Seltorexant for major depressive disorder

Uchimura N., Taniguchi M., Ariyoshi Y., Oka Y., Togo O., Uchiyama M.

This Phase 3 double-blind, placebo-controlled study evaluated the efficacy and safety of daridorexant in Japanese patients with insomnia disorder. 490 patients with insomnia disorder from 95 sites in Japan were randomized to daridorexant 50 mg (n = 163), 25 mg (n = 163) or placebo (n = 164) for 4 weeks, followed by a 7-day placebo run-out and a 30-day safety follow-up. The primary efficacy endpoints, in hierarchical order, were change from baseline at Week 4 in subjective total sleep time (sTST) and subjective latency to sleep onset (sLSO), for daridorexant 50 mg vs placebo. sTST and sLSO were also evaluated (secondary endpoints) for daridorexant 25 mg vs placebo. Safety endpoints included adverse events and next-morning sleepiness (Visual Analog Scale, VAS). Daridorexant 50 mg significantly increased sTST and decreased sLSO versus placebo at Week 4 (least-squares mean difference [LSMD]: sTST 20.3 min [95 % CI 11.4, 29.2] p < 0.001; sLSO −10.7 min [−15.8, −5.5] p < 0.001). Daridorexant 25 mg also significantly improved both endpoints versus placebo (LSMD: sTST 9.2 min [0.3, 18.1] p = 0.042; sLSO −7.2 min [-12.3, −2.0] p = 0.006). Overall incidence of adverse events was similar across groups (50 mg: 22 %; 25 mg: 18 %; placebo 23 %); somnolence, the most common event, increased with increasing dose (50 mg: 6.8 %; 25 mg: 3.7 %; placebo 1.8 %). However, daridorexant did not increase VAS next-morning sleepiness. No rebound or withdrawal-related symptoms were observed after treatment discontinuation. In Japanese patients with insomnia disorder, daridorexant (25 and 50 mg) was well tolerated and significantly improved subjective sleep outcomes, with no evidence of residual effects.

Strumila R., Lengvenyte A., Guillaume S., Nobile B., Olie E., Courtet P.

Glucagon-like peptide-1 (GLP-1) agonists have been successfully used in clinical practice for the treatment of diabetes and obesity, offering significant clinical benefits. However, concerns regarding their potential link to psychiatric side effects, like suicidal thoughts and behaviours (STB) have emerged. This narrative review investigates the complex interplay between GLP-1 agonists and STB, focusing on the biological stress induced by rapid weight loss, psychological and social consequences, similar mechanism with addiction, and the evaluative lens of the Bradford Hill criteria on causality. While GLP-1 agonists can contribute to substantial health improvements, they also introduce biological and psychological stressors. Disruptions in homeostasis from quick weight reduction can elevate cortisol and norepinephrine levels, heightening the risk for, or exacerbation of STB. Psychological factors, including unfulfilled expectations and identity changes after significant weight loss, compound these risks. Utilizing the Bradford Hill criteria reveals insufficient evidence for a direct causal link between GLP-1 agonists and STB. Yet, the indirect effects related to the metabolic and psychological disturbances associated with rapid weight loss call for a cautious approach. Used carefully in targeted populations GLP-1 agonists may even emerge as protective agents against STB. Therefore, it is crucial to monitor patients during the treatment and screen for preexisting mental health conditions. If detected, appropriate clinical management should be applied. Future studies should aim at optimizing dosing schedules to mitigate the adverse effects of rapid weight loss and further investigate GLP-1 agonists in possible STB prevention.

Wong S., Le G.H., Vasudeva S., Teopiz K.M., Phan L., Meshkat S., Kwan A.T., Rhee T.G., Ho R., Choi H., Cao B., Rosenblat J.D., McIntyre R.S.

Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD.

Tempia Valenta S., Nicastri A., Perazza F., Marcolini F., Beghelli V., Atti A.R., Petroni M.L.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for managing metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. Beyond their metabolic benefits, GLP-1 RAs exhibit neuroprotective and psychotropic effects, potentially benefiting mental health conditions like depression and anxiety. This systematic review aims to synthesize existing evidence on the effects of GLP-1 RAs on mental health outcomes, including both potential therapeutic benefits across various psychiatric disorders and the risk of associated adverse mental health effects. This systematic review was conducted across PubMed/MEDLINE and Web of Science. Inclusion criteria encompassed human and animal studies examining the impact of GLP-1 RAs on mental health. Data from 81 selected studies were extracted and analyzed, focusing on mental health outcomes and reported adverse effects. GLP-1 RAs exhibit potential beneficial effects on depressive symptoms, cognitive function, and reduced risk of suicidal ideation in animal and human models through antioxidative, anti-inflammatory mechanisms, and modulation of neurotransmitter pathways. Additionally, GLP-1 RAs were effective in reducing alcohol and substance use and binge eating behaviors. Adverse psychiatric effects associated with GLP-1 RAs, including depression, anxiety, and suicidal ideation, are noted in pharmacovigilance analyses, with variations among different GLP-1 RAs. GLP-1 RAs hold promise for addressing psychiatric conditions such as depression, anxiety, alcohol and substance use disorders. Despite their potential benefits, the risk of psychiatric adverse effects requires cautious administration.

O’Sullivan S.J., Buchanan D.M., Batai J.V., Williams N.R.

Treatment-resistant depression (TRD) is an epidemic with rising social, economic, and political costs. In a patient whose major depressive episode (MDE) persists through an adequate antidepressant trial, insurance companies often cover alternative treatments which may include repetitive transcranial magnetic stimulation (rTMS). RTMS is an FDA-cleared neuromodulation technique for TRD which is safe, efficacious, noninvasive, and well-tolerated. Recent developments in the optimization of rTMS algorithms and targeting have increased the efficacy of rTMS in treating depression, improved the clinical convenience of these treatments, and decreased the cost of a course of rTMS. In this opinion paper, we make a case for why conventional FDA-cleared rTMS should be considered as a first-line treatment for all adult MDEs. RTMS is compared to other first-line treatments including psychotherapy and SSRIs. These observations suggest that rTMS has similar efficacy, fewer side-effects, lower risk of serious adverse events, comparable compliance, the potential for more rapid relief, and cost-effectiveness. This suggestion, however, would be strengthened by further research with an emphasis on treatment-naive subjects in their first depressive episode, and trials directly contrasting rTMS with SSRIs or psychotherapy.

Swartz H.A., Bylsma, Ph.D. L.M.

Hampsey E., Jelen L., Young A.H.

Yerubandi A., Thomas J.E., Bhuiya N.M., Harrington C., Villa Zapata L., Caballero J.

ImportancePsilocybin has been studied in the treatment of depression and anxiety disorders. Clinical studies have mainly focused on efficacy, with systematic reviews showing favorable efficacy; however, none have primarily focused on psilocybin safety.ObjectiveTo evaluate the acute adverse effects of psilocybin at therapeutic doses in the treatment of depression and anxiety.Data SourcesMEDLINE via PubMed, Web of Science, and ClinicalTrials.gov were searched for publications available between 1966 and November 30, 2023.Study SelectionRandomized, double-blind clinical trials that reported adverse effects of psilocybin in patients treated for depression and anxiety were screened.Data Extraction and SynthesisData were independently extracted by 2 authors and verified by 2 additional authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. The inverse variance method with the Hartung-Knapp adjustment for the random-effects model was used, with a continuity correction of 0.5 for studies with 0 cell frequencies. Sensitivity analysis was conducted by sequentially removing 1 study at a time to assess the robustness of the results.Main Outcomes and MeasuresThe primary outcome was considered as the adverse effects of psilocybin at high and moderate (ie, therapeutic) dose regimens and compared with placebo, low-dose psilocybin, or other comparator in the treatment of depression and/or anxiety.ResultsSix studies met the inclusion criteria with a total sample of 528 participants (approximately 51% female; median age 39.8 years; IQR, 39.8-41.2). Seven adverse effects were reported in multiple studies and included in the analysis. Among these, headache (relative risk [RR], 1.99; 95% CI 1.06-3.74), nausea (RR, 8.85; 95% CI, 5.68-13.79), anxiety (RR, 2.27; 95% CI, 1.11-4.64), dizziness (RR, 5.81; 95% CI, 1.02-33.03), and elevated blood pressure (RR, 2.29; 95% CI, 1.15- 4.53) were statistically significant. Psilocybin use was not associated with risk of paranoia and transient thought disorder.Conclusions and RelevanceIn this meta-analysis, the acute adverse effect profile of therapeutic single-dose psilocybin appeared to be tolerable and resolved within 48 hours. However, future studies need to more actively evaluate the appropriate management of adverse effects.

McIntyre R.S., Alsuwaidan M., Baune B.T., Berk M., Demyttenaere K., Goldberg J.F., Gorwood P., Ho R., Kasper S., Kennedy S.H., Ly‐Uson J., Mansur R.B., McAllister‐Williams R.H., Murrough J.W., Nemeroff C.B., et. al.

Treatment‐resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision‐making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision‐making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo‐resistant (e.g., due to inadequacy of treatment trials or non‐adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non‐response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co‐administered with an antidepressant) are established as efficacious in the management of TRD. Some second‐generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine‐fluoxetine combination has been studied in FDA‐defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA‐approved for individuals with TRD, with accelerated theta‐burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non‐inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual‐based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Raison C.L., Sanacora G., Woolley J., Heinzerling K., Dunlop B.W., Brown R.T., Kakar R., Hassman M., Trivedi R.P., Robison R., Gukasyan N., Nayak S.M., Hu X., O’Donnell K.C., Kelmendi B., et. al.

ImportancePsilocybin shows promise as a treatment for major depressive disorder (MDD).ObjectiveTo evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD.Design, Setting, and ParticipantsIn this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days’ duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing.InterventionsInterventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support.Main Outcomes and MeasuresThe primary outcome was change in central rater–assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment.ResultsA total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,−12.3 [95% CI, −17.5 to −7.2]; P &amp;lt;.001) and from baseline to day 8 (mean difference, −12.0 [95% CI, −16.6 to −7.4]; P &amp;lt; .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, −2.31 [95% CI, 3.50-1.11]; P &amp;lt; .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.Conclusions and RelevancePsilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin—when administered with psychological support—may hold promise as a novel intervention for MDD.Trial RegistrationClinicalTrials.gov Identifier: NCT03866174

de A. Simoes Moreira D., Gauer L.E., Teixeira G., Fonseca da Silva A.C., Cavalcanti S., Quevedo J.

ECT is considered the fastest and most effective treatment for TRD. Ketamine seems to be an attractive alternative due to its rapid-onset antidepressant effects and impact on suicidal thoughts. This study aimed to compare efficacy and tolerability of ECT and ketamine for different depression outcomes (PROSPERO/CRD42022349220). We searched MEDLINE, Web of Science, Embase, PsycINFO, Google Scholar, Cochrane Library and trial registries, which were the ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform, without restrictions on publication date. Selection criteria: randomized controlled trials or cohorts comparing ketamine versus ECT in patients with TRD. Eight studies met the inclusion criteria (of 2875 retrieved). Random-effects models comparing ketamine and ECT regarding the following outcomes were conducted: a) reduction of depressive symptoms severity through scales, g = −0.12, p = 0.68; b) response to therapy, RR = 0.89, p = 0.51; c) reported side-effects: dissociative symptoms, RR = 5.41, p = 0.06; nausea, RR = 0.73, p = 0.47; muscle pain, RR = 0.25, p = 0.02; and headache, RR = 0.39, p = 0.08. Influential & subgroup analyses were performed. Methodological issues with high risk of bias in some of the source material, reduced number of eligible studies with high in-between heterogeneity and small sample sizes. Our study showed no evidence to support the superiority of ketamine over ECT for severity of depressive symptoms and response to therapy. Regarding side effects, there was a statistically significant decreased risk of muscle pain in patients treated with ketamine compared to ECT.

Xue T., Wu X., Li J., Chen S., Wang Z., Tan X., Wang Z., Zhang J.

Background: Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited.Methods: PubMed, Embase, Cochrane Library, and Clinicaltrials. gov were systematically searched to identify relevant studies published before 31 October 2022. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework.Results: We pooled 7257 participants from 9 randomized controlled trials (RCTs). Moderate to high certainty evidence demonstrated suvorexant (20 and 40 mg) and daridorexant (10 and 50 mg) as the most effective in latency to persistent sleep (LPS) reduction. Lemborexant at 5 and 10 mg was the most effective in subjective sleep onset time (sTSO) reduction. For wake time after sleep onset (WASO), all drugs except daridorexant 5 mg were more effective than placebo. Lemborexant 5 mg was among the best in subjective WASO (sWASO) (moderate to high certainty) and had the highest surface under the curve ranking area (SUCRA) values for sWASO (100%). For total sleep time (TST), suvorexant and daridorexant, except the respective minimum doses, were more effective than placebo, while suvorexant 40 mg and lemborexant 10 mg may have been the most effective for subjective TST (sTST) (low to very low certainty). Suvorexant 40 mg (RR 1.09), suvorexant 80 mg (RR 1.65), and daridorexant 25 mg (RR 1.16) showed a higher safety risk than placebo.Conclusion: Suvorexant 20 mg, lemborexant 5 mg, lemborexant 10 mg, and daridorexant 50 mg represent suitable approaches for insomnia.Clinical Trial Registration:clinicaltrials.gov, PROSPERO (CRD42022362655).

Bonifazi A., Del Bello F., Giorgioni G., Piergentili A., Saab E., Botticelli L., Cifani C., Micioni Di Bonaventura E., Micioni Di Bonaventura M.V., Quaglia W.

Correll C.U., Solmi M., Cortese S., Fava M., Højlund M., Kraemer H.C., McIntyre R.S., Pine D.S., Schneider L.S., Kane J.M.

Munafò A., Arillotta D., Mannaioni G., Schifano F., Bernardini R., Cantarella G.

Psilocybin has been suggested as a promising transdiagnostic treatment strategy for a wide range of psychiatric disorders. Recent findings showed that psychedelic-assisted/”psycholitic” psychotherapy should provide significant and sustained alleviation of depressive symptoms. However, to date, there have been several study limitations (e.g., small sample sizes, blinding, limited follow-up, highly screened treatment populations) and some health/political issues, including practitioners’ experience, lack of standardized protocols, psychedelics’ legal status, ethical concerns, and potential psychological/psychopathological/medical untoward effects. The focus here is on a range of clinical and methodological issues, also aiming at outlining some possible suggestions. We are confident that newer evidence, more precise protocols, and eventual reclassification policies may allow a better understanding of the real potential of psilocybin as a transdiagnostic therapeutic molecule.