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 This brings up a good point when we look at the biopsychosocial model of how we approach our patients. With presentations where the patient was also involved in psychotherapy, was it the right kind of psychotherapy? I find that that also plays an important part in a patient’s overall wellness. Are they getting CBT [cognitive behavioral therapy] when they should be getting DBT [dialectical behavior therapy]? It’s important to look at the patient as a whole.

When we think about the prevalence of treatment-resistant depression, we go back to thinking about our landmark STAR*D clinical trial. The takeaway point from that clinical trial was that a third of our patients won’t respond to our treatment regimens. When we look at this patient, he definitely meets the qualification for treatment-resistant depression having answered your questions and mine. Was this a full work-up in terms of a good diagnostic psychiatric interview? Were the medical causes ruled out? Given that, by the time he would’ve tried and not responded to 2 antidepressants, for an adequate dose and duration, that is the consensus definition that we have right now for treatment-resistant depression.

Angelos Halaris, MD, PhD, APA, ACNP, CINP:

 Absolutely correct. I couldn’t agree with you more. Taking a thorough psychiatric history and developmental history for any age group, especially someone as young as this 26-year-old man, assessing childhood trauma, mistreatment, abuse, parenting, and family relations are all critical factors that predispose an individual to chronic relapsing nonremitting depression that must be addressed. The best way to address these issues is through psychotherapy. That also depends on what the individual’s psychiatric, family, and developmental history is like. Certainly, psychoanalytic and psychodynamic therapy shouldn’t be excluded. It takes longer and is a major investment, but in my experience, it works and pays off. DBT and CBT could be also considered, and should sometimes be considered in combination. Most definitely, supportive therapy should be done in conjunction with pharmacotherapy. I’m a very strong believer in combined pharmacotherapy with psychotherapy.

This transcript has been edited for clarity.

Drs Harding and Halaris provide an overview of treatment resistant depression, including prevalence and determining a diagnosis.

Case 1: An Overview of Treatment Resistant Depression

Psychiatric Times® Case-Based Psych Perspectives

 titled “Managing Patients With Treatment-Resistant Depression.” I’m Dr Lisa Harding, a board-certified psychiatrist and a clinical instructor of psychiatry at the Yale School of Medicine in New Haven, Connecticut. Joining me is the esteemed Dr Angelos Halaris, a board-certified psychiatrist and a professor of psychiatry at Loyola University Chicago’s Stritch School of Medicine in Maywood, Illinois. The goal of our discussion is to share insights in diagnosing treatment-resistant depression [TRD] and reasons for inadequate treatment response with antidepressant therapy, as well as to provide a brief overview of available treatment options and to offer recommendations on how treat patients with this disorder. Welcome, Dr Halaris.

 Thank you so much for inviting me. I’m honored by your invitation and glad to be here.

 It’s nice to see you again. We’ll start by reviewing a couple of case scenarios. The first case presentation, No. 1, is a patient newly diagnosed with treatment-resistant depression. A 26-year-old man with a history of major depressive disorder for over 7 years presents with complaints of trouble sleeping as well as feeling unhappy, worried, and fatigued. He gradually developed sleeping difficulty as well as low mood and loss of interest. He tried multiple treatments, including escitalopram, fluoxetine, venlafaxine, and bupropion. However, his symptoms weren’t fully relieved. He was subsequently diagnosed with treatment-resistant depression. The patient reports having an average childhood, being an average student, and having good relationships with coworkers and no problems at work. He was always involved in psychotherapy, and denied any drug or alcohol use.

My overall impression of this case is this is a young patient who’s supposed to be living the life actuation part of his life, and he has now tried and failed more than 2 antidepressants. One of the things coming to mind was, is he stopping these antidepressants because of adverse effects, as I see in my clinical practice? What was the adequate dose of the adequate trial in terms of these medications that he was prescribed? Dr Halaris, what are your overall impressions of the case?

 Much like what you just said, Lisa, as presented, this brief case scenario leaves many more unanswered questions, some of which you already touched upon. I’d like to reinforce your own questions and add a few of mine as well. First and foremost, what kind of work-up was done prior to diagnosing the patient and then treating him with the list of mainly SSRIs [selective serotonin reuptake inhibitors] and SNRIs [serotonin and norepinephrine reuptake inhibitors]? By that, I mean where other factors that are known to contribute to depression, and especially TRD, had they been carefully assessed by means of a thorough psychiatric diagnostic evaluation and the pretty much established blood work that we know is essential, such as ruling out endocrinopathies, assessing HPA [hypothalamic-pituitary-adrenal] function, looking at diabetes, inflammatory conditions, any chronic medical illnesses that invariably lead to chronic inflammation, including neuroinflammation. Because if there’s an inflammatory focus elsewhere in the body, these pro-inflammatory substances known as cytokines invariably make their way into the brain parenchyma and stimulate microglia and astrocytes to also become inflamed. So we have a relocation of the peripheral inflammation into the brain leading to neuroinflammation. These are all factors that I’d like to see addressed.

Other issues are obviously vitamin deficiencies, notably vitamin D, especially during the winter months. But this also happens in summer months in susceptible individuals. I’m amazed at the frequency of vitamin D deficiency, including in young people. Unless we make a point to check these issues routinely at the initial evaluation, some of the symptoms of vitamin D deficiency resemble symptoms of depressive disorder with anxiety, low energy, low motivation, sense of desperation, attention-focusing issues and so on. The good news is that it’s fixable by administering the right supplementation of vitamin D.

Lisa Harding, MD, and Angelos Halaris, MD, PhD, APA, ACNP, CINP, review a case of a 26-year-old male patient who was recently diagnosed with treatment resistant depression

Case 1: Newly Diagnosed Treatment Resistant Depression

More good news regarding treatment choices in major depressive disorder (MDD) and postpartum depression (PPD), as the 2 companies working on zuranolone announced that they will submit a New Drug Application (NDA) to the US Food and Drug Administration (FDA).

Following discussions with the FDA, including a pre-NDA meeting this fall, Biogen Inc. and Sage Therapeutics Inc. decided to initially seek FDA approval of zuranolone in the treatment of MDD in late 2022, with plans to file for PPD in the first half of 2023. The initial submission package for MDD will include data from ongoing pharmacology and clinical studies, plus data from the LANDSCAPE and NEST clinical trial program studies, both of which include several studies examining the effectiveness of zuranolone in several thousand patients in various dosing, treatment paradigms, and clinical endpoints. Data from PPD 301-SKYLARK, a NEST program ongoing placebo-controlled study of zuranolone in patients with PPD, will be added to the separate filing for PPD. 

“We are pleased to share what we believe is an efficient filing pathway for zuranolone, with the goal of bringing a new treatment option to the millions of people who suffer from depression worldwide,” said Alfred Sandrock Jr, MD, PhD, Head of Research and Development at Biogen, in a press release.

Zuranolone is a once-daily, 2-week, investigational oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM) in development for the treatment of MDD and PPD that is designed to potentially serve as a rapid-acting sustainable treatment option. The drug received the Breakthrough Therapy Designation from the FDA in February 2018.

Recently, Sage shared results from their SHORELINE study, which found the agent to be safe and effective in the sample of patients with MDD.

 In that trial, investigators found that almost half of all participants who positively responded to the initial 14-day course of zuranolone 30 mg did not require additional treatment to maintain wellness through a year of follow-up.

“In the clinical development programs, zuranolone has shown remarkably consistent, rapid, and sustained reductions in depressive symptoms, including anxiety and sleep loss, in addition to a well-tolerated safety profile,” said Barry Greene, Chief Executive Officer at Sage Therapeutics, in a press release. “We believe we have a solid filing package with four adequate and well controlled trials now in hand and, if approved, zuranolone will fill a real unmet need and be welcomed by people living with depression.” 

1. Sage Therapeutics and Biogen announce plans to submit a New Drug Application (NDA) for zuranolone to the U.S. Food and Drug Administration in the second half of 2022 with rolling submission expected to start in early 2022. News Release. Sage Therapeutics. October 19, 2021. Accessed October 19, 2021. 

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-plans-submit-new-drug 

2. Sage Therapeutics receives FDA Breakthrough Therapy Designation for SAGE-217 for the treatment of major depressive disorder. News Release. Sage Therapeutics. February 7, 2018. Accessed October 19, 2021. 

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-receives-fda-breakthrough-therapy-designation

3. Kuntz L. Anticipated phase 3 interim results for Sage’s depression treatment, zuranolone. Psychiatric Times. October 14, 2021. Accessed October 19, 2021. 

https://www.psychiatrictimes.com/view/anticipated-phase-3-interim-results-for-sage-s-depression-treatment-zuranalone

New Drug Application to be submitted for MDD in late 2022, with separate filing for PPD planned for early 2023. 

New Agent for MDD, PPD Takes a Step Closer to Approval 

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

“I think the DSM gives you one sense of depression,” Sidney Zisook, MD, told attendees of the 2021 Annual 

 World CME Conference. “But I think it's very, very one dimensional. A better way of really understanding what it is to be depressed and the diagnosis is getting firsthand accounts from those who have dealt with depression.”

Zisook, director of the University of California, San Diego (UCSD) Residency Training Program, Distinguished Professor of Psychiatry at UCSD, and last year’s Educator of the Year awardee, shared insights from several famous folks about their experiences with depression. Of depression, David Foster Wallace said:

It is a level of psychic pain wholly incompatible with human life as we know it. It is a sense of radical and thoroughgoing evil not just as a feature but as the essence of conscious existence. It is a sense of poisoning that pervades the self at the self’s most elementary levels. It is a nausea of the cells and soul.

This quote, and others like it, show a sense of hopelessness, even suicidality, more than other aspects of depression, including those recognized by the DSM 5, he noted.

To better understand the current state of diagnosis, Zisook took attendees back in time to discuss the various iterations of depression in the DSM, from being classified as psychoneurotic disorder in DSM I in 1952 through the psychoanalytic approaches through the specifiers in DSM IV. Changes continued into DSM 5, where we now have a variety of disorders: major depressive disorder, disruptive mood dysregulation disorder, persistent depressive disorders, substance- and medication-induced depressive disorder, premenstrual dysphoric disorder, depressive disorder due to another medical condition, and other specified (or unspecified) depressive disorder.

To help illustrate the problems associated with the current system, Zisook shared 2 case examples. Ms A is a 30 year old married woman complaining of stress. Upon further exploration, you learn she has been tearful and increasingly sad since her mother received a diagnosis of cancer. She has little motivation, is overeating and gaining weight, and sleeps about 12 hours a day. She has never felt like this before.

On the other hand, Mr B is a 60 year old man who is brought to you by the police after found wandering on the Coronado Bridge. He is unshaven, slovenly, and demonstrates psychomotor retardation. He shows no interest in answering questions, but an informant tells you he has not been eating or drinking for weeks. He has expressed feeling miserable and worthless. He had a similar episode 30 years prior; he achieved full recovery after responding to electroconvulsive therapy.

“What do they have in common?” Zisook asked rhetorically. “Definitely nothing except the diagnosis of major depressive disorder—without any overlap in functioning.”

In reviewing DSM 5 criteria, he posed a few questions for the authors of DSM 6 to consider. For instance, why must symptoms last 2 weeks? “This never made much sense to me,” he said. “Somebody is undergoing a horrible situation—they lost their job, they've lost their family, they've lost their money—they've never been depressed before, and the depression is relatively mild, moderate. You don't want to label them with a major depressive disorder in 2 weeks. Give me more time to see what happens. Let them take care of some of the situations.”

“On the other hand,” Zisook added, “if they had a history of severe major depressive disorder, and for the last 2 days they're despondent, hopeless, feeling worthless, feeling suicidal, you have got to wait another 12 days to make the diagnosis.”

To better understand the diagnosis, again Zisook looked to patients. He discussed studies conducted by Mark Zimmerman, MD, and colleagues looking at what was needed for patients with depression to consider themselves in remission.

 The top 3 features were: positive mental health, such as optimism and self-confidence; a return to one’s usual, normal self; and a return to a usual level of functioning. Interestingly, one-quarter of respondents who were mildly symptomatic and, per HAM-D scores, not in remission considered themselves remitters. As such, they reported better quality of life, less functional impairment due to depression, higher positive mental health scores, and better coping ability.

I diagnose depression not by counting the number of symptoms for a certain number of weeks. But is the low mood persistent, is it there most of the time, has it been there for a while? It is pervasive—affecting the way you work, the way you interact with other people, the way you function, the way you parent, etc. For me that's better than the screening questionnaire or the DSM 5 criteria.

So, how does Zisook define and diagnosis depression? “There are screening instruments, which is fine for looking at depression,” he told attendees. “But I think there's nothing to substitute for clinical inquiry. And I diagnose depression not by counting the number of symptoms for a certain number of weeks. But is the low mood persistent, is it there most of the time, has it been there for a while? It is pervasive—affecting the way you work, the way you interact with other people, the way you function, the way you parent, etc. For me that's better than the screening questionnaire or the DSM 5 criteria.”

He also reminded attendees that differential diagnosis is very important, adding “Always look for bipolar disorder or general medical conditions.” Bereavement and burnout also need special attention, he explained, since those are often misdiagnosed and/or confused with depression. A careful examination of the criteria and symptoms will help to distinguish the disorders.

Zisook concluded by saying, “I think our diagnostic concepts are a work in progress in terms of helping us communicate with each other, helping us take into account what patients are saying about what it feels like to be depressed, and helping us to prescribe very personalized medications.”

1. Zimmerman M, McGlinchey JB, Posternak MA, et al. 

How should remission from depression be defined? The depressed patient's perspective

2. Zimmerman M, Martinez J, Attiullah N, et al. 

Why do some depressed outpatients who are not in remission according to the hamilton depression rating scale nonetheless consider themselves to be in remission?

Sidney Zisook, MD, shares insights into defining depression diagnosis.

Defining and Diagnosing Depression: Clinical and Patient-Oriented Perspectives

 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

Psychiatrists are not strangers to difficult and even potentially dangerous patients, but James L. Knoll IV, MD, has made these populations one of his specialties. With decades of experience in forensic psychiatry, Knoll takes listeners deep into the US criminal justice system, where he treats both inmates suffering from detention-related psychiatric disorders and an especially challenging group that he has dubbed 

How prisons’ strict social hierarchies can contribute to psychiatric illnesses.

The high prevalence of bipolar disorder and schizophrenia in corrections—and their potential causes.

The different challenges of treating patients in prisons vs jails.

Why inmates with psychiatric illnesses end up in the correctional system for longer than those without psychiatric illnesses.

The role of mental health courts in improving psychiatric care in the correctional system.

The challenges of treating patients who are high in psychopathy or have anti-social personality disorders.

, in which Knoll talks about how he first became interested in forensic psychiatry (at age 10). 

is professor of psychiatry and director of forensic psychiatry at SUNY Upstate Medical University in Syracuse, New York, and clinical director of Central New York Psychiatric Center in Marcy, New York. He is Emeritus Editor-in-Chief of the 

 and President-elect of the American Academy of Psychiatry and the Law (2022-23).

James L. Knoll IV, MD, shares insights from his decades in forensic psychiatry, where he has treated some of the criminal justice system’s most difficult and dangerous patients. 

Treating ‘Morally Objectionable’ Patients

Intra-Cellular Therapies announced the results of their phase 3 clinical trial for Caplyta (lumateperone) as a monotherapy for patients with bipolar I or bipolar II disorder experiencing a major depressive episode, published in 

These results demonstrate treatment with lumateperone resulted in a substantial reduction in depressive symptoms, and support the favorable safety and tolerability profile. Although lumateperone is currently indicated for the treatment of schizophrenia in adults, it has not been approved for other uses; these results show promise for treating bipolar depression.

“Bipolar depression represents the most prevalent and debilitating presentation of bipolar disorder. There is a critical need for more treatments that are effective and have favorable safety profiles,” said Gary S. Sachs, MD, Associate Clinical Professor in Psychiatry at Harvard Medical School and Founding Director of the Bipolar Clinic and Research Program at Massachusetts General. “The strong efficacy and impressive safety results reported in this trial for a broad patient population position lumateperone as a potentially important advancement in the treatment of this disorder.”

The global study, Study 404, randomized 381 patients with moderate to severe depression symptoms to receive either placebo or lumateperone 42 mg for 6 weeks. The primary endpoint, measured by mean change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score, was the efficacy of 42 mg/day of lumateperone when compared with placebo.

Treatment with lumateperone resulted in a substantial reduction in depressive symptoms. Lumateperone 42 mg was associated with a statically significant greater reduction in MADRS score from baseline to day 43 than placebo, even as early as week 1 at the first measurement. Both patients with bipolar I and bipolar II disorder saw significant improvement in MADRS Total Score in the lumateperone group compared with placebo group.

“We are excited about the robust results seen across our bipolar depression program. The study reported on today, Study 404, our monotherapy study, along with Study 402, our adjunctive study with lithium or valproate form the basis of our supplemental NDAs under FDA review. If approved, we plan to launch immediately and look forward to bringing Caplyta to market for the treatment of bipolar depression,” said Sharon Mates, PhD, Chairman and CEO of Intra-Cellular Therapies.

Results support the favorable safety and tolerability profile of lumateperone. The most common adverse events occurring for lumateperone 42 mg were somnolence and nausea.

The results of studies 404 and 402 form the basis of lumateperone supplemental new drug applications for the treatment of bipolar depression currently under review with FDA.

1. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. 

2. Intra-Cellular Therapies. Intra-Cellular Therapies announces publication of lumateperone pivotal phase 3 study in bipolar depression in The American Journal of Psychiatry. News release. September 27, 2021. 

https://ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-publication-lumateperone

Caplyta shows promise as a monotherapy for patients with bipolar I or bipolar II disorder experiencing a major depressive episode

Favorable Results for Bipolar Depression Treatment

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? 

Depression