitive domains. Anosognosia can be conceptualized as a psychotic symptom (delusion), a negative symptom (self-monitoring deficit), or a cognitive failure. However, anosognosia in schizophrenia can be best understood as a symptom of impaired consciousness and self-pathology,²⁶ where the brain fails to process and recognize one’s mental function, which culminates in faulty reality testing.

Schizophrenia is a neurologic syndrome associated with numerous psychiatric manifestations, and anosognosia is one of its fundamental initial symptoms.

Anosognosia is the lack of awareness of a disabling physical or mental illness. The term was coined by Joseph Babinski in 1914 following his observations that patients with left-side paralysis due to right hemisphere stroke do not recognize their hemiplegia and strongly deny that there is anything physically wrong with their body, or that they need treatment or rehabilitation.

Psychiatrists have long observed anosognosia in patients with acute psychoses such as schizophrenia or mania who vehemently deny that there is anything wrong with them, despite experiencing hallucinations, delusions, and/or bizarre behavior. They adamantly refuse medical care and often have to be involuntarily hospitalized to receive urgently needed medications they don’t believe they need.

So is anosognosia in schizophrenia a fixed false belief (delusion), a negative symptom, or a cognitive deficit? Arguments can be made for any of those 3 options, but the evidence suggests that anosognosia is a disorder of consciousness, a “meta-cognitive” deficit, or, as I referred to it in a previous publication, the loss of self-proprioception.¹

Anosognosia in neurologic brain disorders

Although right hemispheric stroke is the most common disease state associated with anosognosia,² other neurologic disorders can be associated with anosognosia, including Anton’s syndrome of cortical blindness,³ traumatic brain injury,⁴ Wernicke’s aphasia,⁵ mild cognitive impairment,⁶ and Alzheimer’s disease.⁷ In addition to anosognosia, those disorders can be accompanied by indifference to the deficit, which is referred to as “anosodiaphoria.”

The neuroanatomy of anosognosia generally implicates right hemisphere deficits, especially the frontal cortex, the right parietal lobe, the temporoparietal cortex, and the thalamus. It can be conceptualized as a disturbance of “body schema” because all motor and sensory functions of the body have a “representation” in brain structure.

Anosognosia in psychiatric brain disorders

Although schizophrenia is most frequently associated with anosognosia, other psychiatric disorders also exhibit this absence of insight. They include delusional disorder,⁸ bipolar disorder,⁹ intellectual disability,¹⁰ and personality disorders.¹¹ In all those psychiatric disorders, there is a lack of self-reflection (metacognition). At the neuroanatomical level, most studies have focused on schizophrenia, and abnormalities have been described in the frontal and parietal regions. Significant pathology in the inferior parietal lobe has been identified in schizophrenia.¹² However, the right insula, which is connected to multiple neural circuits,¹³ appears to be intimately associated with anosognosia when impaired. The insula also regulates interoception and a “sense of self.”¹⁴ The loss of cortical gray matter in schizophrenia is most pronounced in the insula bilaterally. Another neurologic mechanism associated with anosognosia in schizophrenia is the default mode network (DMN). The DMN, which usually is overactive at rest and is deactivated during a focused activity, is involved in both insight and social cognition.¹⁵

Measurement of anosognosia

Several rating scales are used to measure the severity of anosognosia and the loss of insight. They include:

• The Insight and Treatment Attitude Questionnaire¹⁶
• The Scale to Assess Unawareness of Mental Disorder¹⁷
• The Beck Cognitive Insight Scale,¹⁸ the only self-administered scale that measures a patient’s ability to evaluate their psychiatric beliefs and possibly modify them
• The Positive and Negative Syndrome Scale,¹⁹ which is the gold standard for measuring the overall severity of schizophrenia, has only 1 item related to insight within the 16-item General Subscale (G12: Lack of judgement and insight).

Continue to: Consequences of anosognosia...

Consequences of anosognosia

Patients with anosognosia neglect themselves both mentally and physically and fail to seek or accept medical attention. Thus, schizophrenia is associated with many serious and damaging consequences due to the lack of self-monitoring or appraising their health needs. The Table summarizes the multiple consequences of anosognosia.

Is anosognosia treatable or irreversible?

Schizophrenia is well established to be a heterogeneous syndrome with hundreds of biotypes that share a similar phenotype of positive, negative, cognitive, mood, and neuromotor symptoms of variable severities.²⁰ This includes anosognosia, which has been reported in 57% to 98% of patients in various studies.^21,22

So what happens to anosognosia with antipsychotic therapy? In the first study that used a long-acting injectable (LAI) second-generation antipsychotic (SGA) in first-episode psychosis to ensure full adherence, Emsley et al²³ reported a 64% remission rate after 2 years of treatment, and observed that many patients regained their insight after several months of uninterrupted antipsychotic pharmacotherapy. This suggests that avoiding psychotic relapse with uninterrupted antipsychotic therapy with LAIs may help restore insight. I have personally witnessed reversal of anosognosia in patients with first-episode schizophrenia whom I treated with LAI SGAs continuously for several years; these patients not only regained insight into their illness but were able to return to college or to work.

There is also evidence that stroke patients with left-side hemiplegia, or patients with cortical blindness (due to calcarine cortex damage secondary to posterior cerebral artery infarct), who paradoxically deny being blind due to anosognosia, do regain their insight after several months. Cognitive-behavioral therapy (CBT) and adherence therapy, as well as psychoeducation, can help in reversing anosognosia. Bilateral electroconvulsive therapy has been reported to improve insight in schizophrenia. Transcranial magnetic stimulation over the posterior parietal cortex has been reported to restore insight in patients with visuospatial neglect due to a stroke. However, more research targeting anosognosia along with psychotic symptoms is needed. It should be noted that patients with bipolar disorder who have anosognosia during the manic phase of their illness do have insight when they switch to a depressed phase,⁹ which suggests that anosognosia is reversible in bipolar disorder and is phase-dependent (ie, a state, not a trait, variable).
 

A symptom of impaired consciousness

A large body of evidence links lesions in the right hemisphere to delusion and to anosognosia.²⁴ Gazzaniga and Miller²⁵ published a book chapter with the provocative title “the left hemisphere does not miss the right hemisphere.” Such right-hemisphere lesions can lead to a disruption of consciousness, leading to anosognosia. Schizophrenia is a pervasive brain syndrome involving multiple brain regions and a wide range of clinical symptoms ranging across psychotic as well as negative and cognitive domains. Anosognosia can be conceptualized as a psychotic symptom (delusion), a negative symptom (self-monitoring deficit), or a cognitive failure. However, anosognosia in schizophrenia can be best understood as a symptom of impaired consciousness and self-pathology,²⁶ where the brain fails to process and recognize one’s mental function, which culminates in faulty reality testing.

Schizophrenia is a neurologic syndrome associated with numerous psychiatric manifestations, and anosognosia is one of its fundamental initial symptoms.

Anosognosia is the lack of awareness of a disabling physical or mental illness. The term was coined by Joseph Babinski in 1914 following his observations that patients with left-side paralysis due to right hemisphere stroke do not recognize their hemiplegia and strongly deny that there is anything physically wrong with their body, or that they need treatment or rehabilitation.

Psychiatrists have long observed anosognosia in patients with acute psychoses such as schizophrenia or mania who vehemently deny that there is anything wrong with them, despite experiencing hallucinations, delusions, and/or bizarre behavior. They adamantly refuse medical care and often have to be involuntarily hospitalized to receive urgently needed medications they don’t believe they need.

So is anosognosia in schizophrenia a fixed false belief (delusion), a negative symptom, or a cognitive deficit? Arguments can be made for any of those 3 options, but the evidence suggests that anosognosia is a disorder of consciousness, a “meta-cognitive” deficit, or, as I referred to it in a previous publication, the loss of self-proprioception.¹

Anosognosia in neurologic brain disorders

Although right hemispheric stroke is the most common disease state associated with anosognosia,² other neurologic disorders can be associated with anosognosia, including Anton’s syndrome of cortical blindness,³ traumatic brain injury,⁴ Wernicke’s aphasia,⁵ mild cognitive impairment,⁶ and Alzheimer’s disease.⁷ In addition to anosognosia, those disorders can be accompanied by indifference to the deficit, which is referred to as “anosodiaphoria.”

The neuroanatomy of anosognosia generally implicates right hemisphere deficits, especially the frontal cortex, the right parietal lobe, the temporoparietal cortex, and the thalamus. It can be conceptualized as a disturbance of “body schema” because all motor and sensory functions of the body have a “representation” in brain structure.

Anosognosia in psychiatric brain disorders

Although schizophrenia is most frequently associated with anosognosia, other psychiatric disorders also exhibit this absence of insight. They include delusional disorder,⁸ bipolar disorder,⁹ intellectual disability,¹⁰ and personality disorders.¹¹ In all those psychiatric disorders, there is a lack of self-reflection (metacognition). At the neuroanatomical level, most studies have focused on schizophrenia, and abnormalities have been described in the frontal and parietal regions. Significant pathology in the inferior parietal lobe has been identified in schizophrenia.¹² However, the right insula, which is connected to multiple neural circuits,¹³ appears to be intimately associated with anosognosia when impaired. The insula also regulates interoception and a “sense of self.”¹⁴ The loss of cortical gray matter in schizophrenia is most pronounced in the insula bilaterally. Another neurologic mechanism associated with anosognosia in schizophrenia is the default mode network (DMN). The DMN, which usually is overactive at rest and is deactivated during a focused activity, is involved in both insight and social cognition.¹⁵

Measurement of anosognosia

Several rating scales are used to measure the severity of anosognosia and the loss of insight. They include:

• The Insight and Treatment Attitude Questionnaire¹⁶
• The Scale to Assess Unawareness of Mental Disorder¹⁷
• The Beck Cognitive Insight Scale,¹⁸ the only self-administered scale that measures a patient’s ability to evaluate their psychiatric beliefs and possibly modify them
• The Positive and Negative Syndrome Scale,¹⁹ which is the gold standard for measuring the overall severity of schizophrenia, has only 1 item related to insight within the 16-item General Subscale (G12: Lack of judgement and insight).

Continue to: Consequences of anosognosia...

Consequences of anosognosia

Patients with anosognosia neglect themselves both mentally and physically and fail to seek or accept medical attention. Thus, schizophrenia is associated with many serious and damaging consequences due to the lack of self-monitoring or appraising their health needs. The Table summarizes the multiple consequences of anosognosia.

Is anosognosia treatable or irreversible?

Schizophrenia is well established to be a heterogeneous syndrome with hundreds of biotypes that share a similar phenotype of positive, negative, cognitive, mood, and neuromotor symptoms of variable severities.²⁰ This includes anosognosia, which has been reported in 57% to 98% of patients in various studies.^21,22

So what happens to anosognosia with antipsychotic therapy? In the first study that used a long-acting injectable (LAI) second-generation antipsychotic (SGA) in first-episode psychosis to ensure full adherence, Emsley et al²³ reported a 64% remission rate after 2 years of treatment, and observed that many patients regained their insight after several months of uninterrupted antipsychotic pharmacotherapy. This suggests that avoiding psychotic relapse with uninterrupted antipsychotic therapy with LAIs may help restore insight. I have personally witnessed reversal of anosognosia in patients with first-episode schizophrenia whom I treated with LAI SGAs continuously for several years; these patients not only regained insight into their illness but were able to return to college or to work.

There is also evidence that stroke patients with left-side hemiplegia, or patients with cortical blindness (due to calcarine cortex damage secondary to posterior cerebral artery infarct), who paradoxically deny being blind due to anosognosia, do regain their insight after several months. Cognitive-behavioral therapy (CBT) and adherence therapy, as well as psychoeducation, can help in reversing anosognosia. Bilateral electroconvulsive therapy has been reported to improve insight in schizophrenia. Transcranial magnetic stimulation over the posterior parietal cortex has been reported to restore insight in patients with visuospatial neglect due to a stroke. However, more research targeting anosognosia along with psychotic symptoms is needed. It should be noted that patients with bipolar disorder who have anosognosia during the manic phase of their illness do have insight when they switch to a depressed phase,⁹ which suggests that anosognosia is reversible in bipolar disorder and is phase-dependent (ie, a state, not a trait, variable).
 

A symptom of impaired consciousness

A large body of evidence links lesions in the right hemisphere to delusion and to anosognosia.²⁴ Gazzaniga and Miller²⁵ published a book chapter with the provocative title “the left hemisphere does not miss the right hemisphere.” Such right-hemisphere lesions can lead to a disruption of consciousness, leading to anosognosia. Schizophrenia is a pervasive brain syndrome involving multiple brain regions and a wide range of clinical symptoms ranging across psychotic as well as negative and cognitive domains. Anosognosia can be conceptualized as a psychotic symptom (delusion), a negative symptom (self-monitoring deficit), or a cognitive failure. However, anosognosia in schizophrenia can be best understood as a symptom of impaired consciousness and self-pathology,²⁶ where the brain fails to process and recognize one’s mental function, which culminates in faulty reality testing.

Schizophrenia is a neurologic syndrome associated with numerous psychiatric manifestations, and anosognosia is one of its fundamental initial symptoms.