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Last month we taught you how evening light can worsen mood. Today we teach you how to fix that. 

, "the voice of psychiatry." With thoughtful insights into the world of mental health, this podcast provides timely clinical commentary and practical cutting-edge pearls for you and your practice. We hope you enjoy.

I’m Chris Aiken, the Mood Disorders Section Editor for 

, and I’m Kellie Newsome, a psychiatric NP and the cohost of the 

: Evening light worsens sleep and mood, and 

 we unraveled the biology behind that association. To recap, evening light – particularly the blue wavelength suppresses melatonin, worsening 2 systems that are already fragile in people with mood disorders: sleep and circadian rhythms. In animal studies it even altered the core architecture of the brain – shrinking the dendritic spines that 

But you don’t have to go into the woods and live deliberately to fix this problem. Today, we’ll teach you how to use blue light filters to stabilize the circadian rhythms that regulate mood and sleep, and how to use them in 

: There are 2 well-known photoreceptors in the eye. The rods see black and white, and the cones add color vision. But in the 1990s a new photoreceptor was discovered – melanopsin – which only responds to the blue wavelength of light. This photoreceptor doesn’t help us see, but it does regulate our circadian rhythm. In the past, this system worked well because we didn’t have much blue light in the evening. There were candles, starlight, fireplaces – all yellow light.

: Except once a month when the blue moon was full. And it’s no coincidence the word lunatic arose in the middle ages as a term for mental illness. It was believed that some people went into temporary bouts of insanity that followed the lunar cycle – the moon. Seven hundred years later, 

 linking the full moon to worsening of psychiatric disorders continue to roll in.

: And in today’s world, every night is a full moon, because cell phones, plasma TVs, and energy efficient bulbs emit a lot of blue light. But technology has also come to the rescue in the form of blue light filtering glasses. These are amber colored glasses, and when you wear them they filter out close to 100% of blue light. They’ve gained popularity among sports figures and celebrities, because wearing them at night improves sleep – which then raises cognitive and athletic performance. But most models out there do not filter enough blue light to make a meaningful difference in psychiatric disorders. We recommend the glasses that were used in the clinical research – and there are 2 types. Some studies have used Uvex glasses, which are $10 to 15 dollars on Amazon. Any pair on that site will work, and these are much better quality for a higher price, around $50.

: I keep a pair of these glasses at my desk for patients to try on. They’re usually surprised to see the world looks quite pleasant through them. They don’t make things dark, but give the world a relaxing, yellow hue. Some patients find them so soothing that I have to warn patients not to wear them during the day, because doing so will flip their circadian rhythm in the wrong direction. When you wear them, your brain will think it’s in pitch darkness, and we only want that effect at night.

: Wearing them has real biological effects. When you put them on, your melatonin starts to rise, the same as it does in a 

 Sometimes patients ask if they can just take melatonin instead, but that doesn’t have the same effect. In a recent randomized controlled trial, taking artificial melatonin did nothing to stabilize mood in bipolar disorder.

 So it’s not enough to have melatonin drizzled on the brain. There are other biological effects involved in pumping out the brain’s indigenous melatonin that are necessary here.

If you want to know more about the biological effects of light and darkness listen to our August 2nd podcast on 

Blue Light, Depression, and Bipolar Disorder

. Now, let’s move on to the clinical research.

: In the 1980s Thomas Wehr, MD, and Norman Rosenthal, MD, made a surprise discovery while working at the National Institute of Mental Health (NIMH). Some patients had worsened depression in the wintertime that improved with light therapy. Their research suggested that circadian rhythms played a strong role in mood disorders, something that was already hinted at by the high rates of insomnia in major depression and the fact that a night without sleep often triggered an episode of mania. So, Wehr turned his attention from morning light to evening darkness. He began with normal subjects and placed them in a pitch-dark room for 14 hours overnight, imitating a dark winter night where the sun goes down at 6 PM and rises at 8 AM. The subjects were a little sleep deprived before the experiment, getting about 7 hours per night, something Wehr thought might be due to the artificial evening light of modern life. After a few weeks in the dark bedroom, their 

 to 8 hours and 15 minutes per night, closer to the recommended amount an adult needs.

: Then in 1994 a man came to the NIMH seeking help for rapid cycling bipolar disorder. Most patients don’t call up the NIMH to get help, so we can imagine this man had a pretty bad case. He was a successful engineer with a hyperthymic temperament, but in his 40s he became depressed and started fluoxetine and nortriptyline. He got better on this combination, but then went into a 4-year bout of rapid cycling moods cycling in and out of depression and hypomania every 1 to 2 months. Mood stabilizers did not help, so he came to the NIMH. Wehr knew that sleep disruption could trigger rapid cycling, and he wondered if his super-dark room could stabilize it. He put the patient through the same protocol he used for sleep, placing him in a pitch dark room for 14 hours each night. With this dark therapy, he improved so rapidly that they eased the schedule from 14 hours of darkness to 10 hours each night (10:00 PM to 8:00 AM). He stayed well with that regimen, and that is how dark therapy was 

: But the treatment didn’t really take off. First, it’s hard to get patients in a pitch-dark room overnight. We’re talking so dark that you can’t see your hands in front of your face. Second, we need more than an intriguing case report to put this into practice. The first problem was resolved in the early 2000s by James Phelps, MD.

Phelps was working in private practice in Oregon when he chanced upon 3 discoveries that would open up new therapeutic doors in bipolar disorder. First, he learned about Wehr’s research on dark therapy. Then he learned about the new photoreceptor, melanopsin, that set the circadian rhythm by responding to blue light. He wondered if dark therapy could be accomplished by blocking only the blue wavelength of light, and that brought him to the third piece of the puzzle: blue light filtering glasses. Other fields of medicine had already raised alarms about the hazards of evening blue light (such as increased risk of cancer and heart disease) and a company was manufacturing these to improve sleep and health. Phelps called this 

 and tried the glasses out on his patients. For some, the glasses did nothing, but about half of his patients reported their sleep was better when they wore the glasses 1 to 2 hours before bed.

He then discovered that welders used the same blue-light filters to protect their eyes at the local welding shop, and this opened the door to more treatments because these factory grade lenses were only $7. Phelps tested them and the fit the bill. 

later ran tests of blue light blockers and also concluded that the Uvex safety lenses he was using were among the strongest filters.

Phelps tested the waters, but the definitive study was a full-scale randomized trial in patients who were hospitalized for mania. In addition to treatment as usual, half wore amber lenses in the evening, and half wore (placebo) gray lenses, until sleeping in a pitch-dark room. The improvements were dramatic over the first week, with a large effect size of 1.9, while the control group barely changed.

You don’t need to be in the hospital to do this therapy. Phelps has had success using it in an outpatient practice, and we have as well. Here’s how you do it.

The original protocol required manic patients to be in either pitch darkness or virtual darkness (that is, with the amber glasses on) for 14 hours, from 6:00 PM to 8:00 AM. It took about a week for the mania to improve, and as it did the protocol was relaxed a bit, from 14 hours per night to 10 hours per night. So instead of putting the glasses on at 6 PM, they’d put them on at 7:00 PM, then 8:00 PM, and for prevention thy would move it to 9 or 10 PM. They don’t wear the glasses while asleep. That’s what the pitch-dark bedroom is for. But they do put them on if they are awake and the lights are on.

And the pitch darkness really does matter. Even light as dim as a nightlight on can interfere with melatonin secretion. In a large epidemiologic study of older adults, sleeping with a night light on doubled the risk of depression over 2 years compared to a pitch-dark bedroom.

But how do they get their bedroom pitch dark in this electric light world? 

, electrical tape over LEDs, towels or draft snakes under doors, or sleeping in the basement. If there is still stray light, patients can also sleep with a good eye mask.

: One problem we run into is patients who feel they can’t sleep without the TV on. Usually the reason is depressive rumination. These patients rely on the TV to distract them from their negative, ruminating thoughts. If that’s the case, we recommend ambient music or boring audiobooks instead. Another problem is patients who are afraid of the dark, such as those with PTSD. Here we have a technological solution. They can use amber colored nightlights that don’t emit any blue light. They are available for around $12.

: One modification we don’t recommend is to rely on blue-light filters on laptops and cell phones. Most devices have a setting that turns down the blue in the evening, and no doubt this is certainly a good thing and we’d recommend it in conjunction with dark therapy, but it doesn’t filter 100% and it isn’t going to take care of the background lights. You can find this feature in your smart phone’s settings, or if you’re using a laptop try downloading f.lux (spell it out) for windows or Candlelight by Oliver Denman for Mac.

But what if your patient can’t put the glasses on at 6 PM? Remember the 14-hour protocol was used for hospitalized mania, and they loosened it up as the patient got better. In practice, you might use dark therapy for hypomania, mild mixed states or as an intervention for early signs of mania. In those cases, putting the glasses on 2 hours before bed might be enough.

: It’s also important to set up expectations. Tell your patient that dark therapy is going to help stabilize their mood, but it may not help them fall asleep. Here’s an interesting pearl from that controlled trial. The patients who got better with the dark therapy didn’t actually sleep more. They slept a little less than the placebo group, but their sleep did get more regular. It went from sleeping and waking at random times to a more steady, stable circadian pattern.

 A lot of times patients will give up on dark therapy because they think it is supposed to help them sleep.

: Dark therapy improves mania, but what does it do to sleep? We found 3 randomized controlled trials that tested them out in insomnia, and they had a large effect, helping patients stay asleep longer, fall asleep earlier, and deepening sleep quality.

 One of them used the blue light blockers as an adjunct to CBT-insomnia, where half the patients had the behavioral therapy with placebo glasses and half used the blue-light blockers. Not only did sleep improve with the blockers, but so did anxiety and depression.10 Another study looked at performance on cognitive tests after wearing the glasses, and that got better as well, probably because the patients were sleeping better.

 In the sleep studies, patients put the glasses on 1.5 to 2 hours before bedtime.

Blue light blockers have been used successfully in jet lag, and they tend to help night owls fall asleep earlier.

: I wear them myself and I can attest to that. I’m more patient and have better attention, a little quicker on my feet, the next day if I wore them before bed.

: Blue light blockers have a big effect in mania and rapid cycling, and for sleep they deepen sleep quality and turn night owls into morning people. But can they help depression? We know from animal studies and epidemiologic studies that blue light causes depression, but when it comes to clinical studies using blue light blockers to treat depression the results are mixed. In that CBT-insomnia study, they did improve depressive symptoms, but those patients had clinical insomnia, not clinical depression.

 Beyond that, we have only 2 controlled trials, 1 positive, 1 negative. The positive one was small (n = 27) and centered on postpartum depression, where nocturnal awakening is the norm. Women who used blue-light blockers and low-blue light bulbs had greater improvements than those who used placebo glasses and bulbs.

 The negative study was also small (n = 20) and included depressed patients with insomnia. The investigators suspected that the glasses might not have worked because the patients found them uncomfortable and did not wear them as much as they should.

: When worn at night, blue light filters have beneficial, biological effects, but can they have side effects? Nothing major showed up in the studies. Possibly headaches, and there are reports of depression in some patients. This usually improves by putting the glasses on later, say, 7 PM or 8 PM instead of 6 PM. Although you can see pretty clearly through the glasses, color vision is distorted so we don’t recommend them while driving.

: We have links to recommended brands of blue-light blockers in the text to this podcast. We hope to see you again on 

, and you can also catch us every Monday on the 

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

and is also a practicing psychiatric mental health nurse practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

1. Bedrosian TA, Vaughn CA, Galan A, et al. 

Nocturnal light exposure impairs affective responses in a wavelength-dependent manner.

2. Henriksen TE, Skrede S, Fasmer OB, et al. 

Blue-blocking glasses as additive treatment for mania: a randomized placebo-controlled trial.

Lunar cycle and psychiatric hospital admissions for schizophrenia: new findings from Henan province, China.

4. Kayumov L, Casper RF, Hawa RJ, et al. 

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work.

5. Quested DJ, Gibson JC, Sharpley AL, et al. Melatonin In Acute Mania Investigation (MIAMI-UK). 

A randomized controlled trial of add-on melatonin in bipolar disorder.

6. Barbato G, Barker C, Bender C, et al. 

Extended sleep in humans in 14 hour nights (LD 10:14): relationship between REM density and spontaneous awakening.

7. Wehr TA, Turner EH, Shimada JM, et al. 

Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

Dark therapy for bipolar disorder using amber lenses for blue light blockade.

Bedroom light exposure at night and the incidence of depressive symptoms: a longitudinal study of the heijo-kyo cohort.

10. Janků K, Šmotek M, Fárková E, Kopřivová J. 

Block the light and sleep well: Evening blue light filtration as a part of cognitive behavioral therapy for insomnia

11. Zimmerman ME, Kim MB, Hale C, et al. 

Neuropsychological function response to nocturnal blue light blockage in individuals with symptoms of insomnia: A pilot randomized controlled study.

12. Shechter A, Kim EW, St-Onge MP, Westwood AJ. 

Blocking nocturnal blue light for insomnia: A randomized controlled trial.

13. Bennett S, Alpert M, Kubulins V, et al. 

Use of modified spectacles and light bulbs to block blue light at night may prevent postpartum depression.

14. Esaki Y, Kitajima T, Takeuchi I, et al. 

Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized, double-blind, placebo-controlled study.

How to regulate circadian rhythms and regulate mood using dark therapy. 

Blue Light Blockers: A Behavior Therapy for Mania

“There appears to be at least 3 types of major depressive disorder (MDD) based on pharmacology,”Sheldon Preskorn, MD, told attendees of the 2021 Annual 

TM World CME Conference. Preskorn, professor in the Department of Psychiatry and Behavioral Sciences at University of Kansas School of Medicine and Psychopharmacology Section Editor of 

, was also named Educator of the Year at the conference.

The first type of MDD responds to biogenic amine antidepressants. This group represents about 60% to 65% of patients, he added. The next group is nonresponsive to biogenic amine antidepressants, but responsive to glutaminergic (NMDA) antidepressants, and represents about 25% of patients. The third group is nonresponsive to both biogenic amine and glutaminergic antidepressants; this group represents about 15% of patients with MDD.

To get a clearer understanding of this philosophy, Preskorn turned to the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) study, which was funded by the National Institutes of Mental Health to determine the effectiveness of different treatments for MDD in cases in that failed to respond to initial treatment with an antidepressant. In the study, the initial treatment was citalopram. If MDD was not responsive to treatment, patients were switched to bupropion SR, sertraline, or venlafaxine XR, or treatment was augmented with bupropion SR or buspirone.

 In cases that remained unresponsive, participants were switched to mirtazapine or nortriptyline, or had augmentation with lithium of triiodothyronine. Finally, if treatment still failed, participants were switched to tranylcypromine or mirtazapine combined with venlafaxine SR.

What was noteworthy, Preskorn explained, was that acute outcomes worsened with increasing number of prior treatment failures. In the group with no or limited prior medications, 27.5% achieved remission, as measured by HAM-D 17. Those in the group with 1 prior failure saw remission rates drop to 21.1%. And those with 2 and 3 prior failures saw remission rates drop to 16.2% and 6.9%, respectively.

“If you're like me, you see these patients every day in the clinic, because we usually get patients after they have already been tried on an antidepressant in primary care.” 

“If you're like me, you see these patients every day in the clinic, because we usually get patients after they have already been tried on an antidepressant in primary care,” Preskorn said. “So we always are getting someone who has probably not benefited from treatment. And, not only did they not benefit, they also were much more likely to relapse.”

In looking at current treatment strategies, Preskorn said we know the vast majority of people initially receive a selective serotonin reuptake inhibitor. Next, most likely is either a serotonin-norepinephrine reuptake inhibitor or a norepinephrine dopamine reuptake inhibitor. If that does not work, he explained there is the likelihood of augmentation with atypical antipsychotics or other kinds of medications, or a new drug like esketamine. If you still are not seeing a proper response, you would move into monoamine oxidase inhibitors or various kinds of electrical treatments such as transcranial magnetic stimulation.

"There is no requirement that a new drug is superior to antidepressants, be it superior either in efficacy or tolerability… new, does not mean improved."

So, why is there so little benefit from switching among them the various antidepressants, Preskorn asked the audience. “First and foremost, you have to realize that the FDA only requires superiority over placebo for approval. There is no requirement that a new drug is superior to antidepressants, be it superior either in efficacy or tolerability… 

“The second thing is psychiatric drug development for antidepressants and antipsychotics has, for 60 years, mainly been reshuffling the relative receptor binding affinity of biogenic amine mechanisms of action,” he added. “So they all work on the same neurotransmitter system.”

To better help understand the situation, Preskorn gave the example of a patient with pneumonia. Out of the patients treated with penicillin 1, a certain percentage will get better. For those who do not, they receive penicillin 2, and a smaller percentage is likely to get better because you have the infectious agent causing the pneumonia does not respond to penicillin.

Although shuffling identical mechanisms has not necessarily improved efficacy, Preskorn noted it has improved safety and tolerability. “That's the reason why SSRIs, SNRIs, and other newer antidepressants have replaced tricyclic antidepressants—not because they are more efficacious, but because they are safer and better tolerated,” he explained. Preskorn added it is also why there is a meaningful subset of patients with seemingly treatment resistant depression, because they are not responding to biogenic amine antidepressants.

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. 

Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.

2. Trivedi MH, Rush AJ, Wisniewski SR, et al. 

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice.

3. Fava M, Rush AJ, Wisniewski SR, et al.

 A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report.

4. McGrath PJ, Stewart JW, Fava M, et al. 

Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report.

Sheldon Preskorn, MD, shares insights into drug mechanisms and delivery to better help patients with major depressive disorder. 

Understanding Major Depressive Disorder and Treatment Resistance

 was honored and delighted to present Sheldon H. Preskorn, MD, as Educator of the Year at this year’s 

. An academic psychiatrist, a researcher, an educator, and a mentor—Preskorn is, as John J. Miller, MD, described “a pioneer in the field of psychopharmacology.”

Preskorn shared with attendees the unexpected beginning of his more than 40-years-and-running career in psychiatry. On his TV, he watched a video of Jose Delgado being able to stop a ball, “charging in his tracks.” To Preskorn, that meant that the brain was related to behavior—and he wanted to learn more.

Amongst his many honors and awards, Preskorn is known for spending the 1980s establishing the value of the therapeutic drug monitoring of tricyclic antidepressants and understanding toxicity. Additionally, in the 1990s, he helped explain the liver cytochrome P450 enzyme system.

“My personal goal has been, and remains, bringing science to the practice of psychiatry,” Preskorn shared.

During the session, he pointed out the overlap between diagnoses and science in signs and symptoms of borderline personality, bipolar disorder, major depression. He claimed it is not the symptoms that distinguish these disorders, but rather the 

“Psychiatry has been mainly stuck at the level of syndromic diagnoses, but we are making inroads and have over the last 50 years into pathophysiology and etiology,” he stated.

Additionally, Preskorn thinks of his therapeutic drug monitoring focus as toxicity-centric rather than efficacy-centric. The reason? “We've had a better signal to noise ratio in trying to understand toxicity of the drugs and the avoidance of that than we did with antidepressant efficacy. “As a matter of fact, in another article that I published, I showed that it's really almost impossible given the signal to noise problem in clinical trials of antidepressants to show any relationship between our blood levels and clinical benefit.”

Preskorn also shared an equation of his creation. According to him, 

 determine clinical response: sites of action (affinity, intrinsic activity); drug concentration and its site(s) of action (absorption, distribution, metabolism, elimination); and underlying biology of the patient (genetics, age, disease, environment).

“We are born different,” said Preskorn. “Age, how we vary over our lifespan, disease (which is acquired through pathophysiological processes), and then the environment here referring to the internal environment. That is what underlies drug-drug interactions, where a drug enters the environment of the body and interacts with another drug, either pharmacodynamically, which is the first variable, or pharmacokinetically, which is the second variable in this equation.”

Preskorn closed his speech, smiling, with a promise for the future: “It’s been a great pleasure for me to have shared these few minutes with you and to talk about the developments over the last 40 years. But as I would say: You ain’t seen nothing yet.”

1. Preskorn SH, Baker B. The overlap of DSM-IV syndromes: potential implications for the practice of polypsychopharmacology, psychiatric drug development and the human genome project. 

Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors

. Professional Communications, Inc; 1996.

Bringing science to the practice of psychiatry has been the personal goal of Sheldon H. Preskorn, MD—the Educator of the Year. 

Pioneering Psychopharmacology: Educator of the Year Award

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. 

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. 

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