Henry A. Nasrallah, MD

Recently, my umbrage at these prac­tices soared to a new height when a col­league told me that he had to fight for, and then wait to receive, permission from an insurance employee to increase, by a notch, the maintenance dosage of a long-acting antipsychotic for his patient.

Can anyone justify why an absentee person who has never met the patient should, sight-unseen, second-guess our clinical judgment that a patient’s symptoms are still not well-controlled and require upward adjustment of the dosage? Why are insurance compa­nies allowed to micromanage clinical decision-making? Such outrageous intrusiveness is a signal that insur­ance companies have “jumped the shark” in their effort to push business interests ahead of the needs of their subscribers.

Whose interests are being put first?
I recall instances when I refused to buckle to pressure from a patient’s third-party payer to switch from 1 antidepres­sant to another, a move that would save the insurer money but put my patient at risk of relapse. I informed the insurance company representative that my attor­ney was going to file a lawsuit on behalf of my depressed patient if he were to relapse or attempt suicide because he had been switched from an antidepres­sant that was working to another that might not.

Fighting back paid off: In each case, I was told the payer would “make an exception” for that patient.

Frustrations of this kind have become commonplace in psychiatric practice. They tend to detract from the stimulat­ing and gratifying aspects of the care we provide, and reinforce the perception that insurance companies’ primary goal is to fatten profits, not facilitate patients’ return to health.

Here are other reasons for chronic frustration in psychiatric practice. They reflect serious, unmet needs that we hope will be resolved soon.

Improved diagnostic schema. We need a valid—and more than simply reliable—evidence-based diagnostic system that is rooted in scientifically established pathophysiology. The basic clinical elements of DSM-5 should be gradually amalgamated with rap­idly emerging genetics and biological endophenotypes. The continuum of and boundary between “normal” and “pathologic” human behavior should be further clarified.

Biomarkers. Our field eagerly awaits development of biomarkers (laboratory tests) to bolster psychiatric practice in several ways, including:
   • confirming the clinical diagnosis
   • identifying biological subtypes
   • monitoring response
   • guiding selection of drugs
   • predicting side effects
   • measuring severity of disease.

Elusive parity. We’ve been patient, but we’re tired and angry at empty prom­ises of full parity for psychiatric care. We’ve also had it with the stigmatizing and discriminatory “carve-out” status that allows insurance companies to treat reimbursement for psychiatric services more restrictively than for other medical and surgical specialties. Policy makers must end the egregious discrimination that gives half a loaf to some brain disorders (psychiatric) and a full loaf to other brain disorders (neurologic).

Better medications. We need a stron­ger commitment from the pharma­ceutical industry, on which we rely entirely for development of psycho­active drugs, to wage a relentless war on serious mental illness. The private sector should accelerate translation of groundbreaking neuroscientific dis­coveries—thanks to research funded by the public sector, such as the National Institutes of Health—into innovative new mechanisms of action. Patients who suffer from psychiatric brain disorders for which there are no approved treatments await that com­mitment and bold action.

Collaborative care. Psychiatry needs a more consistent, more produc­tive bidirectional relationship with primary care. A stronger bond will improve the care of patients on both sides and would, I believe, increase the satisfaction of clinical practice for both specialists. Because structure can facilitate function, co-locating provid­ers can help achieve this vision.

Legal entanglement. Psychiatry must be unshackled from an oppres­sive set of laws that tie our hands when we treat patients with brain pathology who are incapable of under­standing their illness and their need to be treated. Those laws were imposed long before scientific advances showed that prolonged and untreated episodes of psychosis, mania, depres­sion, and anxiety are associated with neurotoxic processes (neuroinflam­mation, oxidative and nitrosative stress). Medical urgency and patient protection must trump legalisms, just as unconscious stroke and myocardial infarction patients are treated immedi­ately without filing multiple forms or waiting for a court order.

Another legal beef: We psychiatrists are exasperated with the expand­ing criminalization of our patients— hapless victims of brain diseases that impair their reality testing and behav­ior. Should a person who suffers a first epileptic seizure or a stroke while driv­ing and kills the driver of an oncom­ing car be incarcerated with hardened murderers and rapists and treated for epilepsy in a prison instead of a neu­rology ward? Our patients belong in a secure hospital, a medical asylum, where they are given compassionate medical care, not the degrading treat­ment afforded to a felon.

More resources. There is a dire need for psychiatric hospital beds in many parts of the country, because many wards were closed and renovated into more profitable, procedure-oriented specialties. There also is a severe short­age of psychiatrists in our country, as I discussed in my editorial, “Signs, symptoms, and treatment of psychia­trynemia,” (December 2014). The 25% of the population who suffer a mental disorder are clearly underserved at this time.

Furthermore, because today’s research is tomorrow’s new treatment, funding for psychiatric research must increase substantially to find cures and to thus reduce huge direct and indirect costs of mental illness and addictions.

Public enlightenment. A well-informed populace would be a major boon to our sophisticated medical specialty, which remains shrouded by primitive beliefs and archaic attitudes. For many people who desperately need mental health care, negative perceptions of psychiatric disorders and their treat­ment are a major impediment to seek­ing help. Psychiatrists can catalyze the process of enlightenment by dedicating time to elevating public understanding of the biology and the medical basis of mental illness.

All this notwithstanding, our work is gratifying
Despite the hassles and unmet needs I’ve enumerated, psychiatry continues to be one of the most exciting fields in medicine. We provide more thera­peutic face-time and verbal interac­tions with our patients than any other medical specialty. Imagine, then, how much more enjoyable psychiatric prac­tice would be if these pesky obstacles were eliminated and the unmet needs of patients and practitioners were addressed.

Recently, my umbrage at these prac­tices soared to a new height when a col­league told me that he had to fight for, and then wait to receive, permission from an insurance employee to increase, by a notch, the maintenance dosage of a long-acting antipsychotic for his patient.

Can anyone justify why an absentee person who has never met the patient should, sight-unseen, second-guess our clinical judgment that a patient’s symptoms are still not well-controlled and require upward adjustment of the dosage? Why are insurance compa­nies allowed to micromanage clinical decision-making? Such outrageous intrusiveness is a signal that insur­ance companies have “jumped the shark” in their effort to push business interests ahead of the needs of their subscribers.

Whose interests are being put first?
I recall instances when I refused to buckle to pressure from a patient’s third-party payer to switch from 1 antidepres­sant to another, a move that would save the insurer money but put my patient at risk of relapse. I informed the insurance company representative that my attor­ney was going to file a lawsuit on behalf of my depressed patient if he were to relapse or attempt suicide because he had been switched from an antidepres­sant that was working to another that might not.

Fighting back paid off: In each case, I was told the payer would “make an exception” for that patient.

Frustrations of this kind have become commonplace in psychiatric practice. They tend to detract from the stimulat­ing and gratifying aspects of the care we provide, and reinforce the perception that insurance companies’ primary goal is to fatten profits, not facilitate patients’ return to health.

Here are other reasons for chronic frustration in psychiatric practice. They reflect serious, unmet needs that we hope will be resolved soon.

Improved diagnostic schema. We need a valid—and more than simply reliable—evidence-based diagnostic system that is rooted in scientifically established pathophysiology. The basic clinical elements of DSM-5 should be gradually amalgamated with rap­idly emerging genetics and biological endophenotypes. The continuum of and boundary between “normal” and “pathologic” human behavior should be further clarified.

Biomarkers. Our field eagerly awaits development of biomarkers (laboratory tests) to bolster psychiatric practice in several ways, including:
   • confirming the clinical diagnosis
   • identifying biological subtypes
   • monitoring response
   • guiding selection of drugs
   • predicting side effects
   • measuring severity of disease.

Elusive parity. We’ve been patient, but we’re tired and angry at empty prom­ises of full parity for psychiatric care. We’ve also had it with the stigmatizing and discriminatory “carve-out” status that allows insurance companies to treat reimbursement for psychiatric services more restrictively than for other medical and surgical specialties. Policy makers must end the egregious discrimination that gives half a loaf to some brain disorders (psychiatric) and a full loaf to other brain disorders (neurologic).

Better medications. We need a stron­ger commitment from the pharma­ceutical industry, on which we rely entirely for development of psycho­active drugs, to wage a relentless war on serious mental illness. The private sector should accelerate translation of groundbreaking neuroscientific dis­coveries—thanks to research funded by the public sector, such as the National Institutes of Health—into innovative new mechanisms of action. Patients who suffer from psychiatric brain disorders for which there are no approved treatments await that com­mitment and bold action.

Collaborative care. Psychiatry needs a more consistent, more produc­tive bidirectional relationship with primary care. A stronger bond will improve the care of patients on both sides and would, I believe, increase the satisfaction of clinical practice for both specialists. Because structure can facilitate function, co-locating provid­ers can help achieve this vision.

Legal entanglement. Psychiatry must be unshackled from an oppres­sive set of laws that tie our hands when we treat patients with brain pathology who are incapable of under­standing their illness and their need to be treated. Those laws were imposed long before scientific advances showed that prolonged and untreated episodes of psychosis, mania, depres­sion, and anxiety are associated with neurotoxic processes (neuroinflam­mation, oxidative and nitrosative stress). Medical urgency and patient protection must trump legalisms, just as unconscious stroke and myocardial infarction patients are treated immedi­ately without filing multiple forms or waiting for a court order.

Another legal beef: We psychiatrists are exasperated with the expand­ing criminalization of our patients— hapless victims of brain diseases that impair their reality testing and behav­ior. Should a person who suffers a first epileptic seizure or a stroke while driv­ing and kills the driver of an oncom­ing car be incarcerated with hardened murderers and rapists and treated for epilepsy in a prison instead of a neu­rology ward? Our patients belong in a secure hospital, a medical asylum, where they are given compassionate medical care, not the degrading treat­ment afforded to a felon.

More resources. There is a dire need for psychiatric hospital beds in many parts of the country, because many wards were closed and renovated into more profitable, procedure-oriented specialties. There also is a severe short­age of psychiatrists in our country, as I discussed in my editorial, “Signs, symptoms, and treatment of psychia­trynemia,” (December 2014). The 25% of the population who suffer a mental disorder are clearly underserved at this time.

Furthermore, because today’s research is tomorrow’s new treatment, funding for psychiatric research must increase substantially to find cures and to thus reduce huge direct and indirect costs of mental illness and addictions.

Public enlightenment. A well-informed populace would be a major boon to our sophisticated medical specialty, which remains shrouded by primitive beliefs and archaic attitudes. For many people who desperately need mental health care, negative perceptions of psychiatric disorders and their treat­ment are a major impediment to seek­ing help. Psychiatrists can catalyze the process of enlightenment by dedicating time to elevating public understanding of the biology and the medical basis of mental illness.

All this notwithstanding, our work is gratifying
Despite the hassles and unmet needs I’ve enumerated, psychiatry continues to be one of the most exciting fields in medicine. We provide more thera­peutic face-time and verbal interac­tions with our patients than any other medical specialty. Imagine, then, how much more enjoyable psychiatric prac­tice would be if these pesky obstacles were eliminated and the unmet needs of patients and practitioners were addressed.

Recently, my umbrage at these prac­tices soared to a new height when a col­league told me that he had to fight for, and then wait to receive, permission from an insurance employee to increase, by a notch, the maintenance dosage of a long-acting antipsychotic for his patient.

Can anyone justify why an absentee person who has never met the patient should, sight-unseen, second-guess our clinical judgment that a patient’s symptoms are still not well-controlled and require upward adjustment of the dosage? Why are insurance compa­nies allowed to micromanage clinical decision-making? Such outrageous intrusiveness is a signal that insur­ance companies have “jumped the shark” in their effort to push business interests ahead of the needs of their subscribers.

Whose interests are being put first?
I recall instances when I refused to buckle to pressure from a patient’s third-party payer to switch from 1 antidepres­sant to another, a move that would save the insurer money but put my patient at risk of relapse. I informed the insurance company representative that my attor­ney was going to file a lawsuit on behalf of my depressed patient if he were to relapse or attempt suicide because he had been switched from an antidepres­sant that was working to another that might not.

Fighting back paid off: In each case, I was told the payer would “make an exception” for that patient.

Frustrations of this kind have become commonplace in psychiatric practice. They tend to detract from the stimulat­ing and gratifying aspects of the care we provide, and reinforce the perception that insurance companies’ primary goal is to fatten profits, not facilitate patients’ return to health.

Here are other reasons for chronic frustration in psychiatric practice. They reflect serious, unmet needs that we hope will be resolved soon.

Improved diagnostic schema. We need a valid—and more than simply reliable—evidence-based diagnostic system that is rooted in scientifically established pathophysiology. The basic clinical elements of DSM-5 should be gradually amalgamated with rap­idly emerging genetics and biological endophenotypes. The continuum of and boundary between “normal” and “pathologic” human behavior should be further clarified.

Biomarkers. Our field eagerly awaits development of biomarkers (laboratory tests) to bolster psychiatric practice in several ways, including:
   • confirming the clinical diagnosis
   • identifying biological subtypes
   • monitoring response
   • guiding selection of drugs
   • predicting side effects
   • measuring severity of disease.

Elusive parity. We’ve been patient, but we’re tired and angry at empty prom­ises of full parity for psychiatric care. We’ve also had it with the stigmatizing and discriminatory “carve-out” status that allows insurance companies to treat reimbursement for psychiatric services more restrictively than for other medical and surgical specialties. Policy makers must end the egregious discrimination that gives half a loaf to some brain disorders (psychiatric) and a full loaf to other brain disorders (neurologic).

Better medications. We need a stron­ger commitment from the pharma­ceutical industry, on which we rely entirely for development of psycho­active drugs, to wage a relentless war on serious mental illness. The private sector should accelerate translation of groundbreaking neuroscientific dis­coveries—thanks to research funded by the public sector, such as the National Institutes of Health—into innovative new mechanisms of action. Patients who suffer from psychiatric brain disorders for which there are no approved treatments await that com­mitment and bold action.

Collaborative care. Psychiatry needs a more consistent, more produc­tive bidirectional relationship with primary care. A stronger bond will improve the care of patients on both sides and would, I believe, increase the satisfaction of clinical practice for both specialists. Because structure can facilitate function, co-locating provid­ers can help achieve this vision.

Legal entanglement. Psychiatry must be unshackled from an oppres­sive set of laws that tie our hands when we treat patients with brain pathology who are incapable of under­standing their illness and their need to be treated. Those laws were imposed long before scientific advances showed that prolonged and untreated episodes of psychosis, mania, depres­sion, and anxiety are associated with neurotoxic processes (neuroinflam­mation, oxidative and nitrosative stress). Medical urgency and patient protection must trump legalisms, just as unconscious stroke and myocardial infarction patients are treated immedi­ately without filing multiple forms or waiting for a court order.

Another legal beef: We psychiatrists are exasperated with the expand­ing criminalization of our patients— hapless victims of brain diseases that impair their reality testing and behav­ior. Should a person who suffers a first epileptic seizure or a stroke while driv­ing and kills the driver of an oncom­ing car be incarcerated with hardened murderers and rapists and treated for epilepsy in a prison instead of a neu­rology ward? Our patients belong in a secure hospital, a medical asylum, where they are given compassionate medical care, not the degrading treat­ment afforded to a felon.

More resources. There is a dire need for psychiatric hospital beds in many parts of the country, because many wards were closed and renovated into more profitable, procedure-oriented specialties. There also is a severe short­age of psychiatrists in our country, as I discussed in my editorial, “Signs, symptoms, and treatment of psychia­trynemia,” (December 2014). The 25% of the population who suffer a mental disorder are clearly underserved at this time.

Furthermore, because today’s research is tomorrow’s new treatment, funding for psychiatric research must increase substantially to find cures and to thus reduce huge direct and indirect costs of mental illness and addictions.

Public enlightenment. A well-informed populace would be a major boon to our sophisticated medical specialty, which remains shrouded by primitive beliefs and archaic attitudes. For many people who desperately need mental health care, negative perceptions of psychiatric disorders and their treat­ment are a major impediment to seek­ing help. Psychiatrists can catalyze the process of enlightenment by dedicating time to elevating public understanding of the biology and the medical basis of mental illness.

All this notwithstanding, our work is gratifying
Despite the hassles and unmet needs I’ve enumerated, psychiatry continues to be one of the most exciting fields in medicine. We provide more thera­peutic face-time and verbal interac­tions with our patients than any other medical specialty. Imagine, then, how much more enjoyable psychiatric prac­tice would be if these pesky obstacles were eliminated and the unmet needs of patients and practitioners were addressed.

Neuroinflammation is well-established as an underlying mechanism in depres­sion, as well as in other neuropsychiat­ric disorders, including schizophrenia, multiple sclerosis, stroke, Parkinson’s disease, and sleep disorders.¹ There is a dearth of prevention strategies for neuropsychiatric disorders but, given emerging scientific knowledge about immune dysregulation and the asso­ciated rise in inflammatory markers during the course of depression,^2,3 it is logical to postulate that avoiding trig­gers of neuroinflammation might be a useful tactic to prevent depression or, perhaps, to minimize its severity.

Challenge your patients to avoid triggers of depression
What is known about what instigates the rise of inflammatory markers in the body and the brain? Actually, quite a substantial body of knowl­edge exists on the subject.⁴ Consider the 10 risk factors for depression that I enumerate here (Table), and advise patients to avoid them.

Sedentary lifestyle. Physical inac­tivity during childhood is associated with depression in adulthood. This is worrisome because video games seem ever more popular among children these days—more popular and preva­lent than playing outdoors. Use this knowledge about the preventive ben­efit of exercise for long-range preven­tion in young patients.

Adults with a sedentary lifestyle usually have increased adiposity, which increases the risk of depres­sion. Regular exercise has been shown to down-regulate systemic inflammation.

Smoking. Hundreds of toxic and inflammatory components in tobacco smoke (tars, metals, free radicals) can induce inflammation across the body and brain tissue, which explains not only depression but serious pulmo­nary and cerebrovascular diseases seen in smokers. People with depres­sion are more likely to smoke than the general population, possibly because nicotine has a mild mood-elevating effect. Yet smoking might make depression worse by exacerbat­ing inflammation, thus negating any mood-elevating effect of nicotine.

Poor diet. It is well known that the Western diet (processed meats, refined sugars, saturated fats) can increase the body’s level of inflammatory mark­ers. The Mediterranean diet, on the other hand, which comprises fruits, vegetables, fish, legumes, and foods rich in omega-3 fatty acids (fish, nuts, leafy green vegetables), is anti-inflammatory. Furthermore, lycopene-containing foods (tomatoes, papaya, red cabbage, watermelon, carrots, asparagus) are rich in antioxidants and thus reduce inflammation.

The possible epigenetic effects of diet are an interesting phenomenon. Offspring of rats who were fed a diet rich in saturated fats have elevated levels of inflammatory markers, even when they had been fed a normal diet, suggesting a transgenerational effect. What parents eat before they conceive might doom their child’s health— regardless of what they feed them.

Tooth decay, gingivitis, periodon­titis. Oral inflammation afflicts a large percentage of the population. These conditions can lead to sys­temic inflammation with elevated levels of C-reactive protein (CRP) and interleukins, which are conducive to depression.

Poor sleep hygiene. Sleep disorders, such as insomnia and insufficient sleep (which is epidemic in the United States), are risk factors for mood dis­orders. Sleep deprivation disrupts immune function and triggers the cascade of elevated cytokines, CRP, and tumor necrosis factor (TNF)-α. Just as depression is associated with impaired neurogenesis, so is chronic lack of sleep, suggesting a conver­gence of neurobiologic mechanisms.

Vitamin D deficiency. A link between vitamin D deficiency, now common in the United States, and depression and immune function has been recognized. Vitamin D has anti-inflammatory effects and can reduce oxidative stress, which culminates in inflammation. Vitamin D supple­mentation has been shown to allevi­ate neuro-immune disorders, such as multiple sclerosis.

Obesity. Obese people are >50% more likely to develop depression than non-obese people. Technically, obesity is a pro-inflammatory state, and inflam­matory biomarkers, such as cytokines, are abundant in fat cells, especially abdominal (visceral or peri-omental) adiposity. When an obese person loses weight, levels of inflammatory markers (interleukin-6, TNF-α, leptin) decrease. We know that abdominal obesity is associated with neuroin­flammation and early dementia.

Allergy involves inflammation trig­gered by the cascade of events con­sequent to the body’s fight against antigens, and the well-known hyper-sensitivity reaction, causing edema, coughing, sneezing, and itching. It is well-established that the incidence of atopy and allergy is high among peo­ple with depression.

Changes in gut permeability. Intestinal inflammatory diseases, such as ulcerative colitis, are recog­nized as pathways to depression. The mechanism is believed to be the immune response to lipopolysaccha­rides by commensal bacteria that live by the trillions in the gut. The result? Abnormal gut permeability, bacterial translocation, and depressed mood, possibly because serotonin is more abundant in the gut than in the CNS.

Stress. Arguably, the most common pathway to depression is stressful events of daily life. Stress-induced systemic inflammation hastens cardio­vascular disease and leads to neuro-inflammation and neuropsychiatric disorders as well.

Especially malignant is the severe stress of childhood trauma (physi­cal and sexual abuse, parental dis­cord and death), which stimulates pro-inflammatory cytokines and detrimental neurobiological sensiti­zation that lead to psychopathology, including depression and psychosis in adulthood. Childhood trauma has been reported to shorten life by 7 to 15 years.

Posttraumatic stress disorder is the best known clinical model of stress-induced depression and anxiety. The disorder is associated with a signifi­cant increase in pro-inflammatory cytokines and loss of brain tissue.
 

2-fold challenge: Reduce severity of disease, reduce risk before disease
We psychiatrists almost always see patients after they’ve developed depres­sion and other psychiatric disorders in which neuroinflammation is already present. In addition to pharmacother­apy and psychotherapy (both reduce inflammation), educating patients about adopting a healthy lifestyle—not smok­ing, exercising, eating wisely, avoid­ing weight gain, getting enough sleep, maintaining good oral hygiene, and managing stress—might reduce psychi­atric relapse and prolong their life.

We also should be challenged by the fact that the pathways to inflammation, including the 10 I’ve described here, are common among the population at large. Let’s increase our efforts to pre­emptively reduce the risk of brain dis­orders by encouraging parents and their children to adopt a healthy lifestyle and maintain wellness—and thus avoid fall­ing victim to depression.

Neuroinflammation is well-established as an underlying mechanism in depres­sion, as well as in other neuropsychiat­ric disorders, including schizophrenia, multiple sclerosis, stroke, Parkinson’s disease, and sleep disorders.¹ There is a dearth of prevention strategies for neuropsychiatric disorders but, given emerging scientific knowledge about immune dysregulation and the asso­ciated rise in inflammatory markers during the course of depression,^2,3 it is logical to postulate that avoiding trig­gers of neuroinflammation might be a useful tactic to prevent depression or, perhaps, to minimize its severity.

Challenge your patients to avoid triggers of depression
What is known about what instigates the rise of inflammatory markers in the body and the brain? Actually, quite a substantial body of knowl­edge exists on the subject.⁴ Consider the 10 risk factors for depression that I enumerate here (Table), and advise patients to avoid them.

Sedentary lifestyle. Physical inac­tivity during childhood is associated with depression in adulthood. This is worrisome because video games seem ever more popular among children these days—more popular and preva­lent than playing outdoors. Use this knowledge about the preventive ben­efit of exercise for long-range preven­tion in young patients.

Adults with a sedentary lifestyle usually have increased adiposity, which increases the risk of depres­sion. Regular exercise has been shown to down-regulate systemic inflammation.

Smoking. Hundreds of toxic and inflammatory components in tobacco smoke (tars, metals, free radicals) can induce inflammation across the body and brain tissue, which explains not only depression but serious pulmo­nary and cerebrovascular diseases seen in smokers. People with depres­sion are more likely to smoke than the general population, possibly because nicotine has a mild mood-elevating effect. Yet smoking might make depression worse by exacerbat­ing inflammation, thus negating any mood-elevating effect of nicotine.

Poor diet. It is well known that the Western diet (processed meats, refined sugars, saturated fats) can increase the body’s level of inflammatory mark­ers. The Mediterranean diet, on the other hand, which comprises fruits, vegetables, fish, legumes, and foods rich in omega-3 fatty acids (fish, nuts, leafy green vegetables), is anti-inflammatory. Furthermore, lycopene-containing foods (tomatoes, papaya, red cabbage, watermelon, carrots, asparagus) are rich in antioxidants and thus reduce inflammation.

The possible epigenetic effects of diet are an interesting phenomenon. Offspring of rats who were fed a diet rich in saturated fats have elevated levels of inflammatory markers, even when they had been fed a normal diet, suggesting a transgenerational effect. What parents eat before they conceive might doom their child’s health— regardless of what they feed them.

Tooth decay, gingivitis, periodon­titis. Oral inflammation afflicts a large percentage of the population. These conditions can lead to sys­temic inflammation with elevated levels of C-reactive protein (CRP) and interleukins, which are conducive to depression.

Poor sleep hygiene. Sleep disorders, such as insomnia and insufficient sleep (which is epidemic in the United States), are risk factors for mood dis­orders. Sleep deprivation disrupts immune function and triggers the cascade of elevated cytokines, CRP, and tumor necrosis factor (TNF)-α. Just as depression is associated with impaired neurogenesis, so is chronic lack of sleep, suggesting a conver­gence of neurobiologic mechanisms.

Vitamin D deficiency. A link between vitamin D deficiency, now common in the United States, and depression and immune function has been recognized. Vitamin D has anti-inflammatory effects and can reduce oxidative stress, which culminates in inflammation. Vitamin D supple­mentation has been shown to allevi­ate neuro-immune disorders, such as multiple sclerosis.

Obesity. Obese people are >50% more likely to develop depression than non-obese people. Technically, obesity is a pro-inflammatory state, and inflam­matory biomarkers, such as cytokines, are abundant in fat cells, especially abdominal (visceral or peri-omental) adiposity. When an obese person loses weight, levels of inflammatory markers (interleukin-6, TNF-α, leptin) decrease. We know that abdominal obesity is associated with neuroin­flammation and early dementia.

Allergy involves inflammation trig­gered by the cascade of events con­sequent to the body’s fight against antigens, and the well-known hyper-sensitivity reaction, causing edema, coughing, sneezing, and itching. It is well-established that the incidence of atopy and allergy is high among peo­ple with depression.

Changes in gut permeability. Intestinal inflammatory diseases, such as ulcerative colitis, are recog­nized as pathways to depression. The mechanism is believed to be the immune response to lipopolysaccha­rides by commensal bacteria that live by the trillions in the gut. The result? Abnormal gut permeability, bacterial translocation, and depressed mood, possibly because serotonin is more abundant in the gut than in the CNS.

Stress. Arguably, the most common pathway to depression is stressful events of daily life. Stress-induced systemic inflammation hastens cardio­vascular disease and leads to neuro-inflammation and neuropsychiatric disorders as well.

Especially malignant is the severe stress of childhood trauma (physi­cal and sexual abuse, parental dis­cord and death), which stimulates pro-inflammatory cytokines and detrimental neurobiological sensiti­zation that lead to psychopathology, including depression and psychosis in adulthood. Childhood trauma has been reported to shorten life by 7 to 15 years.

Posttraumatic stress disorder is the best known clinical model of stress-induced depression and anxiety. The disorder is associated with a signifi­cant increase in pro-inflammatory cytokines and loss of brain tissue.
 

2-fold challenge: Reduce severity of disease, reduce risk before disease
We psychiatrists almost always see patients after they’ve developed depres­sion and other psychiatric disorders in which neuroinflammation is already present. In addition to pharmacother­apy and psychotherapy (both reduce inflammation), educating patients about adopting a healthy lifestyle—not smok­ing, exercising, eating wisely, avoid­ing weight gain, getting enough sleep, maintaining good oral hygiene, and managing stress—might reduce psychi­atric relapse and prolong their life.

We also should be challenged by the fact that the pathways to inflammation, including the 10 I’ve described here, are common among the population at large. Let’s increase our efforts to pre­emptively reduce the risk of brain dis­orders by encouraging parents and their children to adopt a healthy lifestyle and maintain wellness—and thus avoid fall­ing victim to depression.

Neuroinflammation is well-established as an underlying mechanism in depres­sion, as well as in other neuropsychiat­ric disorders, including schizophrenia, multiple sclerosis, stroke, Parkinson’s disease, and sleep disorders.¹ There is a dearth of prevention strategies for neuropsychiatric disorders but, given emerging scientific knowledge about immune dysregulation and the asso­ciated rise in inflammatory markers during the course of depression,^2,3 it is logical to postulate that avoiding trig­gers of neuroinflammation might be a useful tactic to prevent depression or, perhaps, to minimize its severity.

Challenge your patients to avoid triggers of depression
What is known about what instigates the rise of inflammatory markers in the body and the brain? Actually, quite a substantial body of knowl­edge exists on the subject.⁴ Consider the 10 risk factors for depression that I enumerate here (Table), and advise patients to avoid them.

Sedentary lifestyle. Physical inac­tivity during childhood is associated with depression in adulthood. This is worrisome because video games seem ever more popular among children these days—more popular and preva­lent than playing outdoors. Use this knowledge about the preventive ben­efit of exercise for long-range preven­tion in young patients.

Adults with a sedentary lifestyle usually have increased adiposity, which increases the risk of depres­sion. Regular exercise has been shown to down-regulate systemic inflammation.

Smoking. Hundreds of toxic and inflammatory components in tobacco smoke (tars, metals, free radicals) can induce inflammation across the body and brain tissue, which explains not only depression but serious pulmo­nary and cerebrovascular diseases seen in smokers. People with depres­sion are more likely to smoke than the general population, possibly because nicotine has a mild mood-elevating effect. Yet smoking might make depression worse by exacerbat­ing inflammation, thus negating any mood-elevating effect of nicotine.

Poor diet. It is well known that the Western diet (processed meats, refined sugars, saturated fats) can increase the body’s level of inflammatory mark­ers. The Mediterranean diet, on the other hand, which comprises fruits, vegetables, fish, legumes, and foods rich in omega-3 fatty acids (fish, nuts, leafy green vegetables), is anti-inflammatory. Furthermore, lycopene-containing foods (tomatoes, papaya, red cabbage, watermelon, carrots, asparagus) are rich in antioxidants and thus reduce inflammation.

The possible epigenetic effects of diet are an interesting phenomenon. Offspring of rats who were fed a diet rich in saturated fats have elevated levels of inflammatory markers, even when they had been fed a normal diet, suggesting a transgenerational effect. What parents eat before they conceive might doom their child’s health— regardless of what they feed them.

Tooth decay, gingivitis, periodon­titis. Oral inflammation afflicts a large percentage of the population. These conditions can lead to sys­temic inflammation with elevated levels of C-reactive protein (CRP) and interleukins, which are conducive to depression.

Poor sleep hygiene. Sleep disorders, such as insomnia and insufficient sleep (which is epidemic in the United States), are risk factors for mood dis­orders. Sleep deprivation disrupts immune function and triggers the cascade of elevated cytokines, CRP, and tumor necrosis factor (TNF)-α. Just as depression is associated with impaired neurogenesis, so is chronic lack of sleep, suggesting a conver­gence of neurobiologic mechanisms.

Vitamin D deficiency. A link between vitamin D deficiency, now common in the United States, and depression and immune function has been recognized. Vitamin D has anti-inflammatory effects and can reduce oxidative stress, which culminates in inflammation. Vitamin D supple­mentation has been shown to allevi­ate neuro-immune disorders, such as multiple sclerosis.

Obesity. Obese people are >50% more likely to develop depression than non-obese people. Technically, obesity is a pro-inflammatory state, and inflam­matory biomarkers, such as cytokines, are abundant in fat cells, especially abdominal (visceral or peri-omental) adiposity. When an obese person loses weight, levels of inflammatory markers (interleukin-6, TNF-α, leptin) decrease. We know that abdominal obesity is associated with neuroin­flammation and early dementia.

Allergy involves inflammation trig­gered by the cascade of events con­sequent to the body’s fight against antigens, and the well-known hyper-sensitivity reaction, causing edema, coughing, sneezing, and itching. It is well-established that the incidence of atopy and allergy is high among peo­ple with depression.

Changes in gut permeability. Intestinal inflammatory diseases, such as ulcerative colitis, are recog­nized as pathways to depression. The mechanism is believed to be the immune response to lipopolysaccha­rides by commensal bacteria that live by the trillions in the gut. The result? Abnormal gut permeability, bacterial translocation, and depressed mood, possibly because serotonin is more abundant in the gut than in the CNS.

Stress. Arguably, the most common pathway to depression is stressful events of daily life. Stress-induced systemic inflammation hastens cardio­vascular disease and leads to neuro-inflammation and neuropsychiatric disorders as well.

Especially malignant is the severe stress of childhood trauma (physi­cal and sexual abuse, parental dis­cord and death), which stimulates pro-inflammatory cytokines and detrimental neurobiological sensiti­zation that lead to psychopathology, including depression and psychosis in adulthood. Childhood trauma has been reported to shorten life by 7 to 15 years.

Posttraumatic stress disorder is the best known clinical model of stress-induced depression and anxiety. The disorder is associated with a signifi­cant increase in pro-inflammatory cytokines and loss of brain tissue.
 

2-fold challenge: Reduce severity of disease, reduce risk before disease
We psychiatrists almost always see patients after they’ve developed depres­sion and other psychiatric disorders in which neuroinflammation is already present. In addition to pharmacother­apy and psychotherapy (both reduce inflammation), educating patients about adopting a healthy lifestyle—not smok­ing, exercising, eating wisely, avoid­ing weight gain, getting enough sleep, maintaining good oral hygiene, and managing stress—might reduce psychi­atric relapse and prolong their life.

We also should be challenged by the fact that the pathways to inflammation, including the 10 I’ve described here, are common among the population at large. Let’s increase our efforts to pre­emptively reduce the risk of brain dis­orders by encouraging parents and their children to adopt a healthy lifestyle and maintain wellness—and thus avoid fall­ing victim to depression.

Nowhere is that change in landscape more apparent than in major depression, the No. 1 disabling condition in all of medicine, according to the World Health Organization. The past decade has gen­erated at least 10 paradigm shifts in the neurobiology and pharmacotherapeutics of depression.

Clinging to simplistic tradition
Most contemporary clinicians con­tinue to practice the traditional model of depression, which is based on the assumption that depression is caused by a deficiency of monoamines: sero­tonin (5-HT) and norepinephrine (NE). The entire antidepressant armamentar­ium approved for use by the FDA was designed according to the amine defi­ciency hypothesis. Depressed patients uniformly receive reuptake inhibitors of 5-HT and NE, but few achieve full remission, as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed.¹

As scientific paradigm shifts infil­trate clinical practice, however, the tired notion of “chemical imbalance” will yield to more complex and evidence-based models.

Usually, it would be remarkable to witness a single paradigm shift in the understanding of a brain disor­der. Imagine the disruptive impact of multiple scientific shifts within the past decade! Consider the follow­ing departures from the old dogma about the simplistic old explanation of depression.

1. From neurotransmitters to neuroplasticity
For half a century, our field tenaciously held to the monoamine theory, which posits that depression is caused by a deficiency of 5-HT or NE, or both. All antidepressants in use today were developed to increase brain mono­amines by inhibiting their reuptake at the synaptic cleft. Now, research points to other causes:
   • impaired neuroplasticity
   • a decrement of neurogenesis
   • synaptic deficits
   • decreased neurotrophins (such as brain-derived neurotrophic factor)
   • dendritic pathology.^2,3

2. From ‘chemical imbalance’ to neuroinflammation
The simplistic notion that depression is a chemical imbalance, so to speak, in the brain is giving way to rapidly emerging evidence that depression is associated with neuroinflammation.⁴

Pro-inflammatory cytokines are elevated in the plasma of depressed patients, and subside when the acute episode is treated. Current antidepres­sants actually have anti-inflammatory effects that have gone unrecognized.⁵ A meta-analysis of the use of anti-inflammatory agents (such as nonste­roidal anti-inflammatory drugs and aspirin) in depression shows promising efficacy.⁶ Some inflammatory markers, such as C-reactive protein, already have been reported to predict response to some antidepressants, but not to others.⁷

3. From 5-HT and NE pathways to glutamate NMDA receptors
Recent landmark studies⁸ have, taken together, demonstrated that a single IV dose of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (a psychotogenic drug of abuse FDA-approved only as an anesthetic) can produce clinical improvement of severe depression and even full remission for several days. Such studies demonstrate that the old dogma of 5-HT and NE deficiency might not be a valid over­arching hypothesis of the depression syndrome.

Long-term maintenance studies of ketamine to document its safety and continued efficacy need to be con­ducted. The mechanism of action of ket­amine is believed to be a rapid trigger for enhancing neuroplasticity.

4. From oral to parenteral administration
Several studies have been published showing the efficacy of IV or intranasal administration of new agents for depres­sion. Ketamine studies, for example, were conducted using an IV infusion of a 150-mg dose over 1 hour. Other IV studies used the anticholinergic scopolamine.⁹

Intranasal ketamine also has been shown to be clinically efficacious.¹⁰ Inhalable nitrous oxide (laughing gas, an NMDA antagonist) recently was reported to improve depression as well.¹¹

It is possible that parenteral admin­istration of antidepressant agents may exert a different neurobiological effect and provide a more rapid response than oral medication.

5. From delayed efficacy (weeks) to immediate onset (1 or 2 hours)
The widely entrenched notion that depression takes several weeks to improve with an antidepressant has collapsed with emerging evidence that symptoms of the disorder (even sui­cidal ideation) can be reversed within 1 or 2 hours.¹² IV ketamine isn’t the only example; IV scopolamine,9 inhalable nitrous oxide,¹¹ and overnight sleep deprivation¹³ also exert a rapid thera­peutic effect. This is a major rethinking of how quickly the curtain of severe depression can be lifted, and is great news for patients and their family.

6. From psychological symptoms to cortical or subcortical changes
Depression traditionally has been recog­nized as a clinical syndrome of sadness, self-deprecation, cognitive dulling, and vegetative symptoms. In recent stud­ies, however, researchers report that low hippocampus volume¹⁴ in healthy young girls predicts future depression. Patients with unremitting depression have been reported to have an abnor­mally shaped hippocampus.¹⁵

In addition, gray-matter volume in the subgenual anterior cingulate (Brodmann area 24) is hypoplastic in depressed persons,¹⁶ making that area a target for deep-brain stimulation (DBS). Brain morphological changes such as a hypoplastic hippocampus might become useful biomarkers for identify­ing persons at risk of severe depression, and might become a useful adjunc­tive biomarker for making a clinical diagnosis.

7. From healing the mind to repairing the brain
It is well-established that depression is associated with loss of dendritic spines and arborizations, loss of syn­apses, and diminishment of glial cells, especially in the hippocampus¹⁷ and anterior cingulate.¹⁸ Treating depression, whether pharmaceutical or somatic, involves reversing these changes by increasing neurotrophic factors, enhancing neurogenesis and gliogenesis, and restoring synaptic and dendritic health and cell survival in the hippocampus and frontal cor­tex.^19,20 Treating depression involves brain repair, which is reflected, ulti­mately, in healing the mind.

8. From pharmacotherapy to neuromodulation
Although drugs remain the predomi­nant treatment modality for depression, there is palpable escalation in the use of neuromodulation methods.

The oldest of these neuromodulatory techniques is electroconvulsive ther­apy, an excellent treatment for severe depression (and one that enhances hip­pocampal neurogenesis). In addition, several novel neuromodulation meth­ods have been approved (transcranial magnetic stimulation and vagus nerve stimulation) or are in development (transcranial direct-current stimula­tion, cranial electrotherapy stimulation, and DBS).²¹ These somatic approaches to treating the brain directly to allevi­ate depression target regions involved in depression and reduce the needless risks associated with exposing other organ systems to a drug.

9. From monotherapy to combination therapy
The use of combination therapy for depression has escalated with FDA approval of adjunctive use of atypical antipsychotics in unipolar and bipolar depression. In addition, the landmark STAR*D study¹ demonstrated the value of augmentation therapy with a second antidepressant when 1 agent fails. Other controlled studies have shown that combining 2 antidepressants is superior to administering 1.²²

Just as other serious medical dis­orders—such as cancer and hyper­tension—are treated with 2 or 3 medications, severe depression might require a similar strategy. The field gradually is adopting that approach.

10. From cortical folds to wrinkles on the face
Last, a new (and unexpected) paradigm shift recently emerged, which is genu­inely intriguing—even baffling. Using placebo-controlled designs, several researchers have reported significant, persistent improvement of depressive symptoms after injection of onabotu­linumtoxinA in the corrugator muscles of the glabellar region of the face, where the omega sign often appears in a depressed person.^23,24

The longest of the studies²⁵ was 6 months; investigators reported that improvement continued even after the effect of the botulinum toxin on the omega sign wore off. The proposed mechanism of action is the facial feed­back hypothesis, which suggests that, biologically, facial expression has an impact on one’s emotional state.

Big payoffs coming from research in neuroscience
These 10 paradigm shifts in a single psychiatric syndrome are emblematic of exciting clinical and research advances in our field. Like all syndromes, depression is associated with multiple genetic and environmental causes; it isn’t surprising that myriad treatment approaches are emerging.

The days of clinging to monolithic, serendipity-generated models surely are over. Evidence-based psychiatric brain research is shattering aging dog­mas that have, for decades, stifled inno­vation in psychiatric therapeutics that is now moving in novel directions.

Take note, however, that the only par­adigm shift that matters to depressed patients is the one that transcends mere control of their symptoms and restores their wellness, functional capacity, and quality of life. With the explosive momentum of neuroscience discovery, psychiatry is, at last, poised to deliver—in splendid, even seismic, fashion.

Nowhere is that change in landscape more apparent than in major depression, the No. 1 disabling condition in all of medicine, according to the World Health Organization. The past decade has gen­erated at least 10 paradigm shifts in the neurobiology and pharmacotherapeutics of depression.

Clinging to simplistic tradition
Most contemporary clinicians con­tinue to practice the traditional model of depression, which is based on the assumption that depression is caused by a deficiency of monoamines: sero­tonin (5-HT) and norepinephrine (NE). The entire antidepressant armamentar­ium approved for use by the FDA was designed according to the amine defi­ciency hypothesis. Depressed patients uniformly receive reuptake inhibitors of 5-HT and NE, but few achieve full remission, as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed.¹

As scientific paradigm shifts infil­trate clinical practice, however, the tired notion of “chemical imbalance” will yield to more complex and evidence-based models.

Usually, it would be remarkable to witness a single paradigm shift in the understanding of a brain disor­der. Imagine the disruptive impact of multiple scientific shifts within the past decade! Consider the follow­ing departures from the old dogma about the simplistic old explanation of depression.

1. From neurotransmitters to neuroplasticity
For half a century, our field tenaciously held to the monoamine theory, which posits that depression is caused by a deficiency of 5-HT or NE, or both. All antidepressants in use today were developed to increase brain mono­amines by inhibiting their reuptake at the synaptic cleft. Now, research points to other causes:
   • impaired neuroplasticity
   • a decrement of neurogenesis
   • synaptic deficits
   • decreased neurotrophins (such as brain-derived neurotrophic factor)
   • dendritic pathology.^2,3

2. From ‘chemical imbalance’ to neuroinflammation
The simplistic notion that depression is a chemical imbalance, so to speak, in the brain is giving way to rapidly emerging evidence that depression is associated with neuroinflammation.⁴

Pro-inflammatory cytokines are elevated in the plasma of depressed patients, and subside when the acute episode is treated. Current antidepres­sants actually have anti-inflammatory effects that have gone unrecognized.⁵ A meta-analysis of the use of anti-inflammatory agents (such as nonste­roidal anti-inflammatory drugs and aspirin) in depression shows promising efficacy.⁶ Some inflammatory markers, such as C-reactive protein, already have been reported to predict response to some antidepressants, but not to others.⁷

3. From 5-HT and NE pathways to glutamate NMDA receptors
Recent landmark studies⁸ have, taken together, demonstrated that a single IV dose of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (a psychotogenic drug of abuse FDA-approved only as an anesthetic) can produce clinical improvement of severe depression and even full remission for several days. Such studies demonstrate that the old dogma of 5-HT and NE deficiency might not be a valid over­arching hypothesis of the depression syndrome.

Long-term maintenance studies of ketamine to document its safety and continued efficacy need to be con­ducted. The mechanism of action of ket­amine is believed to be a rapid trigger for enhancing neuroplasticity.

4. From oral to parenteral administration
Several studies have been published showing the efficacy of IV or intranasal administration of new agents for depres­sion. Ketamine studies, for example, were conducted using an IV infusion of a 150-mg dose over 1 hour. Other IV studies used the anticholinergic scopolamine.⁹

Intranasal ketamine also has been shown to be clinically efficacious.¹⁰ Inhalable nitrous oxide (laughing gas, an NMDA antagonist) recently was reported to improve depression as well.¹¹

It is possible that parenteral admin­istration of antidepressant agents may exert a different neurobiological effect and provide a more rapid response than oral medication.

5. From delayed efficacy (weeks) to immediate onset (1 or 2 hours)
The widely entrenched notion that depression takes several weeks to improve with an antidepressant has collapsed with emerging evidence that symptoms of the disorder (even sui­cidal ideation) can be reversed within 1 or 2 hours.¹² IV ketamine isn’t the only example; IV scopolamine,9 inhalable nitrous oxide,¹¹ and overnight sleep deprivation¹³ also exert a rapid thera­peutic effect. This is a major rethinking of how quickly the curtain of severe depression can be lifted, and is great news for patients and their family.

6. From psychological symptoms to cortical or subcortical changes
Depression traditionally has been recog­nized as a clinical syndrome of sadness, self-deprecation, cognitive dulling, and vegetative symptoms. In recent stud­ies, however, researchers report that low hippocampus volume¹⁴ in healthy young girls predicts future depression. Patients with unremitting depression have been reported to have an abnor­mally shaped hippocampus.¹⁵

In addition, gray-matter volume in the subgenual anterior cingulate (Brodmann area 24) is hypoplastic in depressed persons,¹⁶ making that area a target for deep-brain stimulation (DBS). Brain morphological changes such as a hypoplastic hippocampus might become useful biomarkers for identify­ing persons at risk of severe depression, and might become a useful adjunc­tive biomarker for making a clinical diagnosis.

7. From healing the mind to repairing the brain
It is well-established that depression is associated with loss of dendritic spines and arborizations, loss of syn­apses, and diminishment of glial cells, especially in the hippocampus¹⁷ and anterior cingulate.¹⁸ Treating depression, whether pharmaceutical or somatic, involves reversing these changes by increasing neurotrophic factors, enhancing neurogenesis and gliogenesis, and restoring synaptic and dendritic health and cell survival in the hippocampus and frontal cor­tex.^19,20 Treating depression involves brain repair, which is reflected, ulti­mately, in healing the mind.

8. From pharmacotherapy to neuromodulation
Although drugs remain the predomi­nant treatment modality for depression, there is palpable escalation in the use of neuromodulation methods.

The oldest of these neuromodulatory techniques is electroconvulsive ther­apy, an excellent treatment for severe depression (and one that enhances hip­pocampal neurogenesis). In addition, several novel neuromodulation meth­ods have been approved (transcranial magnetic stimulation and vagus nerve stimulation) or are in development (transcranial direct-current stimula­tion, cranial electrotherapy stimulation, and DBS).²¹ These somatic approaches to treating the brain directly to allevi­ate depression target regions involved in depression and reduce the needless risks associated with exposing other organ systems to a drug.

9. From monotherapy to combination therapy
The use of combination therapy for depression has escalated with FDA approval of adjunctive use of atypical antipsychotics in unipolar and bipolar depression. In addition, the landmark STAR*D study¹ demonstrated the value of augmentation therapy with a second antidepressant when 1 agent fails. Other controlled studies have shown that combining 2 antidepressants is superior to administering 1.²²

Just as other serious medical dis­orders—such as cancer and hyper­tension—are treated with 2 or 3 medications, severe depression might require a similar strategy. The field gradually is adopting that approach.

10. From cortical folds to wrinkles on the face
Last, a new (and unexpected) paradigm shift recently emerged, which is genu­inely intriguing—even baffling. Using placebo-controlled designs, several researchers have reported significant, persistent improvement of depressive symptoms after injection of onabotu­linumtoxinA in the corrugator muscles of the glabellar region of the face, where the omega sign often appears in a depressed person.^23,24

The longest of the studies²⁵ was 6 months; investigators reported that improvement continued even after the effect of the botulinum toxin on the omega sign wore off. The proposed mechanism of action is the facial feed­back hypothesis, which suggests that, biologically, facial expression has an impact on one’s emotional state.

Big payoffs coming from research in neuroscience
These 10 paradigm shifts in a single psychiatric syndrome are emblematic of exciting clinical and research advances in our field. Like all syndromes, depression is associated with multiple genetic and environmental causes; it isn’t surprising that myriad treatment approaches are emerging.

The days of clinging to monolithic, serendipity-generated models surely are over. Evidence-based psychiatric brain research is shattering aging dog­mas that have, for decades, stifled inno­vation in psychiatric therapeutics that is now moving in novel directions.

Take note, however, that the only par­adigm shift that matters to depressed patients is the one that transcends mere control of their symptoms and restores their wellness, functional capacity, and quality of life. With the explosive momentum of neuroscience discovery, psychiatry is, at last, poised to deliver—in splendid, even seismic, fashion.

Nowhere is that change in landscape more apparent than in major depression, the No. 1 disabling condition in all of medicine, according to the World Health Organization. The past decade has gen­erated at least 10 paradigm shifts in the neurobiology and pharmacotherapeutics of depression.

Clinging to simplistic tradition
Most contemporary clinicians con­tinue to practice the traditional model of depression, which is based on the assumption that depression is caused by a deficiency of monoamines: sero­tonin (5-HT) and norepinephrine (NE). The entire antidepressant armamentar­ium approved for use by the FDA was designed according to the amine defi­ciency hypothesis. Depressed patients uniformly receive reuptake inhibitors of 5-HT and NE, but few achieve full remission, as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed.¹

As scientific paradigm shifts infil­trate clinical practice, however, the tired notion of “chemical imbalance” will yield to more complex and evidence-based models.

Usually, it would be remarkable to witness a single paradigm shift in the understanding of a brain disor­der. Imagine the disruptive impact of multiple scientific shifts within the past decade! Consider the follow­ing departures from the old dogma about the simplistic old explanation of depression.

1. From neurotransmitters to neuroplasticity
For half a century, our field tenaciously held to the monoamine theory, which posits that depression is caused by a deficiency of 5-HT or NE, or both. All antidepressants in use today were developed to increase brain mono­amines by inhibiting their reuptake at the synaptic cleft. Now, research points to other causes:
   • impaired neuroplasticity
   • a decrement of neurogenesis
   • synaptic deficits
   • decreased neurotrophins (such as brain-derived neurotrophic factor)
   • dendritic pathology.^2,3

2. From ‘chemical imbalance’ to neuroinflammation
The simplistic notion that depression is a chemical imbalance, so to speak, in the brain is giving way to rapidly emerging evidence that depression is associated with neuroinflammation.⁴

Pro-inflammatory cytokines are elevated in the plasma of depressed patients, and subside when the acute episode is treated. Current antidepres­sants actually have anti-inflammatory effects that have gone unrecognized.⁵ A meta-analysis of the use of anti-inflammatory agents (such as nonste­roidal anti-inflammatory drugs and aspirin) in depression shows promising efficacy.⁶ Some inflammatory markers, such as C-reactive protein, already have been reported to predict response to some antidepressants, but not to others.⁷

3. From 5-HT and NE pathways to glutamate NMDA receptors
Recent landmark studies⁸ have, taken together, demonstrated that a single IV dose of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (a psychotogenic drug of abuse FDA-approved only as an anesthetic) can produce clinical improvement of severe depression and even full remission for several days. Such studies demonstrate that the old dogma of 5-HT and NE deficiency might not be a valid over­arching hypothesis of the depression syndrome.

Long-term maintenance studies of ketamine to document its safety and continued efficacy need to be con­ducted. The mechanism of action of ket­amine is believed to be a rapid trigger for enhancing neuroplasticity.

4. From oral to parenteral administration
Several studies have been published showing the efficacy of IV or intranasal administration of new agents for depres­sion. Ketamine studies, for example, were conducted using an IV infusion of a 150-mg dose over 1 hour. Other IV studies used the anticholinergic scopolamine.⁹

Intranasal ketamine also has been shown to be clinically efficacious.¹⁰ Inhalable nitrous oxide (laughing gas, an NMDA antagonist) recently was reported to improve depression as well.¹¹

It is possible that parenteral admin­istration of antidepressant agents may exert a different neurobiological effect and provide a more rapid response than oral medication.

5. From delayed efficacy (weeks) to immediate onset (1 or 2 hours)
The widely entrenched notion that depression takes several weeks to improve with an antidepressant has collapsed with emerging evidence that symptoms of the disorder (even sui­cidal ideation) can be reversed within 1 or 2 hours.¹² IV ketamine isn’t the only example; IV scopolamine,9 inhalable nitrous oxide,¹¹ and overnight sleep deprivation¹³ also exert a rapid thera­peutic effect. This is a major rethinking of how quickly the curtain of severe depression can be lifted, and is great news for patients and their family.

6. From psychological symptoms to cortical or subcortical changes
Depression traditionally has been recog­nized as a clinical syndrome of sadness, self-deprecation, cognitive dulling, and vegetative symptoms. In recent stud­ies, however, researchers report that low hippocampus volume¹⁴ in healthy young girls predicts future depression. Patients with unremitting depression have been reported to have an abnor­mally shaped hippocampus.¹⁵

In addition, gray-matter volume in the subgenual anterior cingulate (Brodmann area 24) is hypoplastic in depressed persons,¹⁶ making that area a target for deep-brain stimulation (DBS). Brain morphological changes such as a hypoplastic hippocampus might become useful biomarkers for identify­ing persons at risk of severe depression, and might become a useful adjunc­tive biomarker for making a clinical diagnosis.

7. From healing the mind to repairing the brain
It is well-established that depression is associated with loss of dendritic spines and arborizations, loss of syn­apses, and diminishment of glial cells, especially in the hippocampus¹⁷ and anterior cingulate.¹⁸ Treating depression, whether pharmaceutical or somatic, involves reversing these changes by increasing neurotrophic factors, enhancing neurogenesis and gliogenesis, and restoring synaptic and dendritic health and cell survival in the hippocampus and frontal cor­tex.^19,20 Treating depression involves brain repair, which is reflected, ulti­mately, in healing the mind.

8. From pharmacotherapy to neuromodulation
Although drugs remain the predomi­nant treatment modality for depression, there is palpable escalation in the use of neuromodulation methods.

The oldest of these neuromodulatory techniques is electroconvulsive ther­apy, an excellent treatment for severe depression (and one that enhances hip­pocampal neurogenesis). In addition, several novel neuromodulation meth­ods have been approved (transcranial magnetic stimulation and vagus nerve stimulation) or are in development (transcranial direct-current stimula­tion, cranial electrotherapy stimulation, and DBS).²¹ These somatic approaches to treating the brain directly to allevi­ate depression target regions involved in depression and reduce the needless risks associated with exposing other organ systems to a drug.

9. From monotherapy to combination therapy
The use of combination therapy for depression has escalated with FDA approval of adjunctive use of atypical antipsychotics in unipolar and bipolar depression. In addition, the landmark STAR*D study¹ demonstrated the value of augmentation therapy with a second antidepressant when 1 agent fails. Other controlled studies have shown that combining 2 antidepressants is superior to administering 1.²²

Just as other serious medical dis­orders—such as cancer and hyper­tension—are treated with 2 or 3 medications, severe depression might require a similar strategy. The field gradually is adopting that approach.

10. From cortical folds to wrinkles on the face
Last, a new (and unexpected) paradigm shift recently emerged, which is genu­inely intriguing—even baffling. Using placebo-controlled designs, several researchers have reported significant, persistent improvement of depressive symptoms after injection of onabotu­linumtoxinA in the corrugator muscles of the glabellar region of the face, where the omega sign often appears in a depressed person.^23,24

The longest of the studies²⁵ was 6 months; investigators reported that improvement continued even after the effect of the botulinum toxin on the omega sign wore off. The proposed mechanism of action is the facial feed­back hypothesis, which suggests that, biologically, facial expression has an impact on one’s emotional state.

Big payoffs coming from research in neuroscience
These 10 paradigm shifts in a single psychiatric syndrome are emblematic of exciting clinical and research advances in our field. Like all syndromes, depression is associated with multiple genetic and environmental causes; it isn’t surprising that myriad treatment approaches are emerging.

The days of clinging to monolithic, serendipity-generated models surely are over. Evidence-based psychiatric brain research is shattering aging dog­mas that have, for decades, stifled inno­vation in psychiatric therapeutics that is now moving in novel directions.

Take note, however, that the only par­adigm shift that matters to depressed patients is the one that transcends mere control of their symptoms and restores their wellness, functional capacity, and quality of life. With the explosive momentum of neuroscience discovery, psychiatry is, at last, poised to deliver—in splendid, even seismic, fashion.

Consider here my journey in psychiatry since my adolescence. Growing up in the 1960s and 1970s, I did not watch much television; my father was convinced TV would be “too distracting” for us children. At first, I was angry about his rule, and would occasionally watch pro­grams such as Bonanza at sleep-overs.

The lure of psychoanalysis
Gradually, I became grateful to my father because—in contrast to my classmates, who sat passively for hours watching TV after school—I voraciously read the piles of fiction and nonfiction books that I checked out from the school library every week, expanding my general knowl­edge and perspectives. One of my favorite genres became psychology and psychiatry, including many of Sigmund Freud’s works.

I was enchanted by psychoanalysis and its explanation of mental illness because, growing up, I had been told that madness is caused by demonic spir­its and bad behavior and it is completely untreatable. By the time I was in high school, I had decided to become a psy­chiatrist, and was practicing what I read by “counseling” my classmates about family conflicts, raging drives, and frus­trating relationships with girlfriends.
 

Rising tide of psychopharmacology
My love for psychiatry never wavered during my undergraduate years. I focused not only on required pre-med courses but enthusiastically took many psychology, sociology, and anthropology electives to expand my understanding of human behavior. In medical school, I enjoyed all rotations, but psychiatry was simply sublime. Often, I offered (to my classmates’ delight) to take their week­end call at the psychiatric hospital so I could see more patients.

After my internship, I married my wife (a behavioral psychologist) and embarked on psychiatry residency train­ing with gusto. I was far better prepared, I realized, than my fellow residents; my faculty supervisors noticed that I answered questions more often than many others during rounds and lec­tures. (Thanks, Dad, for banning televi­sion!) I relished every psychotherapy session and spent hours listening to audiotapes of my patients’ sessions to improve my skills and to discover the psychodynamic nuances of their psy­chopathology. Being supervised by expert psychoanalysts was the highlight of my week as I honed my psychody­namic psychotherapy skills.

But something interesting hap­pened during my residency: Psychopharmacology and electro­convulsive therapy were helping my severely ill psychotic, manic, and depressed patients much faster than psychotherapy could. Length of stay in the wards typically was 30 days (there was no managed care back then to limit stay to an absurd 5 days), and I saw sub­stantial improvement in many of my patients before discharge.

I was so enthralled by the rising tide of psychopharmacology that I decided in PGY-2 to conduct psychopharmacology research—which, I came to realize, was easier than research on psychotherapy. I secured a mentor from the department of pharmacology. In PGY-3, I presented my data at the Annual Meeting of the American Psychiatric Association; in PGY-4, the paper was published in the American Journal of Psychiatry.

By the end of residency, I had applied to the National Institute of Mental Health (NIMH) to pursue a research fel­lowship in the neuropharmacology of schizophrenia to prepare me for an aca­demic career. I participated in numerous studies on the NIMH research ward, brimming with patients who had refrac­tory schizophrenia (before the advent of clozapine in 1989), and I published many articles with mentors and fellow researchers.

Investigating brain biology
Then another funny thing happened: During my fellowship, one of my men­tors shared with me some early studies about postmortem structural changes in the brain of schizophrenia patients. That prompted me to spend hours in the basement of the pathology depart­ment examining the brains of dozens of patients with schizophrenia, noting atro­phic changes and performing measure­ments and histopathologic studies.

Consequently, I embarked on neuro­imaging research to study the mor­phological abnormalities of cortical and subcortical regions in living patients. I found myself going beyond neuro­psychopharmacology and diving into neuroanatomy books and neuroscience journals. I realized that I was continu­ously learning and using a new scientific language in my daily work.

After I left NIMH to begin a career of teaching, research, and patient care in a medical school setting, I was engulfed by meteoric advances in neuroscience producing unprecedented insights about the molecular biology of schizo­phrenia and other severe neuropsychi­atric disorders, leading me to pursue new opportunities in neurobiology while continuing my psychopharma­cology research.

The rate of transformation is mind-boggling
Looking back at the span of time from childhood through the exciting journey of my psychiatry career, I realize how massive a transformation I have wit­nessed and experienced. The specialty has shifted its clinical and scientific paradigms through several conceptual models—from demonic possession to psychoanalysis to psychopharmacol­ogy and, last, to molecular neurobiol­ogy. Four times in my life, the lexicon of psychiatry has undergone a complete make­over. This is a light-speed pace of scien­tific progress over a few decades—truly breathtaking! It’s like rewriting a dic­tionary over and over, with no 2 suc­cessive editions resembling each other whatsoever.

The Table shows 4 sets of examples of psychiatric terminology, each repre­senting 1 of the 4 paradigmatic models that my generation of psychiatrists has had to adopt and use in clinical care and research. I cannot think of any other medical specialty that has come close to evolving and transforming its language and conceptual models of etiology and treatment at such a rapid pace.

When I embraced psychiatry in ado­lescence as my future career, I never imagined, in my wildest dreams, that I would experience such successive scientific earthquakes in my beloved medical specialty. Perhaps that’s what kept me stimulated and eager to come to work every day; I use all the models and treatment tools I have learned in understanding and helping my patients with evolving psychotherapeutic and biopharmaceutical tools; I also teach my students and residents about the multi­faceted wonders of the human mind and the magnificent complexities of the brain in health and disease.

Psychiatry has been, and will continue to be, a Pandora’s box of medicine, full of stunning scientific twists and surprises and a transformative lexicon to match.

Consider here my journey in psychiatry since my adolescence. Growing up in the 1960s and 1970s, I did not watch much television; my father was convinced TV would be “too distracting” for us children. At first, I was angry about his rule, and would occasionally watch pro­grams such as Bonanza at sleep-overs.

The lure of psychoanalysis
Gradually, I became grateful to my father because—in contrast to my classmates, who sat passively for hours watching TV after school—I voraciously read the piles of fiction and nonfiction books that I checked out from the school library every week, expanding my general knowl­edge and perspectives. One of my favorite genres became psychology and psychiatry, including many of Sigmund Freud’s works.

I was enchanted by psychoanalysis and its explanation of mental illness because, growing up, I had been told that madness is caused by demonic spir­its and bad behavior and it is completely untreatable. By the time I was in high school, I had decided to become a psy­chiatrist, and was practicing what I read by “counseling” my classmates about family conflicts, raging drives, and frus­trating relationships with girlfriends.
 

Rising tide of psychopharmacology
My love for psychiatry never wavered during my undergraduate years. I focused not only on required pre-med courses but enthusiastically took many psychology, sociology, and anthropology electives to expand my understanding of human behavior. In medical school, I enjoyed all rotations, but psychiatry was simply sublime. Often, I offered (to my classmates’ delight) to take their week­end call at the psychiatric hospital so I could see more patients.

After my internship, I married my wife (a behavioral psychologist) and embarked on psychiatry residency train­ing with gusto. I was far better prepared, I realized, than my fellow residents; my faculty supervisors noticed that I answered questions more often than many others during rounds and lec­tures. (Thanks, Dad, for banning televi­sion!) I relished every psychotherapy session and spent hours listening to audiotapes of my patients’ sessions to improve my skills and to discover the psychodynamic nuances of their psy­chopathology. Being supervised by expert psychoanalysts was the highlight of my week as I honed my psychody­namic psychotherapy skills.

But something interesting hap­pened during my residency: Psychopharmacology and electro­convulsive therapy were helping my severely ill psychotic, manic, and depressed patients much faster than psychotherapy could. Length of stay in the wards typically was 30 days (there was no managed care back then to limit stay to an absurd 5 days), and I saw sub­stantial improvement in many of my patients before discharge.

I was so enthralled by the rising tide of psychopharmacology that I decided in PGY-2 to conduct psychopharmacology research—which, I came to realize, was easier than research on psychotherapy. I secured a mentor from the department of pharmacology. In PGY-3, I presented my data at the Annual Meeting of the American Psychiatric Association; in PGY-4, the paper was published in the American Journal of Psychiatry.

By the end of residency, I had applied to the National Institute of Mental Health (NIMH) to pursue a research fel­lowship in the neuropharmacology of schizophrenia to prepare me for an aca­demic career. I participated in numerous studies on the NIMH research ward, brimming with patients who had refrac­tory schizophrenia (before the advent of clozapine in 1989), and I published many articles with mentors and fellow researchers.

Investigating brain biology
Then another funny thing happened: During my fellowship, one of my men­tors shared with me some early studies about postmortem structural changes in the brain of schizophrenia patients. That prompted me to spend hours in the basement of the pathology depart­ment examining the brains of dozens of patients with schizophrenia, noting atro­phic changes and performing measure­ments and histopathologic studies.

Consequently, I embarked on neuro­imaging research to study the mor­phological abnormalities of cortical and subcortical regions in living patients. I found myself going beyond neuro­psychopharmacology and diving into neuroanatomy books and neuroscience journals. I realized that I was continu­ously learning and using a new scientific language in my daily work.

After I left NIMH to begin a career of teaching, research, and patient care in a medical school setting, I was engulfed by meteoric advances in neuroscience producing unprecedented insights about the molecular biology of schizo­phrenia and other severe neuropsychi­atric disorders, leading me to pursue new opportunities in neurobiology while continuing my psychopharma­cology research.

The rate of transformation is mind-boggling
Looking back at the span of time from childhood through the exciting journey of my psychiatry career, I realize how massive a transformation I have wit­nessed and experienced. The specialty has shifted its clinical and scientific paradigms through several conceptual models—from demonic possession to psychoanalysis to psychopharmacol­ogy and, last, to molecular neurobiol­ogy. Four times in my life, the lexicon of psychiatry has undergone a complete make­over. This is a light-speed pace of scien­tific progress over a few decades—truly breathtaking! It’s like rewriting a dic­tionary over and over, with no 2 suc­cessive editions resembling each other whatsoever.

The Table shows 4 sets of examples of psychiatric terminology, each repre­senting 1 of the 4 paradigmatic models that my generation of psychiatrists has had to adopt and use in clinical care and research. I cannot think of any other medical specialty that has come close to evolving and transforming its language and conceptual models of etiology and treatment at such a rapid pace.

When I embraced psychiatry in ado­lescence as my future career, I never imagined, in my wildest dreams, that I would experience such successive scientific earthquakes in my beloved medical specialty. Perhaps that’s what kept me stimulated and eager to come to work every day; I use all the models and treatment tools I have learned in understanding and helping my patients with evolving psychotherapeutic and biopharmaceutical tools; I also teach my students and residents about the multi­faceted wonders of the human mind and the magnificent complexities of the brain in health and disease.

Psychiatry has been, and will continue to be, a Pandora’s box of medicine, full of stunning scientific twists and surprises and a transformative lexicon to match.

Consider here my journey in psychiatry since my adolescence. Growing up in the 1960s and 1970s, I did not watch much television; my father was convinced TV would be “too distracting” for us children. At first, I was angry about his rule, and would occasionally watch pro­grams such as Bonanza at sleep-overs.

The lure of psychoanalysis
Gradually, I became grateful to my father because—in contrast to my classmates, who sat passively for hours watching TV after school—I voraciously read the piles of fiction and nonfiction books that I checked out from the school library every week, expanding my general knowl­edge and perspectives. One of my favorite genres became psychology and psychiatry, including many of Sigmund Freud’s works.

I was enchanted by psychoanalysis and its explanation of mental illness because, growing up, I had been told that madness is caused by demonic spir­its and bad behavior and it is completely untreatable. By the time I was in high school, I had decided to become a psy­chiatrist, and was practicing what I read by “counseling” my classmates about family conflicts, raging drives, and frus­trating relationships with girlfriends.
 

Rising tide of psychopharmacology
My love for psychiatry never wavered during my undergraduate years. I focused not only on required pre-med courses but enthusiastically took many psychology, sociology, and anthropology electives to expand my understanding of human behavior. In medical school, I enjoyed all rotations, but psychiatry was simply sublime. Often, I offered (to my classmates’ delight) to take their week­end call at the psychiatric hospital so I could see more patients.

After my internship, I married my wife (a behavioral psychologist) and embarked on psychiatry residency train­ing with gusto. I was far better prepared, I realized, than my fellow residents; my faculty supervisors noticed that I answered questions more often than many others during rounds and lec­tures. (Thanks, Dad, for banning televi­sion!) I relished every psychotherapy session and spent hours listening to audiotapes of my patients’ sessions to improve my skills and to discover the psychodynamic nuances of their psy­chopathology. Being supervised by expert psychoanalysts was the highlight of my week as I honed my psychody­namic psychotherapy skills.

But something interesting hap­pened during my residency: Psychopharmacology and electro­convulsive therapy were helping my severely ill psychotic, manic, and depressed patients much faster than psychotherapy could. Length of stay in the wards typically was 30 days (there was no managed care back then to limit stay to an absurd 5 days), and I saw sub­stantial improvement in many of my patients before discharge.

I was so enthralled by the rising tide of psychopharmacology that I decided in PGY-2 to conduct psychopharmacology research—which, I came to realize, was easier than research on psychotherapy. I secured a mentor from the department of pharmacology. In PGY-3, I presented my data at the Annual Meeting of the American Psychiatric Association; in PGY-4, the paper was published in the American Journal of Psychiatry.

By the end of residency, I had applied to the National Institute of Mental Health (NIMH) to pursue a research fel­lowship in the neuropharmacology of schizophrenia to prepare me for an aca­demic career. I participated in numerous studies on the NIMH research ward, brimming with patients who had refrac­tory schizophrenia (before the advent of clozapine in 1989), and I published many articles with mentors and fellow researchers.

Investigating brain biology
Then another funny thing happened: During my fellowship, one of my men­tors shared with me some early studies about postmortem structural changes in the brain of schizophrenia patients. That prompted me to spend hours in the basement of the pathology depart­ment examining the brains of dozens of patients with schizophrenia, noting atro­phic changes and performing measure­ments and histopathologic studies.

Consequently, I embarked on neuro­imaging research to study the mor­phological abnormalities of cortical and subcortical regions in living patients. I found myself going beyond neuro­psychopharmacology and diving into neuroanatomy books and neuroscience journals. I realized that I was continu­ously learning and using a new scientific language in my daily work.

After I left NIMH to begin a career of teaching, research, and patient care in a medical school setting, I was engulfed by meteoric advances in neuroscience producing unprecedented insights about the molecular biology of schizo­phrenia and other severe neuropsychi­atric disorders, leading me to pursue new opportunities in neurobiology while continuing my psychopharma­cology research.

The rate of transformation is mind-boggling
Looking back at the span of time from childhood through the exciting journey of my psychiatry career, I realize how massive a transformation I have wit­nessed and experienced. The specialty has shifted its clinical and scientific paradigms through several conceptual models—from demonic possession to psychoanalysis to psychopharmacol­ogy and, last, to molecular neurobiol­ogy. Four times in my life, the lexicon of psychiatry has undergone a complete make­over. This is a light-speed pace of scien­tific progress over a few decades—truly breathtaking! It’s like rewriting a dic­tionary over and over, with no 2 suc­cessive editions resembling each other whatsoever.

The Table shows 4 sets of examples of psychiatric terminology, each repre­senting 1 of the 4 paradigmatic models that my generation of psychiatrists has had to adopt and use in clinical care and research. I cannot think of any other medical specialty that has come close to evolving and transforming its language and conceptual models of etiology and treatment at such a rapid pace.

When I embraced psychiatry in ado­lescence as my future career, I never imagined, in my wildest dreams, that I would experience such successive scientific earthquakes in my beloved medical specialty. Perhaps that’s what kept me stimulated and eager to come to work every day; I use all the models and treatment tools I have learned in understanding and helping my patients with evolving psychotherapeutic and biopharmaceutical tools; I also teach my students and residents about the multi­faceted wonders of the human mind and the magnificent complexities of the brain in health and disease.

Psychiatry has been, and will continue to be, a Pandora’s box of medicine, full of stunning scientific twists and surprises and a transformative lexicon to match.

Millions of people suffer because they lack access to psychiatric care that they desperately need. The shortage of psychiatrists grows worse every day.

As a result of this anemic supply of psychiatrists, the mental health of the country’s populace is in jeopardy.

The facts paint the picture
The landmark National Institutes of Health-funded Epidemiologic Catchment Area (ECA) study, pub­lished a quarter of a century ago, found that 25% of the population suf­fered from a psychiatric disorder at some point in their life.¹ In 1990, that translated to 62 million people; today, the number would be 82 million.

Regrettably, the findings of the ECA were not followed by necessary action—simply, ensuring sufficient psychiatrists to meet the significant mental health needs of the nation.

Signs and symptoms
Manifestations of psychiatrynemia continue unabated:
   • frustration by primary care providers when they try to refer a patient to a psychiatrist—with appointments often unavailable for 4 to 6 months
   • lack of access to a psychiatrist within 100 miles in many rural areas
   • a large number of unfilled posi­tions for psychiatrists in many health care settings nationwide, which has created a thriving locum tenens industry
   • emergency rooms packed with psychiatric patients
   • a huge patient load in commu­nity mental health centers
   • a large increase in the percent­age of seriously mentally ill people in jails and prisons because of a lack of psychiatrists and psychiatric beds; according to Torrey et al,² the percentage of mentally ill patients incarcerated in the United States today is the same as it was in 1840, the pre-asylum era—shameful for a civilized country
   • an escalation of cash-only prac­tices and concierge psychiatry
   • a suicide rate that continues to rise (one wonders how many of the 40,600 deaths by suicide and 650,000 suicide attempts in 2012³ could have been prevented by prompt access to psychiatric care)
    • a severe shortage of psychiatric subspecialists (child, geriatric, addic­tion, psychosomatic); their numbers need to rise by 200% to 300% to meet the needs of those populations
    • an alarming overreliance on absurdly brief 15-minute med-checks as a way to cope with a large patient load.

What can be done?
To boost the number of psychiatric clini­cians and provide better access to care, I offer several prescriptions in the Box.⁴ (Yes, polytherapy is needed.)

Curing psychiatrynemia requires bold action on multiple fronts by differ­ent stakeholders. Considering the failure to act over the past 25 years, however, prospects for a quick remission are low.

We’re past needing an ounce of pre­vention; we need many pounds.

Millions of people suffer because they lack access to psychiatric care that they desperately need. The shortage of psychiatrists grows worse every day.

As a result of this anemic supply of psychiatrists, the mental health of the country’s populace is in jeopardy.

The facts paint the picture
The landmark National Institutes of Health-funded Epidemiologic Catchment Area (ECA) study, pub­lished a quarter of a century ago, found that 25% of the population suf­fered from a psychiatric disorder at some point in their life.¹ In 1990, that translated to 62 million people; today, the number would be 82 million.

Regrettably, the findings of the ECA were not followed by necessary action—simply, ensuring sufficient psychiatrists to meet the significant mental health needs of the nation.

Signs and symptoms
Manifestations of psychiatrynemia continue unabated:
   • frustration by primary care providers when they try to refer a patient to a psychiatrist—with appointments often unavailable for 4 to 6 months
   • lack of access to a psychiatrist within 100 miles in many rural areas
   • a large number of unfilled posi­tions for psychiatrists in many health care settings nationwide, which has created a thriving locum tenens industry
   • emergency rooms packed with psychiatric patients
   • a huge patient load in commu­nity mental health centers
   • a large increase in the percent­age of seriously mentally ill people in jails and prisons because of a lack of psychiatrists and psychiatric beds; according to Torrey et al,² the percentage of mentally ill patients incarcerated in the United States today is the same as it was in 1840, the pre-asylum era—shameful for a civilized country
   • an escalation of cash-only prac­tices and concierge psychiatry
   • a suicide rate that continues to rise (one wonders how many of the 40,600 deaths by suicide and 650,000 suicide attempts in 2012³ could have been prevented by prompt access to psychiatric care)
    • a severe shortage of psychiatric subspecialists (child, geriatric, addic­tion, psychosomatic); their numbers need to rise by 200% to 300% to meet the needs of those populations
    • an alarming overreliance on absurdly brief 15-minute med-checks as a way to cope with a large patient load.

What can be done?
To boost the number of psychiatric clini­cians and provide better access to care, I offer several prescriptions in the Box.⁴ (Yes, polytherapy is needed.)

Curing psychiatrynemia requires bold action on multiple fronts by differ­ent stakeholders. Considering the failure to act over the past 25 years, however, prospects for a quick remission are low.

We’re past needing an ounce of pre­vention; we need many pounds.

Millions of people suffer because they lack access to psychiatric care that they desperately need. The shortage of psychiatrists grows worse every day.

As a result of this anemic supply of psychiatrists, the mental health of the country’s populace is in jeopardy.

The facts paint the picture
The landmark National Institutes of Health-funded Epidemiologic Catchment Area (ECA) study, pub­lished a quarter of a century ago, found that 25% of the population suf­fered from a psychiatric disorder at some point in their life.¹ In 1990, that translated to 62 million people; today, the number would be 82 million.

Regrettably, the findings of the ECA were not followed by necessary action—simply, ensuring sufficient psychiatrists to meet the significant mental health needs of the nation.

Signs and symptoms
Manifestations of psychiatrynemia continue unabated:
   • frustration by primary care providers when they try to refer a patient to a psychiatrist—with appointments often unavailable for 4 to 6 months
   • lack of access to a psychiatrist within 100 miles in many rural areas
   • a large number of unfilled posi­tions for psychiatrists in many health care settings nationwide, which has created a thriving locum tenens industry
   • emergency rooms packed with psychiatric patients
   • a huge patient load in commu­nity mental health centers
   • a large increase in the percent­age of seriously mentally ill people in jails and prisons because of a lack of psychiatrists and psychiatric beds; according to Torrey et al,² the percentage of mentally ill patients incarcerated in the United States today is the same as it was in 1840, the pre-asylum era—shameful for a civilized country
   • an escalation of cash-only prac­tices and concierge psychiatry
   • a suicide rate that continues to rise (one wonders how many of the 40,600 deaths by suicide and 650,000 suicide attempts in 2012³ could have been prevented by prompt access to psychiatric care)
    • a severe shortage of psychiatric subspecialists (child, geriatric, addic­tion, psychosomatic); their numbers need to rise by 200% to 300% to meet the needs of those populations
    • an alarming overreliance on absurdly brief 15-minute med-checks as a way to cope with a large patient load.

What can be done?
To boost the number of psychiatric clini­cians and provide better access to care, I offer several prescriptions in the Box.⁴ (Yes, polytherapy is needed.)

Curing psychiatrynemia requires bold action on multiple fronts by differ­ent stakeholders. Considering the failure to act over the past 25 years, however, prospects for a quick remission are low.

We’re past needing an ounce of pre­vention; we need many pounds.

But as professionals, and by virtue of our rigorous training, we continually reflect on our thoughts and feelings when we care for our patients, and we examine the effect of our behavior and communication patterns on them. Such self-reflection is especially important when it comes to countertransference while treating a person who has been made vulnerable by emotional turmoil and who develops strong transference feelings toward the treating psychiatrist.

Personal integrity is paramount in psychiatric practice; it’s an indispens­able ingredient when dealing with the intimate thoughts, feelings, and impulses of people who are seeking psychiatric help. In addition, the wis­dom to recognize one’s limitations as a provider of care is an important attri­butes of seasoned practitioners. Patients might perceive us as demigods, but we know better than to be carried away with hubris and pretend that we are.

Exercising sound judgment isn’t easy
This is especially true when dealing with the varying degrees of ambiguity that shroud complex psychiatric con­ditions. The overriding principle for good clinical judgment in any medical practice is the patient’s welfare, and that must dominate the moral, ethical, medi­cal, and scientific decision-making of all psychiatrists. Those of us in charge of training medical students and residents emphasize this principle every day at the bedside and in the clinic. Upholding those principles, side by side with the knowledge and skills of psychiatric practice, are the hallmarks of good med­ical training.

But missteps occur. Peccadillos, infractions, and even transgressions happen—accidentally by competent, ethical psychiatrists; deliberately, some­times, by a few unethical scoundrels. The sins of psychiatric practice come in a range of gravity and consequences. Here are some I’ve observed among col­leagues over the years:

Becoming sexually intimate with one’s patient. Violating the sacred boundary of the doctor-patient relation­ship is unforgivable; it’s a sin that scars the patient and can destroy the psychia­trist’s reputation and career. We must respect and uphold that boundary—not only during active treatment but even after care is terminated.

Divulging clinical details to other without the patient’s consent. Breach of trust is not only an ethical misstep; it is a violation of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), with substantial penal­ties attached.

Treating the mind while ignoring the body and brain. We are physicians first, psychiatrists second. We must fully assess patients who present with psychiatric signs and symptoms to rule out a general medical condition that could be generating behavioral symp­toms. Such co-occurring medical con­ditions might involve various organ systems, such as endocrinopathies, or might emanate from brain lesions, whether traumatic, degenerative, demyelinating, infectious, or neoplas­tic. Without careful medical evaluation, the wrong diagnosis might be made and inappropriate, even harmful, treat­ment provided while necessary care is delayed.

Treatment plans can sometimes overlook potential harmful effects of some medications on physical health— whether metabolic, cardiovascular, neurologic, gastrointestinal, hormonal, hematologic, or dermatologic. An opti­mal treatment plan embarks on healing the mind without ignoring or harming the body. 

Failing to obtain additional infor­mation from sources who know the patient or who can provide old records. Such information is vital in psychiatry, because the patient’s account often is incomplete, even distorted, because of cognitive deficits or psychopathologic factors. Additional information can be corroborative or contradictory, and is sometimes critical—significantly influ­encing the diagnosis or the treatment plan, or both.

Allowing personal beliefs to influence care. This transgression includes insert­ing one’s views about religion, politics, sexual orientation, ethnic origin, and socioeconomic class into medical care. The same unimpeachable, high caliber of care must be provided to every patient, and must not differ in any way from the care that we would recommend to our own family members.

Reducing psychiatry to prescrib­ing a pill. However unacceptable and deficient this reductionist degradation of psychiatric management is, it is sometimes imposed by organizations in which the caseload is huge and the number of providers insufficient. We must resist the temptation to compromise, and must strive to address not only the biological aspects of illness but psychological and social dimensions as well. Patients will not have an optimal if we don’t.

Practicing with an outdated knowl­edge base—one acquired during residency years, often years or even decades, earlier. There is no medical or ethical justification for using 1985, or even 2005, standards of psychiatric care in 2015.

Psychiatry is rapidly evolving, with many ongoing changes and advances. Updating one’s practice pattern through lifelong learning is an abso­lute must for psychiatrists (and for all health care professionals). Utilizing the latest, evidence-based data to guide diagnosis and treatment is an indispensable component of good psychiatric care. 

Neglecting to consider treatment options. Consider just a few scenar­ios: The recurrently relapsing patient with psychosis who is not switched to a long-acting injectable formulation; the persistently psychotic patient who does not receive a trial of clozapine; the treatment-resistant depression patient who is not referred for electroconvul­sive therapy or transcranial magnetic stimulation; and the patient receiv­ing an atypical antipsychotic who is monitored inconsistently for metabolic dysregulation.

Treating patients but not vigorously advocating for them—thus allowing a broken, convoluted mental health sys­tem to delay or prevent access to care; incarcerate relapsed patients instead of hospitalizing them; permit insur­ance companies to discriminate against coverage of mental illness; and tie the hands of psychiatrists who want to select medication they judge best for their patients.

None of us is 'without sin'
We all aspire to help our patients in the best way we can, and to avoid errors. However, even a seasoned psy­chiatrist can stumble unwittingly, and that is understandable and forgivable. It is willful, recurring neglect of the patient’s welfare that can be deleterious and that, in my opinion, qualifies as a cardinal sin. Fortunately, such neglect is a low-frequency event in psychiatric practice, but even a single occurrence is one too many.

But as professionals, and by virtue of our rigorous training, we continually reflect on our thoughts and feelings when we care for our patients, and we examine the effect of our behavior and communication patterns on them. Such self-reflection is especially important when it comes to countertransference while treating a person who has been made vulnerable by emotional turmoil and who develops strong transference feelings toward the treating psychiatrist.

Personal integrity is paramount in psychiatric practice; it’s an indispens­able ingredient when dealing with the intimate thoughts, feelings, and impulses of people who are seeking psychiatric help. In addition, the wis­dom to recognize one’s limitations as a provider of care is an important attri­butes of seasoned practitioners. Patients might perceive us as demigods, but we know better than to be carried away with hubris and pretend that we are.

Exercising sound judgment isn’t easy
This is especially true when dealing with the varying degrees of ambiguity that shroud complex psychiatric con­ditions. The overriding principle for good clinical judgment in any medical practice is the patient’s welfare, and that must dominate the moral, ethical, medi­cal, and scientific decision-making of all psychiatrists. Those of us in charge of training medical students and residents emphasize this principle every day at the bedside and in the clinic. Upholding those principles, side by side with the knowledge and skills of psychiatric practice, are the hallmarks of good med­ical training.

But missteps occur. Peccadillos, infractions, and even transgressions happen—accidentally by competent, ethical psychiatrists; deliberately, some­times, by a few unethical scoundrels. The sins of psychiatric practice come in a range of gravity and consequences. Here are some I’ve observed among col­leagues over the years:

Becoming sexually intimate with one’s patient. Violating the sacred boundary of the doctor-patient relation­ship is unforgivable; it’s a sin that scars the patient and can destroy the psychia­trist’s reputation and career. We must respect and uphold that boundary—not only during active treatment but even after care is terminated.

Divulging clinical details to other without the patient’s consent. Breach of trust is not only an ethical misstep; it is a violation of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), with substantial penal­ties attached.

Treating the mind while ignoring the body and brain. We are physicians first, psychiatrists second. We must fully assess patients who present with psychiatric signs and symptoms to rule out a general medical condition that could be generating behavioral symp­toms. Such co-occurring medical con­ditions might involve various organ systems, such as endocrinopathies, or might emanate from brain lesions, whether traumatic, degenerative, demyelinating, infectious, or neoplas­tic. Without careful medical evaluation, the wrong diagnosis might be made and inappropriate, even harmful, treat­ment provided while necessary care is delayed.

Treatment plans can sometimes overlook potential harmful effects of some medications on physical health— whether metabolic, cardiovascular, neurologic, gastrointestinal, hormonal, hematologic, or dermatologic. An opti­mal treatment plan embarks on healing the mind without ignoring or harming the body. 

Failing to obtain additional infor­mation from sources who know the patient or who can provide old records. Such information is vital in psychiatry, because the patient’s account often is incomplete, even distorted, because of cognitive deficits or psychopathologic factors. Additional information can be corroborative or contradictory, and is sometimes critical—significantly influ­encing the diagnosis or the treatment plan, or both.

Allowing personal beliefs to influence care. This transgression includes insert­ing one’s views about religion, politics, sexual orientation, ethnic origin, and socioeconomic class into medical care. The same unimpeachable, high caliber of care must be provided to every patient, and must not differ in any way from the care that we would recommend to our own family members.

Reducing psychiatry to prescrib­ing a pill. However unacceptable and deficient this reductionist degradation of psychiatric management is, it is sometimes imposed by organizations in which the caseload is huge and the number of providers insufficient. We must resist the temptation to compromise, and must strive to address not only the biological aspects of illness but psychological and social dimensions as well. Patients will not have an optimal if we don’t.

Practicing with an outdated knowl­edge base—one acquired during residency years, often years or even decades, earlier. There is no medical or ethical justification for using 1985, or even 2005, standards of psychiatric care in 2015.

Psychiatry is rapidly evolving, with many ongoing changes and advances. Updating one’s practice pattern through lifelong learning is an abso­lute must for psychiatrists (and for all health care professionals). Utilizing the latest, evidence-based data to guide diagnosis and treatment is an indispensable component of good psychiatric care. 

Neglecting to consider treatment options. Consider just a few scenar­ios: The recurrently relapsing patient with psychosis who is not switched to a long-acting injectable formulation; the persistently psychotic patient who does not receive a trial of clozapine; the treatment-resistant depression patient who is not referred for electroconvul­sive therapy or transcranial magnetic stimulation; and the patient receiv­ing an atypical antipsychotic who is monitored inconsistently for metabolic dysregulation.

Treating patients but not vigorously advocating for them—thus allowing a broken, convoluted mental health sys­tem to delay or prevent access to care; incarcerate relapsed patients instead of hospitalizing them; permit insur­ance companies to discriminate against coverage of mental illness; and tie the hands of psychiatrists who want to select medication they judge best for their patients.

None of us is 'without sin'
We all aspire to help our patients in the best way we can, and to avoid errors. However, even a seasoned psy­chiatrist can stumble unwittingly, and that is understandable and forgivable. It is willful, recurring neglect of the patient’s welfare that can be deleterious and that, in my opinion, qualifies as a cardinal sin. Fortunately, such neglect is a low-frequency event in psychiatric practice, but even a single occurrence is one too many.

But as professionals, and by virtue of our rigorous training, we continually reflect on our thoughts and feelings when we care for our patients, and we examine the effect of our behavior and communication patterns on them. Such self-reflection is especially important when it comes to countertransference while treating a person who has been made vulnerable by emotional turmoil and who develops strong transference feelings toward the treating psychiatrist.

Personal integrity is paramount in psychiatric practice; it’s an indispens­able ingredient when dealing with the intimate thoughts, feelings, and impulses of people who are seeking psychiatric help. In addition, the wis­dom to recognize one’s limitations as a provider of care is an important attri­butes of seasoned practitioners. Patients might perceive us as demigods, but we know better than to be carried away with hubris and pretend that we are.

Exercising sound judgment isn’t easy
This is especially true when dealing with the varying degrees of ambiguity that shroud complex psychiatric con­ditions. The overriding principle for good clinical judgment in any medical practice is the patient’s welfare, and that must dominate the moral, ethical, medi­cal, and scientific decision-making of all psychiatrists. Those of us in charge of training medical students and residents emphasize this principle every day at the bedside and in the clinic. Upholding those principles, side by side with the knowledge and skills of psychiatric practice, are the hallmarks of good med­ical training.

But missteps occur. Peccadillos, infractions, and even transgressions happen—accidentally by competent, ethical psychiatrists; deliberately, some­times, by a few unethical scoundrels. The sins of psychiatric practice come in a range of gravity and consequences. Here are some I’ve observed among col­leagues over the years:

Becoming sexually intimate with one’s patient. Violating the sacred boundary of the doctor-patient relation­ship is unforgivable; it’s a sin that scars the patient and can destroy the psychia­trist’s reputation and career. We must respect and uphold that boundary—not only during active treatment but even after care is terminated.

Divulging clinical details to other without the patient’s consent. Breach of trust is not only an ethical misstep; it is a violation of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), with substantial penal­ties attached.

Treating the mind while ignoring the body and brain. We are physicians first, psychiatrists second. We must fully assess patients who present with psychiatric signs and symptoms to rule out a general medical condition that could be generating behavioral symp­toms. Such co-occurring medical con­ditions might involve various organ systems, such as endocrinopathies, or might emanate from brain lesions, whether traumatic, degenerative, demyelinating, infectious, or neoplas­tic. Without careful medical evaluation, the wrong diagnosis might be made and inappropriate, even harmful, treat­ment provided while necessary care is delayed.

Treatment plans can sometimes overlook potential harmful effects of some medications on physical health— whether metabolic, cardiovascular, neurologic, gastrointestinal, hormonal, hematologic, or dermatologic. An opti­mal treatment plan embarks on healing the mind without ignoring or harming the body. 

Failing to obtain additional infor­mation from sources who know the patient or who can provide old records. Such information is vital in psychiatry, because the patient’s account often is incomplete, even distorted, because of cognitive deficits or psychopathologic factors. Additional information can be corroborative or contradictory, and is sometimes critical—significantly influ­encing the diagnosis or the treatment plan, or both.

Allowing personal beliefs to influence care. This transgression includes insert­ing one’s views about religion, politics, sexual orientation, ethnic origin, and socioeconomic class into medical care. The same unimpeachable, high caliber of care must be provided to every patient, and must not differ in any way from the care that we would recommend to our own family members.

Reducing psychiatry to prescrib­ing a pill. However unacceptable and deficient this reductionist degradation of psychiatric management is, it is sometimes imposed by organizations in which the caseload is huge and the number of providers insufficient. We must resist the temptation to compromise, and must strive to address not only the biological aspects of illness but psychological and social dimensions as well. Patients will not have an optimal if we don’t.

Practicing with an outdated knowl­edge base—one acquired during residency years, often years or even decades, earlier. There is no medical or ethical justification for using 1985, or even 2005, standards of psychiatric care in 2015.

Psychiatry is rapidly evolving, with many ongoing changes and advances. Updating one’s practice pattern through lifelong learning is an abso­lute must for psychiatrists (and for all health care professionals). Utilizing the latest, evidence-based data to guide diagnosis and treatment is an indispensable component of good psychiatric care. 

Neglecting to consider treatment options. Consider just a few scenar­ios: The recurrently relapsing patient with psychosis who is not switched to a long-acting injectable formulation; the persistently psychotic patient who does not receive a trial of clozapine; the treatment-resistant depression patient who is not referred for electroconvul­sive therapy or transcranial magnetic stimulation; and the patient receiv­ing an atypical antipsychotic who is monitored inconsistently for metabolic dysregulation.

Treating patients but not vigorously advocating for them—thus allowing a broken, convoluted mental health sys­tem to delay or prevent access to care; incarcerate relapsed patients instead of hospitalizing them; permit insur­ance companies to discriminate against coverage of mental illness; and tie the hands of psychiatrists who want to select medication they judge best for their patients.

None of us is 'without sin'
We all aspire to help our patients in the best way we can, and to avoid errors. However, even a seasoned psy­chiatrist can stumble unwittingly, and that is understandable and forgivable. It is willful, recurring neglect of the patient’s welfare that can be deleterious and that, in my opinion, qualifies as a cardinal sin. Fortunately, such neglect is a low-frequency event in psychiatric practice, but even a single occurrence is one too many.

Since clozapine was launched in 1989, miraculous improvements and “awak­enings” have been reported in many patients afflicted with severe schizo­phrenia and considered hopelessly refractory to antipsychotic pharmaco­therapy. Not only do severely disabled patients regain their sanity and return to normal functioning, but the joy that their family and treating psychiatrist experi­ence is priceless.

That’s why I am perplexed by how infrequently clozapine is used in the United States (in about 5% of patients)—even though approximately 25% of patients who have schizophrenia are either treatment-resistant or have refrac­tory hallucinations or delusions.

Consider Bethany’s case. She was one of my young patients, who, after taking clozapine, recovered fully and resumed a productive life, after years of homeless­ness during which she was controlled by auditory hallucinations.

Bethany’s story began well…
Bethany grew up in a loving home, smart and talented, an “A” student in high school and talented violin­ist. She received a scholarship to a prestigious private university at 16 and left her parent’s home in Ohio to major in molecular biol­ogy. Her goal was to attend medical school. She excelled during her first 3 years of college, and even published 2 papers in top-tier science journals.

In her senior year, after returning from a trip to Africa, Bethany began to change. She neglected her studies and focused on raising money for HIV clinics in Africa. She began getting F’s instead of A’s, lost her scholarship and her residence hall room, and had to drop out of college. Soon, she began hearing voices commanding her every action.

..but took a really bad turn
Bethany became homeless for the next 4.5 years. She ate discarded food from garbage cans, had no change of clothes, and slept on a concrete slab behind a downtown church in a major city in California. Her parents lost track of her, although her mother, a retired nurse, frantically and relentlessly tried to find out what happened to her only daughter during that time.

Eventually, Bethany was arrested when she was found screaming back at the voices, at midnight in a residential area of the city. She was hospitalized on a psychiatric ward and given antipsychot­ics, but with only modest improvement.

Her parents were contacted; immedi­ately, they flew to California to see her. The treating psychiatrist told them that their daughter had schizophrenia, and that they should lower their expectations because she would be totally disabled for the rest of her life. They brought Bethany back to Ohio where, after a tumultuous year of failed trials of several antipsy­chotics to suppress the auditory halluci­nations, we gave her clozapine.

Gradually, Bethany improved, but she still could not read a book or maga­zine (which I urged her to do) without the voices intensifying and preventing her from reading.


Bethany recovers
After 6 to 8 months on clozapine, however, Bethany’s auditory hal­lucinations faded away. With my encouragement, she enrolled at the University of Cincinnati and took 1 course at a time. She began to get A’s again—in advanced courses, such as genetics, physics, and molecular biol­ogy. She completed her degree require­ments and graduated with honors, with a Bachelor of Science degree in molecular biology. She also served as a marshal in the commencement ceremony procession.

Over the next year, with strong encouragement, Bethany wrote a book about her remark­able recovery from refractory psychosis.¹ In addition, her mother wrote a deeply emo­tional book that described the gut-wrenching ordeal that she and her husband went through during the years that Bethany disappeared.² I urge you to read these inspiring books (Figure) about the remarkable recovery from refractory psychosis and the heavy family burden of schizophrenia.

No doubt, clozapine is associated with serious side effects¹⁵—but so is chemotherapy for cancer, and oncolo­gists do not hesitate to use it to save their patients from physical death. Severe schizophrenia is like a can­cer of the mind, and clozapine is its chemotherapy.

Fortunately for Bethany, she had almost no physical adverse effects from clozapine except for intense sedation, which was mitigated with modafinil.

We should use clozapine more than we do
Clozapine has the potential to have a healing effect for many patients whose schizophrenia is resistant to treatment. Most such patients, however, never receive a trial of the drug. Furthermore, few practitioners use clozapine for schizophrenia patients with suicidal ten­dencies, despite the high rate of suicide completion in schizophrenia.¹⁶

Clozapine remains, regrettably, an underutilized agent in psychiatry. Until other breakthrough drugs are discovered, its use ought to be double or triple what it is now because there are many people like Bethany who are not being given a chance to recover from their illness.

Since clozapine was launched in 1989, miraculous improvements and “awak­enings” have been reported in many patients afflicted with severe schizo­phrenia and considered hopelessly refractory to antipsychotic pharmaco­therapy. Not only do severely disabled patients regain their sanity and return to normal functioning, but the joy that their family and treating psychiatrist experi­ence is priceless.

That’s why I am perplexed by how infrequently clozapine is used in the United States (in about 5% of patients)—even though approximately 25% of patients who have schizophrenia are either treatment-resistant or have refrac­tory hallucinations or delusions.

Consider Bethany’s case. She was one of my young patients, who, after taking clozapine, recovered fully and resumed a productive life, after years of homeless­ness during which she was controlled by auditory hallucinations.

Bethany’s story began well…
Bethany grew up in a loving home, smart and talented, an “A” student in high school and talented violin­ist. She received a scholarship to a prestigious private university at 16 and left her parent’s home in Ohio to major in molecular biol­ogy. Her goal was to attend medical school. She excelled during her first 3 years of college, and even published 2 papers in top-tier science journals.

In her senior year, after returning from a trip to Africa, Bethany began to change. She neglected her studies and focused on raising money for HIV clinics in Africa. She began getting F’s instead of A’s, lost her scholarship and her residence hall room, and had to drop out of college. Soon, she began hearing voices commanding her every action.

..but took a really bad turn
Bethany became homeless for the next 4.5 years. She ate discarded food from garbage cans, had no change of clothes, and slept on a concrete slab behind a downtown church in a major city in California. Her parents lost track of her, although her mother, a retired nurse, frantically and relentlessly tried to find out what happened to her only daughter during that time.

Eventually, Bethany was arrested when she was found screaming back at the voices, at midnight in a residential area of the city. She was hospitalized on a psychiatric ward and given antipsychot­ics, but with only modest improvement.

Her parents were contacted; immedi­ately, they flew to California to see her. The treating psychiatrist told them that their daughter had schizophrenia, and that they should lower their expectations because she would be totally disabled for the rest of her life. They brought Bethany back to Ohio where, after a tumultuous year of failed trials of several antipsy­chotics to suppress the auditory halluci­nations, we gave her clozapine.

Gradually, Bethany improved, but she still could not read a book or maga­zine (which I urged her to do) without the voices intensifying and preventing her from reading.


Bethany recovers
After 6 to 8 months on clozapine, however, Bethany’s auditory hal­lucinations faded away. With my encouragement, she enrolled at the University of Cincinnati and took 1 course at a time. She began to get A’s again—in advanced courses, such as genetics, physics, and molecular biol­ogy. She completed her degree require­ments and graduated with honors, with a Bachelor of Science degree in molecular biology. She also served as a marshal in the commencement ceremony procession.

Over the next year, with strong encouragement, Bethany wrote a book about her remark­able recovery from refractory psychosis.¹ In addition, her mother wrote a deeply emo­tional book that described the gut-wrenching ordeal that she and her husband went through during the years that Bethany disappeared.² I urge you to read these inspiring books (Figure) about the remarkable recovery from refractory psychosis and the heavy family burden of schizophrenia.

No doubt, clozapine is associated with serious side effects¹⁵—but so is chemotherapy for cancer, and oncolo­gists do not hesitate to use it to save their patients from physical death. Severe schizophrenia is like a can­cer of the mind, and clozapine is its chemotherapy.

Fortunately for Bethany, she had almost no physical adverse effects from clozapine except for intense sedation, which was mitigated with modafinil.

We should use clozapine more than we do
Clozapine has the potential to have a healing effect for many patients whose schizophrenia is resistant to treatment. Most such patients, however, never receive a trial of the drug. Furthermore, few practitioners use clozapine for schizophrenia patients with suicidal ten­dencies, despite the high rate of suicide completion in schizophrenia.¹⁶

Clozapine remains, regrettably, an underutilized agent in psychiatry. Until other breakthrough drugs are discovered, its use ought to be double or triple what it is now because there are many people like Bethany who are not being given a chance to recover from their illness.

Since clozapine was launched in 1989, miraculous improvements and “awak­enings” have been reported in many patients afflicted with severe schizo­phrenia and considered hopelessly refractory to antipsychotic pharmaco­therapy. Not only do severely disabled patients regain their sanity and return to normal functioning, but the joy that their family and treating psychiatrist experi­ence is priceless.

That’s why I am perplexed by how infrequently clozapine is used in the United States (in about 5% of patients)—even though approximately 25% of patients who have schizophrenia are either treatment-resistant or have refrac­tory hallucinations or delusions.

Consider Bethany’s case. She was one of my young patients, who, after taking clozapine, recovered fully and resumed a productive life, after years of homeless­ness during which she was controlled by auditory hallucinations.

Bethany’s story began well…
Bethany grew up in a loving home, smart and talented, an “A” student in high school and talented violin­ist. She received a scholarship to a prestigious private university at 16 and left her parent’s home in Ohio to major in molecular biol­ogy. Her goal was to attend medical school. She excelled during her first 3 years of college, and even published 2 papers in top-tier science journals.

In her senior year, after returning from a trip to Africa, Bethany began to change. She neglected her studies and focused on raising money for HIV clinics in Africa. She began getting F’s instead of A’s, lost her scholarship and her residence hall room, and had to drop out of college. Soon, she began hearing voices commanding her every action.

..but took a really bad turn
Bethany became homeless for the next 4.5 years. She ate discarded food from garbage cans, had no change of clothes, and slept on a concrete slab behind a downtown church in a major city in California. Her parents lost track of her, although her mother, a retired nurse, frantically and relentlessly tried to find out what happened to her only daughter during that time.

Eventually, Bethany was arrested when she was found screaming back at the voices, at midnight in a residential area of the city. She was hospitalized on a psychiatric ward and given antipsychot­ics, but with only modest improvement.

Her parents were contacted; immedi­ately, they flew to California to see her. The treating psychiatrist told them that their daughter had schizophrenia, and that they should lower their expectations because she would be totally disabled for the rest of her life. They brought Bethany back to Ohio where, after a tumultuous year of failed trials of several antipsy­chotics to suppress the auditory halluci­nations, we gave her clozapine.

Gradually, Bethany improved, but she still could not read a book or maga­zine (which I urged her to do) without the voices intensifying and preventing her from reading.


Bethany recovers
After 6 to 8 months on clozapine, however, Bethany’s auditory hal­lucinations faded away. With my encouragement, she enrolled at the University of Cincinnati and took 1 course at a time. She began to get A’s again—in advanced courses, such as genetics, physics, and molecular biol­ogy. She completed her degree require­ments and graduated with honors, with a Bachelor of Science degree in molecular biology. She also served as a marshal in the commencement ceremony procession.

Over the next year, with strong encouragement, Bethany wrote a book about her remark­able recovery from refractory psychosis.¹ In addition, her mother wrote a deeply emo­tional book that described the gut-wrenching ordeal that she and her husband went through during the years that Bethany disappeared.² I urge you to read these inspiring books (Figure) about the remarkable recovery from refractory psychosis and the heavy family burden of schizophrenia.

No doubt, clozapine is associated with serious side effects¹⁵—but so is chemotherapy for cancer, and oncolo­gists do not hesitate to use it to save their patients from physical death. Severe schizophrenia is like a can­cer of the mind, and clozapine is its chemotherapy.

Fortunately for Bethany, she had almost no physical adverse effects from clozapine except for intense sedation, which was mitigated with modafinil.

We should use clozapine more than we do
Clozapine has the potential to have a healing effect for many patients whose schizophrenia is resistant to treatment. Most such patients, however, never receive a trial of the drug. Furthermore, few practitioners use clozapine for schizophrenia patients with suicidal ten­dencies, despite the high rate of suicide completion in schizophrenia.¹⁶

Clozapine remains, regrettably, an underutilized agent in psychiatry. Until other breakthrough drugs are discovered, its use ought to be double or triple what it is now because there are many people like Bethany who are not being given a chance to recover from their illness.

 Recent examples come quickly to mind:
   • $100 million from the Lieber family to fund the Lieber Institute for Brain Development at Johns Hopkins University
   • $300 million from Microsoft co-founder Paul G. Allen to create the Allen Institute for Brain Science
   • $650 million from Ted Stanley for the Stanley Center at the Broad Institute.
Such generosity is cause for celebra­tion by psychiatrists and their long-suffering patients who are disabled by a brain disorder. Private money supple­ments research funding by the National Institutes of Health and will bolster the war against mental illness,¹ which costs >$300 billion annually (Box,²page 12).

Although philanthropy will help, many needs in psychiatry are unmet, and not all can be addressed with money. Consider a number of areas of need.

Unmet clinical needs
Models of disease. Psychiatry is in desperate need of an objective, valid diagnostic system that transcends the DSM model of symptom clusters. The Research Domain Criteria³ repre­sents the effort to find an alternative. To achieve that goal, it’s necessary to identify biomarkers and establish their utility—a task that requires a huge amount of funding.

Therapeutics. Clinicians are hungry for innovative, safe pharmaceuticals and non-drug treatments that modify disease, not just alleviate symptoms. Obsessive-compulsive disorder always has lacked such therapies; so have dementia, schizophrenia, personality disorders, dissociative disorders, and sexual pathologies. In fact, >80% of DSM disorders do not have an FDA-approved, evidence-based treatment,⁴ and many available medications are only partially efficacious, poorly toler­ated, or unsafe.

There are more unmet needs in therapeutics:
   • Development of promising non-drug therapies, such as neuromodula­tion, proceeds slowly.
   • Research into neurobiological mechanisms of psychotherapy is in its infancy.
   • A foolproof method to monitor adherence does not exist, and countless patients relapse needlessly and deterio­rate functionally.
   • Effective, evidence-based rehabili­tation for serious psychiatric disorders is used narrowly and vastly underfunded.
   • Insurers continue to thumb their nose at laws that require parity for treating mental illness—thus impeding access to, delaying, or truncating psy­chiatric care.
 

Unmet scientific needs
Translational investigators. Despite increased funding for basic neuroscien­tific study and breathtaking discover­ies in animal molecular neurobiology, a trickle of findings has been applied to clinical medicine. This translational gap has many causes, including a short­age of translational neuroscientists (MD-PhD psychiatrists and neurolo­gists), insufficient long-term funding to develop such clinician-researchers, and complex regulatory oversight of human research.

Stalled progress in drug devel­opment. Development of novel-mechanism therapeutics for brain disorders is languishing. Some phar­maceutical manufacturers have aban­doned the development of drugs that act on the CNS in favor of less complex, more lucrative areas such as oncology and cardiology; others have reduced their investment in CNS products. Developing treatments for knotty disorders of the most com­plex structure in the known universe requires mammoth investment. Why are stakeholders bailing out on the greatest challenge for science and medicine for easier endeavors?

Discovering new genes for every dev­astating neuropsychiatric syndrome, such as schizophrenia, is cause for cel­ebration, but the champagne won’t flow until the coding of every gene is unscrambled so that specific biological interventions can be developed. The cost of the chase might be orders of mag­nitude greater than what is invested in research today. Conceptualizing new models of brain disorders is a critical part of scientific progress and an antidote to the inertia of perpetual group-think. Depression, for example, is being reconceptualized as a disorder of impaired neuroplasticity and neurotropic deficiency, rather than a shortage of serotonin and norepineph­rine. Rapid reversal of severe depres­sion to euthymia—in 1 or 2 hours—with IV ketamine shattered the dogma that depression takes weeks to lift, and is ushering in unprecedented new think­ing and models likely to revolutionize treatment of severe depression. We need such breakthroughs for other psychiat­ric brain disorders.  

Unmet professional and sociopolitical needs
Broadening of training. Psychiatrists have focused on the mind but insuf­ficiently attended to the biology of the brain. For psychiatry to rise to the next level as a medical specialty and brain discipline, training must incorporate more neurology than it does now. The converse is true in neurology.

Hospitalization not incarceration. It is unconscionable that people suffer­ing from a medical illness that impairs their judgment and behavior are locked up as criminals. Psychiatry must forcefully lobby so that the seriously mentally ill are treated in secure hospitals staffed by physi­cians, nurses, and mental health professionals.

That’s right: Bring back the asylum to address this unmet medical, political, and ethical need for psychiatric patients.^a A serious mental disorder must be accepted as a fault-free illness.

^aTo read more about this, I recommend my March 2008 editorial, “Bring back the asylums?,” at CurrentPsychiatry.com, and Dr. George Paulson’s excellent book, Closing the asylums: Causes and consequences of the deinstitutionalization movement (Jefferson, NC: McFarland & Co. Inc; 2012).

Full integration of psychiatry into the rest of medicine remains an unmet need, despite good progress. Because almost every medical illness can cause psychiatric symp­toms, DSM-5 mandates that general medical conditions be ruled out before a primary psychiatric diagnosis is made.

Along the same lines, most severely mentally ill persons suffer from medical and neurologic ailments before their first episode,⁵ and many die prematurely from cardiovas­cular causes that often are the result of unhealthy lifestyle; iatrogenic complications; and lack of primary care inter­ventions.⁶ Psychiatric patients must always receive stan­dard general medical evaluation and management, side by side with their psychiatric care.

Philanthropy for psychiatry
Philanthropic support of psychiatry is a salutary trend. Some unmet needs in psychiatry, however, require not only money but a change in attitude (such as eliminating the absurd and discriminatory stigma of mental illness), better training, and forceful political activism by all of us.

 Recent examples come quickly to mind:
   • $100 million from the Lieber family to fund the Lieber Institute for Brain Development at Johns Hopkins University
   • $300 million from Microsoft co-founder Paul G. Allen to create the Allen Institute for Brain Science
   • $650 million from Ted Stanley for the Stanley Center at the Broad Institute.
Such generosity is cause for celebra­tion by psychiatrists and their long-suffering patients who are disabled by a brain disorder. Private money supple­ments research funding by the National Institutes of Health and will bolster the war against mental illness,¹ which costs >$300 billion annually (Box,²page 12).

Although philanthropy will help, many needs in psychiatry are unmet, and not all can be addressed with money. Consider a number of areas of need.

Unmet clinical needs
Models of disease. Psychiatry is in desperate need of an objective, valid diagnostic system that transcends the DSM model of symptom clusters. The Research Domain Criteria³ repre­sents the effort to find an alternative. To achieve that goal, it’s necessary to identify biomarkers and establish their utility—a task that requires a huge amount of funding.

Therapeutics. Clinicians are hungry for innovative, safe pharmaceuticals and non-drug treatments that modify disease, not just alleviate symptoms. Obsessive-compulsive disorder always has lacked such therapies; so have dementia, schizophrenia, personality disorders, dissociative disorders, and sexual pathologies. In fact, >80% of DSM disorders do not have an FDA-approved, evidence-based treatment,⁴ and many available medications are only partially efficacious, poorly toler­ated, or unsafe.

There are more unmet needs in therapeutics:
   • Development of promising non-drug therapies, such as neuromodula­tion, proceeds slowly.
   • Research into neurobiological mechanisms of psychotherapy is in its infancy.
   • A foolproof method to monitor adherence does not exist, and countless patients relapse needlessly and deterio­rate functionally.
   • Effective, evidence-based rehabili­tation for serious psychiatric disorders is used narrowly and vastly underfunded.
   • Insurers continue to thumb their nose at laws that require parity for treating mental illness—thus impeding access to, delaying, or truncating psy­chiatric care.
 

Unmet scientific needs
Translational investigators. Despite increased funding for basic neuroscien­tific study and breathtaking discover­ies in animal molecular neurobiology, a trickle of findings has been applied to clinical medicine. This translational gap has many causes, including a short­age of translational neuroscientists (MD-PhD psychiatrists and neurolo­gists), insufficient long-term funding to develop such clinician-researchers, and complex regulatory oversight of human research.

Stalled progress in drug devel­opment. Development of novel-mechanism therapeutics for brain disorders is languishing. Some phar­maceutical manufacturers have aban­doned the development of drugs that act on the CNS in favor of less complex, more lucrative areas such as oncology and cardiology; others have reduced their investment in CNS products. Developing treatments for knotty disorders of the most com­plex structure in the known universe requires mammoth investment. Why are stakeholders bailing out on the greatest challenge for science and medicine for easier endeavors?

Discovering new genes for every dev­astating neuropsychiatric syndrome, such as schizophrenia, is cause for cel­ebration, but the champagne won’t flow until the coding of every gene is unscrambled so that specific biological interventions can be developed. The cost of the chase might be orders of mag­nitude greater than what is invested in research today. Conceptualizing new models of brain disorders is a critical part of scientific progress and an antidote to the inertia of perpetual group-think. Depression, for example, is being reconceptualized as a disorder of impaired neuroplasticity and neurotropic deficiency, rather than a shortage of serotonin and norepineph­rine. Rapid reversal of severe depres­sion to euthymia—in 1 or 2 hours—with IV ketamine shattered the dogma that depression takes weeks to lift, and is ushering in unprecedented new think­ing and models likely to revolutionize treatment of severe depression. We need such breakthroughs for other psychiat­ric brain disorders.  

Unmet professional and sociopolitical needs
Broadening of training. Psychiatrists have focused on the mind but insuf­ficiently attended to the biology of the brain. For psychiatry to rise to the next level as a medical specialty and brain discipline, training must incorporate more neurology than it does now. The converse is true in neurology.

Hospitalization not incarceration. It is unconscionable that people suffer­ing from a medical illness that impairs their judgment and behavior are locked up as criminals. Psychiatry must forcefully lobby so that the seriously mentally ill are treated in secure hospitals staffed by physi­cians, nurses, and mental health professionals.

That’s right: Bring back the asylum to address this unmet medical, political, and ethical need for psychiatric patients.^a A serious mental disorder must be accepted as a fault-free illness.

^aTo read more about this, I recommend my March 2008 editorial, “Bring back the asylums?,” at CurrentPsychiatry.com, and Dr. George Paulson’s excellent book, Closing the asylums: Causes and consequences of the deinstitutionalization movement (Jefferson, NC: McFarland & Co. Inc; 2012).

Full integration of psychiatry into the rest of medicine remains an unmet need, despite good progress. Because almost every medical illness can cause psychiatric symp­toms, DSM-5 mandates that general medical conditions be ruled out before a primary psychiatric diagnosis is made.

Along the same lines, most severely mentally ill persons suffer from medical and neurologic ailments before their first episode,⁵ and many die prematurely from cardiovas­cular causes that often are the result of unhealthy lifestyle; iatrogenic complications; and lack of primary care inter­ventions.⁶ Psychiatric patients must always receive stan­dard general medical evaluation and management, side by side with their psychiatric care.

Philanthropy for psychiatry
Philanthropic support of psychiatry is a salutary trend. Some unmet needs in psychiatry, however, require not only money but a change in attitude (such as eliminating the absurd and discriminatory stigma of mental illness), better training, and forceful political activism by all of us.

 Recent examples come quickly to mind:
   • $100 million from the Lieber family to fund the Lieber Institute for Brain Development at Johns Hopkins University
   • $300 million from Microsoft co-founder Paul G. Allen to create the Allen Institute for Brain Science
   • $650 million from Ted Stanley for the Stanley Center at the Broad Institute.
Such generosity is cause for celebra­tion by psychiatrists and their long-suffering patients who are disabled by a brain disorder. Private money supple­ments research funding by the National Institutes of Health and will bolster the war against mental illness,¹ which costs >$300 billion annually (Box,²page 12).

Although philanthropy will help, many needs in psychiatry are unmet, and not all can be addressed with money. Consider a number of areas of need.

Unmet clinical needs
Models of disease. Psychiatry is in desperate need of an objective, valid diagnostic system that transcends the DSM model of symptom clusters. The Research Domain Criteria³ repre­sents the effort to find an alternative. To achieve that goal, it’s necessary to identify biomarkers and establish their utility—a task that requires a huge amount of funding.

Therapeutics. Clinicians are hungry for innovative, safe pharmaceuticals and non-drug treatments that modify disease, not just alleviate symptoms. Obsessive-compulsive disorder always has lacked such therapies; so have dementia, schizophrenia, personality disorders, dissociative disorders, and sexual pathologies. In fact, >80% of DSM disorders do not have an FDA-approved, evidence-based treatment,⁴ and many available medications are only partially efficacious, poorly toler­ated, or unsafe.

There are more unmet needs in therapeutics:
   • Development of promising non-drug therapies, such as neuromodula­tion, proceeds slowly.
   • Research into neurobiological mechanisms of psychotherapy is in its infancy.
   • A foolproof method to monitor adherence does not exist, and countless patients relapse needlessly and deterio­rate functionally.
   • Effective, evidence-based rehabili­tation for serious psychiatric disorders is used narrowly and vastly underfunded.
   • Insurers continue to thumb their nose at laws that require parity for treating mental illness—thus impeding access to, delaying, or truncating psy­chiatric care.
 

Unmet scientific needs
Translational investigators. Despite increased funding for basic neuroscien­tific study and breathtaking discover­ies in animal molecular neurobiology, a trickle of findings has been applied to clinical medicine. This translational gap has many causes, including a short­age of translational neuroscientists (MD-PhD psychiatrists and neurolo­gists), insufficient long-term funding to develop such clinician-researchers, and complex regulatory oversight of human research.

Stalled progress in drug devel­opment. Development of novel-mechanism therapeutics for brain disorders is languishing. Some phar­maceutical manufacturers have aban­doned the development of drugs that act on the CNS in favor of less complex, more lucrative areas such as oncology and cardiology; others have reduced their investment in CNS products. Developing treatments for knotty disorders of the most com­plex structure in the known universe requires mammoth investment. Why are stakeholders bailing out on the greatest challenge for science and medicine for easier endeavors?

Discovering new genes for every dev­astating neuropsychiatric syndrome, such as schizophrenia, is cause for cel­ebration, but the champagne won’t flow until the coding of every gene is unscrambled so that specific biological interventions can be developed. The cost of the chase might be orders of mag­nitude greater than what is invested in research today. Conceptualizing new models of brain disorders is a critical part of scientific progress and an antidote to the inertia of perpetual group-think. Depression, for example, is being reconceptualized as a disorder of impaired neuroplasticity and neurotropic deficiency, rather than a shortage of serotonin and norepineph­rine. Rapid reversal of severe depres­sion to euthymia—in 1 or 2 hours—with IV ketamine shattered the dogma that depression takes weeks to lift, and is ushering in unprecedented new think­ing and models likely to revolutionize treatment of severe depression. We need such breakthroughs for other psychiat­ric brain disorders.  

Unmet professional and sociopolitical needs
Broadening of training. Psychiatrists have focused on the mind but insuf­ficiently attended to the biology of the brain. For psychiatry to rise to the next level as a medical specialty and brain discipline, training must incorporate more neurology than it does now. The converse is true in neurology.

Hospitalization not incarceration. It is unconscionable that people suffer­ing from a medical illness that impairs their judgment and behavior are locked up as criminals. Psychiatry must forcefully lobby so that the seriously mentally ill are treated in secure hospitals staffed by physi­cians, nurses, and mental health professionals.

That’s right: Bring back the asylum to address this unmet medical, political, and ethical need for psychiatric patients.^a A serious mental disorder must be accepted as a fault-free illness.

^aTo read more about this, I recommend my March 2008 editorial, “Bring back the asylums?,” at CurrentPsychiatry.com, and Dr. George Paulson’s excellent book, Closing the asylums: Causes and consequences of the deinstitutionalization movement (Jefferson, NC: McFarland & Co. Inc; 2012).

Full integration of psychiatry into the rest of medicine remains an unmet need, despite good progress. Because almost every medical illness can cause psychiatric symp­toms, DSM-5 mandates that general medical conditions be ruled out before a primary psychiatric diagnosis is made.

Along the same lines, most severely mentally ill persons suffer from medical and neurologic ailments before their first episode,⁵ and many die prematurely from cardiovas­cular causes that often are the result of unhealthy lifestyle; iatrogenic complications; and lack of primary care inter­ventions.⁶ Psychiatric patients must always receive stan­dard general medical evaluation and management, side by side with their psychiatric care.

Philanthropy for psychiatry
Philanthropic support of psychiatry is a salutary trend. Some unmet needs in psychiatry, however, require not only money but a change in attitude (such as eliminating the absurd and discriminatory stigma of mental illness), better training, and forceful political activism by all of us.