INTRODUCTION:Bipolar II disorder (BD-II) is characterised by hypomanic and depressive episodes with the latter tending to dominate the clinical course of the disorder, and they are often associated with suicidality. Despite available guideline-based recommendations for first-line pharmacological treatments, patient outcomes remain suboptimal, especially for those with chronic depression and suicidal ideation. The dearth of viable treatment options for this population is evident, which is where psychedelics propose an additional alternative path. Psilocybin has recently shown promise in treating major depressive disorder and treatment-resistant depression; however, individuals with bipolar disorder or suicidality are typically excluded from such trials due to safety concerns (ie, risk of emerging suicidal behaviour, psychosis and/or mania). Here, we present the protocol of a study which aims to explore the acceptability, safety and treatment preferences of psilocybin-assisted therapy in patients with BD-II struggling with suicidal ideation. METHODS AND ANALYSIS:This outpatient, single-site, phase II, single-arm, open-label clinical trial feasibility study will include 10 participants diagnosed with BD-II depression and moderately passive suicidal ideation. Participants may receive up to two oral doses of 25 mg psilocybin, approximately 4 weeks apart, alongside a structured therapeutic protocol (based on mindfulness cognitive-behavioural therapy) that includes preparatory therapy sessions, psychological support during administration and post-treatment integration therapy sessions. The purpose is to examine the acceptability and safety of using psilocybin as a therapeutic for mild to moderate suicidality in patients currently diagnosed with BD-II and to obtain preliminary data on its effects. This will be measured using the following: Primary outcomes include change in suicidality, that is, the Interpersonal Needs Questionnaire and the Columbia Suicide Severity Rating Scale from baseline to main endpoint (3 weeks post initial administration) and feasibility and acceptability (as assessed by number of participants who complete the trial, number of therapy sessions attended and number of assessments completed). Secondary outcomes include changes in the following associated measures: Montgomery-Asberg Depression Rating Scale, Quick Inventory of Depressive Symptomatology, Young Mania Rating Scale, Brief Psychiatric Rating Scale Positive Symptom Subscale, Altman Self-Rating Mania Scale. Findings will also be used to estimate effect sizes and inform the design of a future randomised controlled trial. ETHICS AND DISSEMINATION:Ethical approval has been obtained from the UTHealth Committee for the Protection of Human Subjects (CPHS RB# HSC-MS-23-0905). The results of the study will be disseminated to the public (ie, clinicians, researchers, patients and policymakers) through peer-reviewed journals, conferences and scientific meetings and clinical registries. TRIAL REGISTRATION NUMBER:NCT06706232.

Major depressive disorder (MDD) is a common psychiatric condition, and many patients do not respond to standard antidepressant treatments, developing what is known as treatment-resistant depression (TRD). The microbiota-gut-brain axis (MGBA) encompasses the biological processes underlying MDD and TRD. This two-way communication system connects the gut microbiome, the immune system, the central nervous system, and hormone signaling. Changes in the composition and diversity of gut microorganisms can affect neurotransmitter production, blood-brain barrier (BBB) function, immune function, and metabolic processes. These changes may contribute to the development and persistence of TRD. This review describes how the MGBA may influence TRD through mechanisms including BBB function, changes in the kynurenine pathway, variations in short-chain fatty acid (SCFA) production, immune and inflammatory responses, imbalances in the hypothalamic-pituitary-adrenal (HPA) axis, and disruptions in neurotransmitter signaling. The review discusses treatment strategies, focusing on the gut microbiome, including modifications, probiotics, and other approaches.

Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the effects of prenatal stress on behavior, inflammation, oxidative stress, and the HPA-axis in the dams and their offspring treated with lithium. Thirteen pregnant Wistar rats were exposed to a prenatal chronic unpredictable stress protocol from the 14th day of gestation until birth. At the 60th postnatal day (PND), a treatment protocol was carried out in the offspring with lithium (intraperitoneally – 47.5 mg/kg) or saline for seven days (twice a day). The behavior was assessed in the open field test to evaluate free movements. The dams (21 PND) and offspring (after open field) were euthanized, their brains were dissected in frontal cortex, hippocampus, and striatum, and the serum was collected. In the brain and/or serum, the levels of oxidative stress, inflammation, and HPA axis parameters were evaluated. Female offspring from stressed dams showed hyperactivity. Besides behavior alterations, offspring brain and serum showed an increase in pro-inflammatory cytokines, oxidative damage markers, and HPA axis hormones levels. Lithium administration only reduced the biochemical alterations. The prenatal stress protocol induced long-lasting behavior, inflammatory, oxidative stress, and HPA-axis alterations in the offspring which could underlie the development of psychiatric disorders.

Catatonia is a transdiagnostic psychomotor syndrome that occurs across psychiatric, neurologic, neurodevelopmental, autoimmune, and general medical conditions. This clinical breadth argues against schizophrenia-centered models and suggests that catatonia is better understood as a final common phenotype of disturbed psychomotor regulation rather than the expression of a single disease process. Recent dimensional work further indicates that catatonia is internally heterogeneous, with hypokinetic, hyperkinetic, and aberrant-volitional components that often overlap within the same episode. In this review, we evaluate whether current evidence supports conceptualizing catatonia as a disorder of distributed psychomotor network dysfunction and examine how circuit, neurochemical, immune, metabolic, and genetic findings converge on that model. The best-supported mechanistic model to date comes from neuroimaging studies implicating cortico-striatal-thalamic, cortico-cerebellar, orbitofrontal, cingulate, and motor-premotor networks. Nonetheless, key limitations remain, including the overrepresentation of schizophrenia-spectrum samples and limited acute-state data. Neurochemical evidence supports the notion of interacting disturbances in GABAergic inhibition, glutamatergic/NMDA-mediated excitation, and dopaminergic modulation rather than a single-transmitter explanation. Immune mechanisms are particularly relevant in subgroups, especially in autoimmune encephalitis and inflammatory CNS conditions, whereas peripheral biomarkers remain nonspecific. Genetic and developmental data support vulnerability rather than unitarity, implicating synaptic, GABAergic, and microglial processes without a single syndrome-specific architecture. Taken together, the evidence supports a convergent model in which diverse upstream liabilities destabilize shared psychomotor networks, producing a recognizable but heterogeneous syndrome. No single biomarker or unified mechanism fully accounts for catatonia across contexts. Future progress will depend on dimensional phenotyping, multimodal biomarker integration, and subtype-sensitive treatment research.

The present study aimed to investigate the effects of chronic mild stress (CMS) on neurotrophic factors in the brains of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. After 30 days of the CLP procedure, the animals were subjected to CMS. Twenty-four hours after the last stressor, the animals were euthanized, their blood was collected, and their brains were dissected in the frontal cortex and hippocampus. Then, the levels of brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, nerve growth factor, and glial cell line-derived neurotrophic factor were evaluated in the brain structures. The levels of adrenocorticotropic hormone and corticosterone were evaluated in the serum of the rats. The four experimental groups of the present study were: (1) Sham + Non-stressed; (2) Sepsis + Non-stressed; (3) Sham + CMS; (4) Sepsis + CMS. CMS increased adrenocorticotropic hormone and corticosterone levels, whereas sepsis alone did not significantly alter these hormones. Regarding neurotrophic factors, CMS reduced the levels of BDNF, NT-3, NT-4, and NGF in both the hippocampus and frontal cortex, regardless of prior sepsis exposure. Sepsis alone was also associated with reduced levels of these neurotrophins, although the magnitude of the effect varied depending on the specific neurotrophin and brain region, with greater reductions observed for BDNF and NGF. No interaction between sepsis and CMS was detected for these neurotrophins, suggesting independent effects. Our findings suggest that sepsis and CMS independently affect most neurotrophin levels, with no clear evidence that prior sepsis potentiates the effects of subsequent CMS. GDNF represents an exception, pointing to potential region-specific mechanisms that warrant further investigation.

Purpose: Substantial evidence supports the effectiveness of implanted Vagus Nerve Stimulation (VNS) in the management of unipolar difficult-to-treat depression (DTD). While the treatment is included in several national and international guidelines, there is limited information to guide clinicians regarding patient selection and use of VNS in clinical practice. Patients and Methods: A group of 32 experts in the use of VNS were identified from the main countries currently providing the treatment globally. A modified Delphi technique was used to document views on 55 statements regarding the goals, patient selection, and use of VNS treatment in routine clinical practice. Statements were rated on a 9-point Likert scale from "strongly disagree" to "strongly agree". Over the course of three rounds of voting, with statements modified based on anonymous comments from panelists, consensus agreement or disagreement was deemed if at least 75% of panel members scored a statement between 7 and 9, or 1 and 3, respectively. Results: Consensus was reached by the panel on 75% of the statements covering a wide range of issues. There was agreement that the main goals for VNS are long-term management of symptoms and improvement in quality of life, that the treatment is appropriate for all ages of patients and that there are few contraindications. Conclusion: A set of expert recommendations for the use of VNS for DTD was generated. These should be of value to clinicians to ensure current best practices are followed when considering this treatment.

Treatment-resistant depression (TRD) represents a major clinical challenge and a distinct neurobiological syndrome within affective disorders. This chapter outlines the latest progress in therapeutic strategies, highlighting translational models, precision psychiatry, personalized therapeutic strategies, and computational tools. Traditional pharmacotherapy largely targets monoaminergic systems, especially serotonin, dopamine, and norepinephrine; however, with growing mechanistic insights into additional impairment, precision interventions are becoming feasible but remain constrained by clinical trial design, regulatory barriers, and access disparities. We aim not to revisit established advanced treatment strategies but to disseminate experimental developments that have shown enough promise in preclinical studies to spark scientific curiosity and inspire new TRD management strategies.

Objective: To compare effects of adjunctive active versus sham vagus nerve stimulation (VNS) on suicidal ideation (SI) in markedly treatment-resistant depression (TRD). Methods: RECOVER trial participants with nonpsychotic major depressive disorder and insufficient benefit from ≥4 adequate antidepressant trials in the current episode were randomized to adjunctive active or sham VNS plus treatment as usual over 12 months. SI was assessed at baseline and monthly (months 3-12) following VNS parameter titration/ pseudotitration. A composite suicidal ideation (CSI) score (range, 0-9) used SI items from 3 depressive symptom ratings to assess VNS effects on SI for those with (CSI ≥3) and without (CSI ≤2) significant baseline SI. Results: This exploratory study involved a sample (N = 463) who averaged 13.3 failed lifetime antidepressant treatments, with 17.7 years in the current depressive episode; 40.4% had previously attempted suicide. Among individuals with baseline SI, the likelihood of meaningful improvement (CSI score change ≥3) was greater with active than sham VNS (odds ratio [OR] = 1.43; 95% CI, 1.004-2.021; P < .05) over 10 months of evaluation. Additionally, active VNS was superior to sham VNS for SI remission (CSI ≤2) in months 10-12 (OR = 1.67; 95% CI, 1.007-2.763; P < .05). VNS did not significantly worsen SI in participants. Conclusions: This study suggests that, compared to sham VNS, active VNS reduces SI and potentially induces SI remission among participants with chronic TRD and baseline SI. Furthermore, VNS does not appear to worsen or induce SI in participants, regardless of their baseline SI status. Further research is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT03887715.

IMPORTANCE:Greater levels of treatment resistance in major depressive disorder (MDD) are associated with lower rates of initial benefit and higher rates of relapse (lower durability). OBJECTIVE:Characterize depressive symptoms, function, and quality of life (QoL) over 24 months of adjunctive vagus nerve stimulation (VNS) in participants with markedly treatment-resistant depression. DESIGN:Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. SETTING:Outpatient. PARTICIPANTS:Adults with moderate-severe MDD with ≥ 4 failed antidepressant trials in the current episode, randomized to blinded, adjunctive VNS for 12 months, who subsequently received open-label, adjunctive VNS for 12 additional months (n = 214). INTERVENTIONS:Vagus nerve stimulation and concomitant psychotropic medications and interventional psychiatric modalities (electroconvulsive therapy, transcranial magnetic stimulation, and ketamine/esketamine) were characterized over the 12-month extension. MAIN OUTCOMES AND MEASURES:The durability of benefit achieved at 12 months was assessed at 18 and 24 months for depressive symptoms (3 scales), daily function, QoL, a tripartite composite of all 3 domains, and the Clinical Global Impression-Improvement (CGI-I) scale (overall improvement). Loss of benefit and relapse were assessed, along with the emergence of meaningful benefit in participants without benefit at 12 months. Substantial benefit (at least 50% symptom reduction from baseline; CGI-I of 1 or 2; tripartite measures with at least 2 of 3 subscales evidencing benefit) and meaningful benefit thresholds for symptoms (at least 30% reduction from baseline), function, QoL, CGI-I, and the tripartite measure were set a priori. RESULTS:Most participants with substantial benefit maintained their benefit (18-month median = 78.8%; 24-month median = 79.0% across 5 measures), as did participants with at least meaningful benefit at 12 months (18-month median = 83.1%; 24-month median = 81.3% across 7 measures). Furthermore, many participants with no meaningful benefit at 12 months achieved it at 18 (median = 30.6%) and 24 (median = 37.8%) months. The strong maintenance of benefit was not accounted for by changes in psychotropic medications or interventional psychiatric modalities. CONCLUSIONS AND RELEVANCE:Depressive symptom, daily function, and QoL benefits obtained after 12 months of adjunctive VNS were sustained in about 80% of participants continuing VNS. Approximately 30% with no meaningful benefit at 12 months accrued increased benefit over the subsequent year. HIGHLIGHTS:

BACKGROUND:The performances of the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology-Clinician (QIDS-C) and Self-Report (QIDS-SR) ratings have never been evaluated in markedly treatment-resistant depression (TRD). RECOVER, a 12-month randomized, controlled trial, compared adjunctive active to adjunctive sham vagus nerve stimulation, provided data to address this knowledge gap, and to examine the basis for the differential sensitivities of these scales in detecting overall and between-treatment-group symptom changes. METHODS:We employed classical test and item response theory methods to characterize each scale. Effect sizes identified items that were most sensitive to change over time across treatments, best discriminated between the two treatments, and best detected at least a partial symptom response in clinician global ratings. RESULTS:All three inventories were unidimensional, with high retest reliability and strong internal consistency. MADRS total scores were less sensitive in detecting overall and between-treatment-group symptom differences. On each scale, five symptom domains-mood, energy/lassitude, interest/inability to feel, negative self-view/pessimism, and concentration-covaried most strongly with overall depression severity and had the largest effect sizes in detecting overall therapeutic change and between-group difference in efficacy. LIMITATIONS:These findings may not generalize to less treatment-resistant populations or to different treatments. The relative insensitivity of suicidal ideation, sleep, and appetite items may be due to study design or concomitant medications. CONCLUSION:The MADRS, QIDS-C, and QIDS-SR are suitable for use in markedly TRD. Whether sadness, energy, interest, guilt, and concentration are "core" symptoms that are especially sensitive to change deserves further study.

Treatment-resistant depression (TRD) carries a substantial personal and societal burden, yet no universally accepted definition or communication framework exists to guide its clinical management. Current staging models — including the Antidepressant Treatment History Form, Thase and Rush Staging Model, European Staging Model, Massachusetts General Hospital Staging Model, and Maudsley Staging Model — each offer valuable but incomplete approaches to characterizing TRD, and none has achieved broad adoption in routine clinical or research settings. The absence of a standard communication tool results in fragmented treatment histories, inconsistent provider-to-provider handoffs, and missed treatment opportunities for patients. Members of the National Network of Depression Centers (NNDC) Treatment-Resistant Depression Task Group propose the DATAd Tracking System — a simple, scalable framework for documenting and communicating depression treatment history. DATAd organizes prior treatment trials across four clinically meaningful categories: Drugs (primary antidepressants), Augmentation/combination strategies, psychoTherapy, and Advanced treatments (e.g., transcranial magnetic stimulation, electroconvulsive therapy, ketamine/esketamine). For each category, clinicians record both adequate and inadequate trials in the current episode using the notation D#(#) A#(#) T#(#) Ad#(#), with optional lifetime worksheets available to capture historical treatment data. Analogous to the Gravida-Para system in obstetrics and the Tumor-Lymph Nodes-Metastasis (TNM) system in oncology, DATAd provides a common clinical language that highlights treatment gaps, facilitates informed next-step recommendations, and supports both clinical decision-making and research. Ongoing multicenter trials supported by the NNDC will evaluate DATAd's utility, inter-rater reliability, and impact on clinical workflow and patient outcomes.