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Are You Ready for the Annual Psychiatric Times World CME Conference? 

At the Annual Psychiatric Times World CME Conference, an all-star lineup of presenters will share their latest research. Check out this preview of the full agenda. 

Anniversaries help to define generations. Almost everyone can remember where they were when John F. Kennedy was shot, when the Space Shuttle Challenger exploded, and when the World Trade Center collapsed.

These anniversaries can bring patients’ the active symptoms of trauma, from anxiety and depression to panic attacks, anger, and substance use. But anniversaries can also be an occasion for post-traumatic growth. In this Mental Health Minute, Kenneth Yeager, PhD, MSW, LISW, talks about how to help patients reframe these situations—on September 11th or on any other important date.

is the director of the Stress, Trauma, and Resilience Program at the Ohio State University, where he is also a professor in the Department of Psychiatry at the College of Medicine.

How do you help patients handle difficult anniversaries? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

What can be done to help patients turn painful memories into opportunities for posttraumatic growth? 

The Anniversary Effect of 9/11

Antidepressant augmentation is a common practice, and there are many strategies from which to choose. The 

 recommends a menu approach that encourages patients to collaboratively choose an option that best fits their needs.

 In addition to psychotherapy and lifestyle approaches like aerobic exercise, they recommend augmentation with:

1. Natural treatments: omega-3 fatty acids, L-methylfolate, or light therapy

2. Antipsychotics: aripiprazole, risperidone, or quetiapine

3. Antidepressants: bupropion, imipramine, or mirtazapine

When rapid relief is the priority, an antipsychotic might be the best choice. For favorable tolerability, there is bupropion or a natural therapy, and lithium has strong antisuicide effects, if that is a concern. But what if insomnia is the chief complaint? Mirtazapine is tempting here, but this medication carries a risk of weight gain and did not perform well in several recent, well-designed augmentation trials.

 Instead, a standard hypnotic may be a good option when patients continue to have depression and insomnia on an antidepressant, but not just any hypnotic.

Eszopiclone: The Science Behind Its Potential Effect on Depression

In the early 2000s, a group of sleep researchers set out to investigate whether hypnotics could improve mood in patients with depression and insomnia. The results did not pan out exactly as expected, but they point the way toward a medication with unique potential in depression.

But first, investigators had to overcome a hurdle. At the time, it was thought that hypnotics might cause depression through their sedative effects. That concern was partly put to rest in a 1999 study that tested whether zolpidem could relieve selective serotonin reuptake inhibitor [SSRI]-induced insomnia in patients who had otherwise recovered on the antidepressant. The sleep problems improved with zolpidem and, to the investigators’ relief, the sedating medication did not worsen depression.

Buoyed by this result, the manufacturer of eszopiclone funded a large trial to see if depression might actually improve with their hypnotic. Five hundred and forty-five patients with depression and insomnia were randomized to receive either eszopiclone 3mg or placebo while simultaneously starting a trial of fluoxetine. As expected, the hypnotic improved sleep, but it also improved mood symptoms that were unrelated to sleep. Compared to placebo, those who received eszopiclone experienced a more rapid and complete recovery from depression.

The same group repeated the study with zolpidem ER in a large trial of similar design. Once again, the hypnotic improved sleep, but this time there was no change in mood.

 Replication in China brought the same negative results, and last year zolpidem failed again to lift mood or reduce suicidality when added to an SSRI in a randomized trial of patients with depression, insomnia, and suicidality.

Meanwhile, eszopiclone repeated its success, improving mood and insomnia in 2 additional trials, 1 of which involved peri- and postmenopausal women with insomnia and depressive symptoms.

 Generalized anxiety disorder also improved when eszopiclone was added to an SSRI in a large manufacturer-supported trial that replicated the design of eszopiclone’s pivotal depression trial.

Both the zolpidem and eszopiclone studies involved many of the same investigators, who had pursued this work with the idea that any hypnotic that improved sleep would indirectly improve mood. But to this day eszopiclone remains the only hypnotic with distinct antidepressant effects (ramelteon has mild preventative benefits in bipolar disorder but is not known to treat depression).

 Whether this is a statistical fluke or a true difference is difficult to say, as eszopiclone has not gone head-to-head against other hypnotics in depression. However, eszopiclone does have a unique mechanism of action that might explain its antidepressant effects. To understand that we need to turn to the GABAA receptor.

Compared to the benzodiazepines, the z-hypnotics have more limited effects on GABAA, which is thought to explain why they treat sleep but not anxiety. Specifically, the z-hypnotics are selective for the sleep-inducing GABAA α-1 subunit, while benzodiazepines have additional effects on the α-2 and -3 subunits that are involved in anxiety and depression. But eszopiclone is an exception. It acts at all of the α subunits, and may actually be a little more selective for the anxiolytic α-2 and-3.

 This effect is furthered by eszopiclone’s active metabolite, desmethylzopiclone, which is a selective partial agonist at α-2 and -3 with very little α-1 activity (that is a good thing, as it would otherwise cause a lot of daytime sedation).

 In animal models, desmethylzopiclone reduced anxiety without causing sedation or motor impairment.

 Its effects in humans are not well described, but the trials above give us a hint, and the company that launched eszopiclone has patented this metabolite as a potential anxiolytic.

In this way, eszopiclone resembles the benzodiazepines, which have been used to treat depression and hasten the response to antidepressants in over 3 dozen controlled trials.

 In most of those trials, their antidepressant effects were independent of their anxiolytic effects, just as eszopiclone treated symptoms of depression that were unrelated to sleep.

Despite this research, benzodiazepines are not used routinely for depression because of their risk of tolerance and abuse. Those risks may also apply to eszopiclone, but the trials above provide some reassurance. In several of them, eszopiclone was replaced with a placebo after 2 months of treatment without any loss of the antidepressant and anxiolytic gains. Nor was there any rebound insomnia and, in some studies, it stabilized sleep patterns in a way that continued after the hypnotic was stopped.

Does all this elevate eszopiclone to the level of antidepressant augmentation? Possibly. It does have more positive results than some the augmentation strategies that are endorsed by evidence-based guidelines.1 But there are 2 caveats. First, eszopiclone was only studied in patients with comorbid insomnia, but this is not a major hurdle as it is the rare patient with depression who does not struggle with sleep (about 15%).

 More significantly, eszopiclone was started in tandem with an antidepressant in these augmentation trials, so we do not know if it could turn things around when added later, after a few antidepressant failures.

When selecting a hypnotic in depression or generalized anxiety disorder, eszopiclone should be on the list. The treatment need not be long-term. Most patients were able to taper off the hypnotic after recovery. To bolster those odds, start out with the expectation of short-term use and guide the patient toward 

is the Mood Disorders Section Editor for 

 He has written several books on mood disorders, most recently

 with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for

The psychopharmacology algorithm project at the Harvard South Shore Program: an update on unipolar nonpsychotic depression.

Mirtazapine augmentation: Running low on rocket fuel.

. September 2019. Accessed August 27, 2021.

3. Asnis GM, Chakraburtty A, DuBoff EA, et al. 

Zolpidem for persistent insomnia in SSRI-treated depressed patients.

Efficacy and tolerability of Z-drug adjunction to antidepressant treatment for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

5. McCall WV, Benca RM, Rosenquist PB, et al. 

Reducing suicidal ideation through insomnia treatment (rest-it): a randomized clinical trial.

6. McCall WV, Blocker JN, D'Agostino R Jr, et al. 

Treatment of insomnia in depressed insomniacs: effects on health-related quality of life, objective and self-reported sleep, and depression.

7. Joffe H, Petrillo L, Viguera A, et al. 

Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial.

. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.

Melatonin receptor agonists-ramelteon and melatonin-for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

. Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics.

Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone.

12. Carlson JN, Haskew R, Wacker J, et al. 

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite.

13. Benasi G, Guidi J, Offidani E, et al. 

Benzodiazepines as a monotherapy in depressive disorders: a systematic review.

Wisniewski SR, et al. Insomnia in patients with depression: a STAR*D report.

A hypnotic might be a good option for augmenting depression treatment, but which hypnotic has the best evidence for efficacy? 

An Overlooked Strategy for Antidepressant Augmentation?

One of the biggest stories in psychopharmacology in recent years was not a very promising one. Mirtazapine, which has been used since the 1990s to augment antidepressant treatment, failed to work in the first well-designed studies to test that strategy.

 Now a new analysis offers more specific direction on when mirtazapine augmentation might still be useful in major depressive disorder (MDD).

Interest in mirtazapine augmentation began with a theory. Like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine affects serotonergic and noradrenergic transmission, but it does so through a different mechanism, suggesting a potential synergy with combination therapy. Mirtazapine also has the potential to reduce SSRI side effects, including nausea, insomnia, and sexual dysfunction.

The strategy took off from there, aided by the catchy nickname 

 that Stephen Stahl, MD, PhD, coined for the venlafaxine-mirtazapine combination. But the empiric support for the strategy was always thin, mostly resting on a singular placebo-controlled trial that was significantly hindered by its 26-subject size.

After more than 20 years of clinical use, mirtazapine augmentation was finally tested in 2 high quality trials (large, double-blind, randomized, placebo-controlled), 1 from the United Kingdom (UK) and 1 from China.

 Both tested mirtazapine augmentation after unsuccessful treatment with an SSRI or SNRI, and in both mirtazapine worked no better than placebo. These were followed by a third study in which 112 patients who had not recovered on venlafaxine were randomized to either switch to imipramine or augment with mirtazapine. Unfortunately for mirtazapine, the imipramine switch was nearly twice as effective as mirtazapine augmentation.

Those 3 negative trials caused mirtazapine to slide down a few rungs on the augmentation algorithm. But a small signal in the UK trial inspired the investigators to give the data a second look. The study, dubbed the MIR trial, was the largest of the 3 negative trials, and involved 480 primary care patients whose depression did not respond to 6 weeks of an SSRI or SNRI. Although mirtazapine failed to make a difference on the primary outcome of depression, it did improve anxiety on secondary measures.

The investigators reanalyzed the data to see if patients with high levels of anxiety had a more favorable response to mirtazapine augmentation. After stratifying the sample by baseline anxiety level (mild, moderate, or severe on the GAD-7), they found that patients with severe anxiety made significant gains with mirtazapine, while those with no anxiety at baseline did not improve at all with the medication. Those gains included both depressive and anxious symptoms. Patients with moderate anxiety had gains between the 2 extremes.

To test whether anxiety was just a marker for illness severity, they stratified the sample by overall severity of depression. That analysis turned up negative, suggesting that it was the anxious symptoms themselves, and not the overall severity, that was driving the change.

The findings were significant, but are they clinically meaningful? They appear to be, at least in the severe anxiety group where the Generalized Anxiety Disorder-7 scale dropped 2.8 points (out of a max of 21) points and the Beck Depression Inventory II fell 2.8 (max of 63).

Mirtazapine is not the most effective augmentation strategy in depression, but it is worth considering in depressed patients with high anxiety.

1. Rifkin-Zybutz R, MacNeill S, Davies SJ, et al. Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial. 

2. Kessler DS, MacNeill SJ, Tallon D, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). 

3. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. 

4. Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. 

5. Xiao L, Zhu X, Gillespie A, et al. Effectiveness of mirtazapine as add-on to paroxetine 

 paroxetine or mirtazapine monotherapy in patients with major depressive disorder with early non-response to paroxetine: a two-phase, multicentre, randomized, double-blind clinical trial. 

6. Navarro V, Boulahfa I, Obach A, et al. Switching to imipramine versus add-on mirtazapine in venlafaxine-resistant major depression: a 10-week randomized open study. 

After a string of disappointing results, mirtazapine gets another look in a recent study. 

When to Use Mirtazapine Augmentation

“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.

. 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. 

Diagnostic and Statistical Manual of Mental Disorders

, 5th ed. American Psychiatric Association Publishing; 2013.

10. International statistical classification of diseases and related health problems (11th ed.) World Health Organization. 2019. Accessed August 18, 2021. 

11. Meert KL, Shear K, Newth CJ, et al. Follow-up study of complicated grief among parents eighteen months after a child's death in the pediatric intensive care unit. 

12. Kristensen P, Weisæth L, Heir T. Bereavement and mental health after sudden and violent losses: a review. 

13. Tal I, Mauro C, Reynolds CF 3rd, et al. Complicated grief after suicide bereavement and other causes of death. 

14. Zisook S, Reynolds CF 3rd. Complicated grief. 

15. Shear K, Frank E, Houck PR, Reynolds CF 3rd. Treatment of complicated grief: a randomized controlled trial. 

16. Shear MK, Wang Y, Skritskaya N, et al. Treatment of complicated grief in elderly persons: a randomized clinical trial. 

17. Iglewicz A, Shear MK, Reynolds CF 3rd, et al. Complicated grief therapy for clinicians: an evidence-based protocol for mental health practice. 

18. Clayton P, Desmarais L, Winokur G. A study of normal bereavement. 

19. Clayton PJ, Halikes JA, Maurice WL. The bereavement of the widowed. 

20. Clayton PJ, Darvish HS. Course of depressive symptoms following the stress of bereavement. 

, 3rd ed. American Psychiatric Association Publishing; 1980.

22. Zisook S, Corruble E, Duan N, et al. The bereavement exclusion and DSM-5. 

23. Iglewicz A, Seay K, Zetumer SD, Zisook S. The removal of the bereavement exclusion in the DSM-5: exploring the evidence. 

24. Zisook S, DeVaul RA. Grief, unresolved grief, and depression. 

25. Zisook S, Mohamad S, Johnson G, et al. Clinical implications of co-occurring prolonged grief disorder in patients with treatment-resistant major depressive disorder. 

26. Stroebe M, Schut H. Bereavement in times of COVID-19: a review and theoretical framework. 

27. Kokou-Kpolou CK, Fernández-Alcántara M, Cénat JM. Prolonged grief related to COVID-19 deaths: do we have to fear a steep rise in traumatic and disenfranchised griefs? 

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

Bereavement and Depression

In the Wake of 9/11: Mental Health Statistics of First Responders

What toll does trauma take on police officers, firefighters, and EMT workers? 


Mr J is a 33-year-old Caucasian male who was diagnosed with a first episode of a major depressive disorder (MDD) at a recent outpatient visit. He has had individual therapy in the past 3 months, but has never been treated with psychotropic medications. He has no known medical problems. He does not smoke or use illicit drugs, and endorses occasional social alcohol use. Vital signs indicated a body mass index (BMI) of 28. Screening laboratory studies at the outpatient visit were notable for elevated thyroid-stimulating hormone (TSH) levels, but normal free T4, as well as slightly elevated low-density lipoprotein (LDL) cholesterol. In addition to his depression, Mr J voiced concerns about significant anxiety. There was no evidence of psychosis. After consultation with the psychiatrist, he agreed to start treatment with a low dose of a selective serotonin reuptake inhibitor, and to continue individual therapy. 

 and this association may reflect underlying neuroendocrine (eg, thyroid) and neuroimmune (eg, autoantibody) factors. However, the prevalence of overweight and obesity in patients with depression 

 Furthermore, previous studies are varied in terms of methodology (eg, general population samples versus patients with MDD), and consideration of potential confounding or moderating factors (eg, antidepressant treatment).

In order to address these factors and further investigate this association, 

 recruited a large sample of first-episode drug-naïve patients with MDD in a Han Chinese population. They aimed to investigate the relationship between overweight and obesity and risk factors, including lipids, thyroid hormones, and autoantibodies. The authors recruited consecutive outpatients in the First Hospital of Shanxi Medical University. Inclusion criteria were age 18 to 60 Han Chinese, first episode of MDD, disease duration < 2 years, no history of antidepressant treatment, and no pregnancy or lactation. Subjects with central nervous system disease, severe or unstable physical disease, atypical depression, or comorbid drug or alcohol use disorder were excluded.

Exactly 1718 subjects (588 men and 1130 women) met the study inclusion/exclusion criteria. Subjects were trichotomized based on BMI: normal < 24, overweight 24 to 28, and obesity > 28. They were assessed clinically with the Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and the Positive and Negative Syndrome Scale. Fasting blood samples were obtained for lipids and thyroid hormones and antibodies. A chi-square test, analysis of variance, or Kruskall-Wallis rank test was used to compare demographic and clinical variables between the 3 BMI groups. Ordinal logit models were also used to explore relationships between clinical factors and BMI.

The prevalence of overweight and obesity in the study sample was 56% and 4%, respectively. 

 had higher total and LDL cholesterol, and a greater prevalence of elevated TSH than both overweight and normal weight patients. Overweight patients had higher triglycerides and a greater prevalence of elevated TSH than normal weight patients. Obese patients also had a greater prevalence of severe anxiety than overweight and normal weight patients. In an ordinal logit model, only TSH was an independent risk factor for overweight/obesity, with some evidence of a dose-dependent relationship.

The authors concluded that they found a higher prevalence of overweight and a lower prevalence of obesity compared to other North American and European samples, although subjects in these studies were not drug-naïve. They also found that TSH levels were an independent risk factor for overweight and obesity in patients with MDD, which extends findings from general population studies. Strengths of the present study included the large sample of first-episode drug-naïve patients with MDD, which may reduce several potential confounding factors. A primary limitation was the cross-sectional study design, which does not permit causal inferences between BMI and related risk factors.

Overweight is highly prevalent in Han Chinese patients with MDD, and TSH is an independent risk factor for overweight and obesity in this population. Findings support the clinical utility of screening for thyroid dysfunction in this population. Further rigorously-designed studies are needed to clarify the role of 

overweight and obesity in the pathogenesis of depression

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Dreimuller N, Lieb K, Tadic A, et al. 

Body mass index (BMI) in major depressive disorder and its effects on depressive symptomatology and antidepressant response.

Association of depression with body mass index classification, metabolic disease, and lifestyle: a web-based survey involving 11,876 Japanese people.

Prevalence and risk factors of overweight and obesity in Chinese patients with first-episode drug-naive major depressive disorder.

What are the risk factors for and prevalence overweight and obesity in  patients with first-episode drug-naïve major depressive disorder?

Overweight and Obesity in First-Episode Major Depressive Disorder

Repetitive transcranial magnetic stimulation (TMS) is a useful clinical tool that is effective in patients with treatment-resistant depression. This noninvasive treatment is an option for patients with depression who have not found relief from other treatments, such as psychotherapy and antidepressants.

TMS technology was developed in 1985 and has been gaining clinical interest since then. Two-thirds of TMS patients experienced either 

full remission of their depression symptoms or noticeable improvements

 An out-patient procedure, TMS does not have serious side effects.

Approved by the US Food and Drug Administration in 2008, TMS uses an alternating current passed through a metal coil placed against the scalp to generate rapidly alternating magnetic fields. These pass through the skull nearly unimpeded and induce electric currents that depolarize neurons in a focal area of the surface cortex.

The magnetic field generated by TMS is comparable to that of a standard magnetic resonance imaging device (MRI), measured at approximately 1.5 to 3 Teslas. However, the TMS field is focal (beneath the coil), whereas the MRI field is large and fills the room housing the MRI device.

One hypothesis on how TMS works is that the 

stimulation of discrete cortical regions alters pathologic activity

 within a network of gray matter brain regions, specifically those involved in mood regulation and connected to the targeted cortical sites.

support this hypothesis by showing TMS can change activity in brain regions remote from the site of stimulation.

molecular effects comparable to electroconvulsive therapy

 (ECT), including increased monoamine turnover and normalization of the hypothalamic pituitary axis.

 Additionally, in one neuroimaging study of depressed patients, a prefrontal serotonin deficiency at baseline normalized after treatment with TMS.

High-frequency stimulation is thought to excite the targeted neurons and is typically used to activate the left prefrontal cortex. Low-frequency stimulation appears to inhibit cortical activity and is usually directed at the right prefrontal cortex.

 examined 66 studies in depressed patients who were treated with TMS targeting the dorsolateral prefrontal cortex. It found that high-frequency TMS generally increased regional cerebral blood flow, whereas low-frequency TMS generally decreased regional cerebral blood flow, which is reduced in a depressed brain.

A clinical review of an effective approach for treatment-resistant depression.

Depression