Henry A. Nasrallah, MD

The therapeutic consequences can be depressing!

A study published recently found a difference in brain blood flow between unipolar depression, also known as major depressive disorder (MDD), and the depressive phase of bipolar I (BD I) and bipolar II (BD II) disorders, known as bipolar depression.¹ Researchers performed arterial spin labeling and submitted the resulting data to pattern recognition analysis to correctly classify 81% of subjects. This type of investigation augurs that objective biomarkers might halt the unrelenting misdiagnosis of bipolar depression as MDD and end the iatrogenic suffering of millions of bipolar disorder patients who became victims of a “therapeutic misadventure.”

It is perplexing that this problem has festered so long, simply because the two types of depression look deceptively alike.

This takes me back to my days in residency

Although I trained in one of the top psychiatry programs at the time, I was never taught that I must first classify my depressed patient as unipolar or bipolar before embarking on a treatment plan. Back then, “depression was depression” and treatment was the same for all depressed patients: Start with a tricyclic antidepressant (TCA). If there is no response within a few weeks, consider a different TCA or move to a monoamine oxidase inhibitor. If that does not work, perform electroconvulsive therapy (ECT).

Quite a few depressed patients actually worsened on antidepressant drugs, becoming agitated, irritable, and angry—yet clinicians did not recognize that change as a switch to irritable mania or hypomania, or a mixed depressed state. In fact, in those days, patients suffering mania or hypomania were expected to be euphoric and expansive, and the fact that almost one-half of bipolar mania presents with irritable, rather than euphoric, mood was not widely recognized, either.

I recall psychodynamic discussions as a resident about the anger and hostility that some patients with depression manifest. It was not widely recognized that treating bipolar depression with an antidepressant might lead to any of four undesirable switches: mania, hypomania, mixed state, or rapid cycling. We saw patients with all of these complications and simply labeled their condition “treatment-resistant depression,” especially if the patient switched to rapid cycling with recurrent depressions (which often happens with BD II patients who receive antidepressant monotherapy).

Frankly, BD II was not on our radar screen, and practically all such patients were given a misdiagnosis of MDD. No wonder we all marveled at how ECT finally helped out the so-called treatment-resistant patients!

Sadly, the state of the art treatment of bipolar depression back then was actually a state of incomplete knowledge. Okay—call it a state of ignorance wrapped in good intentions.

The dots did not get connected…

There were phenomenologic clues that, had we noticed them, could have corrected our clinical blind spot about the ways bipolar depression is different from unipolar depression. Yet we did not connect the dots about how bipolar depression is different from MDD (Table).

Treatment clues also should have opened our eyes to the different types of depression:

Clue #1: Patients with treatment-resistant depression often responded when lithium was added to an antidepressant. This led to the belief that lithium has antidepressant properties, instead of clueing us that treatment-resistant depression is actually a bipolar type of depression.

Clue #2: Likewise, patients with treatment-resistant depression improved when an antipsychotic agent, which is also anti-manic, was added to an antidepressant (seasoned clinicians might remember the amitriptyline-perphenazine combination pill, sold as Triavil, that was a precursor of the olanzapine-fluoxetine combination developed a few years ago to treat bipolar depression).

Clue #3: ECT exerted efficacy in patients who failed an antidepressant or who got worse taking one (ie, switched to a mixed state).

A new age of therapeutics

In the past few years, we’ve witnessed the development of several pharmacotherapeutic agents for bipolar depression. First, the olanzapine-fluoxetine combination was approved for this indication in 2003. That was followed by quetiapine monotherapy in 2005 and, most recently, in 2013, lurasidone  (both as monotherapy and as an adjunct to a mood stabilizer).

With those three FDA-approved options for bipolar depression, clinicians can now treat this type of depression without putting the patient at risk of complications that ensue when anti­depressants approved only for MDD are used erroneously as monotherapy for bipolar depression.

These days, psychiatry residents are rigorously trained to differentiate unipolar and bipolar depression and to select the most appropriate, evidence-based treatment for bipolar depression. The state of ignorance surrounding this psychiatric condition is lifting, although there are pockets of persisting nonrecognition in some settings. Gaps in knowledge underpin and perpetuate hoary practices, but innovative research—such as the study cited here on brain blood-flow biomarkers—is the ultimate antidote to ignorance.

The therapeutic consequences can be depressing!

A study published recently found a difference in brain blood flow between unipolar depression, also known as major depressive disorder (MDD), and the depressive phase of bipolar I (BD I) and bipolar II (BD II) disorders, known as bipolar depression.¹ Researchers performed arterial spin labeling and submitted the resulting data to pattern recognition analysis to correctly classify 81% of subjects. This type of investigation augurs that objective biomarkers might halt the unrelenting misdiagnosis of bipolar depression as MDD and end the iatrogenic suffering of millions of bipolar disorder patients who became victims of a “therapeutic misadventure.”

It is perplexing that this problem has festered so long, simply because the two types of depression look deceptively alike.

This takes me back to my days in residency

Although I trained in one of the top psychiatry programs at the time, I was never taught that I must first classify my depressed patient as unipolar or bipolar before embarking on a treatment plan. Back then, “depression was depression” and treatment was the same for all depressed patients: Start with a tricyclic antidepressant (TCA). If there is no response within a few weeks, consider a different TCA or move to a monoamine oxidase inhibitor. If that does not work, perform electroconvulsive therapy (ECT).

Quite a few depressed patients actually worsened on antidepressant drugs, becoming agitated, irritable, and angry—yet clinicians did not recognize that change as a switch to irritable mania or hypomania, or a mixed depressed state. In fact, in those days, patients suffering mania or hypomania were expected to be euphoric and expansive, and the fact that almost one-half of bipolar mania presents with irritable, rather than euphoric, mood was not widely recognized, either.

I recall psychodynamic discussions as a resident about the anger and hostility that some patients with depression manifest. It was not widely recognized that treating bipolar depression with an antidepressant might lead to any of four undesirable switches: mania, hypomania, mixed state, or rapid cycling. We saw patients with all of these complications and simply labeled their condition “treatment-resistant depression,” especially if the patient switched to rapid cycling with recurrent depressions (which often happens with BD II patients who receive antidepressant monotherapy).

Frankly, BD II was not on our radar screen, and practically all such patients were given a misdiagnosis of MDD. No wonder we all marveled at how ECT finally helped out the so-called treatment-resistant patients!

Sadly, the state of the art treatment of bipolar depression back then was actually a state of incomplete knowledge. Okay—call it a state of ignorance wrapped in good intentions.

The dots did not get connected…

There were phenomenologic clues that, had we noticed them, could have corrected our clinical blind spot about the ways bipolar depression is different from unipolar depression. Yet we did not connect the dots about how bipolar depression is different from MDD (Table).

Treatment clues also should have opened our eyes to the different types of depression:

Clue #1: Patients with treatment-resistant depression often responded when lithium was added to an antidepressant. This led to the belief that lithium has antidepressant properties, instead of clueing us that treatment-resistant depression is actually a bipolar type of depression.

Clue #2: Likewise, patients with treatment-resistant depression improved when an antipsychotic agent, which is also anti-manic, was added to an antidepressant (seasoned clinicians might remember the amitriptyline-perphenazine combination pill, sold as Triavil, that was a precursor of the olanzapine-fluoxetine combination developed a few years ago to treat bipolar depression).

Clue #3: ECT exerted efficacy in patients who failed an antidepressant or who got worse taking one (ie, switched to a mixed state).

A new age of therapeutics

In the past few years, we’ve witnessed the development of several pharmacotherapeutic agents for bipolar depression. First, the olanzapine-fluoxetine combination was approved for this indication in 2003. That was followed by quetiapine monotherapy in 2005 and, most recently, in 2013, lurasidone  (both as monotherapy and as an adjunct to a mood stabilizer).

With those three FDA-approved options for bipolar depression, clinicians can now treat this type of depression without putting the patient at risk of complications that ensue when anti­depressants approved only for MDD are used erroneously as monotherapy for bipolar depression.

These days, psychiatry residents are rigorously trained to differentiate unipolar and bipolar depression and to select the most appropriate, evidence-based treatment for bipolar depression. The state of ignorance surrounding this psychiatric condition is lifting, although there are pockets of persisting nonrecognition in some settings. Gaps in knowledge underpin and perpetuate hoary practices, but innovative research—such as the study cited here on brain blood-flow biomarkers—is the ultimate antidote to ignorance.

The therapeutic consequences can be depressing!

A study published recently found a difference in brain blood flow between unipolar depression, also known as major depressive disorder (MDD), and the depressive phase of bipolar I (BD I) and bipolar II (BD II) disorders, known as bipolar depression.¹ Researchers performed arterial spin labeling and submitted the resulting data to pattern recognition analysis to correctly classify 81% of subjects. This type of investigation augurs that objective biomarkers might halt the unrelenting misdiagnosis of bipolar depression as MDD and end the iatrogenic suffering of millions of bipolar disorder patients who became victims of a “therapeutic misadventure.”

It is perplexing that this problem has festered so long, simply because the two types of depression look deceptively alike.

This takes me back to my days in residency

Although I trained in one of the top psychiatry programs at the time, I was never taught that I must first classify my depressed patient as unipolar or bipolar before embarking on a treatment plan. Back then, “depression was depression” and treatment was the same for all depressed patients: Start with a tricyclic antidepressant (TCA). If there is no response within a few weeks, consider a different TCA or move to a monoamine oxidase inhibitor. If that does not work, perform electroconvulsive therapy (ECT).

Quite a few depressed patients actually worsened on antidepressant drugs, becoming agitated, irritable, and angry—yet clinicians did not recognize that change as a switch to irritable mania or hypomania, or a mixed depressed state. In fact, in those days, patients suffering mania or hypomania were expected to be euphoric and expansive, and the fact that almost one-half of bipolar mania presents with irritable, rather than euphoric, mood was not widely recognized, either.

I recall psychodynamic discussions as a resident about the anger and hostility that some patients with depression manifest. It was not widely recognized that treating bipolar depression with an antidepressant might lead to any of four undesirable switches: mania, hypomania, mixed state, or rapid cycling. We saw patients with all of these complications and simply labeled their condition “treatment-resistant depression,” especially if the patient switched to rapid cycling with recurrent depressions (which often happens with BD II patients who receive antidepressant monotherapy).

Frankly, BD II was not on our radar screen, and practically all such patients were given a misdiagnosis of MDD. No wonder we all marveled at how ECT finally helped out the so-called treatment-resistant patients!

Sadly, the state of the art treatment of bipolar depression back then was actually a state of incomplete knowledge. Okay—call it a state of ignorance wrapped in good intentions.

The dots did not get connected…

There were phenomenologic clues that, had we noticed them, could have corrected our clinical blind spot about the ways bipolar depression is different from unipolar depression. Yet we did not connect the dots about how bipolar depression is different from MDD (Table).

Treatment clues also should have opened our eyes to the different types of depression:

Clue #1: Patients with treatment-resistant depression often responded when lithium was added to an antidepressant. This led to the belief that lithium has antidepressant properties, instead of clueing us that treatment-resistant depression is actually a bipolar type of depression.

Clue #2: Likewise, patients with treatment-resistant depression improved when an antipsychotic agent, which is also anti-manic, was added to an antidepressant (seasoned clinicians might remember the amitriptyline-perphenazine combination pill, sold as Triavil, that was a precursor of the olanzapine-fluoxetine combination developed a few years ago to treat bipolar depression).

Clue #3: ECT exerted efficacy in patients who failed an antidepressant or who got worse taking one (ie, switched to a mixed state).

A new age of therapeutics

In the past few years, we’ve witnessed the development of several pharmacotherapeutic agents for bipolar depression. First, the olanzapine-fluoxetine combination was approved for this indication in 2003. That was followed by quetiapine monotherapy in 2005 and, most recently, in 2013, lurasidone  (both as monotherapy and as an adjunct to a mood stabilizer).

With those three FDA-approved options for bipolar depression, clinicians can now treat this type of depression without putting the patient at risk of complications that ensue when anti­depressants approved only for MDD are used erroneously as monotherapy for bipolar depression.

These days, psychiatry residents are rigorously trained to differentiate unipolar and bipolar depression and to select the most appropriate, evidence-based treatment for bipolar depression. The state of ignorance surrounding this psychiatric condition is lifting, although there are pockets of persisting nonrecognition in some settings. Gaps in knowledge underpin and perpetuate hoary practices, but innovative research—such as the study cited here on brain blood-flow biomarkers—is the ultimate antidote to ignorance.

For a relatively young medical discipline like psychiatry, the history of discovery of biological therapeutics is replete with twists and turns, the pace of which will likely not abate. These discoveries can be initiated by both observant clinicians and dedicated researchers.

As I contemplated the scientific saga of developing somatic and pharmaceutical treatments for major psychiatric disorders, I recognized several interesting themes: serendipity, evolution, paradigm shifts, and radical breakthroughs. Consider the following examples of those themes.

Neuromodulation

Electroconvulsive therapy (ECT), the original neuromodulation therapy, was discovered (serendipity) when Meduna, mistakenly thinking that schizophrenia and epilepsy are “antagonistic,” used camphor and, later, metrazol, to induce seizures to treat schizophrenia. Later, Cerletti and Bini switched the seizure induction to electricity (evolution), and the use of ECT spread, like a seizure, around the world after their initial report. Later, unilateral ECT and pulse wave ECT were developed to reduce the incidence of side effects (further evolution).

In contemporary psychiatry, a paradigm shift in neuromodulation techniques has emerged over the past decade with the development of an array of novel neuromodulation techniques,¹ some of which do not induce seizures or touch the scalp with electrodes—or even use electricity. These techniques include vagus nerve stimulation, repetitive transcranial magnetic stimulation, epidural cortical stimulation, focused ultrasound, low-field magnetic stimulation, transcranial direct current stimulation, and magnetic seizure therapy. Currently (pun intended!), radical breakthroughs with significant therapeutic promise are being developed, such as optogenetic stimulation and deep brain stimulation.

Antipsychotics

One of the most momentous serendipitous discoveries in psychiatry (one that should have won the Nobel Prize in Medicine or Physiology, like the discovery of penicillin) was the phenothiazine drug chlorpromazine, first used as an adjunct to surgical anesthesia in the late 1940s and early 1950s.² Chlorpromazine eliminated psychotic symptoms in many patients (refuting centuries of dogma that madness is irreversible), led to
deinstitutionalization and community care of patients who suffer a serious psychiatric disorder, and reduced psychiatric beds from 50% of all hospital beds in the United States to about 5% today. Numerous phenothiazines were developed (evolution) followed by six non-phenothiazine classes (paradigm shift).

Another truly felicitous serendipity was the discovery of the first atypical antipsychotic, clozapine (synthesized in 1959, the same year that the antipsychotic thioridazine [Mellaril] was synthesized), which was initially shelved because it did not cause extrapyramidal symptoms (EPS); at the time, EPS were erroneously thought to be indispensable for antipsychotic efficacy! The discovery of clozapine led to the development of the nine atypical antipsychotics that have largely replaced the first-generation agents (paradigm shift) and that mimic clozapine’s far stronger binding of serotonin 5-HT2A receptors than binding of dopamine D2 receptors, thus reducing the occurrence of neurologic movement disorders (ie, EPS).

Clozapine led to a radical breakthrough when it proved to have efficacy in schizophrenia that is refractory to first-generation antipsychotics (the CATIE study showed the same efficacy for second-generation antipsychotics). A follow-up breakthrough was the
discovery of the efficacy of clozapine on suicidality, a significant cause of mortality in patients with schizophrenia.

A recently reported treatment for schizophrenia might be a potentially radical breakthrough. In a pilot study, researchers reported very rapid and significant improvement in positive and negative symptoms (and even anxiety and depressive symptoms, and within 4 hours and persisting for 4 weeks!³), using the antihypertensive sodium nitroprusside, administered IV. Here is another paradigm shift—in drug delivery, similar to what was seen with IV ketamine, which led to a radical breakthrough in treating drug-resistant depression.

Interestingly, the N-methyl-d-aspartate (NMDA) receptor is playing a key role in radical breakthroughs in schizophrenia and depression. A glycine transporter I inhibitor (which potentiates what is strongly suspected to be a hypofunctional NMDA receptor in schizophrenia) is undergoing further study for the treatment of negative and residual symptoms of schizophrenia, after a promising initial trial. This promises to be a radical breakthrough in addressing a major unmet need in psychiatry: treating negative symptoms of schizophrenia.

Antidepressants

Serendipity played a role in the discovery of the first antidepressant, iproniazid, a monoamine oxidase inhibitor (MAOI) that was used to treat tuberculosis in the 1940s and 1950s; medical staff in sanitariums noticed that the drug elevated the mood of depressed tuberculosis patients. Several other clinically useful MAOIs were then developed (evolution).

When the first tricyclic antidepressant (TCA), imipramine, was synthesized, it was intended to be an antipsychotic but—serendipitously—turned out to be a strong antidepressant. A paradigm shift from MAOIs to TCAs then occurred through the 1970s and 1980s, prompted by concerns over adverse effects caused by the interaction of MAOIs and foods that contain tyramine.

A mechanistic breakthrough occurred when the first selective serotonin reuptake inhibitor (SSRI), fluoxetine, was developed in the late 1980s, followed soon by several other SSRIs (evolution). This triggered another massive paradigm shift away from TCAs to SSRIs because of the low cardiotoxicity of SSRIs.

Evolution then led to the development of other heterocyclic antidepressants, such as nefazodone, mirtazapine, venlafaxine, and duloxetine.

The recent exciting (pun intended again!) discovery of the efficacy of the glutamate NMDA receptor-antagonist ketamine for severe, treatment-resistant depression represents a radical breakthrough in the rapidity of remission (within 1 or 2 hours of IV administration) of depression and suicidal impulses. Until now, such rapid response was believed unattainable.

The ketamine treatment model also rep- resents several paradigm shifts: from mono- amines to glutamate; from the oral route to the IV route; from gradual (6 to 8 weeks) to abrupt (1 or 2 hours) resolution of symptoms; and from neurochemistry (monoamine neurotransmitters) to neuroplasticity (mammalian target of rapapmycin [mTOR] and brain- derived neurotrophic factor [BDNF]).

The saga will go on

Explosive growth in molecular neuroscience and deeper understanding of the pathophysiology of major psychiatric disorders bode well for an accelerating pace of radical breakthroughs in psychiatric therapies. The new revelation that symptoms of chronic neuropsychiatric disorders such as depression, mania, and schizophrenia can be re- versed within a few hours, instead of weeks, months, or years, is jubilant news for our long-suffering patients.

But even as science-driven breakthroughs accelerate and prompt paradigm shifts in treatment, we should never under-estimate the importance and value of serendipity in generating new insights that lead to the same transformative paradigm shifts in therapeutics. Scientists are equipped to make discoveries that are breakthroughs, but observant clinicians can make serendipitous discoveries that may reinvent the care of psychotic disorders. The discovery of psychiatric therapies can begin in a clinical setting—not just in the ivory tower of academia.

For a relatively young medical discipline like psychiatry, the history of discovery of biological therapeutics is replete with twists and turns, the pace of which will likely not abate. These discoveries can be initiated by both observant clinicians and dedicated researchers.

As I contemplated the scientific saga of developing somatic and pharmaceutical treatments for major psychiatric disorders, I recognized several interesting themes: serendipity, evolution, paradigm shifts, and radical breakthroughs. Consider the following examples of those themes.

Neuromodulation

Electroconvulsive therapy (ECT), the original neuromodulation therapy, was discovered (serendipity) when Meduna, mistakenly thinking that schizophrenia and epilepsy are “antagonistic,” used camphor and, later, metrazol, to induce seizures to treat schizophrenia. Later, Cerletti and Bini switched the seizure induction to electricity (evolution), and the use of ECT spread, like a seizure, around the world after their initial report. Later, unilateral ECT and pulse wave ECT were developed to reduce the incidence of side effects (further evolution).

In contemporary psychiatry, a paradigm shift in neuromodulation techniques has emerged over the past decade with the development of an array of novel neuromodulation techniques,¹ some of which do not induce seizures or touch the scalp with electrodes—or even use electricity. These techniques include vagus nerve stimulation, repetitive transcranial magnetic stimulation, epidural cortical stimulation, focused ultrasound, low-field magnetic stimulation, transcranial direct current stimulation, and magnetic seizure therapy. Currently (pun intended!), radical breakthroughs with significant therapeutic promise are being developed, such as optogenetic stimulation and deep brain stimulation.

Antipsychotics

One of the most momentous serendipitous discoveries in psychiatry (one that should have won the Nobel Prize in Medicine or Physiology, like the discovery of penicillin) was the phenothiazine drug chlorpromazine, first used as an adjunct to surgical anesthesia in the late 1940s and early 1950s.² Chlorpromazine eliminated psychotic symptoms in many patients (refuting centuries of dogma that madness is irreversible), led to
deinstitutionalization and community care of patients who suffer a serious psychiatric disorder, and reduced psychiatric beds from 50% of all hospital beds in the United States to about 5% today. Numerous phenothiazines were developed (evolution) followed by six non-phenothiazine classes (paradigm shift).

Another truly felicitous serendipity was the discovery of the first atypical antipsychotic, clozapine (synthesized in 1959, the same year that the antipsychotic thioridazine [Mellaril] was synthesized), which was initially shelved because it did not cause extrapyramidal symptoms (EPS); at the time, EPS were erroneously thought to be indispensable for antipsychotic efficacy! The discovery of clozapine led to the development of the nine atypical antipsychotics that have largely replaced the first-generation agents (paradigm shift) and that mimic clozapine’s far stronger binding of serotonin 5-HT2A receptors than binding of dopamine D2 receptors, thus reducing the occurrence of neurologic movement disorders (ie, EPS).

Clozapine led to a radical breakthrough when it proved to have efficacy in schizophrenia that is refractory to first-generation antipsychotics (the CATIE study showed the same efficacy for second-generation antipsychotics). A follow-up breakthrough was the
discovery of the efficacy of clozapine on suicidality, a significant cause of mortality in patients with schizophrenia.

A recently reported treatment for schizophrenia might be a potentially radical breakthrough. In a pilot study, researchers reported very rapid and significant improvement in positive and negative symptoms (and even anxiety and depressive symptoms, and within 4 hours and persisting for 4 weeks!³), using the antihypertensive sodium nitroprusside, administered IV. Here is another paradigm shift—in drug delivery, similar to what was seen with IV ketamine, which led to a radical breakthrough in treating drug-resistant depression.

Interestingly, the N-methyl-d-aspartate (NMDA) receptor is playing a key role in radical breakthroughs in schizophrenia and depression. A glycine transporter I inhibitor (which potentiates what is strongly suspected to be a hypofunctional NMDA receptor in schizophrenia) is undergoing further study for the treatment of negative and residual symptoms of schizophrenia, after a promising initial trial. This promises to be a radical breakthrough in addressing a major unmet need in psychiatry: treating negative symptoms of schizophrenia.

Antidepressants

Serendipity played a role in the discovery of the first antidepressant, iproniazid, a monoamine oxidase inhibitor (MAOI) that was used to treat tuberculosis in the 1940s and 1950s; medical staff in sanitariums noticed that the drug elevated the mood of depressed tuberculosis patients. Several other clinically useful MAOIs were then developed (evolution).

When the first tricyclic antidepressant (TCA), imipramine, was synthesized, it was intended to be an antipsychotic but—serendipitously—turned out to be a strong antidepressant. A paradigm shift from MAOIs to TCAs then occurred through the 1970s and 1980s, prompted by concerns over adverse effects caused by the interaction of MAOIs and foods that contain tyramine.

A mechanistic breakthrough occurred when the first selective serotonin reuptake inhibitor (SSRI), fluoxetine, was developed in the late 1980s, followed soon by several other SSRIs (evolution). This triggered another massive paradigm shift away from TCAs to SSRIs because of the low cardiotoxicity of SSRIs.

Evolution then led to the development of other heterocyclic antidepressants, such as nefazodone, mirtazapine, venlafaxine, and duloxetine.

The recent exciting (pun intended again!) discovery of the efficacy of the glutamate NMDA receptor-antagonist ketamine for severe, treatment-resistant depression represents a radical breakthrough in the rapidity of remission (within 1 or 2 hours of IV administration) of depression and suicidal impulses. Until now, such rapid response was believed unattainable.

The ketamine treatment model also rep- resents several paradigm shifts: from mono- amines to glutamate; from the oral route to the IV route; from gradual (6 to 8 weeks) to abrupt (1 or 2 hours) resolution of symptoms; and from neurochemistry (monoamine neurotransmitters) to neuroplasticity (mammalian target of rapapmycin [mTOR] and brain- derived neurotrophic factor [BDNF]).

The saga will go on

Explosive growth in molecular neuroscience and deeper understanding of the pathophysiology of major psychiatric disorders bode well for an accelerating pace of radical breakthroughs in psychiatric therapies. The new revelation that symptoms of chronic neuropsychiatric disorders such as depression, mania, and schizophrenia can be re- versed within a few hours, instead of weeks, months, or years, is jubilant news for our long-suffering patients.

But even as science-driven breakthroughs accelerate and prompt paradigm shifts in treatment, we should never under-estimate the importance and value of serendipity in generating new insights that lead to the same transformative paradigm shifts in therapeutics. Scientists are equipped to make discoveries that are breakthroughs, but observant clinicians can make serendipitous discoveries that may reinvent the care of psychotic disorders. The discovery of psychiatric therapies can begin in a clinical setting—not just in the ivory tower of academia.

For a relatively young medical discipline like psychiatry, the history of discovery of biological therapeutics is replete with twists and turns, the pace of which will likely not abate. These discoveries can be initiated by both observant clinicians and dedicated researchers.

As I contemplated the scientific saga of developing somatic and pharmaceutical treatments for major psychiatric disorders, I recognized several interesting themes: serendipity, evolution, paradigm shifts, and radical breakthroughs. Consider the following examples of those themes.

Neuromodulation

Electroconvulsive therapy (ECT), the original neuromodulation therapy, was discovered (serendipity) when Meduna, mistakenly thinking that schizophrenia and epilepsy are “antagonistic,” used camphor and, later, metrazol, to induce seizures to treat schizophrenia. Later, Cerletti and Bini switched the seizure induction to electricity (evolution), and the use of ECT spread, like a seizure, around the world after their initial report. Later, unilateral ECT and pulse wave ECT were developed to reduce the incidence of side effects (further evolution).

In contemporary psychiatry, a paradigm shift in neuromodulation techniques has emerged over the past decade with the development of an array of novel neuromodulation techniques,¹ some of which do not induce seizures or touch the scalp with electrodes—or even use electricity. These techniques include vagus nerve stimulation, repetitive transcranial magnetic stimulation, epidural cortical stimulation, focused ultrasound, low-field magnetic stimulation, transcranial direct current stimulation, and magnetic seizure therapy. Currently (pun intended!), radical breakthroughs with significant therapeutic promise are being developed, such as optogenetic stimulation and deep brain stimulation.

Antipsychotics

One of the most momentous serendipitous discoveries in psychiatry (one that should have won the Nobel Prize in Medicine or Physiology, like the discovery of penicillin) was the phenothiazine drug chlorpromazine, first used as an adjunct to surgical anesthesia in the late 1940s and early 1950s.² Chlorpromazine eliminated psychotic symptoms in many patients (refuting centuries of dogma that madness is irreversible), led to
deinstitutionalization and community care of patients who suffer a serious psychiatric disorder, and reduced psychiatric beds from 50% of all hospital beds in the United States to about 5% today. Numerous phenothiazines were developed (evolution) followed by six non-phenothiazine classes (paradigm shift).

Another truly felicitous serendipity was the discovery of the first atypical antipsychotic, clozapine (synthesized in 1959, the same year that the antipsychotic thioridazine [Mellaril] was synthesized), which was initially shelved because it did not cause extrapyramidal symptoms (EPS); at the time, EPS were erroneously thought to be indispensable for antipsychotic efficacy! The discovery of clozapine led to the development of the nine atypical antipsychotics that have largely replaced the first-generation agents (paradigm shift) and that mimic clozapine’s far stronger binding of serotonin 5-HT2A receptors than binding of dopamine D2 receptors, thus reducing the occurrence of neurologic movement disorders (ie, EPS).

Clozapine led to a radical breakthrough when it proved to have efficacy in schizophrenia that is refractory to first-generation antipsychotics (the CATIE study showed the same efficacy for second-generation antipsychotics). A follow-up breakthrough was the
discovery of the efficacy of clozapine on suicidality, a significant cause of mortality in patients with schizophrenia.

A recently reported treatment for schizophrenia might be a potentially radical breakthrough. In a pilot study, researchers reported very rapid and significant improvement in positive and negative symptoms (and even anxiety and depressive symptoms, and within 4 hours and persisting for 4 weeks!³), using the antihypertensive sodium nitroprusside, administered IV. Here is another paradigm shift—in drug delivery, similar to what was seen with IV ketamine, which led to a radical breakthrough in treating drug-resistant depression.

Interestingly, the N-methyl-d-aspartate (NMDA) receptor is playing a key role in radical breakthroughs in schizophrenia and depression. A glycine transporter I inhibitor (which potentiates what is strongly suspected to be a hypofunctional NMDA receptor in schizophrenia) is undergoing further study for the treatment of negative and residual symptoms of schizophrenia, after a promising initial trial. This promises to be a radical breakthrough in addressing a major unmet need in psychiatry: treating negative symptoms of schizophrenia.

Antidepressants

Serendipity played a role in the discovery of the first antidepressant, iproniazid, a monoamine oxidase inhibitor (MAOI) that was used to treat tuberculosis in the 1940s and 1950s; medical staff in sanitariums noticed that the drug elevated the mood of depressed tuberculosis patients. Several other clinically useful MAOIs were then developed (evolution).

When the first tricyclic antidepressant (TCA), imipramine, was synthesized, it was intended to be an antipsychotic but—serendipitously—turned out to be a strong antidepressant. A paradigm shift from MAOIs to TCAs then occurred through the 1970s and 1980s, prompted by concerns over adverse effects caused by the interaction of MAOIs and foods that contain tyramine.

A mechanistic breakthrough occurred when the first selective serotonin reuptake inhibitor (SSRI), fluoxetine, was developed in the late 1980s, followed soon by several other SSRIs (evolution). This triggered another massive paradigm shift away from TCAs to SSRIs because of the low cardiotoxicity of SSRIs.

Evolution then led to the development of other heterocyclic antidepressants, such as nefazodone, mirtazapine, venlafaxine, and duloxetine.

The recent exciting (pun intended again!) discovery of the efficacy of the glutamate NMDA receptor-antagonist ketamine for severe, treatment-resistant depression represents a radical breakthrough in the rapidity of remission (within 1 or 2 hours of IV administration) of depression and suicidal impulses. Until now, such rapid response was believed unattainable.

The ketamine treatment model also rep- resents several paradigm shifts: from mono- amines to glutamate; from the oral route to the IV route; from gradual (6 to 8 weeks) to abrupt (1 or 2 hours) resolution of symptoms; and from neurochemistry (monoamine neurotransmitters) to neuroplasticity (mammalian target of rapapmycin [mTOR] and brain- derived neurotrophic factor [BDNF]).

The saga will go on

Explosive growth in molecular neuroscience and deeper understanding of the pathophysiology of major psychiatric disorders bode well for an accelerating pace of radical breakthroughs in psychiatric therapies. The new revelation that symptoms of chronic neuropsychiatric disorders such as depression, mania, and schizophrenia can be re- versed within a few hours, instead of weeks, months, or years, is jubilant news for our long-suffering patients.

But even as science-driven breakthroughs accelerate and prompt paradigm shifts in treatment, we should never under-estimate the importance and value of serendipity in generating new insights that lead to the same transformative paradigm shifts in therapeutics. Scientists are equipped to make discoveries that are breakthroughs, but observant clinicians can make serendipitous discoveries that may reinvent the care of psychotic disorders. The discovery of psychiatric therapies can begin in a clinical setting—not just in the ivory tower of academia.

A century ago, neurology and psychiatry were one specialty, with unified training, a unified journal (Archives of Neurology and Psychiatry), and a unified board exam through the American Board of Psychiatry and Neurology.^1-3 Kraepelin, Alzheimer, Freud, and Meyer were all neuropsychiatrists who treated patients with all brain disorders—stroke, epilepsy, tertiary syphilis, psychosis, depression, and anxiety. Disorders of the “mind,” such as emotions, thought, or behavior, were rightfully regarded as manifestations of cerebral pathology, and research was based on that model.

That was the rational era, when disorders of the brain and its mind were integrated into one specialty.

Why did psychiatry and neurology drift apart?

Two answers to this question come to mind: 1) Freudian theory and psychoanalysis and 2) the inability to localize the brain “lesion” associated with psychiatric disorders.

Although Freud was a neurologist and psychiatrist, his psychodynamic formulation of human behavior was more speculative than empirical, and his psychoanalytic theory was not evidence-based (to be fair, almost all neurologic disorders lacked any treatment 100 years ago). Furthermore, neuropsychiatry did not have the sophisticated brain assessment tools that are available today to physically localize disorders of thought, affect, or mood in the brain. Knowledge of neurochemistry, receptors, neurotransmitters, and brain circuits was nonexistent—let alone an understanding of molecular and cellular neurobiology. The “mind” was therefore divorced, so to speak, from its physical foundation, the brain, and mental illness was erroneously re-conceptualized as “psychological,” not neurological!

In the 1950s, the American Medical Association’s Archives of Neurology and Psychiatry was split into Archives of Neurology and Archives of General Psychiatry. Since then, the two specialties have drifted apart and reduced to a minimum the overlap of their clinical, educational, and research emphases. Much has been lost over the past five  decades because of the rupture of diseases of the human brain from diseases of the mind, which includes the most advanced functions of that brain.

The pendulum is swinging back

We are at a point at which advances in understanding of the neurological roots of mental disorders show that psychiatry is as much anchored in the brain as its sister specialty neurology is.^4-7 See the box for a list of reasons that explain why the reconciliation and reintegration of neurology and psychiatry are accelerating.

Scientific progress has essentially nullified the reasons that led to the separation of psychiatry and neurology. The road to reintegration is littered with obstacles, however—not the least of which is the stubborn “turfishness” that accumulated over decades of alienation. Clinicians and academicians on both sides are entrenched in their habits and beliefs, and will resist changes to their practice and cherished conceptual models. Why? Bridging the chasm will require new clinical training and revisions to educational and residency curricula.

I believe that the majorities on both sides of the chasm understand the merits of abandoning the fallacious dualism of brain and mind and of merging the two disciplines into the neuropsychiatric specialty that our revered founders upheld and practiced. In fact, neuropsychiatry and behavioral neurology disciplines, which emerged in the 1980s, represent the bridges that recognize the cerebral basis of psychiatric disorders and the psychiatric consequences of neurologic lesions.

Just as all ophthalmologists train as ophthalmologists and then subspecialize into corneal specialists, cataract specialists, vitreoretinal specialists, or neuro-ophthalmologists, so can psychiatrists and neurologists train in neuropsychiatry and then subspecialize to become epileptologists, psychosis specialists, vascular neurologists/neurointensivists, mood disorders specialists, neuromuscular specialists, anxiety experts, and so on. Patients will benefit, because every psychiatric patient deserves a full neurological assessment and treatment and every neurologic patient deserves a full psychiatric assessment and treatment.

The unification of diseases of the brain and diseases of the mind will lead to a higher quality of care and will diminish the stigma of mental illness. In addition, novel strategies for brain repair will advance therapeutics for all brain disorders. Because neuropsychiatric disorders are the leading cause of burden of disease worldwide, early recognition and intervention, as well as prevention, are top public health priorities.

Call to action  

The time has come to tear down the silos of neurology and psychiatry and reunify the disciplines, as they were 100 years ago.⁸ Forward-thinking medical schools should seriously consider this initiative and start moving to consolidate clinical brain disorders and mind disorders into one department. The American Board of Psychiatry and Neurology (which, fortunately, remained integrated during the decades of separation) would then revert to the days when board exam candidates were assessed on neurologic and psychiatric patients—as I was, when I sat for my oral boards.

The reintegration of psychiatry and neurology is good and necessary. It’s a no brainer!

Henry A. Nasrallah, MD

Editor-In-Chief

References

1. Yudofsky SC, Hales EH. Neuropsychiatry and the future of psychiatry and neurology. Am J Psychiatry. 2002;159:1261-1263.

2. Boller F, Dalla Barba G. The evolution of psychiatry and neurology: Two disciplines divided by a common goal? In: Jeste DV, Friedman JH, eds. Psychiatry for neurologists. Totowa, NJ: Human Press, Inc.; 2006:11-18.

3. Martin JB. The integration of neurology, psychiatry, and neuroscience in the 21st century. Am J Psychiatry. 2002;159:695-704.

4. Kandel ER. A new intellectual framework for psychiatry. Am J Psychiatry. 1998;155:457-469.

5. Schiffer RB, Bowen B, Hinderliter J, et al. Neuropsychiatry: a management model for academic medicine. J Neuropsychiatry Clin Neurosci. 2004; 16:336-341.

6. Lee TS, Ng BY, Lee WL. Neuropsychiatry: an emerging field. Ann Acad Med Singapore. 2008;37:601-605.

7. Reynolds CF, Lewis DA, Detre T, et al. The future of psychiatry as a nuclear neuroscience. Acad Med. 2009;84:446-450.

8. White PD, Richards H, Zeman HZ. Time to end the distinction between mental and neurological illnesses. BMJ. 2012;344(e3):4540.

A century ago, neurology and psychiatry were one specialty, with unified training, a unified journal (Archives of Neurology and Psychiatry), and a unified board exam through the American Board of Psychiatry and Neurology.^1-3 Kraepelin, Alzheimer, Freud, and Meyer were all neuropsychiatrists who treated patients with all brain disorders—stroke, epilepsy, tertiary syphilis, psychosis, depression, and anxiety. Disorders of the “mind,” such as emotions, thought, or behavior, were rightfully regarded as manifestations of cerebral pathology, and research was based on that model.

That was the rational era, when disorders of the brain and its mind were integrated into one specialty.

Why did psychiatry and neurology drift apart?

Two answers to this question come to mind: 1) Freudian theory and psychoanalysis and 2) the inability to localize the brain “lesion” associated with psychiatric disorders.

Although Freud was a neurologist and psychiatrist, his psychodynamic formulation of human behavior was more speculative than empirical, and his psychoanalytic theory was not evidence-based (to be fair, almost all neurologic disorders lacked any treatment 100 years ago). Furthermore, neuropsychiatry did not have the sophisticated brain assessment tools that are available today to physically localize disorders of thought, affect, or mood in the brain. Knowledge of neurochemistry, receptors, neurotransmitters, and brain circuits was nonexistent—let alone an understanding of molecular and cellular neurobiology. The “mind” was therefore divorced, so to speak, from its physical foundation, the brain, and mental illness was erroneously re-conceptualized as “psychological,” not neurological!

In the 1950s, the American Medical Association’s Archives of Neurology and Psychiatry was split into Archives of Neurology and Archives of General Psychiatry. Since then, the two specialties have drifted apart and reduced to a minimum the overlap of their clinical, educational, and research emphases. Much has been lost over the past five  decades because of the rupture of diseases of the human brain from diseases of the mind, which includes the most advanced functions of that brain.

The pendulum is swinging back

We are at a point at which advances in understanding of the neurological roots of mental disorders show that psychiatry is as much anchored in the brain as its sister specialty neurology is.^4-7 See the box for a list of reasons that explain why the reconciliation and reintegration of neurology and psychiatry are accelerating.

Scientific progress has essentially nullified the reasons that led to the separation of psychiatry and neurology. The road to reintegration is littered with obstacles, however—not the least of which is the stubborn “turfishness” that accumulated over decades of alienation. Clinicians and academicians on both sides are entrenched in their habits and beliefs, and will resist changes to their practice and cherished conceptual models. Why? Bridging the chasm will require new clinical training and revisions to educational and residency curricula.

I believe that the majorities on both sides of the chasm understand the merits of abandoning the fallacious dualism of brain and mind and of merging the two disciplines into the neuropsychiatric specialty that our revered founders upheld and practiced. In fact, neuropsychiatry and behavioral neurology disciplines, which emerged in the 1980s, represent the bridges that recognize the cerebral basis of psychiatric disorders and the psychiatric consequences of neurologic lesions.

Just as all ophthalmologists train as ophthalmologists and then subspecialize into corneal specialists, cataract specialists, vitreoretinal specialists, or neuro-ophthalmologists, so can psychiatrists and neurologists train in neuropsychiatry and then subspecialize to become epileptologists, psychosis specialists, vascular neurologists/neurointensivists, mood disorders specialists, neuromuscular specialists, anxiety experts, and so on. Patients will benefit, because every psychiatric patient deserves a full neurological assessment and treatment and every neurologic patient deserves a full psychiatric assessment and treatment.

The unification of diseases of the brain and diseases of the mind will lead to a higher quality of care and will diminish the stigma of mental illness. In addition, novel strategies for brain repair will advance therapeutics for all brain disorders. Because neuropsychiatric disorders are the leading cause of burden of disease worldwide, early recognition and intervention, as well as prevention, are top public health priorities.

Call to action  

The time has come to tear down the silos of neurology and psychiatry and reunify the disciplines, as they were 100 years ago.⁸ Forward-thinking medical schools should seriously consider this initiative and start moving to consolidate clinical brain disorders and mind disorders into one department. The American Board of Psychiatry and Neurology (which, fortunately, remained integrated during the decades of separation) would then revert to the days when board exam candidates were assessed on neurologic and psychiatric patients—as I was, when I sat for my oral boards.

The reintegration of psychiatry and neurology is good and necessary. It’s a no brainer!

Henry A. Nasrallah, MD

Editor-In-Chief

References

1. Yudofsky SC, Hales EH. Neuropsychiatry and the future of psychiatry and neurology. Am J Psychiatry. 2002;159:1261-1263.

2. Boller F, Dalla Barba G. The evolution of psychiatry and neurology: Two disciplines divided by a common goal? In: Jeste DV, Friedman JH, eds. Psychiatry for neurologists. Totowa, NJ: Human Press, Inc.; 2006:11-18.

3. Martin JB. The integration of neurology, psychiatry, and neuroscience in the 21st century. Am J Psychiatry. 2002;159:695-704.

4. Kandel ER. A new intellectual framework for psychiatry. Am J Psychiatry. 1998;155:457-469.

5. Schiffer RB, Bowen B, Hinderliter J, et al. Neuropsychiatry: a management model for academic medicine. J Neuropsychiatry Clin Neurosci. 2004; 16:336-341.

6. Lee TS, Ng BY, Lee WL. Neuropsychiatry: an emerging field. Ann Acad Med Singapore. 2008;37:601-605.

7. Reynolds CF, Lewis DA, Detre T, et al. The future of psychiatry as a nuclear neuroscience. Acad Med. 2009;84:446-450.

8. White PD, Richards H, Zeman HZ. Time to end the distinction between mental and neurological illnesses. BMJ. 2012;344(e3):4540.

A century ago, neurology and psychiatry were one specialty, with unified training, a unified journal (Archives of Neurology and Psychiatry), and a unified board exam through the American Board of Psychiatry and Neurology.^1-3 Kraepelin, Alzheimer, Freud, and Meyer were all neuropsychiatrists who treated patients with all brain disorders—stroke, epilepsy, tertiary syphilis, psychosis, depression, and anxiety. Disorders of the “mind,” such as emotions, thought, or behavior, were rightfully regarded as manifestations of cerebral pathology, and research was based on that model.

That was the rational era, when disorders of the brain and its mind were integrated into one specialty.

Why did psychiatry and neurology drift apart?

Two answers to this question come to mind: 1) Freudian theory and psychoanalysis and 2) the inability to localize the brain “lesion” associated with psychiatric disorders.

Although Freud was a neurologist and psychiatrist, his psychodynamic formulation of human behavior was more speculative than empirical, and his psychoanalytic theory was not evidence-based (to be fair, almost all neurologic disorders lacked any treatment 100 years ago). Furthermore, neuropsychiatry did not have the sophisticated brain assessment tools that are available today to physically localize disorders of thought, affect, or mood in the brain. Knowledge of neurochemistry, receptors, neurotransmitters, and brain circuits was nonexistent—let alone an understanding of molecular and cellular neurobiology. The “mind” was therefore divorced, so to speak, from its physical foundation, the brain, and mental illness was erroneously re-conceptualized as “psychological,” not neurological!

In the 1950s, the American Medical Association’s Archives of Neurology and Psychiatry was split into Archives of Neurology and Archives of General Psychiatry. Since then, the two specialties have drifted apart and reduced to a minimum the overlap of their clinical, educational, and research emphases. Much has been lost over the past five  decades because of the rupture of diseases of the human brain from diseases of the mind, which includes the most advanced functions of that brain.

The pendulum is swinging back

We are at a point at which advances in understanding of the neurological roots of mental disorders show that psychiatry is as much anchored in the brain as its sister specialty neurology is.^4-7 See the box for a list of reasons that explain why the reconciliation and reintegration of neurology and psychiatry are accelerating.

Scientific progress has essentially nullified the reasons that led to the separation of psychiatry and neurology. The road to reintegration is littered with obstacles, however—not the least of which is the stubborn “turfishness” that accumulated over decades of alienation. Clinicians and academicians on both sides are entrenched in their habits and beliefs, and will resist changes to their practice and cherished conceptual models. Why? Bridging the chasm will require new clinical training and revisions to educational and residency curricula.

I believe that the majorities on both sides of the chasm understand the merits of abandoning the fallacious dualism of brain and mind and of merging the two disciplines into the neuropsychiatric specialty that our revered founders upheld and practiced. In fact, neuropsychiatry and behavioral neurology disciplines, which emerged in the 1980s, represent the bridges that recognize the cerebral basis of psychiatric disorders and the psychiatric consequences of neurologic lesions.

Just as all ophthalmologists train as ophthalmologists and then subspecialize into corneal specialists, cataract specialists, vitreoretinal specialists, or neuro-ophthalmologists, so can psychiatrists and neurologists train in neuropsychiatry and then subspecialize to become epileptologists, psychosis specialists, vascular neurologists/neurointensivists, mood disorders specialists, neuromuscular specialists, anxiety experts, and so on. Patients will benefit, because every psychiatric patient deserves a full neurological assessment and treatment and every neurologic patient deserves a full psychiatric assessment and treatment.

The unification of diseases of the brain and diseases of the mind will lead to a higher quality of care and will diminish the stigma of mental illness. In addition, novel strategies for brain repair will advance therapeutics for all brain disorders. Because neuropsychiatric disorders are the leading cause of burden of disease worldwide, early recognition and intervention, as well as prevention, are top public health priorities.

Call to action  

The time has come to tear down the silos of neurology and psychiatry and reunify the disciplines, as they were 100 years ago.⁸ Forward-thinking medical schools should seriously consider this initiative and start moving to consolidate clinical brain disorders and mind disorders into one department. The American Board of Psychiatry and Neurology (which, fortunately, remained integrated during the decades of separation) would then revert to the days when board exam candidates were assessed on neurologic and psychiatric patients—as I was, when I sat for my oral boards.

The reintegration of psychiatry and neurology is good and necessary. It’s a no brainer!

Henry A. Nasrallah, MD

Editor-In-Chief

References

1. Yudofsky SC, Hales EH. Neuropsychiatry and the future of psychiatry and neurology. Am J Psychiatry. 2002;159:1261-1263.

2. Boller F, Dalla Barba G. The evolution of psychiatry and neurology: Two disciplines divided by a common goal? In: Jeste DV, Friedman JH, eds. Psychiatry for neurologists. Totowa, NJ: Human Press, Inc.; 2006:11-18.

3. Martin JB. The integration of neurology, psychiatry, and neuroscience in the 21st century. Am J Psychiatry. 2002;159:695-704.

4. Kandel ER. A new intellectual framework for psychiatry. Am J Psychiatry. 1998;155:457-469.

5. Schiffer RB, Bowen B, Hinderliter J, et al. Neuropsychiatry: a management model for academic medicine. J Neuropsychiatry Clin Neurosci. 2004; 16:336-341.

6. Lee TS, Ng BY, Lee WL. Neuropsychiatry: an emerging field. Ann Acad Med Singapore. 2008;37:601-605.

7. Reynolds CF, Lewis DA, Detre T, et al. The future of psychiatry as a nuclear neuroscience. Acad Med. 2009;84:446-450.

8. White PD, Richards H, Zeman HZ. Time to end the distinction between mental and neurological illnesses. BMJ. 2012;344(e3):4540.

Few medications remain in use 50 years after they were launched. Advances in drug development often render older drugs obsolete because newer drugs are more efficacious or safer, or both.  Consider reserpine: Nowadays, no internist would use this drug to treat hypertension, even though it was the top-selling antihypertensive 50 years ago. Why? The adverse effects profile is no longer acceptable, with safer alternatives available.

Astonishingly, almost all first-generation psychotropics discovered 5 decades ago (neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors) are still on the formularies of most health care facilities and are used by many clinicians, especially those working with managed care organizations. Jails and prisons in the United States, where hundreds of thousands of seriously mentally ill patients are incarcerated, also use 50-year-old agents, without regard to the downside of older drugs on the body, brain, and quality of life of those incarcerated medically ill patients.

If clinicians who use these decades-old drugs were to keep up with medical research and advances in knowledge, we would realize what a travesty it is to use a brain-unfriendly drug such as haloperidol when we have many safer alternatives. A massive volume of knowledge has emerged over the past 15 years about the neurotoxicity of older neuroleptics, especially haloperidol—knowledge that was completely unknown before.^a Second-generation antipsychotics have been shown to be much safer for the brain than their older-generation counterparts (although they are not more efficacious).

Changing awareness and changing practice

I used haloperidol for 20 years, and can vouch for its unquestionable efficacy in treating delusions and hallucinations. But I have avoided using it over the past 15 years, as the neuroscience literature about its harmful effects on brain tissue emerged and multiplied.

In addition, I came to realize that most psychiatric practitioners were unaware of the alarming deleterious neurologic effects of haloperidol—largely because the studies that reported those effects were published in neuroscience journals rarely read by practicing psychiatrists and nurse practitioners, and the pharmacists in charge of drug formularies at hospitals.

Evidence for the grave neurotoxicity of haloperidol and other older neuroleptics, compared with atypical antipsychotics, is substantial and multifaceted. The FDA would never approve haloperidol today, given the serious harm it can do to the brain, despite its efficacy for psychosis. (It’s interesting how the FDA bans a drug immediately if it causes tragic birth defects, such as thalidomide, but not if a drug is destructive to the brain tissue of a disabled adult patient. Invisible damage can be less alarming or urgent than visible damage.)

Twenty-eight studies reporting the various destructive effects of older antipsychotics (especially haloperidol) on brain tissue have been published in prominent neuroscience journals, based on work in animal models, cell culture, and post-mortem human tissue. Multiple molecular mechanisms, pathways, and cascades are involved, eventuating in neuronal death. The first review and discussion of these 28 neurotoxicity studies was presented at the annual meetings of the Society of Biological Psychiatry¹ and the American Psychiatric Association²; a manuscript will soon be submitted for publication. See the bibliography below for a list of the 28 published studies.

The molecular mechanisms of neurotoxicity of older-generation antipsychotics, including haloperidol, fall into several major categories:

• apoptosis

• necrosis

• decreased cell viability

• inhibition of cell growth

• increased caspase activity (the “death spiral”)

• impaired glutamate transport

• mitochondrial damage.

Examples of specific mechanisms of neurotoxicity among older-generation antipsychotics appear in this Table.

With this massive evidence of the serious neurotoxic effects of haloperidol, should it be banned? The risks of the drug far exceed the benefits—especially given the availability of 9 atypical antipsychotics that have been shown to exert neuroprotective properties, such as inducing neurogenesis and increasing neurotrophic factors.³ One of our foremost duties as medical professionals is to protect patients from harmful treatments that could exacerbate their disability. It’s time to retire this aging neuroleptic.

Few medications remain in use 50 years after they were launched. Advances in drug development often render older drugs obsolete because newer drugs are more efficacious or safer, or both.  Consider reserpine: Nowadays, no internist would use this drug to treat hypertension, even though it was the top-selling antihypertensive 50 years ago. Why? The adverse effects profile is no longer acceptable, with safer alternatives available.

Astonishingly, almost all first-generation psychotropics discovered 5 decades ago (neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors) are still on the formularies of most health care facilities and are used by many clinicians, especially those working with managed care organizations. Jails and prisons in the United States, where hundreds of thousands of seriously mentally ill patients are incarcerated, also use 50-year-old agents, without regard to the downside of older drugs on the body, brain, and quality of life of those incarcerated medically ill patients.

If clinicians who use these decades-old drugs were to keep up with medical research and advances in knowledge, we would realize what a travesty it is to use a brain-unfriendly drug such as haloperidol when we have many safer alternatives. A massive volume of knowledge has emerged over the past 15 years about the neurotoxicity of older neuroleptics, especially haloperidol—knowledge that was completely unknown before.^a Second-generation antipsychotics have been shown to be much safer for the brain than their older-generation counterparts (although they are not more efficacious).

Changing awareness and changing practice

I used haloperidol for 20 years, and can vouch for its unquestionable efficacy in treating delusions and hallucinations. But I have avoided using it over the past 15 years, as the neuroscience literature about its harmful effects on brain tissue emerged and multiplied.

In addition, I came to realize that most psychiatric practitioners were unaware of the alarming deleterious neurologic effects of haloperidol—largely because the studies that reported those effects were published in neuroscience journals rarely read by practicing psychiatrists and nurse practitioners, and the pharmacists in charge of drug formularies at hospitals.

Evidence for the grave neurotoxicity of haloperidol and other older neuroleptics, compared with atypical antipsychotics, is substantial and multifaceted. The FDA would never approve haloperidol today, given the serious harm it can do to the brain, despite its efficacy for psychosis. (It’s interesting how the FDA bans a drug immediately if it causes tragic birth defects, such as thalidomide, but not if a drug is destructive to the brain tissue of a disabled adult patient. Invisible damage can be less alarming or urgent than visible damage.)

Twenty-eight studies reporting the various destructive effects of older antipsychotics (especially haloperidol) on brain tissue have been published in prominent neuroscience journals, based on work in animal models, cell culture, and post-mortem human tissue. Multiple molecular mechanisms, pathways, and cascades are involved, eventuating in neuronal death. The first review and discussion of these 28 neurotoxicity studies was presented at the annual meetings of the Society of Biological Psychiatry¹ and the American Psychiatric Association²; a manuscript will soon be submitted for publication. See the bibliography below for a list of the 28 published studies.

The molecular mechanisms of neurotoxicity of older-generation antipsychotics, including haloperidol, fall into several major categories:

• apoptosis

• necrosis

• decreased cell viability

• inhibition of cell growth

• increased caspase activity (the “death spiral”)

• impaired glutamate transport

• mitochondrial damage.

Examples of specific mechanisms of neurotoxicity among older-generation antipsychotics appear in this Table.

With this massive evidence of the serious neurotoxic effects of haloperidol, should it be banned? The risks of the drug far exceed the benefits—especially given the availability of 9 atypical antipsychotics that have been shown to exert neuroprotective properties, such as inducing neurogenesis and increasing neurotrophic factors.³ One of our foremost duties as medical professionals is to protect patients from harmful treatments that could exacerbate their disability. It’s time to retire this aging neuroleptic.

Few medications remain in use 50 years after they were launched. Advances in drug development often render older drugs obsolete because newer drugs are more efficacious or safer, or both.  Consider reserpine: Nowadays, no internist would use this drug to treat hypertension, even though it was the top-selling antihypertensive 50 years ago. Why? The adverse effects profile is no longer acceptable, with safer alternatives available.

Astonishingly, almost all first-generation psychotropics discovered 5 decades ago (neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors) are still on the formularies of most health care facilities and are used by many clinicians, especially those working with managed care organizations. Jails and prisons in the United States, where hundreds of thousands of seriously mentally ill patients are incarcerated, also use 50-year-old agents, without regard to the downside of older drugs on the body, brain, and quality of life of those incarcerated medically ill patients.

If clinicians who use these decades-old drugs were to keep up with medical research and advances in knowledge, we would realize what a travesty it is to use a brain-unfriendly drug such as haloperidol when we have many safer alternatives. A massive volume of knowledge has emerged over the past 15 years about the neurotoxicity of older neuroleptics, especially haloperidol—knowledge that was completely unknown before.^a Second-generation antipsychotics have been shown to be much safer for the brain than their older-generation counterparts (although they are not more efficacious).

Changing awareness and changing practice

I used haloperidol for 20 years, and can vouch for its unquestionable efficacy in treating delusions and hallucinations. But I have avoided using it over the past 15 years, as the neuroscience literature about its harmful effects on brain tissue emerged and multiplied.

In addition, I came to realize that most psychiatric practitioners were unaware of the alarming deleterious neurologic effects of haloperidol—largely because the studies that reported those effects were published in neuroscience journals rarely read by practicing psychiatrists and nurse practitioners, and the pharmacists in charge of drug formularies at hospitals.

Evidence for the grave neurotoxicity of haloperidol and other older neuroleptics, compared with atypical antipsychotics, is substantial and multifaceted. The FDA would never approve haloperidol today, given the serious harm it can do to the brain, despite its efficacy for psychosis. (It’s interesting how the FDA bans a drug immediately if it causes tragic birth defects, such as thalidomide, but not if a drug is destructive to the brain tissue of a disabled adult patient. Invisible damage can be less alarming or urgent than visible damage.)

Twenty-eight studies reporting the various destructive effects of older antipsychotics (especially haloperidol) on brain tissue have been published in prominent neuroscience journals, based on work in animal models, cell culture, and post-mortem human tissue. Multiple molecular mechanisms, pathways, and cascades are involved, eventuating in neuronal death. The first review and discussion of these 28 neurotoxicity studies was presented at the annual meetings of the Society of Biological Psychiatry¹ and the American Psychiatric Association²; a manuscript will soon be submitted for publication. See the bibliography below for a list of the 28 published studies.

The molecular mechanisms of neurotoxicity of older-generation antipsychotics, including haloperidol, fall into several major categories:

• apoptosis

• necrosis

• decreased cell viability

• inhibition of cell growth

• increased caspase activity (the “death spiral”)

• impaired glutamate transport

• mitochondrial damage.

Examples of specific mechanisms of neurotoxicity among older-generation antipsychotics appear in this Table.

With this massive evidence of the serious neurotoxic effects of haloperidol, should it be banned? The risks of the drug far exceed the benefits—especially given the availability of 9 atypical antipsychotics that have been shown to exert neuroprotective properties, such as inducing neurogenesis and increasing neurotrophic factors.³ One of our foremost duties as medical professionals is to protect patients from harmful treatments that could exacerbate their disability. It’s time to retire this aging neuroleptic.

This mechanism of action (MOA) has been elevated to dogma because no agent has been approved for treating psychosis that does not exert a dopamine D2 receptor antagonist effect. However, as advances in the neurobiology of psychosis accelerate, several other functions of APs have been identified, which can be considered additional MOAs that may help mitigate psychosis’ deleterious effect on brain tissue.

Consider the following beneficial effects of APs (especially second-generation APs [SGAs]) of which many clinicians are unaware:

APs suppress induction of pro-inflammatory cytokines.¹ It is well established that psychotic episodes of schizophrenia are associated with neuroinflammation and elevations of cytokines such as interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and interferon gamma (IFN-α). These inflammatory biomarkers are released by microglia, which are rapidly activated by psychosis² and mediate brain tissue damage during psychosis. APs’ rapid inhibitory action on pro-inflammatory cytokines obviously is neuroprotective.

APs suppress immune-inflammatory pathways.³ This occurs with atypical agents but not haloperidol⁴ and results in decreased IL-1â and IL-6 and transforming growth factor-α.

APs significantly decrease levels of neurotoxic tryptophan catabolites (TRYCATS) such as 3-OHK and QUIN, which mediate the immune-inflammatory effects on neuronal activity. APs also increase levels of neuroprotective TRYCATS such as kynurenic acid.⁵

APs activate cholesterol-transport proteins such as apolipoprotein E (APOE).⁶ This implies that APs may improve low levels of APOE observed during psychosis and decrease myelination abnormalities and mitigate impairment of synaptic plasticity.^7,8

APs increase neurotrophic growth factors that plummet during psychosis, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor.⁹ This beneficial effect is seen with SGAs but not first-generation APs (FGAs) and is attributed to strong serotonin 5HT-2A receptor antagonism by SGAs.¹⁰

SGAs but not FGAs significantly increase the number of newly divided cells in the subventricular zone by 200% to 300%. This enhancement of neurogenesis and increased production of progenitor cells that differentiate into neurons and glia may help regenerate brain tissue lost during psychotic episodes.

Various SGAs have neuroprotective effects:

•  Clozapine has neuroprotective effects against liposaccharide-induced neurodegeneration and reduces microglial activation by limiting production of reactive oxygen species (free radicals).¹¹

•  Aripiprazole inhibits glutamate-induced neurotoxicity and, in contrast to haloperidol, increases BDNF, glycogen synthase kinase (GSK)-α, and the anti-apoptotic protein Bcl-2.

•  Olanzapine increases BDNF, GSK-3α, and α-catenin, increases mitosis in neuronal cell culture, and protects against neuronal death in cell cultures that lack nutrients (which fluphenazine or risperidone do not).

•  Paliperidone demonstrates a higher antioxidant effect than any other SGA and clearly is better than haloperidol, olanzapine, or risperidone in preventing neuronal death when exposed to hydrogen peroxide.

•  Quetiapine, ziprasidone, and lurasidone have inhibitory effects on nitric oxide release. Quetiapine, but not ziprasidone, inhibits TNF-α.

•  Ziprasidone inhibits apoptosis and microglial activation and synthesis of nitric oxide and other free radicals.

•  Lurasidone increases BDNF expression in the prefrontal cortex of rodents.¹³

Although most clinicians uphold the dopamine neurotransmitter model of schizophrenia (ie, a hyperdopaminergic state that requires treatment with dopamine antagonists), research is moving toward a multi-faceted neurotoxicity and neuroprogression model of impaired neuroplasticity, neuroinflammation, immune dysfunction, oxidative stress, nitrosative stress, apoptosis, and mitochondrial dysfunction.¹² This complex model is shaping not only etio-pathological research in schizophrenia but also its future management, including treatment of negative symptoms and cognitive deficits, not just delusions and hallucinations. Interestingly, the only treatment superior to placebo in preventing conversion to psychosis in ultra high-risk prodrome patients is omega-3 fatty acid, a strong anti-inflammatory agent,¹⁴ which suggests that neuroinflammation may precede dopamine overactivity associated with the first psychotic episode. Future treatments of schizophrenia, mania, and depression may focus on more aggressively diminishing inflammation and oxidative/nitrosative stress, not just modulating dopamine or other neurotransmitters, because progressive major psychiatric disorders have been associated with destructive neuroinflammation and an abundance of reactive oxygen species.

References

1. Drzyzga L, Obuchowicz E, Marcinowska A, et al. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun. 2006;20(6):532-545.

2. Monji A, Kato TA, Mizoguchi Y, et al. Neuro-inflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:115-121.

3. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671.

4. Chen SL, Lee SY, Chang YH, et al. Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan.
J Neuroimmune Pharmacol. 2012;7(3):656-664.

5. Myint AM, Schwarz MJ, Verkerk R, et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain Behav Immun. 2011;25(8):1576-1581.

6. Vik-Mo AO, Fernø J, Skrede S, et al. Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS and liver cells. BMC Pharmacol. 2009;9:10.

7. Dean B, Digney A, Sundram S, et al. Plasma apolipoprotein E is decreased in schizophrenia spectrum and bipolar disorder. Psychiatry Res. 2008; 158(1):75-78.

8. Garver DL, Holcomb JA, Christensen JD. Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia. Int J Neuropsychopharmacol. 2008; 11(1):49-61.

9. Chen CC, Huang TL. Effects of antipsychotics on the serum BDNF levels in schizophrenia. Psychiatry Res. 2011;189(3):327-330.

10. Vaidya VA, Marek GJ, Aghajanian GK, et al. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci. 1997;17(8):2785-2795.

11. Hu X, Zhou H, Zhang D, et al. Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. J Neuroimmune Pharmacol. 2012;7(1):187-201.

12. Anderson G, Berk M, Dodd S, et al. Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:1-4.

13. Dodd S, Maes M, Anderson G, et al. Putative neuroprotective agents in neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:135-145.

14. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.

This mechanism of action (MOA) has been elevated to dogma because no agent has been approved for treating psychosis that does not exert a dopamine D2 receptor antagonist effect. However, as advances in the neurobiology of psychosis accelerate, several other functions of APs have been identified, which can be considered additional MOAs that may help mitigate psychosis’ deleterious effect on brain tissue.

Consider the following beneficial effects of APs (especially second-generation APs [SGAs]) of which many clinicians are unaware:

APs suppress induction of pro-inflammatory cytokines.¹ It is well established that psychotic episodes of schizophrenia are associated with neuroinflammation and elevations of cytokines such as interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and interferon gamma (IFN-α). These inflammatory biomarkers are released by microglia, which are rapidly activated by psychosis² and mediate brain tissue damage during psychosis. APs’ rapid inhibitory action on pro-inflammatory cytokines obviously is neuroprotective.

APs suppress immune-inflammatory pathways.³ This occurs with atypical agents but not haloperidol⁴ and results in decreased IL-1â and IL-6 and transforming growth factor-α.

APs significantly decrease levels of neurotoxic tryptophan catabolites (TRYCATS) such as 3-OHK and QUIN, which mediate the immune-inflammatory effects on neuronal activity. APs also increase levels of neuroprotective TRYCATS such as kynurenic acid.⁵

APs activate cholesterol-transport proteins such as apolipoprotein E (APOE).⁶ This implies that APs may improve low levels of APOE observed during psychosis and decrease myelination abnormalities and mitigate impairment of synaptic plasticity.^7,8

APs increase neurotrophic growth factors that plummet during psychosis, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor.⁹ This beneficial effect is seen with SGAs but not first-generation APs (FGAs) and is attributed to strong serotonin 5HT-2A receptor antagonism by SGAs.¹⁰

SGAs but not FGAs significantly increase the number of newly divided cells in the subventricular zone by 200% to 300%. This enhancement of neurogenesis and increased production of progenitor cells that differentiate into neurons and glia may help regenerate brain tissue lost during psychotic episodes.

Various SGAs have neuroprotective effects:

•  Clozapine has neuroprotective effects against liposaccharide-induced neurodegeneration and reduces microglial activation by limiting production of reactive oxygen species (free radicals).¹¹

•  Aripiprazole inhibits glutamate-induced neurotoxicity and, in contrast to haloperidol, increases BDNF, glycogen synthase kinase (GSK)-α, and the anti-apoptotic protein Bcl-2.

•  Olanzapine increases BDNF, GSK-3α, and α-catenin, increases mitosis in neuronal cell culture, and protects against neuronal death in cell cultures that lack nutrients (which fluphenazine or risperidone do not).

•  Paliperidone demonstrates a higher antioxidant effect than any other SGA and clearly is better than haloperidol, olanzapine, or risperidone in preventing neuronal death when exposed to hydrogen peroxide.

•  Quetiapine, ziprasidone, and lurasidone have inhibitory effects on nitric oxide release. Quetiapine, but not ziprasidone, inhibits TNF-α.

•  Ziprasidone inhibits apoptosis and microglial activation and synthesis of nitric oxide and other free radicals.

•  Lurasidone increases BDNF expression in the prefrontal cortex of rodents.¹³

Although most clinicians uphold the dopamine neurotransmitter model of schizophrenia (ie, a hyperdopaminergic state that requires treatment with dopamine antagonists), research is moving toward a multi-faceted neurotoxicity and neuroprogression model of impaired neuroplasticity, neuroinflammation, immune dysfunction, oxidative stress, nitrosative stress, apoptosis, and mitochondrial dysfunction.¹² This complex model is shaping not only etio-pathological research in schizophrenia but also its future management, including treatment of negative symptoms and cognitive deficits, not just delusions and hallucinations. Interestingly, the only treatment superior to placebo in preventing conversion to psychosis in ultra high-risk prodrome patients is omega-3 fatty acid, a strong anti-inflammatory agent,¹⁴ which suggests that neuroinflammation may precede dopamine overactivity associated with the first psychotic episode. Future treatments of schizophrenia, mania, and depression may focus on more aggressively diminishing inflammation and oxidative/nitrosative stress, not just modulating dopamine or other neurotransmitters, because progressive major psychiatric disorders have been associated with destructive neuroinflammation and an abundance of reactive oxygen species.

References

1. Drzyzga L, Obuchowicz E, Marcinowska A, et al. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun. 2006;20(6):532-545.

2. Monji A, Kato TA, Mizoguchi Y, et al. Neuro-inflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:115-121.

3. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671.

4. Chen SL, Lee SY, Chang YH, et al. Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan.
J Neuroimmune Pharmacol. 2012;7(3):656-664.

5. Myint AM, Schwarz MJ, Verkerk R, et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain Behav Immun. 2011;25(8):1576-1581.

6. Vik-Mo AO, Fernø J, Skrede S, et al. Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS and liver cells. BMC Pharmacol. 2009;9:10.

7. Dean B, Digney A, Sundram S, et al. Plasma apolipoprotein E is decreased in schizophrenia spectrum and bipolar disorder. Psychiatry Res. 2008; 158(1):75-78.

8. Garver DL, Holcomb JA, Christensen JD. Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia. Int J Neuropsychopharmacol. 2008; 11(1):49-61.

9. Chen CC, Huang TL. Effects of antipsychotics on the serum BDNF levels in schizophrenia. Psychiatry Res. 2011;189(3):327-330.

10. Vaidya VA, Marek GJ, Aghajanian GK, et al. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci. 1997;17(8):2785-2795.

11. Hu X, Zhou H, Zhang D, et al. Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. J Neuroimmune Pharmacol. 2012;7(1):187-201.

12. Anderson G, Berk M, Dodd S, et al. Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:1-4.

13. Dodd S, Maes M, Anderson G, et al. Putative neuroprotective agents in neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:135-145.

14. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.

This mechanism of action (MOA) has been elevated to dogma because no agent has been approved for treating psychosis that does not exert a dopamine D2 receptor antagonist effect. However, as advances in the neurobiology of psychosis accelerate, several other functions of APs have been identified, which can be considered additional MOAs that may help mitigate psychosis’ deleterious effect on brain tissue.

Consider the following beneficial effects of APs (especially second-generation APs [SGAs]) of which many clinicians are unaware:

APs suppress induction of pro-inflammatory cytokines.¹ It is well established that psychotic episodes of schizophrenia are associated with neuroinflammation and elevations of cytokines such as interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and interferon gamma (IFN-α). These inflammatory biomarkers are released by microglia, which are rapidly activated by psychosis² and mediate brain tissue damage during psychosis. APs’ rapid inhibitory action on pro-inflammatory cytokines obviously is neuroprotective.

APs suppress immune-inflammatory pathways.³ This occurs with atypical agents but not haloperidol⁴ and results in decreased IL-1â and IL-6 and transforming growth factor-α.

APs significantly decrease levels of neurotoxic tryptophan catabolites (TRYCATS) such as 3-OHK and QUIN, which mediate the immune-inflammatory effects on neuronal activity. APs also increase levels of neuroprotective TRYCATS such as kynurenic acid.⁵

APs activate cholesterol-transport proteins such as apolipoprotein E (APOE).⁶ This implies that APs may improve low levels of APOE observed during psychosis and decrease myelination abnormalities and mitigate impairment of synaptic plasticity.^7,8

APs increase neurotrophic growth factors that plummet during psychosis, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor.⁹ This beneficial effect is seen with SGAs but not first-generation APs (FGAs) and is attributed to strong serotonin 5HT-2A receptor antagonism by SGAs.¹⁰

SGAs but not FGAs significantly increase the number of newly divided cells in the subventricular zone by 200% to 300%. This enhancement of neurogenesis and increased production of progenitor cells that differentiate into neurons and glia may help regenerate brain tissue lost during psychotic episodes.

Various SGAs have neuroprotective effects:

•  Clozapine has neuroprotective effects against liposaccharide-induced neurodegeneration and reduces microglial activation by limiting production of reactive oxygen species (free radicals).¹¹

•  Aripiprazole inhibits glutamate-induced neurotoxicity and, in contrast to haloperidol, increases BDNF, glycogen synthase kinase (GSK)-α, and the anti-apoptotic protein Bcl-2.

•  Olanzapine increases BDNF, GSK-3α, and α-catenin, increases mitosis in neuronal cell culture, and protects against neuronal death in cell cultures that lack nutrients (which fluphenazine or risperidone do not).

•  Paliperidone demonstrates a higher antioxidant effect than any other SGA and clearly is better than haloperidol, olanzapine, or risperidone in preventing neuronal death when exposed to hydrogen peroxide.

•  Quetiapine, ziprasidone, and lurasidone have inhibitory effects on nitric oxide release. Quetiapine, but not ziprasidone, inhibits TNF-α.

•  Ziprasidone inhibits apoptosis and microglial activation and synthesis of nitric oxide and other free radicals.

•  Lurasidone increases BDNF expression in the prefrontal cortex of rodents.¹³

Although most clinicians uphold the dopamine neurotransmitter model of schizophrenia (ie, a hyperdopaminergic state that requires treatment with dopamine antagonists), research is moving toward a multi-faceted neurotoxicity and neuroprogression model of impaired neuroplasticity, neuroinflammation, immune dysfunction, oxidative stress, nitrosative stress, apoptosis, and mitochondrial dysfunction.¹² This complex model is shaping not only etio-pathological research in schizophrenia but also its future management, including treatment of negative symptoms and cognitive deficits, not just delusions and hallucinations. Interestingly, the only treatment superior to placebo in preventing conversion to psychosis in ultra high-risk prodrome patients is omega-3 fatty acid, a strong anti-inflammatory agent,¹⁴ which suggests that neuroinflammation may precede dopamine overactivity associated with the first psychotic episode. Future treatments of schizophrenia, mania, and depression may focus on more aggressively diminishing inflammation and oxidative/nitrosative stress, not just modulating dopamine or other neurotransmitters, because progressive major psychiatric disorders have been associated with destructive neuroinflammation and an abundance of reactive oxygen species.

References

1. Drzyzga L, Obuchowicz E, Marcinowska A, et al. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun. 2006;20(6):532-545.

2. Monji A, Kato TA, Mizoguchi Y, et al. Neuro-inflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:115-121.

3. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671.

4. Chen SL, Lee SY, Chang YH, et al. Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan.
J Neuroimmune Pharmacol. 2012;7(3):656-664.

5. Myint AM, Schwarz MJ, Verkerk R, et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain Behav Immun. 2011;25(8):1576-1581.

6. Vik-Mo AO, Fernø J, Skrede S, et al. Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS and liver cells. BMC Pharmacol. 2009;9:10.

7. Dean B, Digney A, Sundram S, et al. Plasma apolipoprotein E is decreased in schizophrenia spectrum and bipolar disorder. Psychiatry Res. 2008; 158(1):75-78.

8. Garver DL, Holcomb JA, Christensen JD. Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia. Int J Neuropsychopharmacol. 2008; 11(1):49-61.

9. Chen CC, Huang TL. Effects of antipsychotics on the serum BDNF levels in schizophrenia. Psychiatry Res. 2011;189(3):327-330.

10. Vaidya VA, Marek GJ, Aghajanian GK, et al. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci. 1997;17(8):2785-2795.

11. Hu X, Zhou H, Zhang D, et al. Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. J Neuroimmune Pharmacol. 2012;7(1):187-201.

12. Anderson G, Berk M, Dodd S, et al. Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:1-4.

13. Dodd S, Maes M, Anderson G, et al. Putative neuroprotective agents in neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:135-145.

14. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.

Staging of medical illness is common in oncology and cardiology, but not in psychiatry. Staging can provide important information about illness severity, appropriate therapeutic intervention for that stage, treatment outcomes, and long-term prognosis.

In psychiatry, clinicians generally give a DSM label to a disorder once symptoms emerge and if it persists, simply categorize it as chronic. It’s time for psychiatry to adopt a clinically meaningful staging schema for its major disorders. Several researchers already have proposed such staging models.

The momentum for staging major psychiatric disorders such as schizophrenia, bipolar disorder (BD), and major depressive disorder is being stoked by 2 major research advances: 1) accelerating recognition and characterization of the prodrome as a preclinical stage of psychiatric disorders, and 2) rapidly accruing neurobiologic discoveries about the deleterious biochemical and neural changes that evolve with each successive episode. However, early attempts and current proposals for staging psychiatric disorders are broadly clinical and descriptive.^1-4

Clinical staging

McGorry et al⁵ have proposed the following staging model:

Stage 0: Increased risk of psychotic or mood disorders, although no symptoms are present.

Stage 1a: Mild, nonspecific symptoms.

Stage 1b: Moderate, subthreshold symptoms.

Stage 2: Onset of first episode of a psychotic or mood disorder.

Stage 3a: Incomplete remission from the first episode.

Stage 3b: Recurrence or relapse of a psychotic or mood disorder.

Stage 3c: Multiple relapses, worsening of clinical severity and impact of illness.

Stage 4: Severe, persistent, or unremitting illness.

Although this is a good start, it does not incorporate the emerging neurobiologic findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state. These pathologies include inflammation, oxidative stress, loss of neurotropic growth factors, and impaired neuroplasticity, all of which result in deleterious neuropathologic progression of damage to key brain circuits. Acute psychotic or mood episodes are recognized to have serious neurotoxic effects, just as myocardial infarction damages the myocardium. This is why patients who experience a first episode of psychosis, mania, or depression must be protected from relapsing: evidence is mounting that second (and certainly subsequent) episodes can be more damaging to the brain than first episodes and would require more aggressive treatment, similar to more advanced cancer stages. This has been well documented clinically, with excellent response to medication and remission in two-thirds of patients with first-episode schizophrenia,⁶ but far lower remission rates after multiple relapses.

Consider the following advances about the adverse neurobiologic events associated with psychotic or mood episodes at various stages of the illness:

In utero, the risk genes, copy number variations, and random mutations in the thousands of genes involved in brain development probably account for smaller brain volume and hypoplasia of certain brain regions.

In the premorbid phase (childhood and early adolescence), negative symptoms and low cognition are evident as asociality and mediocre grades.

In the prodrome phase (mid-to-late adolescence), cortical changes and cognitive decline as well as mood symptoms are more apparent. Only omega-3 fatty acids—but not atypical antipsychotics—prevented a switch to psychosis better than placebo.⁷ This suggests the emergence of a neuroinflammatory process that may respond to omega-3 fatty acids.

In the first psychotic episode, a stunning new finding⁸ reveals brain edema, with a swollen brain and smaller ventricles, caused by water diffusion into extra cellular space of both gray and white matter. Such water diffusion can trigger neuroinflammation and the beginning of serious tissue damage, which can be slowed down by antipsychotics. Increased dopamine activity is associated with an increase of free radicals (oxidative stress) and suppression of growth factors. Glutamate hypofunction, another putative factor in schizophrenia, may be associated with cognitive decline and impaired neuroplasticity.

In the second episode of psychosis, recurrent water diffusion and continued neuroinflammation lead to axonal damage and more serious neurodegeneration.⁸ This confirms the observation of more serious clinical and functional deterioration after the second episode compared with the first, and becomes much worse if the patient does not adhere to treatment and relapses. Drug response also declines, possibly because of neurodegeneration and further oxidative stress,⁹ inflammation, breakdown in white matter, disruption in neuroplasticity, and further dysconnectivity across brain regions.¹⁰

In the treatment-resistant or refractory phase, clozapine is the only agent that has been shown to improve persistent psychotic symptoms. Although its exact mechanism of action remains unknown, recent studies indicate it may be exerting some of its effects by inhibiting microglial activation,¹¹ which is the main pathway for neuroinflammation in degenerative brain disorders.

Ultimately, after multiple episodes the chromosomal telomere becomes shorter in BD and schizophrenia,¹² which is known to predict mortality. This may explain premature death in chronically mentally ill patients (apart from cardiovascular risk factors caused by obesity).

Based on the above, I propose the following clinico-biologic staging model:

Stage 0: Abnormal brain development in utero due to genetic and nongenetic factors.

Stage 1a: Poor premorbid function in childhood (asociality, mediocre school performance).

Stage 1b: The prodrome, with noticeable negative symptoms, cognitive dysfunction, and gray and white matter changes.

Stage 2: First psychotic episode, with delusions and hallucinations, increasing negative symptoms, and marked cognitive decline, accompanied by frontal, parietal, and hippocampal volume losses, white matter pathology, brain edema, inflammatory markers, oxidative stress, and decreased neurotropic growth factors.

Stage 3: Second psychotic episode, with more intense psychotic and negative symptoms, cognitive dysfunction, and worsening social and vocational functioning. Biologic signs include neuroinflammation, oxidative stress and impaired neuroplasticity biomarkers, axonal degeneration and further brain tissue loss, and slower response to antipsychotics.

Stage 4: Several psychotic episodes (subchronic phase), with residual positive and negative symptoms and continued cognitive impairment especially in memory, executive function, attention and verbal learning, accompanied by glial cell death, decline in dendritic spines, retraction or neurite extension, and low response to antipsychotics, with a Global Assessment of Functioning (GAF) score of 30 to 40.

Stage 5: Refractory, unremitting psychosis (chronic phase), with poor response to antipsychotics, severe clinical, social, and functional deterioration, inability to care for oneself, severe neurodegeneration (widespread brain atrophy and dysconnectivity), and GAF score ≤30.

This staging model implies that early intervention to prevent the first or second episode may be the best approach to arrest (and perhaps reverse) psychobiologic deterioration and modify the trajectory of serious psychiatric brain disorders. More can be done to prevent a downhill course in psychosis, and emphasizing the clinical and neurobiologic features of each stage of illness may serve as a roadmap for aggressive treatment approaches early in the illness course. Until a cure is found, prevention and early intervention are the best approaches. Staging models should be incorporated in future versions of the DSM so that psychiatric practitioners can implement the optimal treatment algorithm at the earliest stage possible. Readers’ opinions are welcome!

Staging of medical illness is common in oncology and cardiology, but not in psychiatry. Staging can provide important information about illness severity, appropriate therapeutic intervention for that stage, treatment outcomes, and long-term prognosis.

In psychiatry, clinicians generally give a DSM label to a disorder once symptoms emerge and if it persists, simply categorize it as chronic. It’s time for psychiatry to adopt a clinically meaningful staging schema for its major disorders. Several researchers already have proposed such staging models.

The momentum for staging major psychiatric disorders such as schizophrenia, bipolar disorder (BD), and major depressive disorder is being stoked by 2 major research advances: 1) accelerating recognition and characterization of the prodrome as a preclinical stage of psychiatric disorders, and 2) rapidly accruing neurobiologic discoveries about the deleterious biochemical and neural changes that evolve with each successive episode. However, early attempts and current proposals for staging psychiatric disorders are broadly clinical and descriptive.^1-4

Clinical staging

McGorry et al⁵ have proposed the following staging model:

Stage 0: Increased risk of psychotic or mood disorders, although no symptoms are present.

Stage 1a: Mild, nonspecific symptoms.

Stage 1b: Moderate, subthreshold symptoms.

Stage 2: Onset of first episode of a psychotic or mood disorder.

Stage 3a: Incomplete remission from the first episode.

Stage 3b: Recurrence or relapse of a psychotic or mood disorder.

Stage 3c: Multiple relapses, worsening of clinical severity and impact of illness.

Stage 4: Severe, persistent, or unremitting illness.

Although this is a good start, it does not incorporate the emerging neurobiologic findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state. These pathologies include inflammation, oxidative stress, loss of neurotropic growth factors, and impaired neuroplasticity, all of which result in deleterious neuropathologic progression of damage to key brain circuits. Acute psychotic or mood episodes are recognized to have serious neurotoxic effects, just as myocardial infarction damages the myocardium. This is why patients who experience a first episode of psychosis, mania, or depression must be protected from relapsing: evidence is mounting that second (and certainly subsequent) episodes can be more damaging to the brain than first episodes and would require more aggressive treatment, similar to more advanced cancer stages. This has been well documented clinically, with excellent response to medication and remission in two-thirds of patients with first-episode schizophrenia,⁶ but far lower remission rates after multiple relapses.

Consider the following advances about the adverse neurobiologic events associated with psychotic or mood episodes at various stages of the illness:

In utero, the risk genes, copy number variations, and random mutations in the thousands of genes involved in brain development probably account for smaller brain volume and hypoplasia of certain brain regions.

In the premorbid phase (childhood and early adolescence), negative symptoms and low cognition are evident as asociality and mediocre grades.

In the prodrome phase (mid-to-late adolescence), cortical changes and cognitive decline as well as mood symptoms are more apparent. Only omega-3 fatty acids—but not atypical antipsychotics—prevented a switch to psychosis better than placebo.⁷ This suggests the emergence of a neuroinflammatory process that may respond to omega-3 fatty acids.

In the first psychotic episode, a stunning new finding⁸ reveals brain edema, with a swollen brain and smaller ventricles, caused by water diffusion into extra cellular space of both gray and white matter. Such water diffusion can trigger neuroinflammation and the beginning of serious tissue damage, which can be slowed down by antipsychotics. Increased dopamine activity is associated with an increase of free radicals (oxidative stress) and suppression of growth factors. Glutamate hypofunction, another putative factor in schizophrenia, may be associated with cognitive decline and impaired neuroplasticity.

In the second episode of psychosis, recurrent water diffusion and continued neuroinflammation lead to axonal damage and more serious neurodegeneration.⁸ This confirms the observation of more serious clinical and functional deterioration after the second episode compared with the first, and becomes much worse if the patient does not adhere to treatment and relapses. Drug response also declines, possibly because of neurodegeneration and further oxidative stress,⁹ inflammation, breakdown in white matter, disruption in neuroplasticity, and further dysconnectivity across brain regions.¹⁰

In the treatment-resistant or refractory phase, clozapine is the only agent that has been shown to improve persistent psychotic symptoms. Although its exact mechanism of action remains unknown, recent studies indicate it may be exerting some of its effects by inhibiting microglial activation,¹¹ which is the main pathway for neuroinflammation in degenerative brain disorders.

Ultimately, after multiple episodes the chromosomal telomere becomes shorter in BD and schizophrenia,¹² which is known to predict mortality. This may explain premature death in chronically mentally ill patients (apart from cardiovascular risk factors caused by obesity).

Based on the above, I propose the following clinico-biologic staging model:

Stage 0: Abnormal brain development in utero due to genetic and nongenetic factors.

Stage 1a: Poor premorbid function in childhood (asociality, mediocre school performance).

Stage 1b: The prodrome, with noticeable negative symptoms, cognitive dysfunction, and gray and white matter changes.

Stage 2: First psychotic episode, with delusions and hallucinations, increasing negative symptoms, and marked cognitive decline, accompanied by frontal, parietal, and hippocampal volume losses, white matter pathology, brain edema, inflammatory markers, oxidative stress, and decreased neurotropic growth factors.

Stage 3: Second psychotic episode, with more intense psychotic and negative symptoms, cognitive dysfunction, and worsening social and vocational functioning. Biologic signs include neuroinflammation, oxidative stress and impaired neuroplasticity biomarkers, axonal degeneration and further brain tissue loss, and slower response to antipsychotics.

Stage 4: Several psychotic episodes (subchronic phase), with residual positive and negative symptoms and continued cognitive impairment especially in memory, executive function, attention and verbal learning, accompanied by glial cell death, decline in dendritic spines, retraction or neurite extension, and low response to antipsychotics, with a Global Assessment of Functioning (GAF) score of 30 to 40.

Stage 5: Refractory, unremitting psychosis (chronic phase), with poor response to antipsychotics, severe clinical, social, and functional deterioration, inability to care for oneself, severe neurodegeneration (widespread brain atrophy and dysconnectivity), and GAF score ≤30.

This staging model implies that early intervention to prevent the first or second episode may be the best approach to arrest (and perhaps reverse) psychobiologic deterioration and modify the trajectory of serious psychiatric brain disorders. More can be done to prevent a downhill course in psychosis, and emphasizing the clinical and neurobiologic features of each stage of illness may serve as a roadmap for aggressive treatment approaches early in the illness course. Until a cure is found, prevention and early intervention are the best approaches. Staging models should be incorporated in future versions of the DSM so that psychiatric practitioners can implement the optimal treatment algorithm at the earliest stage possible. Readers’ opinions are welcome!

Staging of medical illness is common in oncology and cardiology, but not in psychiatry. Staging can provide important information about illness severity, appropriate therapeutic intervention for that stage, treatment outcomes, and long-term prognosis.

In psychiatry, clinicians generally give a DSM label to a disorder once symptoms emerge and if it persists, simply categorize it as chronic. It’s time for psychiatry to adopt a clinically meaningful staging schema for its major disorders. Several researchers already have proposed such staging models.

The momentum for staging major psychiatric disorders such as schizophrenia, bipolar disorder (BD), and major depressive disorder is being stoked by 2 major research advances: 1) accelerating recognition and characterization of the prodrome as a preclinical stage of psychiatric disorders, and 2) rapidly accruing neurobiologic discoveries about the deleterious biochemical and neural changes that evolve with each successive episode. However, early attempts and current proposals for staging psychiatric disorders are broadly clinical and descriptive.^1-4

Clinical staging

McGorry et al⁵ have proposed the following staging model:

Stage 0: Increased risk of psychotic or mood disorders, although no symptoms are present.

Stage 1a: Mild, nonspecific symptoms.

Stage 1b: Moderate, subthreshold symptoms.

Stage 2: Onset of first episode of a psychotic or mood disorder.

Stage 3a: Incomplete remission from the first episode.

Stage 3b: Recurrence or relapse of a psychotic or mood disorder.

Stage 3c: Multiple relapses, worsening of clinical severity and impact of illness.

Stage 4: Severe, persistent, or unremitting illness.

Although this is a good start, it does not incorporate the emerging neurobiologic findings of progressive psychotic and mood disorders from the preclinical stage to chronic deteriorative state. These pathologies include inflammation, oxidative stress, loss of neurotropic growth factors, and impaired neuroplasticity, all of which result in deleterious neuropathologic progression of damage to key brain circuits. Acute psychotic or mood episodes are recognized to have serious neurotoxic effects, just as myocardial infarction damages the myocardium. This is why patients who experience a first episode of psychosis, mania, or depression must be protected from relapsing: evidence is mounting that second (and certainly subsequent) episodes can be more damaging to the brain than first episodes and would require more aggressive treatment, similar to more advanced cancer stages. This has been well documented clinically, with excellent response to medication and remission in two-thirds of patients with first-episode schizophrenia,⁶ but far lower remission rates after multiple relapses.

Consider the following advances about the adverse neurobiologic events associated with psychotic or mood episodes at various stages of the illness:

In utero, the risk genes, copy number variations, and random mutations in the thousands of genes involved in brain development probably account for smaller brain volume and hypoplasia of certain brain regions.

In the premorbid phase (childhood and early adolescence), negative symptoms and low cognition are evident as asociality and mediocre grades.

In the prodrome phase (mid-to-late adolescence), cortical changes and cognitive decline as well as mood symptoms are more apparent. Only omega-3 fatty acids—but not atypical antipsychotics—prevented a switch to psychosis better than placebo.⁷ This suggests the emergence of a neuroinflammatory process that may respond to omega-3 fatty acids.

In the first psychotic episode, a stunning new finding⁸ reveals brain edema, with a swollen brain and smaller ventricles, caused by water diffusion into extra cellular space of both gray and white matter. Such water diffusion can trigger neuroinflammation and the beginning of serious tissue damage, which can be slowed down by antipsychotics. Increased dopamine activity is associated with an increase of free radicals (oxidative stress) and suppression of growth factors. Glutamate hypofunction, another putative factor in schizophrenia, may be associated with cognitive decline and impaired neuroplasticity.

In the second episode of psychosis, recurrent water diffusion and continued neuroinflammation lead to axonal damage and more serious neurodegeneration.⁸ This confirms the observation of more serious clinical and functional deterioration after the second episode compared with the first, and becomes much worse if the patient does not adhere to treatment and relapses. Drug response also declines, possibly because of neurodegeneration and further oxidative stress,⁹ inflammation, breakdown in white matter, disruption in neuroplasticity, and further dysconnectivity across brain regions.¹⁰

In the treatment-resistant or refractory phase, clozapine is the only agent that has been shown to improve persistent psychotic symptoms. Although its exact mechanism of action remains unknown, recent studies indicate it may be exerting some of its effects by inhibiting microglial activation,¹¹ which is the main pathway for neuroinflammation in degenerative brain disorders.

Ultimately, after multiple episodes the chromosomal telomere becomes shorter in BD and schizophrenia,¹² which is known to predict mortality. This may explain premature death in chronically mentally ill patients (apart from cardiovascular risk factors caused by obesity).

Based on the above, I propose the following clinico-biologic staging model:

Stage 0: Abnormal brain development in utero due to genetic and nongenetic factors.

Stage 1a: Poor premorbid function in childhood (asociality, mediocre school performance).

Stage 1b: The prodrome, with noticeable negative symptoms, cognitive dysfunction, and gray and white matter changes.

Stage 2: First psychotic episode, with delusions and hallucinations, increasing negative symptoms, and marked cognitive decline, accompanied by frontal, parietal, and hippocampal volume losses, white matter pathology, brain edema, inflammatory markers, oxidative stress, and decreased neurotropic growth factors.

Stage 3: Second psychotic episode, with more intense psychotic and negative symptoms, cognitive dysfunction, and worsening social and vocational functioning. Biologic signs include neuroinflammation, oxidative stress and impaired neuroplasticity biomarkers, axonal degeneration and further brain tissue loss, and slower response to antipsychotics.

Stage 4: Several psychotic episodes (subchronic phase), with residual positive and negative symptoms and continued cognitive impairment especially in memory, executive function, attention and verbal learning, accompanied by glial cell death, decline in dendritic spines, retraction or neurite extension, and low response to antipsychotics, with a Global Assessment of Functioning (GAF) score of 30 to 40.

Stage 5: Refractory, unremitting psychosis (chronic phase), with poor response to antipsychotics, severe clinical, social, and functional deterioration, inability to care for oneself, severe neurodegeneration (widespread brain atrophy and dysconnectivity), and GAF score ≤30.

This staging model implies that early intervention to prevent the first or second episode may be the best approach to arrest (and perhaps reverse) psychobiologic deterioration and modify the trajectory of serious psychiatric brain disorders. More can be done to prevent a downhill course in psychosis, and emphasizing the clinical and neurobiologic features of each stage of illness may serve as a roadmap for aggressive treatment approaches early in the illness course. Until a cure is found, prevention and early intervention are the best approaches. Staging models should be incorporated in future versions of the DSM so that psychiatric practitioners can implement the optimal treatment algorithm at the earliest stage possible. Readers’ opinions are welcome!

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

The lack of laboratory tests to validate the clinical diagnosis of schizophrenia is widely accepted and lamented by psychiatric practitioners. In a recent survey I conducted on CurrentPsychiatry.com, most respondents guessed there are 3 known biomarkers for schizophrenia and 4 for major depression.

The media’s view tends to be harsh, exploiting the ostensible absence of diagnostic biomarkers in psychiatry to cast unfair aspersions on the scientific validity of DSM-5 and its diagnostic guidelines.¹ They seem to believe that lab tests for mental illness will never be feasible. Clearly, they have not done their homework.

Consider schizophrenia. It would come as a surprise to most people inside or outside the psychiatric community that 365 biomarkers for schizophrenia have been discovered, 273 of which are identifiable in plasma.² Of these, 81 are diagnostic, 77 are markers of drug response, and 115 are for both. Some of these tests have been replicated at least 5 times (brain-derived neurotrophic factor, S100B, prolactin, interleukin (IL) 6, IL2, IN5, leptin, IL 1 receptor antagonist, IL8, and IL2 receptor α). The biologic functions of these 273 biomarkers include inflammatory disease or response, respiratory disease, cellular movement, lipid metabolism, molecular transport, immunologic disease, hematologic disease, renal and urologic disease, cell-to-cell signaling, cellular growth and proliferation, cardiovascular disease, genetic disorders, psychological disorders, metabolic disease, small molecule biochemistry, molecular transport, nutritional disease, endocrine system disorders, cell death, tissue morphology, organismal survival, lymphoid tissue structure and development, antigen presentation, tissue development, carbohydrate metabolism, organ morphology, embryonic development, behavior, and digestive system development and functions.² Obviously, schizophrenia biomarkers overlap with multiple tissues and key biochemical and cellular processes in brain and body.

So why do none of these 273 blood tests appear in DSM-5, which had aspired to include objective methods in psychiatric diagnosis? The answer: heterogeneity. Schizophrenia and other major psychiatric illnesses are not 1 disorder but syndromes comprised of numerous clinically similar but biologically different disorders. There is extensive variability among the “schizophrenias” in genetic and nongenetic etiological factors and significant heterogeneity in neurobiology, treatment response, and clinical and functional outcomes. None of the individual 273 biomarkers alone can serve as a diagnostic tool for the schizophrenias because there will be high rates of false positives and false negatives. A lab test for a syndrome is impossible!

One company recently attempted to develop a blood test for schizophrenia. It used 51 biomarkers to comprise that test because none of them alone is a viable test (Table).³ The totality of the 51 biomarkers significantly increases the likelihood of diagnostic utility but still will be short of 100% specificity.

What is the point of identifying 273 blood tests if they have not been used to diagnose a heterogeneous syndrome? I believe there are many potentially useful applications for these biomarkers:

• To identify biologic subtypes of schizophrenia
• To shed light on the multiple pathophysiologies of schizophrenia, which may provide valuable clues for new treatments
• To help identify and characterize stages of schizophrenia. Some biomarkers have been found in the early stages, while others appear only in the chronic stages
• To help predict biologic predisposition to 1 of the schizophrenias. It is possible that the various susceptibility genes that have been identified in schizophrenia may be associated with certain biomarkers during fetal neurodevelopment, childhood, or the prodrome stage
• To explore the overlapping biologic features of psychotic disorders. For example, 21 biomarkers have been found to differentiate schizophrenia or bipolar disorder from healthy controls. Some biomarkers may point to the likelihood of psychiatric comorbidities such as depression or obsessive-compulsive disorder or medical comorbidities such as cardiovascular, immunologic, or gastrointestinal diseases
• Some biomarkers may identify state (ie, the psychotic phase only) vs trait (throughout life). Other biomarkers may be associated with the presence of a specific type of hallucination (auditory, visual, olfactory, or gustatory), delusion (bizarre vs simple), negative symptom (flat affect vs apathy vs avolition) or cognitive deficit (verbal memory vs learning deficit vs executive dysfunction)
• Biomarkers may assist in developing personalized medicine and designing customized evaluations and treatments for patients suffering from 1 of the many schizophrenias.

Lab tests for psychiatric disorders are indeed available but their use will not mirror traditional physical exam tests. The complex heterogeneity of most psychiatric syndromes means that biomarkers will help unravel the rich neurobiology of those disorders and help elucidate the multiple neurobiologic underpinnings of these syndromes. Psychiatrists should look forward with great optimism to a bright future for psychiatric diagnosis, combining a set of clinical signs and symptoms with a confirmatory cluster of lab tests. It may take time, but psychiatric clinicians will be using biomarkers in the future and the media and the public finally will perceive psychiatry as a “mature” medical discipline.

In the survey I mentioned at the beginning of this editorial, 60.5% of responders predicted that the DSM-6 (approximately a decade from now) will contain laboratory tests for psychiatric diagnosis. They may very well be right!

Table

Biomarkers for schizophrenia

The lack of laboratory tests to validate the clinical diagnosis of schizophrenia is widely accepted and lamented by psychiatric practitioners. In a recent survey I conducted on CurrentPsychiatry.com, most respondents guessed there are 3 known biomarkers for schizophrenia and 4 for major depression.

The media’s view tends to be harsh, exploiting the ostensible absence of diagnostic biomarkers in psychiatry to cast unfair aspersions on the scientific validity of DSM-5 and its diagnostic guidelines.¹ They seem to believe that lab tests for mental illness will never be feasible. Clearly, they have not done their homework.

Consider schizophrenia. It would come as a surprise to most people inside or outside the psychiatric community that 365 biomarkers for schizophrenia have been discovered, 273 of which are identifiable in plasma.² Of these, 81 are diagnostic, 77 are markers of drug response, and 115 are for both. Some of these tests have been replicated at least 5 times (brain-derived neurotrophic factor, S100B, prolactin, interleukin (IL) 6, IL2, IN5, leptin, IL 1 receptor antagonist, IL8, and IL2 receptor α). The biologic functions of these 273 biomarkers include inflammatory disease or response, respiratory disease, cellular movement, lipid metabolism, molecular transport, immunologic disease, hematologic disease, renal and urologic disease, cell-to-cell signaling, cellular growth and proliferation, cardiovascular disease, genetic disorders, psychological disorders, metabolic disease, small molecule biochemistry, molecular transport, nutritional disease, endocrine system disorders, cell death, tissue morphology, organismal survival, lymphoid tissue structure and development, antigen presentation, tissue development, carbohydrate metabolism, organ morphology, embryonic development, behavior, and digestive system development and functions.² Obviously, schizophrenia biomarkers overlap with multiple tissues and key biochemical and cellular processes in brain and body.

So why do none of these 273 blood tests appear in DSM-5, which had aspired to include objective methods in psychiatric diagnosis? The answer: heterogeneity. Schizophrenia and other major psychiatric illnesses are not 1 disorder but syndromes comprised of numerous clinically similar but biologically different disorders. There is extensive variability among the “schizophrenias” in genetic and nongenetic etiological factors and significant heterogeneity in neurobiology, treatment response, and clinical and functional outcomes. None of the individual 273 biomarkers alone can serve as a diagnostic tool for the schizophrenias because there will be high rates of false positives and false negatives. A lab test for a syndrome is impossible!

One company recently attempted to develop a blood test for schizophrenia. It used 51 biomarkers to comprise that test because none of them alone is a viable test (Table).³ The totality of the 51 biomarkers significantly increases the likelihood of diagnostic utility but still will be short of 100% specificity.

What is the point of identifying 273 blood tests if they have not been used to diagnose a heterogeneous syndrome? I believe there are many potentially useful applications for these biomarkers:

• To identify biologic subtypes of schizophrenia
• To shed light on the multiple pathophysiologies of schizophrenia, which may provide valuable clues for new treatments
• To help identify and characterize stages of schizophrenia. Some biomarkers have been found in the early stages, while others appear only in the chronic stages
• To help predict biologic predisposition to 1 of the schizophrenias. It is possible that the various susceptibility genes that have been identified in schizophrenia may be associated with certain biomarkers during fetal neurodevelopment, childhood, or the prodrome stage
• To explore the overlapping biologic features of psychotic disorders. For example, 21 biomarkers have been found to differentiate schizophrenia or bipolar disorder from healthy controls. Some biomarkers may point to the likelihood of psychiatric comorbidities such as depression or obsessive-compulsive disorder or medical comorbidities such as cardiovascular, immunologic, or gastrointestinal diseases
• Some biomarkers may identify state (ie, the psychotic phase only) vs trait (throughout life). Other biomarkers may be associated with the presence of a specific type of hallucination (auditory, visual, olfactory, or gustatory), delusion (bizarre vs simple), negative symptom (flat affect vs apathy vs avolition) or cognitive deficit (verbal memory vs learning deficit vs executive dysfunction)
• Biomarkers may assist in developing personalized medicine and designing customized evaluations and treatments for patients suffering from 1 of the many schizophrenias.

Lab tests for psychiatric disorders are indeed available but their use will not mirror traditional physical exam tests. The complex heterogeneity of most psychiatric syndromes means that biomarkers will help unravel the rich neurobiology of those disorders and help elucidate the multiple neurobiologic underpinnings of these syndromes. Psychiatrists should look forward with great optimism to a bright future for psychiatric diagnosis, combining a set of clinical signs and symptoms with a confirmatory cluster of lab tests. It may take time, but psychiatric clinicians will be using biomarkers in the future and the media and the public finally will perceive psychiatry as a “mature” medical discipline.

In the survey I mentioned at the beginning of this editorial, 60.5% of responders predicted that the DSM-6 (approximately a decade from now) will contain laboratory tests for psychiatric diagnosis. They may very well be right!

Table

Biomarkers for schizophrenia

The lack of laboratory tests to validate the clinical diagnosis of schizophrenia is widely accepted and lamented by psychiatric practitioners. In a recent survey I conducted on CurrentPsychiatry.com, most respondents guessed there are 3 known biomarkers for schizophrenia and 4 for major depression.

The media’s view tends to be harsh, exploiting the ostensible absence of diagnostic biomarkers in psychiatry to cast unfair aspersions on the scientific validity of DSM-5 and its diagnostic guidelines.¹ They seem to believe that lab tests for mental illness will never be feasible. Clearly, they have not done their homework.

Consider schizophrenia. It would come as a surprise to most people inside or outside the psychiatric community that 365 biomarkers for schizophrenia have been discovered, 273 of which are identifiable in plasma.² Of these, 81 are diagnostic, 77 are markers of drug response, and 115 are for both. Some of these tests have been replicated at least 5 times (brain-derived neurotrophic factor, S100B, prolactin, interleukin (IL) 6, IL2, IN5, leptin, IL 1 receptor antagonist, IL8, and IL2 receptor α). The biologic functions of these 273 biomarkers include inflammatory disease or response, respiratory disease, cellular movement, lipid metabolism, molecular transport, immunologic disease, hematologic disease, renal and urologic disease, cell-to-cell signaling, cellular growth and proliferation, cardiovascular disease, genetic disorders, psychological disorders, metabolic disease, small molecule biochemistry, molecular transport, nutritional disease, endocrine system disorders, cell death, tissue morphology, organismal survival, lymphoid tissue structure and development, antigen presentation, tissue development, carbohydrate metabolism, organ morphology, embryonic development, behavior, and digestive system development and functions.² Obviously, schizophrenia biomarkers overlap with multiple tissues and key biochemical and cellular processes in brain and body.

So why do none of these 273 blood tests appear in DSM-5, which had aspired to include objective methods in psychiatric diagnosis? The answer: heterogeneity. Schizophrenia and other major psychiatric illnesses are not 1 disorder but syndromes comprised of numerous clinically similar but biologically different disorders. There is extensive variability among the “schizophrenias” in genetic and nongenetic etiological factors and significant heterogeneity in neurobiology, treatment response, and clinical and functional outcomes. None of the individual 273 biomarkers alone can serve as a diagnostic tool for the schizophrenias because there will be high rates of false positives and false negatives. A lab test for a syndrome is impossible!

One company recently attempted to develop a blood test for schizophrenia. It used 51 biomarkers to comprise that test because none of them alone is a viable test (Table).³ The totality of the 51 biomarkers significantly increases the likelihood of diagnostic utility but still will be short of 100% specificity.

What is the point of identifying 273 blood tests if they have not been used to diagnose a heterogeneous syndrome? I believe there are many potentially useful applications for these biomarkers:

• To identify biologic subtypes of schizophrenia
• To shed light on the multiple pathophysiologies of schizophrenia, which may provide valuable clues for new treatments
• To help identify and characterize stages of schizophrenia. Some biomarkers have been found in the early stages, while others appear only in the chronic stages
• To help predict biologic predisposition to 1 of the schizophrenias. It is possible that the various susceptibility genes that have been identified in schizophrenia may be associated with certain biomarkers during fetal neurodevelopment, childhood, or the prodrome stage
• To explore the overlapping biologic features of psychotic disorders. For example, 21 biomarkers have been found to differentiate schizophrenia or bipolar disorder from healthy controls. Some biomarkers may point to the likelihood of psychiatric comorbidities such as depression or obsessive-compulsive disorder or medical comorbidities such as cardiovascular, immunologic, or gastrointestinal diseases
• Some biomarkers may identify state (ie, the psychotic phase only) vs trait (throughout life). Other biomarkers may be associated with the presence of a specific type of hallucination (auditory, visual, olfactory, or gustatory), delusion (bizarre vs simple), negative symptom (flat affect vs apathy vs avolition) or cognitive deficit (verbal memory vs learning deficit vs executive dysfunction)
• Biomarkers may assist in developing personalized medicine and designing customized evaluations and treatments for patients suffering from 1 of the many schizophrenias.

Lab tests for psychiatric disorders are indeed available but their use will not mirror traditional physical exam tests. The complex heterogeneity of most psychiatric syndromes means that biomarkers will help unravel the rich neurobiology of those disorders and help elucidate the multiple neurobiologic underpinnings of these syndromes. Psychiatrists should look forward with great optimism to a bright future for psychiatric diagnosis, combining a set of clinical signs and symptoms with a confirmatory cluster of lab tests. It may take time, but psychiatric clinicians will be using biomarkers in the future and the media and the public finally will perceive psychiatry as a “mature” medical discipline.

In the survey I mentioned at the beginning of this editorial, 60.5% of responders predicted that the DSM-6 (approximately a decade from now) will contain laboratory tests for psychiatric diagnosis. They may very well be right!

Table

Biomarkers for schizophrenia