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The rolling submission of a new drug application (NDA) for zuranolone to the US Food and Drug Administration (FDA) has been completed.

Zuranolone is an investigational drug by Sage Therapeutics and Biogen that is being evaluated as a potential rapid-acting, once-daily, 14-day, oral short course treatment for major depressive disorder (MDD) and postpartum depression (PPD) in adults. According to data from its LANDSCAPE and NEST development programs, zuranolone has demonstrated rapid and sustained improvement of depressive symptoms, a consistent safety profile, and generally good tolerability.

This week’s submission completes the NDA that was 

 by Sage Therapeutics and Biogen in May 2022.

 Zuranolone has already received FDA Fast Track and Breakthrough Therapy Designations for MDD in 2017 and 2018, respectively, as well as Fast Track Designation for PPD in 2022.

“Based on the data in the LANDSCAPE and NEST programs, we believe that zuranolone has the potential to be a meaningful new therapy for depression,” said Priya Singhal, MD, MPH, head of global safety and regulatory sciences and interim head of R&D at Biogen, in a press release. “We look forward to working with the FDA as this filing progresses.”

1. Sage Therapeutics and Biogen complete rolling submission of new drug application for zuranolone in the treatment of major depressive disorder and postpartum depression. Press release. Business Wire. December 6, 2022. Accessed December 7, 2022. 

https://www.businesswire.com/news/home/20221205005815/en/Sage-Therapeutics-and-Biogen-Complete-Rolling-Submission-of-New-Drug-Application-for-Zuranolone-in-the-Treatment-of-Major-Depressive-Disorder-and-Postpartum-Depression

2. Kuntz L. Rolling NDA submission of zuranolone for treatment of major depressive disorder. 

. May 2, 2022. Accessed December 7, 2022. 

https://www.psychiatrictimes.com/view/rolling-nda-submission-of-zuranolone-for-treatment-of-major-depressive-disorder

This latest submission completes the FDA filing that was initiated in May.

  Rolling NDA Submission of Zuranolone for MDD, PPD is Completed

“Mr King” is a 50-year-old African-American male with a history of severe, recurrent major depressive disorder (MDD) without psychotic features. He has had partial or non-response, or tolerability issues with multiple classes of medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and second-generation antipsychotics. He presents to the outpatient clinic to discuss a trial of ketamine. He asks whether there are any differences in efficacy between intravenous and intranasal routes of administration. As his psychiatrist, how would you respond?

There is evidence for efficacy of the N-methyl-D-aspartate receptor antagonist ketamine in the treatment of depression. Ketamine produces rapid antidepressant effects, within minutes to hours, that are most pronounced 24 to 48 hours after administration.

 Ketamine has 2 primary routes of administration: intravenous (IV) and intranasal (IN). The bioavailability for IV ketamine is 100% and 45% to 50% for IN.

In 2019, IN esketamine was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for MDD as well as acute suicidality. By contrast, IV ketamine is considered an off-label treatment for MDD.

A recent meta-analysis found that IV ketamine was superior to IN esketamine with regards to efficacy and dropout rates.

 However, a US study found evidence for superior cost-effectiveness of IN esketamine compared to IV ketamine from the patient perspective.

 Whether there are significant differences in the adverse effect profiles between IN esketamine and IV ketamine remains unclear. No previous studies have statistically compared the antidepressant effectiveness of IN and IV ketamine.

 performed a meta-analysis of randomized controlled trials in adults with MDD regarding the efficacy of a single dose of IN and IV ketamine to induce antidepressant response 24 hours after administration. They included randomized double-blind controlled trials of IV ketamine 0.5 ± 0.05 mg/kg body weight or IN esketamine 50 to 84 mg in patients aged 18-65 years with MDD. 

Studies were published in international peer-reviewed journals, included data on response rates, and assessed depression with either the Montgomery-Asberg Depression Rating Scale or the Hamilton Depression Rating Scale (HDRS). They excluded investigations of ketamine for disorders other than MDD, studies with non-saline placebos, studies without a control group, and case studies.

The authors searched PubMed, EBSCO, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Antidepressant response was defined as a 50% reduction in depression severity. Response rates for ketamine versus placebo were calculated as odds ratios (ORs). Individual studies were assessed for risk of bias. Data were analyzed using random effects meta-analysis. 

Potential publication bias was tested using rank correlation and regression tests for funnel plot asymmetry. Differences in efficacy between IV and IN ketamine were assessed by a z-test of the mean log ORs derived from the meta-analysis.

The authors screened 77 full-text articles for eligibility, and 11 studies met the study inclusion/exclusion criteria. The risk of bias was assessed as low for 7 and high for 1 of these studies. The 4 IN trials included 586 patients who received esketamine and 479 who received placebo. The 7 IV trials included 145 patients who received ketamine and 130 who received placebo. 

In the IV trials, the response rate at 24 hours was 42% for ketamine and 4.6% for placebo (OR=9.4, 95% CI 3.9-22.8), with no evidence of funnel plot asymmetry. In the IN trials, the response rate at 24 hours was 25% for esketamine and 16.5% for placebo (OR=3.3, 95% CI 1.2-9.0). Analysis of funnel plot asymmetry was limited due to the small number of studies. Despite the magnitude of the difference in the ORs for response to IV versus IN ketamine, this difference was not statistically significant (p=0.13).

The authors concluded that the odds of antidepressant response at 24 hours was 6 times greater for a single dose of ketamine versus placebo. There was not a statistically significant difference in the ORs for response to IV (9.4) and IN (3.3) ketamine. 

A strength of the meta-analysis was the stringent inclusion/exclusion criteria. A major limitation of the meta-analysis was the lack of statistical power to detect a difference between the routes of administration due to the small number of studies. Furthermore, the authors investigated the effect of a single dose of ketamine, so the present study does not inform on potential differential efficacy of multiple doses of ketamine.

A single dose of IN or IV ketamine is associated with a 6-fold increased odds of antidepressant response at 24 hours compared to placebo. Due to the small number of studies, data are inadequate to make definitive conclusions about the relative efficacy of IN versus IV routes of administration.

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

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

Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies

2. Zanos P, Moaddel R, Morris PJ, et al. 

Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms

 [published correction appears in Pharmacol Rev. 2018 Oct;70(4):879]. 

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

 [published correction appears in J Affect Disord. 2020 Nov 20;:]. 

Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimates

5. Meiering MS, Weigner D, Gärtner M, et al. 

Does route of administration affect antidepressant efficacy of ketamine? a meta-analysis of double-blind randomized controlled trials comparing intravenous and intranasal administration

 [published online ahead of print, 2022 Nov 9]. 

Does route of administration affect antidepressant efficacy of ketamine? Researchers performed a meta-analysis of trials comparing intravenous and intranasal administration.

Meta-Analysis of Intravenous vs Intranasal Ketamine

Regular reports are published in the lay media regarding the alleged lack of efficacy of antidepressants. This time, it was 

 highlighting, amongst other reports, a new analysis by Stone et al,

 in which it was found that antidepressants work better than placebo only 15% of the time.

As usual in this type of reporting, “critical” voices are heard mostly unopposed, and little room is made for actual evidence-based interpretation of the data presented. In this article, I will review some of the claims made, provide evidence that the statistic 15% is most likely an underestimation of real-world antidepressant effects, and cast doubt on some other claims made about the (lack of) efficacy of 

In their analysis, Stone et al included all antidepressants and possible age groups. Thus, their estimate represents the average effects across all antidepressant trials submitted to the US Food and Drug Administration (FDA), but not necessarily one of the average antidepressants used. The 5 worst drugs, according to their analysis, are very rarely used for 

. Thus, the much more commonly used SSRIs outscore the least efficacious antidepressant, dothiepine, by a considerable margin. Further, antidepressants are probably less effective in treating depression in children and adolescents than in adults.

 However, they are also much less prescribed in the younger population, but the researchers did not account for that.

The main outcome measure in the Stone et al analysis is the sum score of the 17 items of the Hamilton Depression Rating Scale (HDRS-17-sum). The use of this measure has been widely criticized for many reasons: it lacks one-dimensionality,

 it might reflect factors other than depressive symptoms,

 and the majority of the measured symptoms are not present in many individuals with depression.

 Drug-placebo differences were found to be substantially larger when the sum score of 6 core depressive symptoms included in the unidimensional HDRS-6 scale were used.

 It was also found that drug-placebo differences for this subscale are similar in those with severe and nonsevere depression,

 article made a contrary claim against antidepressants.

HDRS items not included in the HDRS-6 are prone to pick up 

 from treatment, thus further diminishing apparent drug-placebo differences as measured using HDRS-17 sum score.

 Although adverse effects are certainly important to consider, including them in an efficacy measure is unreliable; for example, this measure is unable to distinguish between a treatment with low efficacy but no adverse effects and a highly effective treatment with more adverse effects.

Dosing is also an important issue. Drug-placebo differences are about twice as large at doses above the common starting one for the most frequently prescribed SSRIs compared.

 Yet, in the Stone et al analysis, all possible doses were included, including those shown to not be significantly more effective than placebo. In a recent publication,

 for example, a 22.3% drug-placebo difference was found for optimal SSRI doses in adults when using response (50% score reduction from baseline) on the HDRS-6 sum score as outcome measure; however, this number is more likely an underestimation than an overestimation.

Other issues in clinical trials include difficulties in finding drug-placebo separation, noncompliance to randomized drugs,

 Further difficulties are presented by the diagnosis itself, 

 being a multi-faceted, highly heterogenous disorder with low diagnostic reliability.

 Thus, it is unreasonable to expect substantial response and remission rates for any treatment for depression. Additionally, using strictly regulated trial protocols disallowing many concurrent treatments also impacts response and remission rates.

Although only company-sponsored trials were analyzed in most papers cited here, as well as in the Stone et al paper, unsponsored trials were found to show about 50% higher drug-placebo differences.

 It is possible that the studied populations in the latter more accurately reflect patients receiving treatment in clinical practice. This is another issue not reflected in most critical opinions about antidepressants, where it is instead stressed that trials are funded by pharmaceutical companies, with the results thus being inflated and untrustworthy.

, which is heralded as safer and more effective than antidepressants. Since safety data are very rarely collected in psychotherapy trials, comparisons in this regard are thus impossible. Also, neither the assumption of better efficacy holds true. In those few trials in which psychotherapy is compared to pill placebo, there is a difference of about 0.25 standardized mean differences (SMD),

 effects similar to the average antidepressant. However, every one of those trials was unblinded, as the patient was certainly able to distinguish psychotherapy from pills. This fact is entirely overlooked by Irving Kirsch, PhD, associate director of the Program in Placebo Studies and lecturer in medicine at the Harvard Medical School and Beth Israel Deaconess Medical Center, and others when interviewed by 

. (This is ironic, considering that he used the possibility of unblinding in antidepressant trials, which evidence shows is a nonissue,

 as an argument to dismiss the similar differences between antidepressants and placebo.

Understandably, the first author of the Stone et al paper—Marc B. Stone, MD, of the Center for Drug Evaluation and Research, US Food and Drug Administration—declined to comment in the 

 article, perhaps because media discussion lies beyond the obligations of FDA employees. My personal primary take-away point from this analysis is not the 15% number itself, but the finding of a subgroup of patients with 

 responding uniquely to antidepressants but not to placebo. Previously, other authors including Kirsch attempted to dismiss the average drug-placebo difference as being smaller than a “minimum clinically important difference,” assuming that the average difference is what is being experienced by all patients who are treated with antidepressants. It was, however, pointed out that their suggested “minimal difference” instead corresponds to the maximum achievable effect in this type of trial, and that the average difference does not reflect a general effect, but a higher likelihood of lower depression scores in the drug-treatment group.

In all, it might be that only 15% of those with depression experience significantly positive effects from antidepressant treatment compared to placebo, if the material studied was indeed representative of the average treatment, setting, and patient group. In real-world practice, the actual number might instead substantially differ depending on the drug used, the drug dose, the patient group treated, and the efficacy measure used. Effect estimates in clinical trials are more likely to underestimate than overestimate treatment effects.

The 15% number is then contrasted with 56%—the percentage of patients who apparently experience withdrawal effects. The author leaves us with a take-away that more people have withdrawal effects than antidepressant effects. Unfortunately, the 56% estimate was taken from a flawed

 that were uncontrolled and thus disregarded potential nocebo effects. Tapering was often abrupt—which is against guidelines—and again no difference was made between different drugs, even though drugs with short half-life (eg, paroxetine, venlafaxine) were driving the results. Ignoring these issues and contrasting estimates from uncontrolled surveys to drug-placebo differences from randomized controlled trials is nothing short of a woeful misuse of statistics. A more honest view could have been obtained by contrasting the withdrawal estimate to an efficacy estimate from the largest survey study, which showed that 83% of those taking antidepressants believed the drugs had reduced their depression.

Unfortunately, even more factual inaccuracies were presented in the 

 article. It was stated that antidepressants do not aid loss of energy, loss of interest, nor motivation, all being common symptoms in depression. In item-based analyses of SSRIs and the SNRI duloxetine, the opposite was revealed to be true, with small but replicable effects on all these symptoms.

 To the best of my knowledge, no better evidence exists on the contrary, thus rendering these statements by Joanna Moncrieff, MD, in the 

Another statement by the same author claims that the superiority of antidepressants can be attributed not to actual antidepressant effects, but to emotional numbing. A recent article in 

™ by Dawson and Pies rebutted this claim,

 and even more evidence was found in a recent analysis of SSRI trials using the Montgomery-Åsberg Depression Rating Scale (MADRS) as outcome measure.

 Here, an opposite effect to what was stated by the 

 interviewees was found, with a significant and positive drug effect against 

, as measured on the corresponding MADRS item. Thus, although emotional numbing may also be an adverse effect of SSRI treatment, the average effect instead corresponds to the individual with depression experiencing an improved ability to feel emotions.

 article is just another unfortunate example of one-sided media reporting, ignoring evidence contradicting claims of those critical to drug treatment, and casting unnecessary doubt on drugs that, while not perfect, are more than useful in alleviating symptoms of major depression, as well as many other disorders (eg, anxiety syndromes, obsessive compulsive disorder, and premenstrual dysphoric disorder). Unfortunately, I expect this tradition of antidepressant bashing will continue. Lay media seem disinterested in correcting their claims (neither the journalist in question nor 

 themselves responded when I shared my concerns) and instead will likely continue to seek sensationalist headlines and short-term profit.

The opinions expressed in the interviews are those of the participants and do not necessarily reflect the opinions of 

is in the Department of pharmacology at the Institute of Neuroscience and Physiology, Sahlgrenska Academy, at the University of Gothenburg, Sweden.

1. Piore A. Antidepressants work better than sugar pills only 15 percent of the time. 

 September 9, 2022. Accessed November 29, 2022. 

https://www.newsweek.com/2022/09/30/antidepressants-work-better-sugar-pills-only-15-percent-time-1744656.html

2. Stone MB, Yaseen ZS, Miller BJ, et al. 

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.

Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis.

4. Fried EI, van Borkulo CD, Epskamp S, et al. 

Measuring depression over time . . . Or not? Lack of unidimensionality and longitudinal measurement invariance in four common rating scales of depression.

Quantitative rating of depressive states.

6. Lisinski A, Hieronymus F, Nilsson S, Eriksson E. 

Impact of chosen cutoff on response rate differences between selective serotonin reuptake inhibitors and placebo.

7. Hieronymus F, Lisinski A, Nilsson S, Eriksson E. 

Influence of baseline severity on the effects of SSRIs in depression: an item-based, patient-level post-hoc analysis.

8. Hieronymus F, Lisinski A, Eriksson E, Ostergaard SD. 

Do side effects of antidepressants impact efficacy estimates based on the Hamilton Depression Rating Scale? A pooled patient-level analysis.

A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors.

10. Reis M, Aberg-Wistedt A, Agren H, et al. 

Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations.

11. Cipriani A, Furukawa TA, Salanti G, et al.

 Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

Antidepressant clinical trials and subject recruitment: just who are symptomatic volunteers?

13. Hieronymus F, Lisinski A, Hieronymus M, et al. 

Determining maximal achievable effect sizes of antidepressant therapies in placebo-controlled trials.

Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study.

15. Munkholm K, Paludan-Muller AS, Boesen K. 

Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis.

16. Cuijpers P, Turner EH, Mohr DC, et al. 

Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis.

17. Hieronymus F, Lisinski A, Nilsson S, Eriksson E. 

Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression.

The emperor's new drugs: medication and placebo in the treatment of depression.

The war on antidepressants: what we can, and can't conclude, from the systematic review of antidepressant withdrawal effects by Davies and Read.

A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence-based?

Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants.

22. Lisinski A, Hieronymus F, Naslund J, et al. 

Item-based analysis of the effects of duloxetine in depression: a patient-level post hoc study.

23. Hieronymus F, Emilsson JF, Nilsson S, Eriksson E. 

Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression.

24. Dawson G, Pies RW. Antidepressants do not work by numbing emotions. 

https://www.psychiatrictimes.com/view/antidepressants-do-not-work-by-numbing-emotions

25. Hieronymus F, Lisinski A, Ostergaard SD, Eriksson E. 

The response pattern to SSRIs as assessed by the Montgomery-Asberg Depression Rating Scale: a patient-level meta-analysis.

Here’s why most of the claims recently made about antidepressants in Newsweek are wrong. 

Hooked on Hype? A Critical Examination of Recent Anti-Antidepressant Reporting

The first patient has been enrolled in a phase 2/3 clinical study to evaluate ulotaront (SEP-363856), a trace amine-associated receptor 1 (TAAR1) agonist with 5HT1A agonist activity, as an adjunctive therapy in the treatment of adults living with 

 (MDD). Ulotaront is also being evaluated in phase 3 clinical development for the treatment of schizophrenia, and it is the first TAAR1 agonist to be studied as an adjunctive therapy for MDD.

“The initiation of the phase 2/3 study evaluating the use of ulotaront as an adjunctive treatment of [MDD] is an important step towards exploring the full medical potential of this novel TAAR1 agonist,” said Armin Szegedi, MD, PhD, senior vice president and chief medical officer at Sunovion. “We have been encouraged by the pre-clinical data showing that ulotaront could have benefits for those living with mood disorder and look forward to enhancing the understanding of this innovative compound.”

The global, multicenter, randomized, double-blind, placebo-controlled study is designed to examine the efficacy, safety, and tolerability of ulotaront as an adjunctive therapy in the treatment of adults with MDD. Participants who do not respond to current 

 will be randomized to receive ulotaront or placebo along with their antidepressant therapy.

The primary endpoint for the study is the reduction of depressive symptoms, as measured by the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, compared to placebo at the end of the study.

“MDD is a disabling mental health condition that often requires a combination of first-line antidepressant medication and adjunctive treatments to alleviate symptoms,” said John Kraus, MD, PhD, executive vice president and chief medical officer at Otsuka. “Even with available approaches, many patients do not achieve optimal responses to treatment, in part due to the heterogeneous nature of the condition, highlighting the need for new and different treatment modalities.”

1. OTSUKA and Sunovion initiate clinical development of ulotaront for the adjunctive treatment of major depressive disorder. Sunovion. News release. December 1, 2022. 

https://news.sunovion.com/press-releases/press-releases-details/2022/Otsuka-and-Sunovion-Initiate-Clinical-Development-of-Ulotaront-for--the-Adjunctive-Treatment-of-Major-Depressive-Disorder/default.aspx

The first patient in a phase 2/3 study evaluating ulotaront for MDD has been enrolled. 

First TAAR1 Agonist Studied as Adjunctive Therapy for MDD

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

The goal of this activity is to help readers understand and apply novel treatment approaches for patients with bipolar depression.

1. Evaluate nonpharmacologic and pharmacologic treatments for bipolar depression.

2. Distinguish evidence-based novel treatments for bipolar 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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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 

™. 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.

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For content-related questions, email us at 

. For questions concerning the accreditation of this CE activity or how to claim credit, please contact 

“Thinking Beyond the Guidelines: Evidence-Based Novel Therapies for Bipolar Depression”

(This is the second part of a 2-part article discussing novel treatments for bipolar depression. 

 appeared in the September issue and discussed the need for novel treatments for bipolar depression. –Ed.)

Bipolar depression (BD) can be difficult to treat due to several factors, and choosing the most appropriate treatment approaches should be based upon patient-specific factors (eg, comorbidities, preferences). Based on treatment response and these patient-specific issues, there are a variety of nonpharmacologic therapies and novel pharmacologic options that can be considered as part of the treatment plan.

Although many clinicians tend to focus on pharmacologic treatments for BD, nonpharmacologic interventions have been shown to be effective in bipolar depression, many of which contribute to an overall healthy lifestyle and can be recommended in addition to medications (

). Additionally, some of these interventions pose only a low risk, and they may be preferable to the use of medications for select patients. Barriers associated with implementation include cost and accessibility. Clinicians should familiarize themselves with the following interventions and recommend them to patients whenever possible.

The International Society for Bipolar Disorder recommends the use of chronotherapeutic treatments.

 Its guidelines recommend the use of bright light therapy and sleep deprivation/wake therapy for BD and dark therapy for mania. Several meta-analyses and systematic reviews found positive results for bright light therapy in BD.

 Although studies are relatively small, bright light has few to no adverse effects and should be considered for patients who have the resources to purchase a light box. In several meta-analyses, the brightness of the light box and length of time utilized varied, depending on the study. In most trials, the light provided ranged from 2500 to 10,000 lux, and the administration time ranged from 7.5 to 60 minutes delivered upon awakening in the morning.

 Participants were maintained on medication regimens during the studies. Clinicians should be aware of the hypothetical risk for affective switching; however, based on available studies, the risk is minimal.

 and light therapy conducted together can effectively treat BD. Sikkens et al studied 60 participants with drug-resistant BD who underwent sleep deprivation periods along with daily bright light therapy sessions.

 After 1 week of treatment, 44% of patients showed significant improvement. Of this group, 17% remained euthymic at 1 year of follow up. For those interested in this approach, Veale provides an easy-to-follow method (

 Although the directions are relatively simple, this protocol may be quite challenging for many patients due to the sleep restriction requirements.

The use of blue light-blocking sunglasses in the evening reduces depressive and manic symptoms.

 If patients have difficulty following the sleep deprivation and light therapy protocols, a middle ground might include wearing blue light–blocking glasses in the evening starting at 7 PM and doing bright light therapy every morning. Blue light–blocking sunglasses can be purchased for about $10, and light boxes with the appropriate specifications can be purchased for $100 to $200. There is some variability in 

 specifications in the research; typically, a box measuring 12 ×17 inches is recommended. The brightness should be between 2500 and 10,000 lux, and patients should use the light box for about 30 minutes per day as soon as possible after waking up. The light box should be placed above eye level while in use, and sunglasses should not be worn.

The cost of the light box may be prohibitive for some patients. In those cases, clinicians should adapt suggested interventions to meet the patient’s needs. For example, patients may be able to sit outdoors in bright sunlight for 15 to 30 minutes in the morning.

 Exercise has been shown to reduce inflammatory markers, and physical activity may be beneficial in BD. For example, Paolucci et al studied 61 university students engaged in various levels of exercise intensity.

 The investigators found moderate, continuous exercise produced the best results. Participants reported reductions in depression and anxiety, and they had lower levels of inflammatory markers. Of note, high-intensity interval training also improved depression, but it increased the participants’ perception of stress and increased the inflammatory markers TNF-α and interleukin-6.

According to available literature related to the impact of 

 on numerous psychiatric conditions, exercise improves depressive symptoms, reduces stress, decreases inflammatory markers, and promotes the synthesis of monoamine neurotransmitters in patients with bipolar disorder.

 Although exercise alone may not lead to remission, it has clear benefits, and should be recommended at moderate levels. Easily accessible forms of exercise—such as walking—may be easiest for patients to implement. For patients who have mobility issues or who live in areas where walking is not possible, chair exercise or 

 might be good alternatives. Other patients may find it easier to set up an exercise schedule at a gym or with a personal trainer. Generally, an exercise program that the patient is most likely to maintain is the best choice.

 and mental illness show a clear negative impact of smoking on the symptoms of BD.

 Indeed, smoking is a risk factor for the development of BD. Cigarette smoking is also well known to negatively affect inflammatory markers.

Although there is no evidence that smoking cessation will treat BD successfully, it makes sense to encourage all patients to 

. Several effective pharmacologic and nonpharmacologic treatments are available to assist with this goal. Early evidence suggested that varenicline might worsen mood and increase the risk of suicidal ideation, but more recent analyses have not shown an increase in neuropsychiatric adverse effects with use of varenicline, 

There are no concerning drug interactions with varenicline or bupropion and medications typically used to treat BD, but clinicians should be aware that cigarette smoking is a cytochrome P450 inducer. If patients quit smoking, the blood levels of some psychotropics can increase. Because the effect is related to smoking itself, the same interaction does not exist with nicotine replacement therapy.

 Healthy dietary patterns improve overall health and reduce symptoms of psychiatric illnesses.

 Specifically, the results of numerous studies have shown that following an anti-inflammatory diet can improve overall health and, potentially, psychiatric symptoms.

Implementation of the Mediterranean diet and MIND (Mediterranean-Dietary Approaches to Stop Hypertension [DASH] Intervention for Neurodegenerative Delay) diets has anti-inflammatory properties. The Mediterranean diet is rich in antioxidants and flavonoids. It uses liberal amounts of whole grains, fruits, vegetables, nuts, olive oil, and omega-3 fatty acids, primarily through the consumption of fish. The MIND combines the benefits of the DASH, which was developed to prevent cardiovascular disease. It encourages reduced consumption of saturated fat, sodium, and sugar intake and promotes healthy proteins, whole grains, fruits, and vegetables. All of these diets have a variety of health benefits and anti-inflammatory properties that may aid in relieving depressive symptoms. Additionally, they may help combat the metabolic effects of numerous psychiatric medications.

In this CME article, learn how to apply novel treatment approaches for patients with bipolar depression. 

Major Depressive Disorder

Rolling NDA Submission of Zuranolone for MDD, PPD is Completed

Meta-Analysis of Intravenous vs Intranasal Ketamine

Hooked on Hype? A Critical Examination of Recent Anti-Antidepressant Reporting

First TAAR1 Agonist Studied as Adjunctive Therapy for MDD

Thinking Beyond the Guidelines: Evidence-Based Novel Therapies for Bipolar Depression

Promising New Treatments for Postpartum Depression

Psychiatric Times™ Conference: Clinical Pearls for Treating MDD

Antidepressants, Placebos, and Lithium—Some Parting Thoughts

Vitamin D Augmentation in Major Depression With Comorbid Vitamin D Deficiency

Treating Depression to Prevent Dementia