Search Results (421)

Background: This systematic review and meta-analysis evaluates the efficacy and safety of psilocybin-assisted psychotherapy (PAP) for adults with major depressive disorder (MDD). Methods: A PROSPERO-registered search (CRD42024561979) of CENTRAL, Scopus, PsycINFO, and MEDLINE (2010–2024) identified clinical trials assessing PAP. Risk of bias was assessed using RoB 2 for randomized controlled trials (RCTs), while non-randomized studies were appraised separately. Evidence certainty was evaluated using GRADE. Results: Ten trials were included; eight provided quantitative data. PAP was associated with large short-term reductions in depressive symptom severity. The overall pooled effect was large (d = 1.15, 95% CI 0.83–1.48), though within-subject designs yielded larger estimates (d = 1.63) than between-subject controlled comparisons (d = 0.96). Adverse events were transient and manageable, with no increased risk of serious adverse events on dosing days. Primary risk-of-bias concerns included functional unblinding. Conclusions: PAP may produce clinically meaningful, large short-term reductions in depressive symptoms. However, long-term efficacy remains understudied, and the overall certainty of evidence is low to moderate. Larger, rigorously blinded trials are required. Full article

Background: Treatment-resistant depression (TRD) poses a major clinical challenge, particularly when accompanied by suicidal behavior. Intranasal esketamine has demonstrated rapid antidepressant effects in TRD, but real-world comparative evidence remains limited. Methods: We conducted a six-month naturalistic prospective cohort study in two Spanish mental health centers, including 62 TRD patients with high suicide risk undergoing fourth-line treatment. Thirty patients received intranasal esketamine and thirty-two alternative pharmacological interventions. Suicidal ideation (C-SSRS), depressive symptoms (HAM-D-17) and functional status (FAST) were assessed at baseline and at 1-, 3- and 6-month follow-ups. Results: Both groups showed significant improvement during follow-up; however, esketamine-treated patients exhibited a faster and greater reduction in suicidal ideation and depressive symptoms than those receiving alternative pharmacological strategies. The number needed to treat to prevent one case of high suicide risk was 1.35. Functional improvement was comparable between groups. Conclusions: In real-world clinical settings, intranasal esketamine was associated with a faster and greater reduction in suicidal ideation and depressive symptoms among TRD patients with high suicide risk, supporting its role as a rapid-acting therapeutic option within comprehensive and closely monitored care. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric disorder with a high prevalence. Neuroinflammation may define biologically distinct patient subgroups with different mechanisms, clinical phenotypes, and treatment responses. This narrative review integrates current evidence around three linked questions: how neuroinflammatory processes contribute to depression, how biomarkers can identify clinically relevant inflammatory phenotypes, and how these findings can inform anti-inflammatory treatment strategies. The major mechanisms discussed include microglial activation and neuroimmune signaling, hypothalamic–pituitary–adrenal axis dysregulation and glucocorticoid receptor resistance, kynurenine pathway alterations, and cytokine-driven impairment of neurogenesis and synaptic plasticity. These pathways interact with stress responses, neurotransmitter systems, and neuronal function, while their expression may vary according to sex, age, hormonal status, disease stage, and treatment exposure. These interconnected pathways may contribute to depressive symptoms by disrupting neurotransmitter systems and impairing neural plasticity. In addition, this review discusses several candidate biomarkers, including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF) and transforming growth factor-β1 (TGF-β), which may support patient stratification, treatment prediction, and assessment of target engagement. Clinical trials of anti-inflammatory agents have shown inconsistent and generally modest effects in unselected MDD populations. By integrating mechanistic evidence with biomarker-guided therapeutic implications, this review aims to clarify how neuroinflammatory research may inform more precise and individualized treatment strategies for depression. Full article

Background/Objectives: Treatment-resistant depression (TRD) remains one of the most urgent unmet needs in psychiatry, while its therapeutic pipeline is evolving rapidly. To characterize current development trajectories, we conducted a registry-anchored mapping of interventional trials in adults with major depressive disorder and treatment resistance (MDD-TRD), with the aim of defining the distribution of intervention types, endpoint choices, and key design features across the active trial landscape. Methods: We systematically searched ClinicalTrials.gov, the EU Clinical Trials Information System, and ISRCTN for interventional MDD-TRD trials registered up to 18 September 2025. After data cleaning and cross-registry deduplication, 237 unique trials were retained. Interventions were categorized through a taxonomy distinguishing device-based neuromodulation, pharmacological strategies, biologic/novel agents, multimodal non-digital combinations, digital–hybrid programs, psychotherapy, and lifestyle interventions, with classification anchored on structured registry intervention tags and whole-word matching across title and intervention text. Primary endpoints were flagged as standard when they explicitly referenced the Montgomery–Åsberg Depression Rating Scale or Hamilton Depression Rating Scale. We also examined developmental phase, sample size, and recurrent methodological features. Results: Device-based neuromodulation accounted for the largest share of the active pipeline (114/237, 48.1%), followed by pharmacological strategies (86/237, 36.3%), biologic/novel agents (16/237, 6.8%), and multimodal non-digital combinations (11/237, 4.6%). Digital–hybrid programs represented a small but distinctive stratum (5/237, 2.1%), with the remaining records comprising lifestyle interventions (3/237, 1.3%) and psychotherapy (2/237, 0.8%). Standard clinician-rated primary endpoints were used in 63.3% of studies. Trial development was concentrated in mid-phase designs, whereas sample sizes were generally modest (median 49; interquartile range, 19–87). Across modalities, increasing attention was directed to durability of response, functioning, and patient-reported outcomes, with adaptive and enrichment-based designs appearing with greater frequency. Conclusions: The contemporary TRD trial ecosystem is structured around two co-active developmental tracks—device-based neuromodulation and pharmacology with novel mechanisms—accompanied by a smaller but measurably expanding biologic/novel stratum and a still-marginal digital–hybrid presence. This registry-based mapping provides a near-real-time overview of the field and may support future harmonization of trial endpoints and design standards. Full article

Background/Objectives: Bipolar disorder affects about 40 million people worldwide, and the greatest burden of the disease is associated with depressive episodes. About 25% of patients experience drug-resistant depression, in which standard treatment turns out to be insufficient, and monotherapy often does not bring full remission. Despite the use of second-generation antipsychotics, the effectiveness of therapy in TRBD remains limited, which necessitates rational polypharmacotherapy and augmentation strategies. The paper discusses the receptor mechanisms of drug combination, current therapeutic regimens and new interventions such as ketamine acting on the glutamate anergic system. The aim was to synthetically compare the efficacy and safety of available augmentation strategies and polypharmacotherapy. Methods: The material consists of published clinical, observational and randomized trials on pharmacotherapy of drug-resistant bipolar depression, including atypical neuroleptics, ketamine, pramipexole, modafinil, lamotrigine, celecoxib and memantine. The authors analyze receptor mechanisms, neurobiological data and clinical trial results, comparing them with current definitions of TRBD according to ISBD and CINP. Biomarker data, such as the Systemic Immune-Inflammation Index, and the results of neuroimaging and metabolomic studies were also used in the work. Results: The analysis showed that atypical neuroleptics showed limited efficacy and high rates of side effects, while ketamine has the fastest and most pronounced antidepressant effect with a low risk of phase change. Pramipexole has shown promise in terms of long-term efficacy, but its use reduces the high risk of induction of mania and impulse control disorders. Celecoxib as an anti-inflammatory therapy significantly increased response and remission rates compared to escitalopram alone, and memantine showed only an early, short-term antidepressant effect. The results highlight that TRBD requires targeted polypharmacotherapy, with the most promising directions being glutamatergic modulation and anti-inflammatory therapies. Conclusions: Drug-resistant bipolar depression requires a departure from classical monotherapy in favor of rational, mechanistically justified polypharmacotherapy, targeting complex monoaminergic, glutamatergic and neuroinflammatory disorders. Available data indicate that ketamine has the greatest clinical potential among the current strategies, characterized by a rapid onset of action and a favorable safety profile compared to atypical neuroleptics or dopamine agonists. Modulation of inflammatory processes with the use of celecoxib also has promising results, which highlights the importance of biomarkers and personalization of therapy. However, further, large, and well-designed studies are needed to unambiguously determine optimal treatment strategies for TRBD and to verify the effectiveness of new pharmacological interventions. Full article

Background: Treatment-resistant depression (TRD) represents a major clinical challenge and is increasingly associated with persistent neuroinflammatory processes. Evidence suggests that dysregulation of the immune system, particularly the imbalance between pro-inflammatory and anti-inflammatory cytokines, contributes to poor therapeutic response. In this context, interleukin-10 (IL-10) has emerged as a key mediator in regulating the inflammatory response. Objective: To systematically analyze the evidence on neuroimmune dysregulation in depression, with an emphasis on TRD, and to evaluate the potential role of IL-10 as a biomarker and modulator of therapeutic response. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Fourteen studies were included, comprising randomized clinical trials, longitudinal studies, a prospective cohort study, and exploratory designs. Methodological quality was assessed using the RoB 2 tool and complementary approaches. Data were integrated through a qualitative analysis focused on inflammatory biomarkers and clinical outcomes. Results: The studies consistently showed an association between elevated levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, and the severity of depressive symptoms, as well as reduced response to conventional treatments. Immunomodulatory interventions, including ketamine, pentoxifylline, and minocycline, were associated with clinical improvement, particularly in patients with elevated baseline inflammation. IL-10 appears to be involved in counter-regulatory neuroimmune processes associated with inflammatory balance. Conclusions: Neuroinflammation plays a central role in TRD. IL-10 may serve as a relevant biomarker and a potential target for personalized therapeutic strategies informed by immune profiles, through modulation of neuroinflammatory pathways. Full article

This scoping review synthesized evidence on the psychosocial burden of tuberculosis (TB) and on evidence-based psychosocial interventions aimed at improving treatment adherence. Specifically, it examined: (a) the most frequent mental health problems associated with TB; (b) the main barriers to adherence; (c) the components and effects of psychosocial interventions; and (d) gaps in the literature and directions for future research. Bibliographic searches were conducted in PubMed and Scopus, covering articles published between 2005 and 2025. Nineteen studies met the inclusion criteria. Depression and anxiety were the most frequently reported mental health problems, while psychosis appeared mainly in multidrug-resistant TB (MDR-TB) populations. Across studies, stigma, fear of transmission, socioeconomic disadvantage, treatment duration, and medication side effects emerged as major barriers to adherence. Evidence-based interventions—including psychoeducation, motivational enhancement therapy, cognitive behavioral therapy, acceptance and commitment therapy, and multicomponent psychosocial support—were associated with improved psychological outcomes and, in several studies, better adherence-related indicators. Overall, the evidence suggests that psychosocial distress is common among people with TB and may compromise treatment engagement. Integrating psychosocial and mental health support into TB services may therefore strengthen adherence and improve patient-centered outcomes, although more rigorous and context-sensitive research is still needed. Full article

Background and Objectives: Treatment-resistant depression (TRD) is a major clinical challenge in the management of major depressive disorder (MDD). While pharmacogenetics has been suggested to be clinically useful in guiding antidepressant treatment, few studies have explored if and how pharmacogenes can be involved in TRD pathophysiology and its clinical outcomes. Material amd Methods: We explored the role of differences in metabolizer phenotypes, gene expression levels, and microRNAs of three key pharmacogenes (CYP2D6, CYP2C19, CYP2B6) in TRD pathophysiology and antidepressant response in a cohort of 300 patients with MDD from the PROMPT consortium. Results: CYP2D6 phenotype distribution did not differ significantly between TRD and non-TRD groups, but mRNA expression was significantly upregulated in TRD. Hsa-miR-26b-5p, a microRNA predicted to regulate CYP2D6, was significantly downregulated in TRD. For CYP2C19, intermediate metabolizers (IMs) were underrepresented in TRD versus non-TRD (IMs vs. normal metabolizers (NMs): χ² = 6.07, p = 0.019). microRNA hsa-let-7d-5p and hsa-miR-27a-3p, predicted to regulate CYP2C19, were significantly downregulated in TRD. No significant differences were found for CYP2B6. Conclusions: This study contributes valuable insights to the PROMPT project on how pharmacokinetic gene variants and their expression and regulatory mechanisms may influence antidepressant response and resistance in MDD. Full article

Trauma-related autobiographical memories can manifest as involuntary, vivid, emotionally charged intrusions that perpetuate avoidance, negative emotions, and functional impairment. While these memories are central to post-traumatic stress disorder (PTSD), they also occur across diagnoses and are often reported in depressive disorders, including treatment-resistant depression (TRD). Although trauma-focused psychotherapies are effective, their routine implementation can be limited by dropout, residual symptoms, and difficulty engaging patients with severe depression, dissociation, or complex comorbidities. Intranasal esketamine is an approved rapid-acting treatment for TRD and has been hypothesized to create transient conditions that may facilitate psychotherapeutic work on traumatic memories. This narrative review synthesizes clinical and translational evidence on ketamine and esketamine for PTSD and trauma-related symptoms, with particular attention to the distinction between intravenous ketamine studies, intranasal esketamine data, and studies combining these compounds with psychotherapy. Currently, the most robust evidence in this area comes from three randomised trials of intravenous ketamine for PTSD. In contrast, data on intranasal esketamine and psychotherapy-combination approaches are mainly from pilot studies, retrospective analyses, or case reports. We additionally propose a pragmatic, feasibility-oriented protocol integrating intranasal esketamine with a structured traumatic-memory intervention for TRD patients with clinically relevant trauma-memory symptoms. The novelty of the proposal does not lie in claiming efficacy, but in specifying a standardised imagery rescripting module and predefining two timing hypotheses. The proposal targets patients with TRD with relevant trauma-memory symptoms, and it embeds the intervention within existing esketamine-care infrastructure. Overall, the available literature supports mechanistic plausibility and preliminary feasibility more than clinical efficacy. The evidence base remains small, heterogeneous, and largely uncontrolled, and controlled studies are needed before efficacy claims can be made. Full article

Aging is associated with chronic, low-grade inflammation (“inflammaging”), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer’s disease, and Parkinson’s disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug–drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a partial agonist at the 5-HT_2A receptor and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT_2A receptor-mediated signaling modulates cortical glutamatergic transmission, enhances tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathways, and modulates neuroimmune cascades (includingnuclear factor kappa B (NF-κB), with convergent systems-level effects such as reorganization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these findings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin’s neuroimmune and pharmacokinetic mechanisms relevant to aging, outlining its potential role in inflammation-related disorders and highlighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research. Full article

Recent Phase 3 clinical trials of selective kappa-opioid (KOP) receptor antagonists aticaprant and navacaprant failed to demonstrate sufficient clinical efficacy in treatment-resistant depression (TRD). This highlights a critical gap in current strategies that target opioid-mediated hedonic suppression. We propose two hypotheses to explain these setbacks: (1) neutral antagonists are inherently ineffective in blocking constitutively active KOP receptor hyperactivation and (2) the nociceptin opioid (NOP) receptor provides functional redundancy that compensates for KOP receptor blockade. Gaining insights from paralogous compensation in drug-resistant tumors, we argue for shifting from selective opioid antagonists to dual KOP/NOP receptor blockers to meaningfully improve reward function. This concept provides a theoretical framework for overcoming clinical resistance where selective KOP targeting with neutral antagonists has failed. Thus, we advocate for the development of opioid inverse agonists (such as nor-BNI, CAS: 105618-26-6), pan-antagonists (such as AT-076, CAS: 1657028-64-2), and combinations of selective blockers. Full article

Background/Objectives: Major depressive disorder (MDD) remains a leading cause of disability worldwide and exhibits substantial biological heterogeneity that is not adequately captured by current symptom-based diagnostic systems. While the classical monoamine hypothesis has historically guided antidepressant development, it does not fully account for variability in treatment response, delayed therapeutic onset, or the persistence of cognitive and anhedonic symptoms. Converging evidence from molecular, neuroimaging, and translational studies increasingly implicates glutamatergic dysregulation and impaired neuroplasticity as key mechanisms in depressive pathology. This narrative review aims to integrate monoaminergic and glutamatergic perspectives within a dimensional framework that may help explain clinical heterogeneity and inform mechanism-based treatment strategies. Methods: A narrative synthesis of the literature was conducted using major biomedical databases including PubMed, Scopus, and Web of Science. Preclinical studies, neuroimaging investigations, biomarker research, randomized clinical trials, and meta-analyses examining monoaminergic dysfunction, glutamatergic signaling, neuroplasticity pathways, and rapid-acting antidepressants were reviewed and thematically integrated. Results: Evidence indicates that depressive syndromes may reflect varying contributions of monoaminergic dysregulation and glutamatergic–neuroplastic impairment. Monoaminergic disturbances interact with inflammatory and neuroendocrine processes, including cytokine-driven activation of the kynurenine pathway. In parallel, alterations in glutamatergic signaling, glial function, and BDNF–TrkB–mTOR pathways contribute to synaptic atrophy and network dysfunction. Rapid-acting antidepressants such as ketamine, esketamine, and dextromethorphan–bupropion provide clinical proof-of-concept that direct engagement of synaptic plasticity mechanisms can accelerate symptom improvement, particularly in treatment-resistant depression. Conclusions: Integrating monoaminergic and glutamatergic mechanisms within a “monoamine–glutamate continuum” offers a conceptual framework for understanding depressive heterogeneity and treatment response. Multimodal approaches combining clinical phenotyping with inflammatory, neuroimaging, and molecular markers may ultimately support mechanism-informed precision psychiatry strategies in major depressive disorder. Full article

Home has been recognized as a health infrastructure through hospital-at-home, home care, and direct-to-consumer wellness and fitness products. However, the patient home environment has been largely overlooked by healthcare as a means to improve therapy outcomes for difficult-to-treat chronic conditions, such as migraine; high-impact pain; and treatment-resistant depression, anxiety, or insomnia. Growing research evidence enables the formulation of a therapeutic home environment standard consisting of three pillars: biophilic design, indoor environmental quality, and intentional self-care spaces that serve as habit cues and foster sleep hygiene, stress management, relaxation, physical activity, and social interactions. Together, these environmental and behavioral interventions can transform real-world inputs into clinical benefits through autonomic, circadian, and emotional regulation. We also highlight the converging roles of self-management, self-efficacy, self-regulation, and self-compassion in sustaining patient engagement and healing at home. The applicability of the therapeutic home environment as an adjunct is illustrated in the case of chronic migraine, a debilitating neurological condition commonly associated with comorbidities. Current challenges in achieving migraine freedom with FDA-approved pharmacotherapies, neuromodulation devices, and digital health technologies are underscored by the high prevalence of refractory, chronic, episodic, and pediatric migraine. Perspectives on developing a personalized, multimodal cure for migraine are illustrated through a hypothetical drug + digital combination therapy comprising anti-CGRP drugs and an AI-powered digital health platform that promotes daily self-care practices within the therapeutic home environments. In conclusion, achieving sustained freedom from high-morbidity conditions requires end-to-end care ecosystems that integrate pharmacological, cognitive, behavioral, and environmental interventions into real-world settings. Full article

Major depressive disorder (MDD) affects over 330 million people globally, yet up to 30% of patients fail initial pharmacotherapy due to genetic variability in drug metabolism. This narrative review synthesizes evidence on pharmacogenomic (PGx) guided approaches for MDD, emphasizing their integration with POC diagnostics and engineering solutions. Approximately 40–50% of patients carry actionable variants in CYP2C19 or CYP2D6, which govern the metabolism of selective serotonin reuptake inhibitors. Landmark trials (GUIDED, PRIME Care, GAPP-MDD) and meta-analyses demonstrate that PGx-informed prescribing modestly but significantly improves remission and response rates, particularly in treatment-resistant depression. Established guidelines from CPIC and the Dutch Pharmacogenetics Working Group provide actionable recommendations for CYP2D6 and CYP2C19 phenotypes. Emerging POC platforms, including Genomadix Cube and Genedrive, now deliver CYP2C19 results within one hour, supporting rapid clinical decisions. However, psychiatric-specific implementation data remain limited compared to cardiology; current POC devices lack multi-gene capabilities, and most studies underrepresent diverse populations. Persistent barriers include variable reimbursement, limited clinician education, and fragmented electronic health record integration. Future directions include pre-emptive genotyping, expanded multi-gene panels, and embedded clinical decision support. With continued engineering innovation and rigorous validation, PGx-guided care holds promise for reducing the trial-and-error burden and advancing precision psychiatry. Full article

Autism Spectrum Disorder (ASD) is a lifelong condition marked by challenges in social communication and repetitive behaviors. Current treatments, primarily behavioral therapies, often fail to address the core symptoms. Recent research has explored the potential of psychedelics, such as LSD, psilocybin, and MDMA, as a new therapeutic approach. While these substances primarily modulate the serotonin 5-HT_2A receptor, their therapeutic effects also involve interactions with other serotonergic, dopaminergic, and glutamatergic pathways, collectively promoting neuroplasticity—the brain’s ability to change and adapt. The specific receptors’ activation leads to structural and functional changes in the brain that can enhance social behavior and emotional regulation. Studies show that psychedelics may reduce symptoms of conditions like treatment-resistant depression and PTSD, highlighting their therapeutic potential. For ASD specifically, psychedelics may improve psychological flexibility, reduce distress, and enhance social interaction. While promising, the use of these substances requires careful consideration. Psychedelics can induce intense experiences and altered states of consciousness, necessitating strict monitoring and support during therapy. Ethical guidelines, including informed consent, are crucial, especially for vulnerable populations. In conclusion, psychedelics hold significant promise for treating ASD and other psychiatric disorders by promoting neuroplasticity and modulating complex signaling pathways. Continued research and clinical trials, conducted with strong ethical oversight, are essential to realizing their full therapeutic potential. Full article