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Recent evidence suggests that reduced peripheral levels of brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of bipolar disorder (BD), although its relevance in young populations remains uncertain. This systematic review synthesized studies that evaluated serum BDNF levels in children and adolescents with BD, examining its potential as a risk marker. Following PRISMA 2020 guidelines and a protocol registered in PROSPERO, searches were conducted in the Cochrane, MEDLINE, SciELO, and Scopus databases. Studies including participants aged 0-19 years diagnosed with BD according to DSM criteria were included. Studies with mixed samples (adults, children and adolescents) without separate age-group analyses were excluded. After screening and eligibility assessment, seven studies were included. Five of them included a control group, from which a meta-analysis was performed. Moderate methodological heterogeneity was observed and corrected after sensitivity analysis, reinforcing the robustness of the findings, although no statistically significant difference in serum BDNF levels was found between patients with bipolar disorder and controls. Current evidence does not support BDNF as a diagnostic biomarker for pediatric BD. Future studies with greater sample power and methodological standardization are needed to clarify its role in the risk and course of early-onset bipolar disorder. Show less

Major Depressive Disorder (MDD) is a multifactorial psychiatric disease influenced by a combination of genetic and environmental factors. Among the genes linked to MDD, the Melanocortin 1 Receptor (MC1R), Catechol-O-Methyltransferase (COMT), Brain-Derived Neurotrophic Factor (BDNF), and the serotonin transporter (5-HTT) are of particular interest due to their critical roles in stress regulation and neural function. Despite their biological significance, the contribution of specific polymorphisms within these genes to MDD risk remains understudied. This retrospective observational case-control study included 87 Colombian patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The control group comprised Latino/admixed individuals without, sourced from the gnomAD v2.1.1 database. The complete coding region of the MC1R gene and three polymorphisms: 5-HTTLPR Insertion/Deletion 44 bp, BDNF-c.196G>A, and COMT-c.472G>A were genotyped using PCR and Sanger sequencing. The polymorphisms rs885479 and rs4680 were identified as protective factors against MDD, while the polymorphisms rs796296176, rs779504604, rs1805005 were associated with an increased risk of developing MDD (OR:22.87, OR:51.26, OR: 1.97, respectively). Several of the analyzed polymorphisms (rs796296176, rs779504604, rs1805005) increase the risk for MDD. Notably, we provide novel evidence of these polymorphisms in MC1R as a risk to MDD. Show less

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application. Show less

We aim to verify clinical (depressive symptoms, rates of psychiatric admissions, and suicide attempts) and neurobiological (Brain-Derived Neurotrophic Factor - BDNF) changes in outpatients with depression undergoing evidence-based psychotherapies (EBP) over a 6-month follow-up. Longitudinal, naturalistic, prospective study, with 47 outpatients undergoing EBP, and 48 healthy controls (HC) for the BDNF levels comparisons. Data were collected at baseline and 6-month follow-up. Statistical analysis was performed using a paired t-test and a multiple linear regression model. BDI scores did not differ between baseline and 6-month follow-up (p = 0.253), and the rates of hospitalizations and suicide attempts at 6-month follow-up were 4.2% (2 cases reported). All patients were using psychotropics. BDNF levels at baseline and after 6-month follow-up did not vary significantly in the patient group (p = 0.314). There was no difference between patients' BDNF levels at baseline and HC BDNF levels (p = 0.211) and between patients' BDNF levels at 6-month follow-up and HC BDNF levels (p = 0.772). Using a mood stabilizer increased the BDNF levels. BDNF levels remained stable. Adding psychotherapy to medication may be associated with low rates of suicide attempts and psychiatric admissions in our sample. Our findings reinforce the importance of combined treatment in preventing adverse outcomes in naturalistic settings. Evidence supports the clinical effectiveness and economic efficiency of psychotherapy for patients with mental disorders, suggesting that outpatient psychotherapy can benefit healthcare systems and patients. Our findings corroborate the literature and reinforce the importance of psychotherapy associated with pharmacotherapy (combined treatment) to prevent outcomes such as further hospitalizations and suicide attempts, even in individuals with a history of severe psychiatric conditions. Research on how psychotherapy works, in terms of psychological mechanisms and its underlying effects on biological processes, is crucial. Scientific evidence makes it possible to include psychotherapies in public health policies worldwide, benefiting individuals suffering from mental disorders. Evidence from naturalistic designs is scarce in the literature. Show less

Despite available therapies for depression, many patients do not achieve adequate improvement, illustrating the need for innovative treatment strategies. Nutritional psychiatry is an emerging area, with increasing evidence that microbially derived butyrate contributes to the beneficial effects of dietary, pre-, pro- and synbiotics interventions - raising the exciting possibility that direct butyrate administration might alleviate depressive symptoms. The main objective was to systematically review the effects of butyrate on depressive symptoms in humans and depressive-like behavior in animals (PROSPERO; CRD42023g0739). A search was conducted in MEDLINE, Embase, PsycINFO, and Web of Science, ICTPR and ClinicalTrials.gov up to October 2025. Studies were included if they examined depressive symptoms in humans or relevant behaviors in animal models of depression/anxiety, involved treatment with butyrate formulations, included a control or pre-post comparison, and reported behavioral or clinical outcomes. Eligible designs included case-control, cohort, (randomized) controlled trials, experimental, or in vivo studies published in English or Dutch. Studies were excluded if depression was not the primary focus or if butyrate was combined with another treatment. Risk of bias was assessed with SYRCLE for animal studies and RoB 2 for the human studies. Of the two randomized controlled trials, one found no measurable effect of 1-week oral butyrate in healthy males, whereas the other found reductions in depressive and anxiety symptoms in patients with ulcerative colitis after 12-weeks oral butyrate. Thirty-two animal studies showed that butyrate generally modulated depressive- and anxiety-like phenotypes in rodents, potentially via anti-inflammatory, neuroplastic, epigenetic and gut-mediated mechanisms. Preclinical findings support the therapeutic promise of butyrate as a novel intervention for depression, warranting further clinical investigation. BDNF, Brain-derived neurotrophic factor; CRS, Chronic restraint stress; CSD, Chronic social defeat; CUMS, Chronic unpredictable mild stress; DASS, Depression, anxiety, Stress Scales; EPM, Elevated plus maze; FMT, Fecal microbiota transplant; FST, Forced swim test; HDAC, Histone deacetylase; HFD, High-fat diet; HPA, Hypothalamic-pituitary-adrenal; ICTRP International Clinical Trials Registry Platform; IL, Interleukin; LDB, Light-dark box; LEIDS-R, Leiden Index of Depression Severity-Revised; LPS, Lipopolysaccharide; MD, Maternal deprivation; MDD, Major depressive disorder; MGBA, Microbiota-gut-brain axis; NORT, Novel object recognition test; OFT, Open field test; PFC, Prefrontal cortex; PRISMA Preferred reporting items for systematic reviews and meta-analyses; SCFA, Short-chain fatty acid; SPT, Sucrose preference test; SYRCLE, Systematic Review Centre for Laboratory Animal Experimentation; TCA, Tricarboxylic acid; TNF, Tumor necrosis factor; TST, Tail suspension test; ZO-1, Zonulin-1. Show less