Mood Disorders in the News

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Psychiatric Times provides up-to-the-minute coverage of US Food and Drug Administration (FDA) decisions and landmark studies associated with a wide variety of psychiatric treatments. Here are some highlights from our recent coverage of potential treatments for mood disorders.

FDA Authorizes Rejoyn as First Prescription Digital Therapeutic for MDD Treatment

Rejoyn (CT-152) has received clearance from the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) symptoms, making it the first prescription digital therapeutic to be authorized for the treatment of MDD. The treatment is now authorized as an adjunct to clinician- managed outpatient care for adults aged 22 years and older with MDD who are taking antidepressant medication.¹

The medical device has a novel approach to managing depression symptoms. Rejoyn offers a 6-week program with clinically proven cognitive emotional training exercises for the brain, along with short therapeutic lessons. It is theorized to target the neural networks affected by depression and potentially use the brain’s inherent neuroplasticity to alter emotional connections, thus leading to a reduction in symptoms.

“Rejoyn represents a novel and exciting adjunctive treatment option to address MDD symptoms that complements the current standard of care,” said John Kraus, MD, PhD, executive vice president and chief medical officer at Otsuka Pharmaceutical, Co Ltd. “While traditional approaches are often effective, many are left with only a partial response to treatment.”

This clearance is based on data from a 13-week pivotal, multicenter, remote, double-blinded, randomized, controlled trial of 386 participants aged 22 to 64 years who were diagnosed with MDD and taking antidepressants. Participants were randomly assigned to receive either Rejoyn or a sham control app. Those treated with Rejoyn showed an improvement in depression symptom severity from baseline, and symptom improvement was consistently observed across multiple patient and clinician-reported scales, including the Montgomery-Åsberg Depression Rating Scale, the Patient Health Questionnaire-9, and the Clinical Global Impression-Severity scale. Participants in the Rejoyn arm showed continued improvement 1 month after completing the 6-week treatment program. No adverse effects from Rejoyn were observed during the trial.

“Only a third of patients diagnosed with depression and who receive antidepressants as their first-line treatment are successful. These patients need new options that capitalize on proven-effective treatment strategies,” said David Benshoof Klein, cofounder and chief executive officer at Click Therapeutics, Inc. “The clearance of Rejoyn signals a fundamental change in how clinicians can treat symptoms of major depressive disorder.”

Rejoyn introduces Emotional Faces Memory Task (EFMT) exercises²—designed to help participants appropriately process emotions—that were created by a team of psychologists, psychiatrists, and neuroscientists.

Brian Iacoviello, PhD, coinventor of EFMT, assistant professor in the Department of Psychiatry at Icahn School of Medicine at Mount Sinai, and scientific advisor at Click Therapeutics, commented: “Rejoyn has a neuromodulatory mechanism designed to act like physical therapy for the brain by delivering personalized, consistent brain-training exercises designed to help improve connections in the brain regions affected by depression. When stronger and more balanced connections are created, the regions of the brain responsible for processing and regulating emotions are better able to work together and symptoms of depression can improve.”

Rejoyn is expected to be available for download from app stores for iOS and Android operating systems later in 2024.

References

1. Otsuka and Click Therapeutics announce the US Food and Drug Administration (FDA) clearance of Rejoyn, the first prescription digital therapeutic authorized for the adjunctive treatment of major depressive disorder (MDD) symptoms. News release. Otsuka Pharmaceutical Co Ltd/Click Therapeutics Inc. April 1, 2024. https://www.businesswire.com/news/home/20240401758231/en/

2. Iacoviello BM, Murrough JW, Hoch MM, et al. A randomized, controlled pilot trial of the Emotional Faces Memory Task: a digital therapeutic for depression. NPJ Digit Med. 2018:1:21.

Positive Results From Study on Lumateperone as Adjunctive Therapy to Antidepressants

Positive topline results from study 501 showed that lumateperone (Caplyta) was an effective adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD).¹

Investigators in study 501 found that lumateperone 42 mg, when given once daily as adjunctive therapy to antidepressants, met the primary end point by demonstrating a statistically significant and clinically meaningful reduction in the MADRS total score when compared with placebo at week 6. They randomized 485 patients with MDD to lumateperone 42 mg plus antidepressant or placebo plus antidepressant (1:1) in order to evaluate the efficacy and safety of lumateperone as an adjunct to antidepressants. The baseline MADRS total score was 30.4 for lumateperone 42 mg and 30.0 for placebo. In the modified intent-to-treat study population, the least squares (LS) mean reduction from baseline for lumateperone 42 mg was 14.7 points, versus 9.8 points for placebo (LS mean difference = -4.9 points; p<0.0001; ES= 0.61).

“The positive phase 3 results in MDD represent a significant step towards our goal of further establishing Caplyta as a first-choice treatment across mood disorders,” said Sharon Mates, PhD, chairman and CEO of Intra-Cellular Therapies. “We believe that these robust efficacy results coupled with its favorable safety and tolerability profile and convenient dosing make Caplyta a compelling option as an adjunctive treatment for MDD, if approved.”

Lumateperone 42 mg also met the key secondary endpoint by demonstrating a statistically significant and clinically meaningful reduction in the CGI-S score when compared with placebo at week 6 (P<0.0001; ES = 0.67). This efficacy was seen early at the first time point tested (week 1) and maintained throughout the study.

Additionally, lumateperone 42 mg improved patient-reported depressive symptoms as measured by the Quick Inventory of Depressive Symptomatology Self Report (P<0.0001).

Lumateperone was generally safe and well tolerated. The most commonly reported adverse events were dry mouth (10.8%), fatigue (9.5%), and tremor (5.0%). These were observed at a rate greater than or equal to 5% and at least twice the rate of placebo in the total population, but they were mostly mild to moderate and resolved within a short period of time. Similar adverse events were seen in prior studies of lumateperone as a treatment for bipolar depression and schizophrenia.²

“MDD is a highly prevalent condition and there is a need for efficacious treatments with favorable safety and tolerability profiles given the majority of patients do not benefit from their initial therapy or suffer from side effects associated with existing therapies,” said Suresh Durgam, executive vice president and chief medical officer of Intra-Cellular Therapies. “In this phase 3 study, lumateperone demonstrated a robust effect as an adjunctive treatment to antidepressants in patients with MDD who had inadequate response to antidepressant therapy. This study contributes to the growing body of evidence of lumateperone’s efficacy and safety across mood disorders.”

References

1. Intra-Cellular Therapies announces positive phase 3 topline results from study 501 evaluating lumateperone as adjunctive therapy in patients with major depressive disorder. Intra-Cellular Therapies. News release. April 16, 2024. https://ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-positive-phase-3-topline

2. Kuntz L. Positive results for lumateperone in patients with mixed features in major depressive disorder, bipolar depression. Psychiatric Times. March 29, 2023. https://www.psychiatrictimes.com/view/positive-results-for-lumateperone-in-patients-with-mixed-features-in-major-depressive-disorder-bipolar-depression

Phase 2 Trial Shows Positive Results for Rapid, Durable TRD Treatment

Beckley Psytech shared positive initial results from its phase 2a open-label study of BPL-003—a novel, synthetic, intranasally administered benzoate salt formulation of mebufotenin—for treatment-resistant depression (TRD). A single 10-mg dose of BPL-003 resulted in the rapid and durable reduction of depression symptoms in patients with TRD.¹

The study investigated the safety, tolerability, and efficacy of the 10-mg dose of BPL-003 combined with psychological support in participants with moderate to severe TRD who were not taking antidepressants. Investigators followed participants for 12 weeks after dosing and assessed them multiple times using the Montgomery-Åsberg Depression Rating Scale (MADRS). A single dose of BPL-003 induced a rapid antidepressant response in 55% of patients the day after dosing, and this effect was durable with a 55% response rate maintained at week 4 and through to week 12. By week 4, 55% of patients had achieved remission, and 45% had achieved remission at week 12. This clinical study is the longest known follow-up of depression outcomes for mebufotenin.

“With around half of patients [with TRD] in remission 3 months after just a single dose of BPL-003 in this study, we are particularly excited about its antidepressant durability potential. The results indicate that BPL-003 could offer a scalable, single-dose administration within the 2-hour in-clinic treatment paradigm successfully established by Spravato,” said Florian Brand, chief executive officer and cofounder of atai Life Sciences.

The acute effects of BPL-003 resolved in less than 2 hours on average, suggesting that this treatment could offer a shorter in-clinic treatment time when compared with other in-development psychedelics.

BPL-003 was well tolerated among participants, with predominantly mild or moderate adverse events. The most common (>10%) were nasal discomfort, headaches, nausea, and vomiting, all consistent with previous phase 1 results. No serious adverse events were reported.

BPL-003 received investigational new drug (IND) approval from the US Food and Drug Administration back in February 2023, the first time IND approval given for a phase 2b study of a short-acting psychedelic.²

Further research is currently underway. First, a part 2 extension of this study is now enrolling participants to assess the safety and efficacy of coadministered BPL-003 in patients with TRD who take oral antidepressants (NCT05660642). Additionally, a randomized, quadruple-masked, controlled phase 2b study is in progress (NCT05870540), investigating the effects of a single 12-mg or 8-mg dose of BPL-003 against a subperceptual dose of 0.3 mg in 225 participants with TRD. Investigators will assess efficacy using the MADRS scale at several time points; the primary end point is at week 4, and the final assessment is at week 8. Top-line results are expected later in 2024.

References

1. atai Life Sciences announces positive initial results from Beckley Psytech’s phase 2a open label study of BPL-003 (intranasal 5-MeO-DMT) in treatment resistant depression. News release. atai Life Sciences. March 27, 2024. Accessed March 27, 2024. https://ir.atai.life/news-releases/news-release-details/atai-life-sciences-announces-positive-initial-results-beckley

2. Beckley Psytech receives FDA investigational new drug (IND) approval for phase IIb study of BPL-003, a novel synthetic formulation of 5-MeO-DMT (mebufotenin). News release. BioSpace. February 21, 2023. Accessed March 27, 2024. https://www.biospace.com/article/releases/beckley-psytech-receives-fda-investigational-new-drug-ind-approval-for-phase-iib-study-of-bpl-003-a-novel-synthetic-formulation-of-5-meo-dmt-mebufotenin-/