Brain and Cognition Discovery Foundation

Anhedonia, a core symptom of depression, is often resistant to conventional treatments and significantly impacts quality of life. This secondary analysis aimed to evaluate the effects of psilocybin-assisted psychotherapy (PAP) on anhedonia severity in individuals with treatment-resistant depression (TRD). Participants (n=30) with TRD and a primary diagnosis of Major Depressive Disorder or Bipolar II Disorder received at least one 25mg dose of oral psilocybin with psychotherapy as part of a randomized, waitlist-controlled trial (NCT05029466). The primary outcome of the present secondary analysis was changes in anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Exploratory analysis examined whether changes in anhedonia were mediated through changes in overall depression severity, measured by the Montgomery-Asberg Depression Rating Scale (MADRS). A mixed ANOVA, adjusted for sex and age, revealed a statistically significant reduction in SHAPS scores following PAP at the 2-week primary endpoint (F(8, 143.48)=3.43, p=0.001, n=29) with clinically significant improvements observed at 3-month and 6-month secondary endpoints. Our findings from this preliminary analysis suggest that PAP may offer a promising intervention for addressing anhedonia in TRD, but further research with larger, placebo-controlled trials are needed to confirm these effects and elucidate potential mediators. This study adds to a growing body of evidence supporting the therapeutic potential of PAP.

Reports of aspects of suicidality and exposure to select GLP-1 RAs exist; notwithstanding, no causality between GLP-1 RA exposure and suicidality is apparent.

Functional impairment is commonly reported amongst individuals with major depressive disorder (MDD) or treatment-resistant depression (TRD). Extant evidence suggests that ketamine and esketamine, N-methyl-D-aspartate (NMDA) receptor antagonists and glutamatergic modulators, have shown efficacy in treating MDD/TRD. While symptom reduction remains central to treatment, many individuals with TRD continue to experience work, social and family difficulties even when mood symptoms remit. Hence, this review synthesizes evidence on the effect of es/ketamine on functional outcomes, as measured by workplace productivity and psychosocial function. A systematic search was conducted in PubMed, OVID (Embase) and PsychInfo through February 1, 2025. Eligible studies were randomized controlled trials (RCTs) or post hoc RCT analyses in adults (≥18 years) with MDD or TRD, examining ketamine (R- or S-enantiomer, intravenous) or intranasal esketamine. Comparators included placebo, standard care, antidepressants or other active agents. Primary outcomes were functional impairment, workplace performance and related domains. No controlled studies were identified for ketamine, emphasizing a considerable gap in literature. Nine studies investigated esketamine and functional impairment. Significant mean [sd] reduction in Sheehan Disability Scale (SDS) scores were observed with esketamine (-13.6, [8.31]) versus placebo (-9.4, [8.43]). Workplace productivity also significantly improved; notably, reduced productivity loss (p=0.0045), presenteeism (p=0.0098), and activity impairment (p=0.0172) relative to controls. Esketamine alleviates depressive symptoms and improves functioning, notably in workplace domains. Future studies should include functional outcomes as key secondary or co-primary outcomes, reflecting the ultimate goal of recovery in TRD/MDD.

Extant literature pertaining to the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Alzheimer’s disease, Parkinson’s disease, major depressive disorder, bipolar disorder, substance-, alcohol- and nicotine-use disorders, suggests promising efficacy beyond the current FDA-approved indications (e.g., type 2 diabetes mellitus, obesity). The implicated brain regions of the aforementioned mental disorders contain glucagon-like peptide 1 (GLP-1) receptors associated with improving cognitive and behavioral functioning. Therefore, we aimed to systematically review the treatment effects of GLP-1RAs in various neurocognitive and psychiatric disorders. Online databases including PubMed, OVID, MEDLINE, Embase, PsycINFO and Google Scholar, were searched from inception until October 1, 2024. Additional studies were identified from the reference lists of the included articles. 22 studies were identified, with a total of 186,847 participants included. Results reported that GLP-1RAs meaningfully improved cognitive and affective functioning (e.g., memory), which in some cases was sustained beyond exposure to the agent. Separately, multiple epidemiological studies reported that GLP-1RAs have protective effects, with a suggestion of decrease in the incidence of mental disorders. These results provides the impetus for large, long-term, randomized controlled trials for GLP-1 RAs for the treatment of various mental disorders. This review is not registered in PROSPERO or any other registry.

Background: N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the brain and pancreas. Preliminary evidence indicates that aberrant NMDAR-mediated glutamatergic signaling may disrupt pancreatic islet function and glucose-insulin homeostasis. The frequent comorbidity of depression and diabetes underscores the potential role of NMDAR signaling in pancreatic function as a shared pathophysiological mechanism. Herein, this systematic review aims to evaluate the effects of NMDAR antagonism on pancreatic cells (i.e., alpha, beta, delta) viability and function (i.e., activation, hormone production, and release). Methods: We performed a systematic search on PubMed and Ovid databases from inception to September 11, 2024. A manual search was also conducted on Google Scholar and Scopus databases. Eligible studies were primary, controlled in vitro or in vivo studies investigating the effects of NMDAR antagonism on pancreatic islet function and viability. Results were synthesized and presented descriptively. Risk of bias was assessed independently by two reviewers using a modified SYRCLE risk of bias tool. Results: We reviewed 14 studies evaluating NMDA receptor antagonism in whole islets, beta and alpha cells; however, no studies evaluated delta cells. Within beta cells, NMDAR antagonism improved glucose-stimulated insulin secretion and increased cell proliferation and viability. Similarly, alpha cells were protected against stress-induced apoptosis. Conclusion: Our results suggest that NMDAR antagonism improves alpha and beta cell function and viability, which may have translational relevance to comorbid metabolic dysfunction in depression. These mechanisms may subserve the antidepressant effects of select NMDA antagonists (e.g., ketamine/esketamine, dextromethorphan). Further research should aim to investigate the effects of subanesthetic doses of ketamine/esketamine on pancreatic function and on delta cells.

BackgroundMajor depressive disorder (MDD) is often accompanied by somatic symptoms, but their longitudinal relationship with suicidal ideation (SI) remains insufficiently characterized. This longitudinal study in MDD patients aimed to (1) examine the associations between somatic symptoms (including total, pain, autonomic, energy, and CNS symptoms) and SI, and (2) investigate potential non-linear relationships among somatic symptoms and their subtypes with SI.MethodsData was collected from patients with MDD in the Depression Cohort in China. The 28-item Somatic Symptoms Inventory (SSI) was used to assess somatic symptoms. SI was measured using the Beck Scale for Suicide Ideation (BSSI). Assessments were conducted at baseline and at weeks 4, 8, 12, 24, 48, and 72. Generalized estimating equations were utilized for exploring the associations of somatic symptoms and their subtypes with SI. GEE across three distinct models: Model 1 (unadjusted); Model 2 adjusted for sociodemographic and lifestyle factors; and Model 3 additionally adjusted for clinical characteristics. All models accounted for baseline SI.ResultsThese studies consisted of 1274 individuals with MDD (mean [SD], 27.7 [6.8] years; 399 (31.3%) males). The adjusted odds ratios (ORs) for SI across quartiles of total somatic symptom scores were 1.0 (reference), 0.95 (95% CI: 0.85-1.07, P = 0.419), 1.20 (95% CI: 1.03-1.41, P = 0.022), and 1.71 (95% CI: 1.39-2.11, P < 0.001) for quartiles 1,2, 3, and 4, respectively. Pain, autonomic, energy, and CNS symptoms showed similar results. A non-linear association (P for nonlinear < 0.001) was observed between total somatic symptom scores and SI. When the total somatic symptom score is below 49, the risk of SI remains at a relatively low level. However, when these scores exceeded the mentioned values, the risk of SI increases rapidly.ConclusionsOur findings suggest that in patients with MDD, there is a significant association between somatic symptoms and their subtypes with SI. Notably, the risk of SI is significantly increased by somatic symptoms in a nonlinear manner. These findings highlight the necessity of addressing somatic symptoms in the management of depression and emphasize the importance of developing targeted interventions to mitigate suicide risk in this vulnerable population.

Psychedelics have re-emerged as promising treatments for mood disorders. The current model provides a moderate-to-high dose of a psychedelic agent (e.g., psilocybin) to reliably induce an altered state of consciousness. Unfortunately, the hallucinatory effects limit the treatment's potential scalability given patients' vulnerability and extensive monitoring costs, leading to growing interest in non-hallucinatory psychedelics (NHPs). This review's objective was to identify, summarize and synthesize all published pre-clinical and clinical studies evaluating NHPs for mood and anxiety disorders. We included five animal studies demonstrating antidepressant-like effects through assessments like forced swim test (FST) and open field test (OFT) without observing head-twitch response (HTR), and one case report that identified a patient who inadvertently combined trazodone and psilocybin and experienced potent antidepressant effects without psychedelic effects. These preliminary findings provide a strong impetus for further investigation in human samples with rigorously designed clinical trials that may delineate the potential antidepressant effects of psychedelics without hallucinatory effects.