Sidney Zisook, MD

Despite the prevalence of disability, chronicity, morbidity, comorbidity, and premature mortality associated with MDD, most individuals with MDD receive inadequate treatment, if any. Members of low-income and minority populations are especially unlikely to receive treatment. But even in high-income countries, the World Mental Health Survey Initiative showed that only 22% of all individuals with 12-month MDD received minimally adequate treatment.

 Several factors contribute to this lack of treatment, including stigma about mental health in general and mental health care in particular, lack of knowledge about treatment availability and effectiveness, and the shortage of mental health providers both globally and in the United States.

In addition, out-of-pocket expenses may be prohibitive for individuals. Even for those with mental health insurance, it is increasingly difficult to find a provider, especially a psychiatrist, who accepts insurance. Clinicians who do accept insurance often have long waiting lists with available times that do not work for individuals with children or jobs.

Thus, unmet needs include increasing efforts to destigmatize mental health and its treatment; educating the public and clinicians about recognition, diagnosis, and effective treatments of MDD and its variants; increasing the mental health workforce; and providing better mental health care coverage.

Diagnostic reliability has been a problem since DSM-I and remains so through DSM-5-TR. MDD is a heterogeneous construct that limits communication, prognostic accuracy, and drug development, and it may be a key reason none of the current treatments are effective for more than about one-third of those receiving MDD diagnoses. There are 227 possible combinations of symptoms that can meet DSM-5 criteria for MDD, and 2 different patients with no overlapping symptoms can receive MDD diagnoses.

Attempts to subtype MDD by clinical features (ie, anxious, mixed, atypical, catatonic, melancholic, psychotic), onset (ie, first episode, recurrent, childhood, seasonal, premenstrual, peripartum, menopausal, late life), trigger (ie, autonomous or after life adversity), state (ie, prodrome, episode, response, remission, recovery, treatment resistant, difficult to treat), comorbidity (ie, substance use, posttraumatic stress disorder, obsessive-compulsive disorder, generalized anxiety disorder, eating disorders, borderline personality disorder, pain, chronic and disabling general medical and neurological conditions), and other associated features (ie, early life adversity, suicidality, neurocognition, isolation, poverty, cultural diversity) by and large have not identified specific treatment targets.

Other questions remain. For example, why does a diagnosis take 2 weeks? It may not make sense to wait 2 weeks when an individual has a history of severe, life-threatening episodes and a very recent onset of anhedonia, feelings of worthlessness, and suicidal thoughts. On the other hand, it may be wise to wait more than 2 weeks for first onset with mild symptoms ostensibly triggered by overwhelming interpersonal, health, or environmental stress. And why not include such common and disruptive symptoms as physical or psychic pain, anxiety, cognitive problems, irritability, or rumination?

The diagnosis of MDD does not yet map very well with underlying biology or treatment outcomes. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) was an attempt to improve upon our current symptom-based diagnostic system, but it has not been widely accepted or implemented. There are no easy solutions, but the quest to find a more reliable diagnosis for this all-important condition must continue.

 Two additional diagnostic issues of import in contemporary psychiatry are the relationships of MDD to burnout and bereavement. About 40% of health care workers experience distressing symptoms of burnout, likely even more so since the start of the COVID-19 pandemic. In working in the physician wellness arena, I see many physicians complaining of burnout. Some come to me on previously prescribed antidepressant medications, which have essentially no positive effect on burnout. Others present with significant underlying MDD that has been misattributed to burnout.

This diagnostic confusion is at least in part explained by overlapping clinical features, such as unhappiness, low energy, poor sleep, and a defeatist attitude. But burnout is predominantly a job-related condition, the core feature of which is mental and emotional exhaustion related to ongoing work stress. MDD, on the other hand, is a persistent, pervasive, and pathological mental condition, the core features of which are unhappiness and the inability to find joy in anything. In burnout, self-esteem is preserved, whereas feelings of low self-worth and even worthlessness often predominate one’s self-view in MDD. In contrast to the experiences of those with MDD, individuals with burnout often retain the capacity to laugh, to appreciate the comfort and support of relatives and neighbors, to be consoled, and to recognize that what they are going through will lessen in time. The importance of differentiating burnout from depression may not be primarily an either/or proposition —wondering whether something is burnout or MDD—but one of identifying when an individual who presents with features and symptoms of burnout may also have MDD. Failure to do so risks the potential of missing the detection and opportunity to provide effective treatment for individuals suffering a serious, if not life-threatening, mental disorder.

The DSM relationship between bereavement and MDD has had a somewhat convoluted history. In a well-intentioned effort to avoid medicalizing ordinary grief and the subsequent overprescription of antidepressants, DSM-III introduced the “bereavement exclusion,” which cautioned against diagnosing MDD after the death of a loved one. Subsequent research suggested that major depressive syndromes following bereavement did not meaningfully differ in nature, course, or outcome from depression of equal severity in any other context, or from MDD appearing out of the blue. Disqualifying a patient from a diagnosis of MDD simply because the clinical picture emerged after the death of a loved one risks closing the door on potentially life-preserving interventions.

DSM-5 provides useful guidance on when to diagnose MDD in the postbereavement period. For example, in bereavement-related grief not accompanied by MDD, loss and preoccupation with the deceased person are predominant themes and self-esteem is usually preserved. In contrast, in MDD, persistent and pervasive unhappiness and the inability to enjoy anything are predominant themes, and feelings of worthlessness and self-loathing are common. In ordinary grief, waves of emotional pain are usually accompanied by positive emotions and fond recollections of the deceased. In MDD, pervasive misery and unhappiness are the norm. Despite these differential diagnostic guidelines, DSM-5 does not compel the diagnoses of MDD after bereavement but instead allows for clinical judgment by retaining the V code “uncomplicated bereavement.”

DSM-5-TR has added a new diagnosis, prolonged grief disorder (PGD), which is sometimes misdiagnosed as MDD or masked in someone who also has MDD. The DSM-5-TR criteria for PGD require that distressing symptoms of grief continue for at least 12 months following the death of someone close. The grief response is characterized by intense longing/yearning for the deceased person and/or preoccupation with thoughts and memories of the lost person to a clinically significant (ie, impairing) degree, nearly every day for at least the past month, along with at least 3 of the following 8 symptoms: (1) feeling as though part of oneself has died, (2) a marked sense of disbelief about the death, (3) avoidance of reminders that the person has died (often coupled with intense searching for things reminiscent of the deceased person and/or evidence that they are still alive, such as mistaking others for the person who died), (4) intense emotional pain (anger, bitterness, sorrow) related to the death, (5) difficulty with reintegration into life after the death, (6) emotional numbness (particularly regarding an emotional connection to others), (7) feeling that life is meaningless as a result of the death, and (8) intense loneliness as a result of the death. The burden of these symptoms causes clinically significant distress or impairment, and the duration and severity of the bereavement reaction clearly exceeds social, cultural, or religious norms for the individual’s culture and context.

PGD is a serious mental disorder that puts the patient at risk for intense distress, poor physical health, and shortened life expectancy. PGD can be differentiated from MDD in a similar manner to differentiating ordinary grief from MDD. In PGD, the dysphoria is more tied to yearning, pining, and preoccupied thoughts and memories of a loved one who has died rather than the more persistent, pervasive, all-encompassing misery of MDD. PGD can also be successfully treated, as shown in a series of randomized clinical trials comparing a 16-session PGD-targeted therapy versus treatments efficacious for major depression.

 Indeed, many patients in those trials had been aggressively treated for MDD for years before enrolling. Thus, clinicians who learn to accurately assess PGD and to offer or refer individuals for appropriate, targeted treatment can spare their patients years of suffering.

 Despite many clinicians’ best efforts to select the antidepressant medication most likely to benefit their patient, many patients cannot tolerate a high enough dose to optimize benefits; of those who can, only about half to two-thirds respond and only about one-third achieve remission. Even among those who remit, relapse and recurrence are the norms, often within weeks to months after remission and many more times over the life span. At least one-third are considered to have treatment-resistant depression (TRD). Individuals with TRD have a much more debilitating form of illness than those with MDD, including increased mortality from suicide as well as all-causes mortality.

 Yet clinicians do not yet have solid, evidence-based, optimal pharmacologic choices for either first-step or next-step treatments. Given the prevalence of MDD and its associated morbidity and mortality, the search for optimal first-line and next-step treatments should be a national priority.

The concept of TRD, based solely upon failure to achieve remission with 2 or more adequately delivered medication trials, may have outlived its usefulness. A broader, perhaps more empathic, concept of difficult-to-treat depression (DTD) has been proposed to replace TRD.

 DTD is defined as “depression that continues to cause significant burden despite usual treatment efforts.” It considers not only symptomatic remission and response but also treatment intolerance, “poop-out,” relapse, recurrence, functioning, and quality of life.

In the DTD model, treatment combines optimization of symptom control, maximizing function and minimizing treatment burden where remission cannot be obtained.

 Although TRD may be seen to suggest a defeatist attitude to treatment, DTD is a more open concept that incorporates lifelong management and fosters a collaborative approach between the physician, patient, family members, and other providers to overcome difficulties and challenges. A patient-centered approach to lifelong disease management, based on shared decision-making around all aspects of treatment, is recommended.

6. The role of “out-of-the-box” interventional therapeutics.

 When I was training as a psychiatrist more than 50 years ago, we had tricyclic and monoamine oxidase inhibitor antidepressants, and we began the search for medications that were better tolerated, worked more quickly, were more effective for a broader range of patients, and had more sustainable effects. Several new medications and classes of antidepressants have been developed in the ensuing decades, but until very recently the search was focused exclusively on monoaminergic-based strategies.

More recently, the discovery of ketamine’s rapidly acting, profound antidepressant and antisuicidal effects has spurred great interest in finding other, nonmonoaminergic, “out of the box” treatments. Intranasal esketamine was the first of these to be approved, initially as an adjunctive treatment for TRD and more recently for depressive symptoms in adults with MDD and suicidal thoughts and behaviors. At the same time, we are seeing a resurgence of interest in psychedelic therapies. Several studies have suggested safety and rapidly acting effectiveness of psilocybin therapy for MDD and TRD, and more large, multisite randomized controlled trials are coming.

 Many unanswered questions about psychedelic therapy remain, involving ideal dosing; what forms of psychotherapy might best augment the drug’s effectiveness; how to best sustain effects and deal with relapse, recurrence, and long-term maintenance; and how to make these labor-intensive treatments feasible in outpatient treatment settings.

One of the most exciting aspects of psychedelic therapies is the marriage of pharmacotherapy and psychotherapy inherent in these interventions. This may present an aspirational model for all interventions and an important component of future training. Although great enthusiasm greets the promise of psychedelic therapies, we also are seeing increased interest and improvements in other nonpharmacologic treatments, such as repetitive transcranial magnetic stimulation.

 Thus, our tools for treating MDD are finally and rapidly extending beyond monoaminergic pharmaceuticals and a few evidence-based psychotherapies to new, innovative, and potentially game-changing interventions.

An abundance of literature documents the superiority of antidepressant medication plus psychotherapy over medication alone for MDD. Yet when it comes to training the next generation of psychiatrists, we are observing a monumental paradox. Since 2013, the Accreditation Council for Graduate Medical Education (ACGME) standards and requirements for psychotherapy training in psychiatric residencies call for developing competencies in the areas of cognitive behavioral therapy, psychodynamic psychotherapy, and supportive psychotherapy in both brief and long-term formats, with optional experiences in group and couples/family therapy. However, fewer psychiatrists than ever are providing psychotherapy to patients with MDD, or any diagnoses for that matter.

 Fifty percent of psychiatrists do no psychotherapy, and only 10% regularly provide psychotherapy along with medications.

 This current state and evolving trend is unacceptable. The ACGME requirements have not served their purpose,

 and future training may benefit from fewer top-down mandates and more trust in training programs to implement their own standards and innovations.

8. Physician burnout, depression, and suicide. 

Physician distress is increasingly recognized as a professional and public health crisis. High rates of suffering including career dissatisfaction, secondary trauma or second victim phenomena (in psychiatry, often related to coping with patient suicide), burnout, substance abuse, depression, and suicide are all receiving national attention and calls for action.

 Although there has been outpouring of attention to recognize and attenuate physician burnout, far less attention has been allocated to the recognition and treatment of MDD in physicians. Yet, perhaps the most actionable prevention strategy for suicide is prompt recognition in optimal treatment of MDD.

Physicians have rates of MDD similar to the rest of the population but are no more likely—perhaps less so—to access treatment. This is due, in part, to continued stigma related to mental illness, but also to fears regarding the consequences of diagnosis and treatment on standing in the professional community and licensing, promotion, and insurance concerns. No doubt, avoidance of treatment relates to the high suicide rates noted in physicians. Distinguishing features of physician suicide include: female physicians die by suicide more often than females in the general population; suicide is the leading cause of death among male residents and the second-leading cause of death among female residents; physicians are more likely to have a job problem (hence, attention to improving well-being and reducing burnout cannot be overestimated); a higher proportion of physician and nurse suicide deaths are by overdose compared with the general population; depression is as significant a risk factor as among nonphysician suicide deaths; and physicians who took their lives were no more likely to be receiving mental health treatment compared with nonphysicians who took their lives.

Preventing physician suicide requires evidence-based actions that multiple stakeholder groups can take, including regulatory agencies, licensing boards, and hospital privileging boards; specialty boards, professional associations, and continuing education organizations; medical educators; and individual clinicians.

 The key is that each of these constituencies prioritizes the well-being and mental health of the health care workforce—not just physicians, but the entire teams physicians work with—so they can live fully and practice their profession at the top of their game.

The very recently passed Dr. Lorna Breen Health Care Provider Protection Act, which requires the US Department of Health & Human Services (HHS) to take actions to improve mental and behavioral health and prevent burnout among health care providers, is a major step forward. Several national initiatives to address the issues of physician well-being, burnout, and suicide have emerged. What these programs have in common is attention to evidence-based practices, safe and accessible avenues for physicians to address mental health concerns, confidential and timely follow-up, and stigma reduction.

 At UC San Diego, the Healer Education Assessment and Referral (HEAR) Program offers a comprehensive educational program, proactive screening and warm referrals, crisis intervention and critical incident debriefing, ongoing confidential counseling/therapy for house staff, group support, peer supporter training, and interdisciplinary Schwartz Center Rounds.

 Each aspect of this comprehensive program is readily transportable to other institutions.

In summary, although there has been an explosion of knowledge in the neuroscientific basis of mental disorders, genomics, neuroimaging, and neuropsychology, there remains considerable room for growth in how we provide equitable access to evidence-based treatments; define and diagnose MDD; create evidence-informed first-step and next-step, personalized treatment decisions; conceptualize TRD and consider replacing or supplementing it with DTD; develop novel interventions that provide options for better tolerated, more effective, more sustainable treatments; more effectively train future clinicians to competently employ a broader spectrum of evidence-based treatments than the current norm; and shift the culture of medicine to one that prioritizes optimizing our own wellness and mental health.

No doubt readers will have their own ideas of what deserves to be in a top 8 list and may have different perspectives on my somewhat subjective views. We would love to hear from you!

 is a Distinguished Professor of psychiatry at the University of California, San Diego.

1. Thornicroft G, Chatterji S, Evans-Lacko S, et al. 

Undertreatment of people with major depressive disorder in 21 countries

2. Zimmerman M, Ellison W, Young D, et al. 

How many different ways do patients meet the diagnostic criteria for major depressive disorder?

The clinical characterization of the adult patient with depression aimed at personalization of management

A key differential diagnosis for physicians—major depression or burnout?

6. Shear MK, Reynolds CF 3rd, Simon NM, et al. 

Optimizing treatment of complicated grief: a randomized clinical trial

7. Prigerson HG, Shear MK, Reynolds CF 3rd. 

Prolonged grief disorder diagnostic criteria—helping those with maladaptive grief responses

All-cause mortality in patients with treatment-resistant depression: a cohort study in the US population

9. McAllister-Williams RH, Arango C, Blier P, et al. 

Reconceptualising treatment-resistant depression as difficult-to-treat depression

10. Rush AJ, Sackeim HA, Conway CR, et al. 

Clinical research challenges posed by difficult-to-treat depression

The therapeutic potential of psilocybin: a systematic review

12. Rossi S, Antal A, Bestmann S, et al. 

Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert guidelines

Making therapy widely available: clinical research triumph or existential catastrophe?

Trends in outpatient psychotherapy provision by U.S. psychiatrists: 1996-2016

Bureaucrapathologies: galloping regulosis, assessment degradosis, and other unintended organizational maladies in post-graduate medical education

16. Moutier CY, Myers MF, Feist JB, et al. 

Preventing clinician suicide: a call to action during the COVID-19 pandemic and beyond

17. Ye GY, Davidson JE, Kim K, Zisook S. 

Physician death by suicide in the United States: 2012–2016

Physician suicide in the United States: updated estimates from the National Violent Death Reporting System

19. Norcross WA, Moutier C, Tiamson-Kassab M, et al. 

Update on the UC San Diego Healer Education Assessment and Referral (HEAR) program

Articles

What are the biggest challenges facing both clinicians and patients, and how can we address them?

8 Key Issues in the World of Major Depressive Disorder

The Major Issues in Major Depressive Disorder

Slideshows

A psychiatrist lists the top 8 most pressing issues in MDD, from training to accessibility.

When asked to comment on what I consider some of the key issues in the world of major depressive disorder (MDD), these are what came to mind. Here is my idiosyncratic top 8.

 Despite the prevalence of disability, chronicity, morbidity, 

, and premature mortality associated with MDD, most individuals with MDD receive inadequate—if any—treatment. Low-income and minority groups are especially unlikely to receive treatment. But even in high-income countries, World Mental Health surveys showed that only 22% of all individuals with 12-month MDD received minimally adequate treatment.

 Several factors contribute to this lack of treatment, including stigma about mental health in general and mental health care in particular; lack of knowledge about the availability and effectiveness of treatments; and the shortage of mental health providers both globally and in the United States.

Out-of-pocket expenses may be prohibitive for many individuals. Even if an individual has mental health insurance, it is increasingly difficult to find a provider, especially a psychiatrist, who accepts insurance these days. For those few providers who do accept insurance, they are often booked with long waiting lists and available times do not work for individuals with children or who are working. Thus, unmet needs include increasing efforts to destigmatize mental health and its treatment; educate the public and health care providers on the recognition, diagnosis, and effective treatments of MDD and its variants; increasing the mental health workforce; and providing better mental health care coverage for all.

Diagnostic reliability has been a problem since DSM-1 and remains so through 

. MDD is a heterogeneous construct that limits communication, prognostic accuracy, and drug development, and it may be a key reason none of the current treatments are effective for more than about a third of those diagnosed with MDD. There are 227 possible combinations of symptoms that can meet DSM-5 criteria for MDD, and 2 different patients can be diagnosed with MDD without a single overlapping symptom.

Attempts to subtype MDD by clinical features (anxious, mixed, atypical, catatonic, melancholic, psychotic), onset (1st episode, recurrent, childhood, seasonal, premenstrual, peri-partum, menopausal, late life), trigger (autonomous or after life adversity), state (prodrome, episode, response, remission, recovery, treatment resistant, difficult to treat), comorbidity (substance use, 

, obsessive-compulsive disorder, generalized anxiety disorder, eating disorders, borderline personality disorder, pain, chronic and disabling general medical and neurological conditions), and other associated features (early life adversity, suicidality, neurocognition, isolation, poverty, cultural diversity) by and large have not identified specific treatment targets.

Other questions remain. For example, why 2 weeks for the diagnosis? It may not make sense to wait 2 weeks to diagnose an individual with a history of severe, life-threatening episodes and a very recent onset of anhedonia, feelings of worthlessness, and 

. On the other hand, it may be wise to wait more than 2 weeks for first onset with mild symptoms ostensibly triggered by overwhelming interpersonal, health, or environmental stress. And why not include such common and disruptive symptoms as physical or psychic pain, anxiety, cognitive problems, irritability, or rumination?

The diagnosis of MDD does not yet map very well with underlying biology or treatment outcomes. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDOC) was an attempt to improve upon our current symptom based diagnostic system, but it has not been widely accepted or implemented by many clinicians. There are no easy solutions, but the quest to find a more reliable diagnosis for this all-important condition must continue.

3. Relationships to burnout and bereavement. 

Two additional diagnostic issues of import in contemporary psychiatry are the relationships of MDD to 

 and bereavement. About 40% of health care workers experience distressing symptoms of burnout, likely even more so since the start of the COVID-19 pandemic. As someone working in the physician wellness arena, I see many physicians complaining of burnout, some of whom come to me on previously prescribed antidepressant medications, which have essentially no positive effect on burnout, and others who present with significant underlying MDD that has been misattributed to 

This diagnostic confusion is at least in part explained by overlapping clinical features, such as unhappiness, low energy, poor sleep, and a defeatist attitude. But burnout is predominantly a job-related condition, the core feature of which is mental and emotional exhaustion related to ongoing work stress. 

, on the other hand, is a persistent, pervasive, and pathological mental condition, the core features of which are unhappiness and the inability to find joy in anything. In burnout, self-esteem is preserved while feelings of low self-worth and even of worthlessness often predominate one’s self-view in MDD. In contrast to the experiences of those with MDD, individuals with burnout often retain the capacity to laugh, to appreciate the comfort and support of relatives and neighbors, to be consoled, and to recognize that what they are going through will lessen in time. The importance of differentiating burnout from depression may not be primarily an either/or proposition—wondering if something is burnout 

MDD—but one of identifying when an individual who presents with features and symptoms of burnout may also have MDD. Failure to do so risks the potential of missing the detection and opportunity to provide effective treatment for individuals suffering a serious, if not life-threatening, mental disorder.

The DSM relationship between bereavement and MDD has had a somewhat convoluted history. In a well-intentioned effort to avoid medicalizing ordinary grief and the subsequent over-prescription of antidepressants, the DSM-III introduced the “bereavement exclusion,” which cautioned against diagnosing MDD after the death of a loved one. But subsequent research suggested that major depressive syndromes following bereavement did not meaningfully differ in nature, course, or outcome from depression of equal severity in any other context, or from MDD appearing out of the blue. Disqualifying a patient from a diagnosis of MDD simply because the clinical picture emerged after the death of a loved one risks closing the door on potentially life-preserving interventions.

 provides useful guidance on when to diagnose MDD in the post-bereavement period. For example, in bereavement-related grief not accompanied by MDD, loss and preoccupation with the deceased person are the predominant themes and self-esteem is usually preserved. In contrast, in MDD, persistent and pervasive unhappiness and the inability to enjoy anything are the predominant themes, and feelings of worthlessness and self-loathing are common. In ordinary 

, waves of emotional pain are usually accompanied by positive emotions and fond recollections of the deceased. In MDD, pervasive misery and unhappiness are the norm. Despite these differential diagnostic guidelines, the DSM-5 does not compel the diagnoses of MDD after bereavement, but instead allows for clinical judgement by retaining the V-code “uncomplicated bereavement.”

DSM-5 TR has added a new diagnosis, prolonged grief disorder (PGD), which is sometimes misdiagnosed as MDD or masked in someone who also has MDD. The 

 criteria for PGD require that distressing symptoms of grief continue for at least 12 months following the death of someone close. The grief response is characterized by intense longing/yearning for the deceased person and/or preoccupation with thoughts and memories of the lost person to a clinically significant (ie, impairing) degree, nearly every day for at least the past month, along with at least 3 of the following 8 symptoms: (1) feeling as though a part of oneself has died, (2) a marked sense of disbelief about the death, (3) avoidance of reminders that the person has died (often coupled with intense searching for things reminiscent of the deceased person and/or evidence that they are still alive, such as mistaking others for the person who died), (4) intense emotional pain (anger, bitterness, sorrow) related to the death, (5) difficulty with reintegration into life after the death, (6) emotional numbness (particularly with respect to an emotional connection to others), (7) feeling that life is meaningless as a result of the death, and (8) intense loneliness as a result of the death. The burden of these symptoms causes clinically significant distress or impairment, and the duration and severity of the bereavement reaction clearly exceeds social, cultural, or religious norms for the individual’s culture and context.

 is a serious mental disorder that puts the patient at risk for intense distress, poor physical health, and shortened life expectancy. PGD can be differentiated from MDD in a similar manner to differentiating ordinary grief from MDD. In PGD, the dysphoria is more tied to yearning, pining, and preoccupated thoughts and memories of a loved one who has died rather than the more persistent, pervasive, and all-encompassing misery of MDD. PGD can also be successfully treated, as shown in a series of randomized clinical trials comparing a 16-session PGD-targeted therapy versus treatments efficacious for major depression.

 Indeed, many patients in those trials had been aggressively treated for MDD for years before enrolling. Thus, clinicians who learn how to accurately assess PGD and to offer or refer patients for the appropriate, targeted treatment can spare their patients years of suffering.

Despite many clinicians’ best efforts to select the antidepressant medication most likely to benefit their patient, many patients cannot tolerate a high enough dose to optimize benefits, and of those who do, only about half to two-thirds respond and only about a third achieve remission. Even among those who remit, relapse and recurrence are the norms, often within weeks to months after remission, and many more times over the life span. At least a third are considered to have 

 (TRD). Individuals with TRD have a much more debilitating form of illness than those with MDD, including increased mortality from suicide as well as all-causes mortality.

 The concept of TRD, based solely upon failure to achieve remission with 2 or more adequately delivered medication trials, may have outlived its usefulness. A broader, perhaps more empathic, concept of difficult to treat depression (DTD) has been proposed to replace TRD.

 DTD is defined as “depression that continues to cause significant burden despite usual treatment efforts.” It takes into account not only symptomatic remission and response, but also treatment intolerance, “poop-out,” relapse, recurrence, functioning, and quality of life.

 Although TRD may be seen to suggest a defeatist attitude to treatment, DTD is a more open concept that incorporates life-long management and fosters a collaborative approach between the physician, the patient/family members, and other providers to overcome difficulties and challenges. A patient-centered approach to life-long disease management, based on shared decision-making around all aspects of treatment, is recommended.

6. The role of “out of the box,” interventional therapeutics. 

When I was in my training as a psychiatrist more than 50 years ago, we had tricyclic and monoamine oxidase inhibitor 

, and we began the search for medications that were better tolerated, worked more quickly, were more effective for a broader range of patients, and had more sustainable effects. Although several new medications and classes of antidepressants have been developed in the ensuing decades, until very recently the search was focused exclusively on monoaminergic-based strategies.

More recently, the discovery of ketamine’s rapidly acting and profound antidepressant and antisuicidal effects has spurred great interest in finding other, non-monoaminergic, “out-of-the-box” treatments. Intranasal esketamine was the first of these to be approved, initially as an adjunctive treatment for TRD and more recently for depressive symptoms in adults with MDD and suicidal thoughts and behaviors. At the same time, we are seeing a resurgence of interest in psychedelic therapies. Several studies have suggested safety and rapidly acting effectiveness of 

 for MDD and TRD, and more large, multisite randomized controlled trials are coming.

 Many questions about psychedelic therapy remain to be answered, such as ideal dosing; what forms of psychotherapy might best augment the drug’s effectiveness; how to best sustain effects and deal with relapse, recurrence, and long-term maintenance; and how to make these labor-intensive treatments feasible in outpatient treatment settings.

One of the most exciting aspects on psychedelic therapies is the marriage of pharmacotherapy and psychotherapy inherent in these interventions. This may present an aspirational model for all interventions and an important component of future training. While great enthusiasm greets the promise of psychedelic therapies, we also are seeing increased interest and improvements in other nonpharmacologic treatments, such as 

repetitive transcranial magnetic stimulation

An abundance of literaturedocuments the superiority of antidepressant medication plus psychotherapy over medication alone for MDD. Yet, when it comes to training the next generation of psychiatrists, we are observing a monumental paradox. Since 2013, the Accreditation Council for Graduate Medical Education (ACGME) standards and requirements for psychotherapy training in psychiatric residencies call for developing competencies in the areas of 

 (CBT), psychodynamic psychotherapy, and supportive psychotherapy in both brief and long-term formats, with optional experiences in group and couples/family therapy. Yet, currently, fewer psychiatrists than ever are providing psychotherapy to patients with MDD, or any diagnoses for that matter.

Physician distress is increasingly recognized as a professional and public health crisis. High rates of suffering including career dissatisfaction, secondary trauma or second victim phenomena (in psychiatry, often related to coping with patient suicide), burnout, 

, depression, and suicide are all receiving national attention and calls for action.

 While there has been outpouring of attention to recognize and attenuate physician burnout, far less attention has been allocated to the recognition and treatment of MDD in physicians. Yet, perhaps the most actionable prevention strategy for suicide is prompt recognition in optimal treatment of MDD.

Physicians have rates of MDD similar to the rest of the population, but are no more likely—perhaps less likely—to access treatment. This is due, in part, to continued stigma related to mental illness, but also to fears regarding the consequences of diagnosis and treatment on standing in the professional community and licensing, promotion, and insurance concerns. No doubt, avoidance of treatment relates to the high suicide rates noted in physicians. Distinguishing features of 

 include: Female physicians die by suicide more often than other females in the general population; suicide is the leading cause of death among male residents and the second leading cause of death among female residents; physicians are more likely to have a job problem (hence, attention to improving well-being and reducing burnout cannot be overestimated); a higher proportion of physician and nurse suicide deaths are by overdose compared with the general population; depression is as significant a risk factor as among nonphysician suicide deaths; and physicians who took their lives were no more likely to be receiving mental health treatment compared with nonphysicians who took their lives.

Lorna Breen Health Care Provider Protection Act

, which requires the Department of Health and Human Services (HHS) to take actions to improve mental and behavioral health and prevent burnout among health care providers, is a major step forward. Several national initiatives to address the issues of physician well-being, burnout, and suicide have emerged. What these programs have in common is attention to evidence-based practices, safe and accessible avenues for physicians to address mental health concerns, confidential and timely follow-up, and stigma reduction.

 At UC San Diego, the Healer Education, Assessment and Referral (HEAR) Program offers a comprehensive educational program, proactive screening and warm referrals, crisis intervention and critical incident debriefing, ongoing confidential counseling/therapy for house-staff, group support, peer supporter training, and interdisciplinary Schwartz Center Rounds.

In summary, while there has been an explosion of knowledge in the neuroscientific basis of mental disorders, genomics, neuroimaging and neuropsychology, there remains considerable room for growth in the way we provide equitable access to evidence-based treatments; define and diagnose MDD; create evidence-informed first- and next-step, personalized treatment decisions; conceptualize TRD and consider replacing or supplementing it with DTD; develop novel interventions that provide options for better tolerated, more effective, more sustainable treatments; and more effectively train future clinicians to competently employ a broader spectrum of evidence-based treatments than the current norm; and shift the culture of medicine to one that prioritizes optimizing our own wellness and mental health.

No doubt readers of this manuscript will have their own ideas of what deserves to be in a top 8 list and may have different perspectives on some of my somewhat subjective views. We would love to hear from you.

Want to learn more? Join Dr Zisook in San Diego for the 2022 Annual 

World CME Conference this August in San Diego. Save your spot by registering 

 is distinguished professor in the department of psychiatry at the University of California, San Diego.

Undertreatment of people with major depressive disorder in 21 countries.

The clinical characterization of the adult patient with depression aimed at personalization of management.

6. Shear MK, Reynolds CF, Simon NM, et al. 

Prolonged grief disorder diagnostic criteria—helping those with maladaptive grief responses. 

All-cause mortality in patients with treatment-resistant depression: a cohort study in the US population.

Clinical research challenges posed by difficult-to-treat depression.

The therapeutic potential of psilocybin: a systematic review.

Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert guidelines.

Trends in outpatient psychotherapy provision by us psychiatrists: 1996–2016. 

Bureaucrapathologies: galloping regulosis, assessment degradosis, and other unintended organizational maladies in post-graduate medical education. 

Preventing clinician suicide: a call to action during the COVID-19 pandemic and beyond.

17. Yeh G, Davidson JE, Kim K, Zisook S. 

Physician death by suicide in the United States: 2012–2016.

Physician suicide in the United States: updated estimates from the National Violent Death Reporting System.

Update on the UC San Diego healer education assessment and referral (HEAR) program.

Sidney Zisook, MD, lists these as the top 8 issues in MDD. 

Top 8 Issues in Major Depressive Disorder 

“The risk of love is loss and the price of loss is grief. But the pain of grief is only a shadow when compared with the pain of never risking love.” — Hilary Stanton Zunin

The figurative and literal losses associated with the COVID-19 pandemic are profound. These losses highlight the need for mental health professionals to gain sophistication in understanding, recognizing, and approaching grief in all its myriad forms in the clinical setting. The term “grief” describes the emotional, cognitive, functional, and behavioral responses to a meaningful loss. Throughout life, individuals face a number of losses capable of triggering grief. These include, but are not limited to, loss of their youth, opportunities, functional abilities, health, jobs, and meaningful relationships.

Bereavement is a nearly universal phenomenon, often experienced many times throughout life. Of all the events and stressors in ordinary life, bereavement may have the most powerful impact. Yet, bereaved individuals, their family and friends, and even mental health clinicians often are perplexed about its nature, course, and prognosis. In this article, we describe key characteristics of the acute grief response, the natural transition to integrated grief, and 2 related conditions that often require clinical attention: prolonged grief disorder (PGD) and major depressive disorder (MDD). PGD is a condition that occurs when the transition from acute to integrated grief is derailed. Meanwhile, MDD, a mood disorder that is not necessarily linked to grief, may be precipitated or exacerbated by meaningful losses, including bereavement.

. Bereavement usually triggers an acute grief response. Although not unique in all respects, some aspects of grief following bereavement are distinctive. As death is final and irreversible, bereaved individuals often experience their grief with a sense of helplessness and disconnection. The hallmark of acute grief is the intense focus on thoughts and memories of the deceased individual, accompanied by sadness, yearning, and longing. Acute grief is not a linear process with concrete stages or boundaries. Rather, it is a composite of overlapping and fluid cognitions, emotions, and behaviors that vary across individuals and even in the same person after different losses and over time.

 The experience of grief is influenced by social, religious, and cultural norms as well as by age, health, ethnic identity, coping style, attachment style, circumstances of the death, prior losses, and available social support and material resources.2 Yet, despite the variation and individual nuances, there are some common features and challenges of acute grief that many bereaved individuals face.

First are frequent strong feelings of yearning and sorrow. These are powerful feeling states, generally occurring in periodic waves of intense emotional distress that are often accompanied by somatic discomfort. These feelings may include a wrenching of the gut, shortness of breath, chest pain, lightheadedness, weakness, rapid welling up of tears, and uncontrollable crying. During the early days and weeks, these responses tend to erupt often, suddenly, and unexpectedly. Over time, their occurrences tend to be increasingly tied to specific thoughts and reminders of the deceased. As a result, their frequency and intensity diminish.

Second is a mixture of other feelings (positive and negative). Some common challenging thoughts, emotions, and experiences include: a sense of disbelief; intrusive thoughts and images focused on the deceased; decreased interest in ongoing life; feelings of insecurity, emptiness, loss, anger, guilt, anxiety, and loneliness; feeling overwhelmed or helpless; and varying degrees of distractibility, poor concentration, confusion, forgetfulness, or lack of clarity and coherence. Yet, even during acute grief, these painful experiences often are intermingled with positive feelings. For example, a grieving individual may experience warmth, amusement, or pride when thinking about their loved one and recollecting tender and/or humorous memories. There can be a sense of relief at the end of suffering. Depending upon the grieving individuals’ beliefs about death and the afterlife, they may feel joy, peace, and contentedness alongside the more painful feelings and thoughts.

. Although grief following bereavement is painful and associated with emotional and somatic distress, most individuals adapt to their loss, find a way through the acute grief period, and ultimately continue with their lives without professional assistance. Mourning is the process of adapting to loss, and this process can transform acute grief into what we call 

 Adaptation entails coming to grips with the reality, permanence, and consequences of the loss; establishing a new relationship with the deceased through memory and deeds; and looking forward to a future where life can be meaningful and joyful, even without the deceased. When mourning is successful, the painful and disruptive experience of acute grief transforms into an experience of integrated grief that is bittersweet but no longer all consuming. In integrated grief, individuals who are bereaved recognize what the loss has meant to them and that they are once again capable of experiencing happiness and meaning. They are thus able to shift attention from their loss to the world around them.

ICD-11 and DSM-5-TR Criteria for Prolonged Grief Disorder

. For a meaningful minority of grieving individuals, perhaps as high as 7% to 10%, the natural transition from acute to integrated grief is forestalled.

 For these individuals, maladaptive thoughts, feelings, and/or behaviors derail both adaptation to the loss and restoration of a life with meaning, joy, and purpose.

 Instead, the agony, yearning, and preoccupation with the loss remains intense and debilitating. This state has been formally recognized by both the ICD-11 and DSM-5-TR as “Prolonged Grief Disorder” 

); in the past it was often called complicated grief (CG), and it was called persistent complex bereavement disorder in the DSM-5.

 The distinguishing characteristics are persistent and intense grief that lasts well beyond the period expected by social and cultural norms (6 months in ICD-11 and 1 year in DSM-5-TR) and results in impairments in daily functioning. Many of the features noted in the acute grief section above, in a heightened state, characterize PGD, with the key difference being their persistent intensity without a substantial trajectory toward adaptation to the loss. In brief, healing is stalled and bereaved individuals who have PGD appear figuratively frozen in grief.

PGD may follow the loss of any close relationship but occurs more often in parents who have lost a child and after the death of a spouse or romantic partner.

 It is more likely when the death is unexpected, sudden, or violent, such as after suicide, homicide, or an accident.

 Multiple factors appear to increase the risk of PGD, including depression, anxiety disorders, current substance use/abuse, multiple losses, particularly stressful circumstances surrounding the death, lack of social supports, uncertainty about the death, and the unavailability of usual mourning rituals.

Psychotherapy is the treatment of choice for PGD. A focused, manualized form of psychotherapy has been found to be robustly effective in 3 separate randomized trials.

 The primary goals of this grief focused therapy are to identify and resolve processes that derail adaptation and thereby get in the way of acute grief transforming into integrated grief. In our experience, PGD often remains undiagnosed and/or is misdiagnosed as MDD. However, in each of the studies noted above, participants treated with psychotherapy more specific to depression

 or antidepressant pharmacotherapy3 did not respond nearly as well as those treated with the grief focused therapy. In the latter study, antidepressant medication, either alone or in combination with psychotherapy, was not found to alleviate grief, but antidepressant medication demonstrated some promise for decreasing depressive symptoms when given along with the therapy.

When formal therapy for PGD is not available, there is still much the clinician can do. The first step is to include an inquiry about bereavement as part of all initial evaluations and to have an open ear for issues related to grief in ongoing clinical management. Questions to help identify and guide the inquiry include: Has anyone close to you died? If so, have you been able to grieve and adjust to life without him/her? Are you still struggling with your loss in any way? Do you mind if I ask you more about it?

If the answers suggest an issue with grief, the next step is to invite an open inquiry into the relationship, death, mourning process, and impact of the loss. Supportive, nonjudgmental, empathic communication can let patients know they are not alone and can aid in the healing process. Other components of grief-informed clinical management include monitoring symptoms, letting the patients know you are there for them, and providing gentle encouragement for re-engaging in daily activities.

 In addition, optimizing treatment of cooccurring conditions and providing information about available support resources, such as the Center for Complicated Grief website and the American Foundation for Suicide Prevention website for suicide-loss survivors, can be invaluable. Left untreated, PGD is a debilitating and often chronic condition. Recognition and proper intervention can be life promoting and, in some cases, life saving.

The relationship between depression and bereavement is complicated and often perplexing to even the most seasoned clinicians. Based largely on Clayton’s pioneering studies on the relationships between grief and depression,

 the DSM-III introduced the Bereavement Exclusion (BE) for the diagnosis of MDD.

 This was meant to protect against grief being mistaken for depression, mislabeled as an illness, pathologized, and/or inappropriately treated. The BE disallowed the diagnosis of MDD during the first 2 months of bereavement unless the depressive symptoms and dysfunction were particularly severe, defined by symptoms of morbid worthlessness, psychomotor retardation, suicidal ideation, psychotic features, or marked disability.

The BE was subsequently eliminated in the DSM-5, as the DSM-5 mood disorders task force concluded it had become a roadblock to the diagnosis and treatment of MDD.

 Instead, the revised diagnostic criteria for MDD included a note that promoted the use of clinical judgment “based on the individual’s history of the cultural norms for the expression of distress in the context of loss” and provided guidelines to help differentiate MDD from grief that is not complicated by co-occurring MDD.

For example, in grief the predominant affect is emptiness and loss as opposed to the persistent depressed mood and anhedonia of MDD. In grief, the dysphoria decreases in intensity over days to weeks and occurs in waves that are associated with thoughts or reminders of the deceased. In contrast, with MDD, the dysphoria tends to be persistent and is not tied to specific thoughts or images. Grief is characterized by a preoccupation with thoughts and memories of the deceased, whereas in MDD the preoccupation is with self-critical or pessimistic ruminations. Similarly, self esteem is preserved in grief, while feelings of worthlessness predominate one’s self-view in MDD. Thoughts of death and dying in grief are generally focused on the deceased and possibly about joining or reuniting with the deceased loved one, while thoughts about dying in MDD more often are focused on ending one’s life in the setting of feeling worthless, undeserving of life, or unable to cope with the pain and misery of depression.

 In contrast to the experiences of those with MDD, bereaved individuals often retain the capacity to laugh, to appreciate the comfort and support of relatives and neighbors, to be consoled, and to recognize that what they are going through will lessen in time (

But the key question may not be one of either/or. Rather, knowing that bereavement triggers grief in most, and MDD in some, changes the question from whether a bereaved individual is grieving or depressed, to whether they are grieving and experiencing cooccurring MDD. Changing the question in this way may open the door to prompt diagnosis and treatment when indicated.

The importance of appreciating both the uniqueness and confluence of these conditions is underscored by several factors. MDD is a risk factor for developing PGD as well as a potential consequence of the death of a loved one in an individual already predisposed to MDD. Studies have confirmed high rates of both past and current MDD in bereaved individuals with PGD.

 While research on the influence of MDD on the severity or treatment outcome of PGD is sparse, the collective clinical experiences of the authors of this article suggest an adverse effect on intensity, duration, function, and treatment response of PGD in direct proportion to the severity of the cooccurring depression. Furthermore, while the only systematic, large, randomized controlled study on the effects of antidepressant medications for PGD did not demonstrate an effect of antidepressants on grief symptoms, it did suggest antidepressants relieved symptoms of depression in participants who also received grief-focused psychotherapy, and only in those.

More is known about the effects of PGD on MDD. In a large multisite study of treatment resistant MDD, a surprisingly large proportion of the patients had symptoms of PGD, which had not been noted in the clinical charts and had not been the focus of any treatments. Importantly, those with symptoms of PGD had more severe depression, increased suicide risk, and were significantly less likely to respond or remit to treatment.

Clinicians must carefully distinguish between grief, PGD, and MDD. A disorder that can occur when the natural grieving process is derailed, PGD is a painful and debilitating condition that can last for years in the absence of PGD-focused treatment. For PGD, the treatment of choice is either providing evidence-based PGD therapy or making a referral to a grief specialist. The aim is to provide support for healthy lifestyle and activities while also treating potential co-occuring conditions. If a bereavement specialist is not available, grief-informed clinical management can be enormously helpful. It is the authors’ hope that the guidance delineated in this article allows for a more refined, therapeutic approach to grief in various clinical settings—an approach that is especially relevant during this unique time in history when themes of loss and grief are so salient and pervasive.

is a resident in psychiatry at the University of California, San Diego.

 is an associate clinical professor in the department of psychiatry at the University of California, San Diego.

 is distinguished professor in the department of psychiatry at the University of California, San Diego.

Learn more about grief from Dr Iglewicz or mood disorders from Dr Zisook, please join us for the 

Annual Psychiatric Times World CME Conference

 September 30, 2021 through October 2, 2021. 

1. Shear K, Reynolds C, Simon N, Zisook S. Grief and bereavement in adults: clinical features. UpToDate. 2017. Accessed August 27, 2021. 

https://www.uptodate.com/contents/grief-and-bereavement-in-adults-clinical-features

2. Zisook S, Simon NM, Reynolds C, et al. Phenomenology of acute and persistent grief. In: Simon N, Hollander E, Rothbaum BO, & Stein D J, eds. 

The American Psychiatric Association Publishing Textbook of Anxiety, Trauma, and OCD-Related Disorders

, 3rd ed. American Psychiatric Association Publishing; 2020:557-570.

3. Shear MK, Reynolds CF 3rd, Simon NM, et al. Optimizing treatment of complicated grief: a randomized clinical trial. 

4. Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. 

5. Kersting A, Brähler E, Glaesmer H, Wagner B. Prevalence of complicated grief in a representative population-based sample. 

6. Lundorff M, Holmgren H, Zachariae R, et al. Prevalence of prolonged grief disorder in adult bereavement: a systematic review and meta-analysis. 

7. Prigerson HG, Bierhals AJ, Kasl SV, et al. Traumatic grief as a risk factor for mental and physical morbidity. 

8. Shear MK. Clinical practice. Complicated grief. 

How can clinicians distinguish between ordinary grief, depression, and prolonged grief disorder? 

Sidney Zisook, MD

Articles

8 Key Issues in the World of Major Depressive Disorder

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Top 8 Issues in Major Depressive Disorder

Bereavement and Depression

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DSM5 and the Medicalization of Grief: Two Perspectives