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According to the results of a new study, individuals seeking treatment for depression with lower incomes, lower education levels, and those who identify as minorities tend to have worse outcomes even when receiving equal access to treatment.

 Jeffrey Mills, PhD, and Jeffrey Strawn, MD, led the University of Cincinnati cross-college collaborative research.

Investigators analyzed data from a large clinical trial, the Combining Medications to Enhance Depression Outcomes study, that enrolled 665 participants seeking treatment for depression. All participants had the same access to treatment without differences due to health insurance or income. The study also controlled for sex, age, and treatment type. Following 12 weeks of antidepressant medication treatment, participants who were nonwhite improved 11.3% less compared to white patients. Participants who were unemployed saw 6.6% less improvement compared to employed patients. Participants the 25th percentile of income distribution had 4.8% reduced improvement when compared to participants in the 75th percentile. Patients who were nonwhite, unemployed, without degree, and in the 25th income percentile had 26% less improvement compared to patients who were white, employed, with a college degree, and in the 75th income percentile.

“We think about these things in terms of access, we think about them in terms of income inequality, and I realize that education does track with those, but just having a college degree while controlling for all of these other factors still had a significant impact,” said Strawn, professor in the Department of Psychiatry and Behavioral Neuroscience in UC’s College of Medicine and a UC Health adolescent psychiatrist.

Strawn also noted that while the findings are still preliminary, results suggest that participants without a college degree had 9.6% less improvement compared to college graduates. Furthermore, previous research indicates that individuals seeking treatment for depression with lower income and less education have worse outcomes because of a lack of access to quality health care, but socioeconomic factors are hard to isolate.

Mills, professor of economics in UC’s Carl H. Lindner College of Business, said that the findings do not negate the fact that a lack of access makes an impact on treatment outcomes, but it does show the importance of including a patients’ home environment when analyzing the effectiveness of treatment.

“If you’re going home to a wealthy neighborhood with highly educated parents or spouse, then you’re arguably in a much better environment for the treatment to be effective than if you’re going to a poor neighborhood with other problems,” said Mills.

Strawn believes future studies should consider socioeconomic variables that may have been previously overlooked.

“When we don’t control for these variables, which we often do not in our clinical trials because of differences in populations, we may miss detecting an effective treatment because its effect is obscured,” Strawn said. “It can potentially jeopardize our treatment development by not accounting for these factors.”

Moving forward, the investigators want to combine data from other depression trials to produce more powerful results with a larger dataset.

Socioeconomic predictors of treatment outcomes among adults with major depressive disorder.

2. Socioeconomic factors affect response to depression treatment. News release. April 15, 2022. Accessed May 6, 2022. 

https://www.newswise.com/articles/socioeconomic-factors-affect-response-to-depression-treatment

Home environments have a clear impact on depression treatment outcomes. 

The Effect of Socioeconomic Factors on Depression Treatment

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

Consider novel, promising strategies for treatment-resistant depression in order to help guide discussions with patients about appropriate treatments.

1. Understand novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

2. Understand currently available and promising neurostimulation treatment options for treatment-resistant depression.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC, and Psychiatric Times™. Physicians’ Education Resource®, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST (COI) MITIGATION

The staff members of Physicians’ Education Resource®, LLC, and Psychiatric Times™ have no relevant financial relationships with commercial interests. Dr Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation; as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a coinventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. The peer reviewer has participated in Speaker’s Bureaus for Sunovion, Otsuka/Lundbeck, Allergan, Teva, Neurocrine, Janssen, and Intra-Cellular Therapies.

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Treatment-resistant depression (TRD), which is broadly defined as “the failure to achieve and sustain euthymia with adequate antidepressant treatment,”

 remains a commonly encountered clinical challenge. Treatment response in depression has been characterized by a response curve that demonstrates diminished improvement of symptoms over successive adequate courses of treatment (

 Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study confirm what we know from clinical practice—namely that the chances of adequate symptom resolution are very low (single digits) after 2 initial unsuccessful treatment trials. Approximately one-third of patients do not achieve remission after trials with 4 different conventional treatments. In this context, one definition of TRD is nonresponse to 2 or more antidepressant trials, reflecting this sharp drop-off in response after the second treatment.

A number of organizations (eg, the Canadian Network for Mood and Anxiety Treatments, the National Institute of Health and Care Excellence, and the American Psychiatric Association) have put forth clinical algorithms for the treatment of 

. Current standard treatment options across these guidelines include conventional antidepressant medications (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), other antidepressant drugs (eg, 

, mirtazapine, vilazodone, and vortioxetine), combining antidepressants (eg, bupropion [Wellbutrin, Forfivo] or mirtazapine [Remeron] added to an SSRI or SNRI, augmentation strategies that target associated symptoms such as sleep or anxiety (eg, second-generation antipsychotics, 

, lamotrigine [Lamictal], buspirone [Buspar], and thyroid hormone), and psychotherapy. Furthermore, new and developing advances in depression therapeutics now offer the prospect of significant improvement when administered in conjunction with, or as alternatives to, standard treatments. These promising therapies include rapid-acting novel antidepressant drugs as well as neurostimulation interventions.

, a glutamatergic modulator, has antidepressant properties has led to a mechanistically new treatment option for individuals with TRD.

 Furthermore, its rapid antidepressant effects manifest within hours compared with weeks for conventional antidepressants. Currently, intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as 

, available off-label) and intranasal esketamine (FDA approved with a required risk evaluation and mitigation strategy [REMS] monitoring protocol) are the only routes of administration that have sufficient evidence to support their use. The initial controlled trials of IV ketamine (a single infusion of 0.5 mg/kg over 40 minutes) for TRD found that ketamine exerted rapid (typically within hours) antidepressant effects that peaked at 24 hours, with about 70% of patients demonstrating response.

 Response typically lasted 3 to 7 days postinfusion. Ketamine appears to have broad therapeutic properties, demonstrating particular effectiveness for anxious depression, depression with anhedonic features, and suicidal ideation.

Preliminary evidence also suggests its usefulness in treating other disorders comorbid with major depressive disorder (MDD), including obsessive-compulsive disorder (OCD), posttraumatic stress disorder, social anxiety disorder, and 

 Notably, ketamine has also proven effective for difficult-to-treat atypical features.

 Adverse events associated with subanesthetic-dose ketamine (0.5 mg/kg) are typically transient (eg, somnolence/sedation, hypertension, nausea, dissociation), although risk of abuse and/or dependence have not been sufficiently studied. One key limitation is the short duration of antidepressant effects in response to a single administration, which has prompted use of repeat doses of IV ketamine. Such repeat infusions are typically administered twice per week, and treatments are tapered when maximal response has been reached, which appears to maintain remission.

Esketamine is the S-enantiomer of ketamine and demonstrates greater potency at the glutamate NMDA receptor than the R-enantiomer. In clinical trials, intranasal esketamine (twice weekly, 56 or 84 mg) added to conventional antidepressant therapy significantly improved symptoms compared with placebo.

 Intranasal esketamine (Spravato) received FDA approval for the treatment of adults with TRD in March 2019 and for the treatment of adults with MDD with acute suicidal ideation or behavior in August 2020. Given concerns about adverse events, the FDA approved 

 under a REMS, requiring administration and observation in a medically supervised setting. In terms of adverse effects, reports to the FDA through 2020 noted that esketamine was significantly associated with increased risk of dissociation, sedation, and “feeling drunk.”

 Unexpectedly, a small percentage (2.81%) of patients reported onset of suicidal ideation after starting esketamine treatment. Compared with data for venlafaxine, signals remained for suicidal and self-injurious ideation but not for suicide attempt or completed suicide. Despite the difficulty in attributing causality in the population of patients with TRD who receive esketamine, this safety signal warrants further investigation.

A recent systematic review and meta-analysis that conducted a head-to-head comparison of IV ketamine and esketamine found that IV ketamine may hold a slight edge in efficacy in treating both MDD and bipolar depression, despite intranasal esketamine’s FDA approval.

In terms of risks, a few studies have reported relatively minor adverse events associated with IV ketamine. However, given the lack of a REMS protocol with IV ketamine, and a REMS report following each dose of 

, it is likely that the adverse events of esketamine are extensively reported, whereas they are likely underreported for IV ketamine. There is a need for ongoing vigilant adverse events reporting for both treatments.

While consensus on where ketamine should reside in the depression treatment algorithm is still developing, a recent overview suggests that IV ketamine and intranasal esketamine have both demonstrated efficacy for this patient population.

 Both agents may be more efficacious than second-generation antipsychotic drugs, although their relative efficacy compared with electroconvulsive therapy (ECT) has not been established. In selecting next-step and/or adjunctive treatments, important issues to consider include patient preference, adverse event profile, and accessibility (ie, cost, insurance coverage, and availability).

On the investigational side, interest in the use of arketamine (the R-enantiomer of ketamine) for TRD has also grown. Animal models suggest that arketamine may have more potential antidepressant-like effects than esketamine, and human trials have just begun. The ketamine metabolite (2

)-hydroxynorketamine has also generated significant interest as a treatment for TRD that potentially lacks dissociative adverse events and abuse potential. It is currently being studied in phase 1 human trials.

Another newly developed treatment for depression has a novel mechanism of action. Brexanolone (Zulresso), a neurosteroid and injectable form of allopregnanolone (a GABA

 positive allosteric modulator), was developed as a treatment for 

. Levels of allopregnanolone, which gradually rise throughout pregnancy, fall precipitously post pregnancy. Slowed downregulation of GABA

 receptors is thought to contribute to postpartum depression. Significant improvement in depressive symptoms was noted within 24 hours of brexanolone infusion, which is administered as a 60-hour IV infusion during inpatient care; this antidepressant response lasted up to 30 days.

 Brexanolone received FDA approval for postpartum depression in March 2020. An orally administered allopregnanolone analogue, Zuranolone, is currently in phase 3 clinical trials for both MDD and postpartum depression.

The success of ketamine has revived interest in the use of psychedelic agents, particularly psilocybin, for the treatment of depression. Controlled trials of psilocybin offer some evidence of efficacy for MDD patients, although further studies are needed.

 Psychedelic-assisted psychotherapy—that is, the use of 

 as an adjunctive treatment to psychotherapy—is in the early stages of investigation. In addition to concerns about prompting illicit use, it should be noted that psilocybin may increase the risk of seizures when coadministered with lithium.

In addition to new pharmacological treatments for TRD, several viable neurostimulation options currently exist or are emerging. ECT remains the most established treatment for severe TRD, and the FDA reaffirmed ECT’s importance as a treatment option when it reclassified ECT devices in December 2018 as a Class II (moderate risk) device for the indication of major depressive episodes associated with MDD or bipolar depression.

 With response rates greater than 50% by the first week of treatment, ECT should be a serious consideration for patients who have not responded to conventional treatment.

 Patients with psychotic depression and catatonic depression, as well as elderly patients, may particularly benefit from ECT.

However, ECT use remains limited by 2 main issues: the short duration of its effects and the cooccurrence of cognitive adverse events. After a successful course of ECT, relapse rates are quite high without effective relapse prevention strategies. To decrease the chance of relapse after a course of ECT, patients are often given maintenance medication or ECT therapy. The Prolonging Remission in Depressed Elderly study demonstrated that relapse rates can be dramatically reduced by introducing a Symptom-Titrated Algorithm-Based ECT (STABLE) approach that combines pharmacotherapy with continued ECT on a schedule adjusted to individual patient response.

 The STABLE intervention reduced relapse rates more effectively than medications alone and achieved these benefits without substantially worsening cognitive function.

The most concerning cognitive adverse events of ECT involve short-term and long-term memory. While studies confirm that short-term memory effects usually resolve within weeks of a treatment course, long-term memory deficits may be prolonged. Mitigation strategies used to minimize risk of memory loss include right unilateral electrode placement, ultrabrief pulse width, square wave electrical stimulation, and increasing the length of time between treatments. In addition, new technologies such as magnetic seizure therapy (MST) are under investigation as an alternative method to initiate seizures (which are thought to be the essential aspect of the therapy).

 By shaping the magnetically induced electric field that initiates the seizure to minimize the effect on brain areas related to memory function, MST may ultimately be associated with significantly fewer cognitive adverse events. Published study results suggest that MST leads to fewer cognitive adverse events than ECT while preserving efficacy.

Repetitive Transcranial Magnetic Stimulation

Another neurostimulation modality for TRD is 

repetitive transcranial magnetic stimulation

 (rTMS), which was cleared by the FDA for TRD in 2008. It has an excellent safety profile, with the primary significant adverse event being the rare occurrence of seizures. It was initially unclear whether rTMS demonstrated the speed of response and high degree of effectiveness needed for patients with severe depression or TRD. However, recent work to optimize the dosage of rTMS (including neuronavigated individualized spatial targeting and accelerated delivery of multiple treatment sessions) have improved treatment outcomes. Intermittent theta-burst stimulation (iTBS)—a form of rTMS—was recently cleared by the FDA for use in TRD. iTBS, which cuts treatment session times from 50 minutes to 3 minutes, was cleared based on studies demonstrating comparable results with standard 10 Hz rTMS.

 In addition, further refinements to the treatment (ie, functional-connectivity-guided targeting) may lead to even greater rates of effectiveness.

 Another recently reported approach couples iTBS with individualized circuit-based neuronavigation and an accelerated treatment schedule called the SNT protocol. A randomized controlled trial of SNT found a 52.5% drop in depression scores with active SNT compared with an 11.1% drop with sham.

Vagus nerve stimulation (VNS), which initially received FDA approval for epilepsy, was later discovered to have antidepressant effects; it received FDA approval for TRD in 2005 as an adjunctive treatment for depression that has failed to respond to at least 4 adequately dosed antidepressant treatments. Although the pivotal randomized controlled trial failed to find definitive evidence of efficacy, a 1-year, nonrandomized comparison of open-label VNS versus treatment as usual found a significant advantage in the VNS group.

 A new randomized controlled trial is currently underway to provide more definitive evidence (NCT03887715).

A final consideration for severe and refractory TRD patients is deep brain stimulation (DBS). DBS is not FDA approved for depression but is on the US market to treat Parkinson disease, epilepsy, essential tremor, dystonia, and OCD. For TRD, DBS may be accessible in the context of research studies. DBS treatment consists of electrode placement and electrical stimulation of the ventral capsule/ventral striatum or subgenual cingulate cortex. In smaller investigations and case studies, DBS appeared to demonstrate immediate and striking improvements in 

. However, 2 phase 3 trials were terminated early after interim analyses of the results, and further large-scale trials have not yet been undertaken. Research on DBS has continued, but in a different direction (including identification of novel targets, predictors of response, and novel stimulation approaches). One promising strategy has been the development of closed-loop systems, pairing chronic deep-brain sensing to individualize stimulation programs for patients with TRD.

In summary, a number of viable new options offer the possibility of optimizing care for patients with TRD. The 

 summarizes the currently available, developing, and promising new treatments previously described. Given the field’s relative lack of clinical experience with these treatments, these treatments should be considered cautiously after a comprehensive assessment of benefits and risks. However, given the risks of inadequately treated depression, they deserve consideration. In addition, these mechanistically novel treatments may further our collective understanding of depression and serve to further transform depression therapeutics.

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002927).

is the medical director of the clinical research unit in the experimental therapeutics and pathophysiology branch at the National Institute of Mental Health.

is director of the NIMH’s Division of Translational Research and director of the Noninvasive Neuromodulation Unit in the NIMH Intramural Research Program; she is also JP Gibbons Professor Emeritus in the Duke University School of Medicine’s Department of Psychiatry and Behavioral Sciences.

is an NIH Distinguished Investigator as well as chief, Section on Neurobiology and Treatment of Mood and Anxiety Disorders, of NIMH’s Experimental Therapeutics and Pathophysiology Branch. He is also clinical professor of psychiatry and behavioral sciences at George Washington University.

Definition and epidemiology of treatment-resistant depression.

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

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

3. Berman RM, Cappiello A, Anand A, et al. 

Antidepressant effects of ketamine in depressed patients.

4. Zarate CA Jr, Singh JB, Carlson PJ, et al. 

A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

Novel glutamatergic modulators for the treatment of mood disorders: current status.

6. Zarate CA Jr, Park L. Ketamine and esketamine. In: Ruiz P, Sadock BJ, Sadock VA, eds. 

 Lippincott Williams & Wilkins; In press.

7. Rodriguez CI, Kegeles LS, Levinson A, et al. 

Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept.

8. Feder A, Parides MK, Murrough JW, et al. 

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

9. Taylor JH, Landeros-Weisenberger A, Coughlin C, et al. 

Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial.

10. Jones JL, Mateus CF, Malcolm RJ, et al. 

Efficacy of ketamine in the treatment of substance use disorders: a systematic review.

11. Papakostas GI, Salloum NC, Hock RS, et al. 

Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis.

12. Gastaldon C, Raschi E, Kane JM, et al. 

Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System.

Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis.

14. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. 

Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation.

15. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. 

Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.

16. Carhart-Harris R, Giribaldi B, Watts R, et al. 

Trial of psilocybin versus escitalopram for depression.

17. Nayak SM, Gukasyan N, Barrett FS, et al. 

Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports.

18. FDA in Brief: FDA takes action to ensure regulation of electroconvulsive therapy devices better protects patients, reflects current understanding of safety and effectiveness. FDA. News release. December 21, 2018. Accessed March 10, 2022. 

https://www.fda.gov/news-events/fda-brief/fda-brief-fda-takes-action-ensure-regulation-electroconvulsive-therapy-devices-better-protects

Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report.

20. Kellner CH, Husain MM, Knapp RG, et al; CORE/PRIDE Work Group. 

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21. Lisanby SH, McClintock SM, McCall WV, et al; Prolonging Remission in Depressed Elderly (PRIDE) Work Group. 

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neurocognitive effects of combined electroconvulsive therapy (ECT) and pharmacotherapy in major depressive disorder in older
adults: phase 2 of the PRIDE study.

22. Lisanby SH, Luber B, Schlaepfer TE, Sackeim HA. 

Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy. 

Comparative efficacy and cognitive function of magnetic seizure therapy vs. electroconvulsive therapy for major depressive disorder: a systematic review and meta-analysis.

24. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. 

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial.

25. Cole EJ, Phillips AL, Bentzley BS, et al. 

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26. George MS, Rush AJ, Marangell LB, et al. 

A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression.

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Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

28. Scangos KW, Khambhati AN, Daly PM, et al. 

Closed-loop neuromodulation in an individual with treatment-resistant depression.

In this CME, review novel, currently available, and promising pharmacological treatment options for treatment-resistant depression.

Promising Strategies for Treatment-Resistant Depression

Sage Therapeutics and Biogen initiated a rolling submission of a new drug application (NDA) to the US Food and Drug Administration (FDA) for zuranolone in the treatment of major depressive disorder (MDD). Zuranolone is a 2-week, once-daily oral drug for the treatment of MDD and postpartum depression (PPD). The companies submitted the nonclinical module to the FDA and plan to submit all remaining components for MDD in the latter half of 2022.

“Zuranolone has the potential to help address a significant unmet medical need in depression as an innovative option in a therapeutic area where little has changed in the past 30 years,” said Priya Singhal, MD, MPH, Head of Global Safety and Regulatory Sciences and Interim Head of R&D at Biogen. “We are committed to advancing the science and developing new approaches to treating mental health, a major public health challenge that was exacerbated by the COVID-19 pandemic.”

The submission package will include: data from the completed studies of zuranolone in the LANDSCAPE and NEST clinical development programs, data from the ongoing open-label SHORELINE Study in MDD, and data from completed clinical pharmacology studies.

“There are millions of people living with depression and the initiation of the rolling NDA submission brings us one step closer to our goal of offering zuranolone as a potential new treatment option,” said Barry Greene, Chief Executive Officer at Sage. “We believe the results from the LANDSCAPE and NEST programs, in which zuranolone demonstrated rapid and sustained effects and a well-tolerated safety profile in clinical trials, support zuranolone as a potential novel treatment option for MDD, if approved. We look forward to providing an update when the rolling submission for zuranolone in MDD is complete, which we expect to occur in the second half of this year.”

In 2017, zuranolone was granted fast track designation by the FDA in MDD, and breakthrough therapy designation in 2018. Sage and Biogen intend to submit an associated NDA filing for PPD in the first half of 2023.

1. Sage Therapeutics and Biogen initiate rolling submission of new drug application (NDA) to U.S. Food and Drug Administration for zuranolone for the potential treatment of major depressive disorder (MDD). Sage Therapeutics. May 2, 2022. 

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-and-biogen-initiate-rolling-submission-new

Zuranolone, a drug for the treatment of major depressive disorder and postpartum disorder, is on a rolling submission of a new drug application. 

Rolling NDA Submission of Zuranolone for Treatment of Major Depressive Disorder

, we worked with experts from multiple areas in psychiatry to bring you thoughtful articles about a wide variety of psychiatric issues, from managing depression in older adults and differences in trauma response to the effects of the COVID-19 pandemic on youth and the growing US mental health crisis. Here are some highlights.

Psychiatric Care in the US: Are We Facing a Crisis?

By the end of 2021, many American adults found themselves inthe worst mental state in years. According to the US Census Bureau’s Household Pulse Survey, 47% of adults reported symptoms of anxiety,

 and 1 in 5 adults disclosed suffering from a mental illness.

 Despite this, it is estimated that less than half of Americans with a mental disorder get adequate treatment.

“It has been just over a year now since the COVID-19 pandemic struck the United States full force. A year of hunkering down and Zooming in, teleworking and telepsychiatry, economic and social upheaval, and steady scientific progress. Looking back to last March, we knew this would be difficult. But we didn’t know how difficult. And we certainly didn’t know that the challenge of COVID-19 would last this long,” said Joshua A. Gordon, MD, PhD, director of the National Institute of Mental Health, in a 2021 director’s message.

Why Men and Women May Respond Differently to Psychological Trauma

Posttraumatic stress disorder (PTSD) is a mental health disorder that arises after experiencing a traumatic event in about 10% of exposed individuals. A hallmark symptom is the reexperiencing of the traumatic event in the form of nightmares or flashbacks or reliving the event upon certain triggers. 

These unwanted memories cannot be controlled, and the event may feel like it is happening again. Individuals with PTSD will try to avoid these memories by not talking about them or by staying away from situations where potential triggers might be present (eg, the store where the robbery took place or watching the news about current combat events or natural disasters).

Several cognitive and mood alterations—such as memory problems, negative thoughts or feelings, and high arousal levels—may manifest themselves in several ways. These include being easily startled and having angry outbursts, sleeping problems, or difficulty concentrating on everyday tasks. 

The Management of Depression Among Older Adults

Depression is not an uncommon condition among older adults, and it is often underdiagnosed in this population. Depression also results in greater rates of morbidity and mortality among older adults. 

The neurobiology of depression includes a complex interaction among various biological, psychological, and social factors. The identification of depression among older adults requires a thorough history, a focused physical examination, appropriate laboratory studies, and the use of neuropsychological testing when necessary.

Current available treatments for older adults with depression include psychotherapy, pharmacotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and collaborative care approaches.

 In addition, some evidence indicates that aerobic and supervised group exercise regimens may improve depressive symptoms among older adults.

 In this review, we assess the evidence for using psychotherapy, pharmacotherapy, ECT, TMS, and collaborative care approaches for the treatment of depression among older adults. 

Here’s How the COVID-19 Pandemic is Shaping the Next Generation

The full picture of teenagers’ experience of COVID-19 is just beginning to emerge. The school closures, canceled proms, and separation from friends seemed a small price to pay to save the lives of thousands—but in exchange, the adolescents who represent the younger side of Generation Z were robbed of the capstone of their formative years. It created an atmosphere of uncertainty and anxiety among some teens, about both the future and their place in it.

As if the pandemic was not enough, teens watched as police violence and racial tensions reached breaking points. They saw angry mobs take over cities and storm the Capitol. Then Mother Nature swept in with deadly wildfires and other natural disasters that underscored the threat of climate change. 

. And be sure to stay up-to-date by subscribing to the 

Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

The experts weighed in on a wide variety of psychiatric issues for the April 2022 issue of Psychiatric Times.

From the Pages of Psychiatric Times: April 2022

A study found that exercising and playing online games were the most common means of addressing mental health issues during the COVID-19 pandemic.

The international study, conducted by digital board game publisher Marmalade Game Studio, highlighted the mental health issues individuals have experienced during the pandemic and the steps these individuals have taken to address the issues. The study included adults from across France, Germany, Hong Kong, Singapore, and the United States. Nearly 6 out of 10 (57%) of all participating individuals reported experiencing mental health issues, with individuals in Singapore (65%) and Hong Kong (64%) the most affected, followed by France (57%), Germany (56%), and the United States (52%). The most commonly cited mental health issues were stress (38%), anxiety (30%), and depression (22%), with 4% of individuals reporting that they have had suicidal thoughts.

In order to address these issues, 38% of individuals reported exercising more, and 30% reported playing online games, with 29% visiting with friends and family more often, 27% seeking help from a doctor, 26% speaking to their loved ones, and 25% seeking help from mental health professionals. The study also found that 42% of gamers from the European Union said playing multiplayer games during lockdown made them happier, while 16% said that playing games online and connecting with others—particularly family—helped them during lockdown.

“The pandemic has had a huge effect on mental health globally, and millions have at points suffered from a range of conditions caused by worries about their own and others physical health as well as financial worries,” said Cristina Mereuta, Marmalade Game Studio co-CEO, in a press release. “Many people are clearly taking action, with increased exercise and online gaming appearing to be the most popular ways of relieving stress and anxiety. It is important, however, that people seek professional help where appropriate.”

Exercise and online gaming are helping beat mental health issues.

 News release. The Worldliness. April 6, 2022. Accessed April 21, 2022.

The most common issues during the COVID-19 pandemic included stress, anxiety.

Individuals Cite Exercise, Gaming as Top Ways to Address Mental Health Issues

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

 Despite the prevalence of disability, chronicity, morbidity, 

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

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

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

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

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

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

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

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

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

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

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

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