Major depressive disorder (MDD) is a severe mental disorder associated with significant functional impairment and decreased quality of life. Growing evidence suggests that immune-inflammatory mechanisms, particularly cytokine dysregulation, take part in its development and course. This systematic review and meta-analysis aimed to evaluate whether cytokine alterations are present in early stages of MDD, specifically in first-episode (FE) and drug-naïve (DN) patients. Following PRISMA guidelines a comprehensive search of PubMed, Scopus, and Web of Science was conducted in March 2025. Studies were eligible if they compared levels of inflammatory cytokines between adult FE or DN MDD patients and healthy controls (HCs). Meta-analyses using random-effects models were performed, including subanalyses depending on the source of the sample and the quality of the studies. In total, 17 eligible studies involving 1371 MDD patients were included. The meta-analysis showed significantly elevated levels of interleukin 6 (IL-6), interleukin 2 (IL-2), and tumor necrosis factor alfa (TNF-α) in FE patients compared to HCs. DN patients’ quantitative analysis showed increased levels of IL-6, IL-2, interleukin 4 (IL-4), interleukin 10 (IL-10), TNF-α, and interferon gamma (IFN-γ) compared to healthy individuals. Moreover, in the case of TNF-α, IL-2, interleukin 1 beta (IL-1β), and IL-4, there was a difference in results depending on the sample source (plasma/serum). Cytokine dysregulation is present in first-episode and drug-naïve MDD individuals. These findings highlight that the immune–inflammatory response exists in the early stages of this disorder. Moreover, since more cytokines were elevated in DN patients, pharmacological antidepressant treatment might be a significant factor involved in inflammatory regulation in MDD. Nonetheless, future prospective studies with standardized protocols and division by clinical subtypes are needed to better understand the dynamics and clinical relevance of cytokine alterations in depression.

Background: Psychedelic-assisted therapy is gaining renewed attention as a potential treatment for various mental disorders. Despite increasing numbers of randomized controlled trials (RCTs) and meta-analyses, a comprehensive synthesis of the evidence across different substances and indications is lacking. This umbrella review aims to evaluate the effectiveness and safety of psychedelic-assisted therapy—primarily psilocybin, MDMA, and LSD—across major psychiatric disorders, including depression, post-traumatic stress disorder (PTSD), and substance use disorders. Methods: We systematically identified and synthesized data from 23 meta-analyses encompassing over 100 primary studies. Outcomes were standardized and re-expressed as Hedges’ g to enable cross-study comparisons. Study quality was assessed using AMSTAR2, and certainty of evidence was evaluated via the GRADE framework. Results: The number of identified meta-analyses differed markedly depending on the substance and clinical indication: psilocybin for depression (n = 9) and MDMA for PTSD (n = 10) had the strongest evidence base, while fewer meta-analyses were available for LSD in alcohol use disorder (n = 2) and depression (n = 2), ayahuasca in depression (n = 2), and MDMA in autism spectrum disorder (n = 2). Psilocybin demonstrated large effect sizes in major depression (Hedges’ g ≈ 1.05), with some evidence of sustained benefits up to six months. MDMA showed very large effects in reducing PTSD symptoms (Hedges’ g ≈ 1.24), often after 2–3 sessions. LSD yielded short-term benefits for alcohol use disorder (OR ≈ 2.0), though effects declined over time. Across studies, adverse events were generally mild and transient, with no consistent signal for serious harm. Considerable methodological variability was observed, including small and sometimes overlapping samples, heterogeneity, risk of bias, and limited long-term data. These constraints should be taken into account when interpreting the overall findings. Conclusions: Current evidence supports the short-term efficacy and safety of psychedelic-assisted therapy for selected psychiatric disorders, particularly depression and PTSD. However, the low methodological quality of studies and most meta-analyses, as well gaps in long-term safety data highlight the need for high-quality studies.

Major depressive disorder (MDD) and diabetes mellitus (DM) remain among the most prevalent diseases and the most significant challenges faced by medicine in the 21st century. The frequent co-occurrence and bidirectional relationship between the two conditions necessitates the identification of treatment strategies that benefit both. The purpose of this study was to systematically review and meta-analyze data on the efficacy and safety of agomelatine (AGO) in the treatment of patients with depression with comorbid diabetes to explore its potential mechanism of action in both diseases and its impact on diabetic parameters. Following PRISMA guidelines, a total of 11 studies were identified, both preclinical and clinical trials. Agomelatine has shown great potential as a treatment option for patients with diabetes and comorbid depression and anxiety. In addition to improving depressive and anxiety symptoms, it is also beneficial in glycemic control. A meta-analysis demonstrated a statistically significant reduction in glycated hemoglobin (HbA1C) and fasting blood glucose (FBG) levels following AGO administration over a period of 8–16 weeks. The administration of agomelatine was found to result in a significantly greater reduction in HbA1C than that observed with the selective serotonin reuptake inhibitor (SSRI) medications (namely fluoxetine, sertraline, and paroxetine) during 12–16 weeks of therapy. Furthermore, AGO has been found to be at least as effective as SSRIs in reducing depressive symptoms and more effective than SSRIs in reducing anxiety symptoms. The safety of such treatment is similar to SSRIs; no severe adverse events were reported, and the incidence of some side effects, such as insomnia and sexual dysfunction, are even less often reported. Particularly promising is also its potential action in improving some diabetic complications reported in preclinical trials. This might be through mechanisms involving the reduction in oxidative stress, anti-inflammatory effects, and potentially noradrenergic or NMDA receptor modulation. Further clinical studies on larger sample sizes, as well as elucidating its mechanisms of action, especially in the context of diabetic complications, are needed. Research should also focus on identifying the patient subpopulations most likely to benefit from agomelatine treatment.