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A recent study suggests vitamin D, via its effects on the brain, may play a pivotal role in the pathophysiology of major depressive disorder (MDD).

Depression often follows a seasonal pattern, peaking in summer and winter.

, through its action on the brain, might account for this link between seasonal light changes and seasonal mood swings.

 Key for neuronal development and brain function, vitamin D exerts its effects on the brain via binding to vitamin D receptors,

 distributed in the prefrontal cortex, cingulate cortex, and limbic system.

To discover more, investigators took a look at the association between gender, serum concentration of 

, and depression in a large sample of 122 participants with MDD and 119 healthy controls. Resting-state functional MRI data were collected with independent component analysis adopted to examine large-scale inter- and intranetwork functional connectivity. Serum concentration of vitamin D and depression symptoms were also assessed.

1. There was a significant group-by-gender interaction effect on serum concentration of vitamin D. Participants with MDD exhibited lower vitamin D levels than control participants, specifically in females rather than males.

2. Female participants with lower serum concentration of vitamin D had poorer cognitive performance (ie, prospective memory and sustained attention).

3. There was a connection between MDD-related functional network connectivity changes and serum concentration of vitamin D, as well as depression and anxiety symptoms in female participants with MDD.

4. MDD- and serum concentration of vitamin D-related functional network connectivity alterations mediated the associations between vitamin D levels and cognition in females.

Investigators found that vitamin D insufficiency and deficiency was more common in females than males. MDD patients had significantly lower vitamin D levels relative to healthy controls, again specifically in females. This 

 could be a result of insufficient sunlight exposure, higher BMI, more fat tissue, and more sedentary life in females relative to males. Overall, this may suggest a female-specific involvement of vitamin D in the pathogenesis of depression.

“More broadly, these findings may inform a novel conceptualization that adjuvant vitamin D supplementation therapy may yield clinical benefits in improving treatment outcomes in female patients with MDD,” concluded the study authors.

The relationship between vitamin D, clinical manifestations, and functional network connectivity in female patients with major depressive disorder.

Vitamin D deficiency may play a role in depression

Pleiotropic activities of vitamin D receptors - adequate activation for multiple health outcomes.

Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.

Are lower vitamin D levels in women related to depressive mood? 

The Relationship Between MDD and Lower Vitamin D Levels in Women 

University of California San Diego School of Medicine, Weill Cornell Medicine, and Stanford Medicine investigators have teamed up to launch a collaborative, 3-year study to investigate new ways to treat or prevent major depression. They also hope to encourage the application of effective treatments and develop predictive models for identifying ideal treatments for individual patients.

“Depression is not a singular condition, and there is no singular remedy,” said 

, chair of the Department of Psychiatry at UC San Diego School of Medicine. “It is an extraordinarily complex disease that, in many ways, is not yet well-understood. It is a different disease in every person, and every person requires a personalized therapeutic strategy.”

Daskalakis will colead the program with Conor Liston, MD, PhD, an associate professor of psychiatry and neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, and Nolan Williams, MD, an assistant professor of psychiatry and behavioral sciences at Stanford Medicine.

For some patients with depression, pharmaceutical treatments are ineffective. Because of this, the investigators will focus on current and novel uses of 

“TMS requires patients to come to the clinic daily, and medications do not,” said Liston. “So for many people, medications are a good first treatment to try, but TMS is a great option for people who do not respond to medications.”

Study participants will receive various treatments, including different types of TMS and the antidepressant escitalopram, one of the most used SSRI treatments for depression. Participants will be evaluated clinically through assessments and brain scans. The resulting analysis is intended to yield algorithms that can match patients with more effective, personalized treatment plans.

1. University of California San Diego Health. Major contract fuels three-university study of TMS for treating depression. Newswise. February 22, 2022. Accessed February 28, 2022. 

https://www.newswise.com/articles/major-contract-fuels-three-university-study-of-tms-for-treating-depression

Investigators have launched a 3-year study to develop predictive models that will help identify better treatment plans for patients with depression.  

Study Intends to Find New Ways to Treat or Prevent Major Depression 

AbbVie has submitted a supplemental New Drug Application (sNDA) to the United States Food and Drug Administration (FDA) for cariprazine (Vraylar) for the adjunctive treatment of major depressive disorder (MDD) in patients engaged in ongoing antidepressant therapy.

This submission follows clinical trial results demonstrating clinical and statistically significant improvement in patients with MDD who were treated with cariprazine and an antidepressant. Using the Montgomery-Åsberg Depression Rating Scale (MADRS), 2 phase 3 studies—3111-301-001 and RGH-MD-75—showed improvement in patients treated with cariprazine at 1.5mg/day compared with placebo from baseline to week 6, and in patients treated with cariprazine at 2-4.5mg/day compared with placebo from baseline to week 8, respectively. Both studies were consistent with cariprazine’s established safety profile across indications. Another study supporting the sNDA submission was RGH-MD-76, which examined the long-term tolerability and safety of cariprazine over 26 weeks.

“Many people living with major depressive disorder struggle to find a treatment that reduces their depressive symptoms, with many taking years to find the right treatment,” said Michael Severino, MD, AbbVie vice chairman and president, in a press release. “Cariprazine, when added to ongoing antidepressant treatment in patients with major depressive disorder, demonstrated that it can reduce depressive symptoms.”

Cariprazine is already FDA-approved for the treatment of adults with depressive, acute manic, and mixed episodes related to bipolar I disorder and schizophrenia. Its efficacy and safety in the treatment of multiple psychiatric disorders has been evaluated in more than 8000 patients in over 20 clinical trials worldwide. If approved for the adjunctive treatment of MDD in patients receiving ongoing antidepressant therapy, cariprazine may help reduce depressive symptoms associated with MDD, which is one of the most common psychiatric disorders in the United States, with around 21 million adults experiencing at least 1 major depressive episode in 2020 alone.

“We look forward to working closely with the FDA during the review of our submission to bring a potential new adjunctive therapy to patients with major depressive disorder who are taking an antidepressant and seeking additional relief,” Severino said in a press release. “This submission demonstrates our strong commitment to addressing additional gaps in the care of people affected by psychiatric disorders.”

AbbVie submits supplemental New Drug Application to U.S. FDA for cariprazine (VRAYLAR®) for the adjunctive treatment of major depressive disorder

. AbbVie. News Release. February 22, 2022. Accessed February 22, 2022.

If approved, this will be the fourth indication for the drug, joining its approvals for episodes associated with bipolar I disorder and schizophrenia.

New sNDA Submitted to FDA for Major Depressive Disorder

Sage Therapeutics and Biogen recently announced the CORAL Study examining zuranolone treatment in patients with major depressive disorder (MDD) demonstrated a rapid and statistically significant reduction in depressive symptoms at day 3 and over the 2-week treatment period.

This significance was demonstrated at day 3, with zuranolone 50 mg initiated concurrently with an open-label standard of care antidepressant. Significance was assessed by change from baseline in the 17-item Hamilton Rating Scale for Depression (HAMD-17). Zuranolone with a standard of care antidepressant also demonstrated a statistically significant improvement in depressive symptoms compared to ADT with placebo over the 2-week treatment period. Zuranolone was well-tolerated overall.

By meeting its objectives, the CORAL Study supports the potential usefulness of zuranolone.

Priya Singhal, MD, MPH, Head of Global Safety and Regulatory Sciences and Interim Head of R&D at Biogen, said this of the results: “These positive results from the CORAL Study indicate that zuranolone co-initiated with standard of care may offer more rapid relief from depressive symptoms than current standard of care taken alone. Based on the collective results observed across the LANDSCAPE clinical development program, we believe that zuranolone has the potential to offer a new clinically meaningful treatment option for people with major depressive disorder.”

“We believe the CORAL Study is clinically meaningful and with the addition of this data, the LANDSCAPE program now demonstrates zuranolone has 3 potential real world uses for the treatment of MDD. The LANDSCAPE data support zuranolone as a monotherapy, and since many people in the previously completed studies were already on maintenance antidepressants, we believe our data also support zuranolone as additive therapy. The CORAL Study further supports the use of zuranolone to accelerate the benefit of conventional antidepressants in treating MDD with a well-tolerated safety profile,” added Barry Greene, Chief Executive Officer at Sage.

“Including the CORAL Study, zuranolone now has 6 positive clinical studies, and we remain on track to start the rolling submission for a New Drug Application in MDD early this year with completion targeted for the second half of 2022,” Greene said further.

“The CORAL Study results were particularly interesting because the data demonstrated that zuranolone worked within days to provide rapid reduction in depressive symptoms as compared to current antidepressants, which in clinical practice can take weeks or months to work,” said Sagar Parikh, MD, Professor of Depression and Clinical Neuroscience, and Psychiatry Sciences, University of Michigan. “In my experience, people with MDD deserve to feel better as soon as possible with a treatment with tolerable side effects. These data suggest that zuranolone has the potential to offer this option and to provide physicians the opportunity to think differently about treating MDD.”

1. Sage Therapeutics and Biogen announce the phase 3 CORAL Study met its primary and key secondary endpoints. BioSpace. News release. February 16, 2022. 

https://www.biospace.com/article/sage-therapeutics-and-biogen-announce-the-phase-3-coral-study-met-its-primary-and-key-secondary-endpoints/

A new study showed zuranolone treatment in patients with major depressive disorder demonstrates a rapid and statistically significant reduction in depressive symptoms. 

Improving Depression Symptoms: Study Meets Endpoints 

A new study found that a form of digital cognitive behavioral therapy (dCBT) may help prevent 

 in women for up to 6 months after they give birth.

The study, which was conducted by researchers at the University of California San Francisco (UCSF), tested the efficacy of Sleepio, a self-paced sleep app and form of dCBT, to determine whether treating insomnia would also help prevent depression in postpartum women.

 The study was a follow-up to a study by UCSF researchers in January 2020,

 which found that dCBT treatment helped reduce insomnia and symptoms of anxiety and depression in participants during pregnancy.

“We were curious to see whether the benefits of dCBT for insomnia would maintain after the birth of the child, especially given the demands of having a young infant,” said Jennifer Felder, PhD, lead author of the study; assistant professor of psychiatry; and core research faculty at the UCSF Osher Center for Integrative Health, in a press release. “We were particularly excited to see the benefits lasted to 6 months not just for insomnia, but for mental health more broadly.”

In the study, 105 out of 208 participants were randomized to the dCBT treatment, which involved up to 6 20-minute sessions using the Sleepio app. At 3 months postpartum, 4% of participants who had the dCBT treatment were rated as likely depressed, in comparison to 18% of the remaining participants, who received usual treatments such as medication or general sleep hygiene tips from their providers. According to Felder, part of what set the dCBT treatment apart from usual care is that it was more individualized and addressed common causes of insomnia.

“The magic of the treatment is what happens between sessions—the tactics the participants put into practice, such as keeping a sleep diary, stabilizing their wake time, spending less time in bed tossing and turning, and prioritizing an adequate wind-down before bed,” Felder said in a press release.

With its focus on the connection between postpartum insomnia and depression, the study’s results are significant, as up to 15% of women are affected by postpartum depression; around 38% of pregnant women experience insomnia; and insomnia is associated with a 30% increased risk of pre-term birth.

“I’ve heard patients say, over and over, that their postpartum mental health began to suffer when their insomnia started, suggesting there is a link,” Felder said in a press release. “We know that postpartum can be a vulnerable time for becoming depressed, and it is possible that this intervention may prevent that.”

Digital therapy for prenatal insomnia may prevent postpartum depression

. News Release. University of California San Francisco. December 15, 2021.

2. Felder JN, Epel ES, Neuhaus J, et al. 

Efficacy of digital cognitive behavioral therapy for the treatment of insomnia symptoms among pregnant women: a randomized clinical trial

 [published correction appears in JAMA Psychiatry. 2020 Jul 1;77(7):768]. 

Study also suggests link between postpartum depression and insomnia.

Research Shows dCBT May Help Prevent Postpartum Depression

Sage Therapeutics and Biogen presented new data from the LANDSCAPE clinical program evaluating the efficacy and safety of zuranolone for the treatment of 

 (MDD) at the American College of Neuropsychopharmacology (ACNP) Congress in San Juan, Puerto Rico.

Collected data from the SHORELINE and WATERFALL studies, both part of the LANDSCAPE clinical program, demonstrate the potential efficacy and safety profile of zuranolone for the treatment of MDD. Zuranolone treatment led to improvements in depressive symptoms and elevated anxiety symptoms, as assessed by multiple scales (HAMD-17, MADRS and HAM-A, respectively).

ACNP presentations included data from the WATERFALL Study, a phase 3 placebo-controlled trial that evaluated the efficacy and safety of 

 50 mg in adults aged 18 to 64 years old with MDD as well as the ongoing open-label SHORELINE Study in MDD. In the WATERFALL Study, a rapid onset of effect as measured by HAMD-17 was observed compared to placebo by day 3, reaching statistical significance. A stabilization of depressive symptoms followed.

“The new data shared at ACNP further our confidence in the potential of zuranolone to help rapidly mitigate various symptoms associated with depression, including elevated anxiety,” said Priya Singhal, MD, MPH, head of Global Safety and Regulatory Sciences and interim head of Research and Development at Biogen. “As we continue to evaluate the totality of the data from the LANDSCAPE clinical develop program—which includes the Phase 3 WATERFALL and SHORELINE Studies—we aim to gain a more comprehensive understanding of how zuranolone may one day be a valuable option for people worldwide who seek a new way to treat depression.”

In an oral session at ACNP, presenters shared an analysis from the WATERFALL Study assessing zuranolone (50 mg) on symptoms of anxiety as measured by the Hamilton Anxiety Rating Scale (HAM-A). Participants treated with 

 showed improvements in symptoms of anxiety compared with placebo at days 8 and 15. Similar results have been observed across the LANDSCAPE program. Furthermore, data from the SHORELINE Study support the potential of zuranolone as an oral, as-needed treatment for patients with MDD, including those aged 65 and older.

“The data shared at ACNP continue to provide insight to help us better understand how zuranolone could impact the treatment of depression and potentially differentiate further from current antidepressants, if approved,” said Barry Greene, Chief Executive Officer at Sage Therapeutics. “The analysis conducted evaluating zuranolone’s effects on measures of anxiety in patients with MDD is critical. Symptoms of anxiety are highly present in patients with depression, which can pose unique challenges to care. We are also pleased with the data for those 65 and older, who can struggle with current therapies to treat their depression. Zuranolone has consistently demonstrated rapid and sustained improvements in depressive symptoms and a well-tolerated safety profile in our clinical trials to date without the adverse events that are often associated with discontinuation of standard of care antidepressants.”

1. Sage Therapeutics. Sage Therapeutics and Biogen announce new analyses from the LANDSCAPE clinical development program of zuranolone in MDD presented at the American College of Neuropsychopharmacology (ACNP) Congress. News release. December 8, 2021. Accessed December 9, 2021. 

https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-new-analyses-landscape

Data from a clinical program evaluating the efficacy and safety of zuranolone was presented at the American College of Neuropsychopharmacology Congress. What new developments did they share? 

Zuranolone: New Data Presented at American College of Neuropsychopharmacology Congress

A study found that racial and ethnic minority children experienced increased rates of anxiety, depression, and social risks during the first year of the COVID-19 pandemic.

The study, led by researchers from Boston Medical Center (BMC),

 included 168 caregivers of racially and ethnically diverse children between ages 5 and 11 who had completed screenings for behavioral and emotional risks as part of a well visit at an urban, safety-net pediatric primary care practice before the onset of the pandemic. The pre-pandemic visits occurred between September 2019 and February 2020, and participants were reassessed mid-pandemic between August 2020 and January 2021.

 Of the participating caregivers, 54% identified as non-Hispanic Black and 29% as Hispanic, and 22% did not speak English. Study visits were conducted in 3 languages: English (79%), Haitian Creole (16%), and Spanish (5%). The Pediatric Symptom Checklist (PSC) was used to measure behavioral and emotional symptoms of anxiety and depression, including attention and internalization and externalization of symptoms. Results showed that the rate of both depression and anxiety rose from 5% pre-pandemic to 18% mid-pandemic.

According to the researchers, the aim of the study was to compare negative symptoms of mental health among urban, racially and ethnically diverse children before and during the pandemic.

 This study is also among the first to include both pre- and mid-pandemic data in research involving urban children.

 “Our fear is that the pandemic has led to a 

 for both caregivers and children following the incredible stressors that COVID-19 has put on families,” said Andrea Spencer, MD, lead author of the study, in a press release. “We specifically looked at our urban and diverse patient population who are already at higher psychosocial risk and also most susceptible to the impacts of the pandemic, therefore raising particular concern for their mental health.”

To this end, the study also analyzed the children and caregivers’ social risk and unmet social needs—including food and housing insecurity, unemployment, difficulty paying bills, and difficulty with dependent care and transportation—pre- and mid-pandemic using BMC’s THRIVE screening tool.

 Higher social risks were reported, with all THRIVE items except for difficulty with transportation being ranked as significantly more prevalent mid-pandemic compared to pre-pandemic. For example, 50% of participants reported food insecurity mid-pandemic compared to 16% pre-pandemic.

“These findings point to the critical need for public health efforts to mitigate the psychosocial effects of the pandemic on racial and ethnic minority children and communities while searching for solutions to support the increased demand,” said Spencer, who is also an adult, child, and adolescent psychiatrist at BMC and an assistant professor of psychiatry at Boston University School of Medicine, in a press release. “We need new or expanded community-based, school-based, family-based, and trauma-informed treatment and prevention programs to reach the most affected families.”

New study finds COVID-19 pandemic exacerbated anxiety and depression in racial and ethnic minority children

. News Release. Boston Medical Center. December 8, 2021. Accessed December 13, 2021.

2. Spencer AE, Oblath R, Dayal R, et al. 

Changes in psychosocial functioning among urban, school-age children during the COVID-19 pandemic

Research also shows increased prevalence of social risks and unmet social needs.

Higher Rates of Anxiety, Depression Reported Among Minority Children

An open-label study of psilocybin therapy for depression in patients with cancer found that 50% of participants achieved remission of depression symptoms within 1 week of receiving COMP360 psilocybin therapy.

The study, conducted by Maryland Oncology Hematology at the Aquilino Cancer Center in Rockville, included 30 patients who had been diagnosed with major depressive disorder (MDD) and cancer at various stages. All participants were actively receiving cancer treatment, half of them had been treated with antidepressants for their current depressive episode, and 19 had no prior experience with psychedelic substances. Patients received a 25 mg dose of COMPASS Pathways’ COMP360, followed by psychological support from specially trained therapists. Remission of depressive symptoms was reported following only 1 dose of the drug, with patients generally tolerating COMP360 psilocybin therapy well with no serious adverse events related to treatment. Remission was sustained for the study’s 8-week follow-up period.

“It’s an exciting study for the team at Aquilino Cancer Center, my colleagues at COMPASS, and the mental health care and oncology communities. It is pioneering a new approach to the mental health problems of people living with cancer. It suggests that simultaneous administration of COMP360 psilocybin therapy appears to be well tolerated and feasible,” Guy Goodwin, FMedSCI, DPhil, FRCPsych, chief medical officer of COMPASS Pathways, told 

. Goodwin is also emeritus professor of psychiatry at the University of Oxford and a former WA Handley Chair of Psychiatry and head of the university’s Department of Psychiatry.

Psilocybin therapy, as administered in this study, usually involves 

: preparatory, medication administration, and integration. During the preparatory stage, therapists help the patient understand their symptoms and prepare for the psychological or emotional effect of the medication. During the administration session, therapists observe the patient and maintain patient safety for 6-8 hours. In the integration stage, therapists discuss any psychedelic experiences from the medication and help the patient interpret these experiences.

 In the COMPASS Pathways open-label study, “between 2 to 4 patients were given a 25mg dose of COMP360 psilocybin therapy at the same time, in conjunction with 1-on-1 support from a specially-trained therapist, throughout their 6- to 8-hour experience,” Goodwin told 

. “This makes it the first clinical trial to test the safety and feasibility of psilocybin therapy with simultaneous administration to several patients and 1-on-1 psychological support.”

Patients in this study received COMP360, a synthesized formulation of psilocybin, the active ingredient in some species of mushrooms known as “magic mushrooms.”

 The drug received Breakthrough Therapy Designation from the US Food and Drug Administration in February 2018.

 Importantly, as neither participants nor raters were blinded to the selection of treatment, the researchers acknowledged that the results might have been influenced by expectancy bias.

Improving treatment methods for MDD and other depressive disorders in patients with cancer is of interest because research shows that poorer prognosis is reported in patients with comorbid cancer and depressive disorders,

 and that these patients are at higher risk for both 

 “For complete cancer care, we need to focus on whole-person healing and include the mental wellbeing of our patients. This is not widely addressed today, but it’s time to do something about it. These study results have shown that psilocybin therapy may be helpful with MDD in cancer, and we look forward to doing further analysis and following up with additional studies,” said Manish Agrawal, MD, principal investigator of the study, in a press release. Agrawal is co-director of clinical research at the Aquilino Cancer Center.

“More than 80% of cancer patients in the US are treated in community cancer centers, so conducting research in this setting offers a real-world environment to test treatments in a location where patients are already seeking and receiving care,” Goodwin told 

. “We believe the results of this trial could contribute to transforming the way we help cancer patients cope with the psychological impact of their diagnosis. Improving the mental health of patients is the inspiration for everything we do.”

1. Open-label study of COMP360 psilocybin therapy for depression in cancer patients demonstrates feasibility of simultaneous psilocybin administration in small groups. News Release. COMPASS Pathways. October 20, 2021. Accessed October 20, 2021.

https://ir.compasspathways.com/news-releases/news-release-details/open-label-study-comp360-psilocybin-therapy-depression-cancer

2. Jann MW. Psilocybin revisited: The science behind the drug and its surprising therapeutic potential. 

. 2021;38(3). Accessed October 21, 2021. 

https://www.psychiatrictimes.com/view/psilocybin-revisited-science-behind-drug-surprising-therapeutic-potential

3. About psilocybin therapy. COMPASS Pathways. Accessed October 21, 2021. 

https://compasspathways.com/our-research/psilocybin-therapy/about-psilocybin-therapy/

4. COMPASS Pathways receives FDA Breakthrough Therapy designation for psilocybin therapy for treatment-resistant depression. News Release. COMPASS Pathways. October 23, 2018. Accessed October 20, 2021.

https://compasspathways.com/compass-pathways-receives-fda-breakthrough-therapy-designation-for-psilocybin-therapy-for-treatment-resistant-depression/

5. Sherrill C, Smith M, Mascoe C, et al. Effect of treating depressive disorders on mortality of cancer patients. 

. 2017;9:e1740. Accessed October 21, 2021. 

https://www.cureus.com/articles/8003-effect-of-treating-depressive-disorders-on-mortality-of-cancer-patients

6. Myers CJ, Retamero C. Suicidal ideation and behaviors in oncology patients. 

. 2021;37(8). Accessed October 21, 2021. 

https://www.psychiatrictimes.com/view/suicidal-ideation-and-behaviors-oncology-patients

Results suggest that psilocybin therapy may prove to be helpful in improving quality of life for patients with cancer. 

Study Finds Psilocybin Improves MDD in Patients With Cancer

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, eg Uvex Skyper S1933X and Uvex Ultra-spec 2000, 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 

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

Major Depressive Disorder