2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T489,A total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder.31:Tbef,Psilocybin shows promise in treating depression, although limitations of previous research warrant further research. To investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD). This was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active placebo-controlled randomized clinical trial. Participants were randomized to 4 groups in ratios 2:2:1:1, receiving 2 doses 6 weeks apart (week 0, week 6) as follows: (1) placebo (nicotinamide, 100 mg) then psilocybin, 25 mg; (2) psilocybin, 5 mg, then 25 mg; and (3) psilocybin, 25 mg, then 5 mg or psilocybin, 25 mg, twice embedded in psychotherapeutic sessions. Participants aged 25 to 65 years with TRD and withdrawn from antidepressant medication were recruited predominantly from 2 outpatient settings in Germany. Study data were analyzed from April 2024 to November 2025. Oral synthetic psilocybin, 25 mg; psilocybin, 5 mg; or nicotinamide, 100 mg administered with psychotherapeutic sessions. The primary end point was treatment response (≥50% reduction on the Hamilton Rating Scale for Depression [HAMD17]) at week 6 before the second dose. Key secondary end points were response on the Beck Depression Inventory II (BDI-II) and mean change from baseline on the HAMD17 and BDI-II at week 6. A total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder. In this randomized clinical trial, psilocybin, 25 mg, with adjunct psychotherapy, was associated with a clinically meaningful reduction in depressive symptoms in individuals with TRD, although findings did not show a significant effect on the primary outcome. The treatment was well tolerated by most participants, although safety signals were observed. While overall this constituted an inconclusive trial, these results add to the existing evidence on the potential of psilocybin treatment for depression. ClinicalTrials.gov Identifier: NCT04670081.32:T126e, Importance Psilocybin shows promise in treating depression, although limitations of previous research warrant further research. Objective To investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD). Design, Setting, and Participants This was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active placebo-controlled randomized clinical trial. Participants were randomized to 4 groups in ratios 2:2:1:1, receiving 2 doses 6 weeks apart (week 0, week 6) as follows: (1) placebo (nicotinamide, 100 mg) then psilocybin, 25 mg; (2) psilocybin, 5 mg, then 25 mg; and (3) psilocybin, 25 mg, then 5 mg or psilocybin, 25 mg, twice embedded in psychotherapeutic sessions. Participants aged 25 to 65 years with TRD and withdrawn from antidepressant medication were recruited predominantly from 2 outpatient settings in Germany. Study data were analyzed from April 2024 to November 2025. Interventions Oral synthetic psilocybin, 25 mg; psilocybin, 5 mg; or nicotinamide, 100 mg administered with psychotherapeutic sessions. Main Outcomes and Measures The primary end point was treatment response (≥50% reduction on the Hamilton Rating Scale for Depression [HAMD17]) at week 6 before the second dose. Key secondary end points were response on the Beck Depression Inventory II (BDI-II) and mean change from baseline on the HAMD17 and BDI-II at week 6. Results A total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder. Conclusion and Relevance In this randomized clinical trial, psilocybin, 25 mg, with adjunct psychotherapy, was associated with a clinically meaningful reduction in depressive symptoms in individuals with TRD, although findings did not show a significant effect on the primary outcome. The treatment was well tolerated by most participants, although safety signals were observed. While overall this constituted an inconclusive trial, these results add to the existing evidence on the potential of psilocybin treatment for depression. Trial Registration ClinicalTrials.gov Identifier: NCT04670081 33:T9e7,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). 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. Prospective, open-label, single-arm, long-term extension study (RECOVER) conducted from September 2019 to April 2025. Outpatient. 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). 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. 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. 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. 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.34:Tff1,Abstract 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 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Treatment-Resistant Depression: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Treatment-Resistant Depression (condition). Clinician-written summaries and actionable practice insights. 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The midazolam active control is a methodological strength, but partial unblinding (47% correct guesses) may have introduced expectancy bias. The study excluded participants outside the 21–65 age range, limiting applicability to older adults or younger adults below 21.","value_numeric":null}],"summaries":{"what_studied":"This double-blind RCT (Ket-BD) evaluated adjunctive IV ketamine (0.5–0.75 mg/kg, 4 infusions over 2 weeks) vs. midazolam (active control) in 68 adult outpatients aged 21–65 with treatment-resistant bipolar I or II depression (TRBD), all on a stable mood stabilizer or antipsychotic, across 3 sites in Ontario, Canada.","key_result":"Ketamine produced a significantly greater reduction in MADRS score at day 14 vs. midazolam (between-group difference = −7.3 points; 95% CI, −12.0 to −2.5; P = .003; Cohen d = 0.7). No mania, hypomania, psychosis, or suicide attempts occurred in either group; 1 case of mixed features was seen per arm.","limitations":"- Small sample (n=68 randomized, 63 analyzed), limiting generalizability.\n- Blinding was partially compromised: 47% of participants correctly guessed treatment allocation after the first infusion.\n- Short follow-up (14 days) leaves durability of antidepressant effect unknown.","practice_takeaway":"For patients with bipolar I or II depression who have failed ≥2 evidence-based pharmacotherapies, adjunctive IV ketamine (on a mood stabilizer backbone) showed a clinically meaningful antidepressant effect with no treatment-emergent mania or psychosis in this trial. Clinicians should note the small sample size and brief observation window before broad adoption."}},{"doi":"10.3389/fpsyt.2026.1930167","pmid":null,"title":"Metabolic dysfunction and insulin resistance in depression: mechanisms, evidence, and therapeutic implications","journal_title":"Frontiers in Psychiatry","journal_issn":"1664-0640","published_at":"2026-08-20T00:00:00.000Z","url":"https://doi.org/10.3389/fpsyt.2026.1930167","source_score":12,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-08-26T06:20:08.620Z","updated_at":"2026-08-26T06:20:08.620Z","tags":[{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Insulin Resistance","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Major Depressive Disorder","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Metabolic Dysfunction","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Obesity","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"modality","value":"Insulin Sensitizer","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"warning","value":"Age group tagged as 'adult' by inference from the clinical context; the review does not explicitly restrict to any age group.","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"warning","value":"Full text body pages (1–7) contain minimal extractable content beyond the abstract and metadata; summary is based primarily on the abstract. Specific studies cited, effect sizes, and detailed mechanistic findings could not be verified from the provided text.","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"warning","value":"No specific GLP-1 agonist brand or generic names beyond metformin are individually named in the extractable text; 'GLP-1 Receptor Agonist' is listed as a keyword.","value_numeric":null}],"summaries":{"what_studied":"This narrative review examines the bidirectional relationship between major depressive disorder (MDD) and metabolic dysfunction — including obesity, insulin resistance, and HPA axis dysregulation — and evaluates the potential antidepressant effects of insulin-sensitizing agents (e.g., metformin, GLP-1 receptor agonists).","key_result":"Evidence for insulin-sensitizing therapies improving depressive symptoms is mixed and mechanisms remain poorly elucidated; up to 30% of MDD patients are treatment-resistant, with higher rates in those with comorbid metabolic dysfunction.","limitations":"- Narrative review design limits causal inference and is subject to selection bias.\n- Mechanisms by which insulin-targeting agents may improve depression are not clearly established in current studies.\n- No original data; conclusions depend entirely on the quality of cited primary literature.","practice_takeaway":"Consider routine metabolic screening (glucose, insulin resistance markers) in patients with MDD, especially those who are treatment-resistant, as metabolic dysfunction may identify candidates for precision therapies targeting insulin pathways.\nInsulin-sensitizing agents show promise but lack sufficient evidence to recommend routine use for depression at this time."}},{"doi":"10.1038/s41380-026-03777-z","pmid":"42521762","title":"Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics","journal_title":"Molecular Psychiatry","journal_issn":"1359-4184","published_at":"2026-07-28T00:00:00.000Z","url":"https://doi.org/10.1038/s41380-026-03777-z","source_score":36,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-04T18:17:55.052Z","updated_at":"2026-08-04T18:17:55.052Z","tags":[{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"brand","value":"Ketamine","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"condition","value":"Major Depressive Disorder","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"generic","value":"hydroxynorketamine","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"generic","value":"ketamine","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"generic","value":"lysergic acid diethylamide","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"generic","value":"psilocybin","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"modality","value":"NMDA Receptor Antagonist","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"modality","value":"Serotonergic Psychedelic","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"sample_size","value":"n=64","value_numeric":64},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"study_design","value":"Multimodal Translational Study (Proteomics, Transcriptomics, Neuroimaging, Cytokine Analysis)","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"warning","value":"LSD and psilocybin were used only in iPSC in vitro models, not administered to human participants in this study.","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"warning","value":"Sample sizes differ substantially across modalities (MEG n=55, transcriptomics n=27, cytokines n=64); the 'n=64' used for sample_size tag reflects the largest cohort (plasma cytokines), which may not represent the full study.","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"warning","value":"Study design is complex and multimodal—labeling as a single study design is an approximation; it combines observational clinical data with in vitro iPSC experiments.","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03777-z","tag_type":"warning","value":"The 'practice_changing' impact flag is applied cautiously—findings are mechanistic and biomarker-level; clinical translation requires prospective validation.","value_numeric":null}],"summaries":{"what_studied":"This study investigated shared molecular mechanisms underlying rapid antidepressant effects of ketamine and serotonergic psychedelics (LSD, psilocybin) in treatment-resistant depression (TRD), using CSF proteomics from healthy volunteers (HVs), iPSC-derived neurons, whole-blood transcriptomics, plasma cytokines, and MEG neuroimaging in TRD and HV participants receiving IV ketamine (0.5 mg/kg) or placebo.","key_result":"IL-15 and MCP-1 emerged as conserved immune hubs across CSF and iPSC data; plasma IL-7 correlated with baseline MEG gamma power brain-wide (pFDR < 0.05), with the strongest effect in TRD subcortical regions (pFDR < 10⁻¹⁴); post-ketamine, the IL-7–gamma relationship inverted alongside widespread gamma reductions in default-mode network regions; cytokine ratios predicted response (IL-4/IFN-γ, pFDR < 0.041) and non-response (MCP-1/IL-7, pFDR < 0.009).","limitations":"- Healthy volunteer CSF proteomics cannot fully represent TRD biology, and iPSC models may not recapitulate in vivo neuronal complexity.\n- Sample sizes vary considerably across modalities (transcriptomics n=27, MEG n=55, plasma cytokines n=64), limiting cross-modal comparisons.\n- The study is observational/mechanistic rather than a powered clinical trial, so causal relationships between cytokine shifts and antidepressant response remain inferential.","practice_takeaway":"The IL-7/IL-15 cytokine axis—measurable in plasma—may serve as a clinically accessible biomarker to predict and monitor rapid antidepressant response to ketamine; specifically, a high MCP-1/IL-7 ratio may flag likely non-responders before treatment. Validation in larger prospective cohorts is needed before clinical application."}},{"doi":"10.1038/s41380-026-03768-0","pmid":"42498781","title":"Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers","journal_title":"Molecular Psychiatry","journal_issn":"1359-4184","published_at":"2026-07-24T00:00:00.000Z","url":"https://doi.org/10.1038/s41380-026-03768-0","source_score":32,"is_retracted":false,"is_open_access":null,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":false},"created_at":"2026-08-01T13:21:52.910Z","updated_at":"2026-08-01T13:21:52.910Z","tags":[{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"generic","value":"2,5-Dimethoxy-4-iodoamphetamine","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"generic","value":"hydroxynorketamine","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"generic","value":"ketamine","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"generic","value":"lysergic acid diethylamide","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"generic","value":"psilocybin","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"modality","value":"NMDA Receptor Antagonist","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"modality","value":"Serotonergic Psychedelic","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"study_design","value":"In Vitro Experimental Study with Translational Validation","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"warning","value":"LSD and DOI are research compounds not approved for clinical use; clinical applicability of findings for these agents is highly speculative.","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"warning","value":"No sample size (N) for the iPSC donor cohort is reported in the abstract; the sample_size tag was omitted.","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"warning","value":"Sex of iPSC donors is not reported in the abstract.","value_numeric":null},{"paper_doi":"10.1038/s41380-026-03768-0","tag_type":"warning","value":"Study design is primarily in vitro (cell culture); the 'translational validation' component uses a separate human CSF proteomics dataset, which may introduce confounds.","value_numeric":null}],"summaries":{"what_studied":"iPSC-derived cortical-like neurons from individuals with treatment-resistant depression (TRD) and healthy volunteers (HVs) were treated for 6 and 24 h with four putative rapid-acting antidepressants — (2R,6R)-HNK, psilocybin, LSD, and DOI — and assessed via bulk and single-cell RNA sequencing, Western blotting, immunocytochemistry, and comparison to CSF proteomics from ketamine-treated HVs.","key_result":"Despite distinct initial pharmacological targets, gene expression profiles across all four compounds were highly correlated at matched timepoints vs. vehicle, converging on inflammation, mTORC1 signaling, and cellular growth pathways; (2R,6R)-HNK uniquely showed excitatory neuron upregulation and inhibitory neuron downregulation, and its transcriptomic signature overlapped with CSF proteomic data from ketamine-treated humans.","limitations":"- iPSC-derived neurons are an in vitro model and may not fully recapitulate in vivo brain complexity or cell-type diversity.\n- TRD vs. HV group-specific differences are not prominently detailed, limiting conclusions about disease-specific drug responses.\n- CSF proteomics comparison used HVs treated with ketamine, not TRD patients, constraining direct translational inference.","practice_takeaway":"Rapid-acting antidepressants from both glutamatergic and serotonergic classes converge on shared molecular pathways (mTORC1, inflammation) in human neurons, supporting their grouped investigation in TRD. iPSC-derived neuron platforms show early promise for antidepressant drug discovery but are not yet ready to replace clinical validation."}},{"doi":"10.1001/jamapsychiatry.2026.1100","pmid":"42340706","title":"Connectivity- vs Scalp-Based Targeting of Accelerated Transcranial Magnetic Stimulation for Depression","journal_title":"JAMA Psychiatry","journal_issn":"2168-622X","published_at":"2026-06-24T00:00:00.000Z","url":"https://doi.org/10.1001/jamapsychiatry.2026.1100","source_score":118,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-27T13:27:31.049Z","updated_at":"2026-06-27T13:27:31.049Z","tags":[{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"condition","value":"Major Depressive Disorder","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"modality","value":"Transcranial Magnetic Stimulation","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"sample_size","value":"n=40","value_numeric":40},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"warning","value":"Paper is dated June 24, 2026 — very recently published; independent replication is not yet available.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"warning","value":"Small sample size (n=40) means the wide 95% CI (0.26–1.54) should be interpreted cautiously; the authors themselves frame this as a hypothesis-generating study pending a confirmatory trial.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1100","tag_type":"warning","value":"The 'practice_changing' flag is applied cautiously — the results are promising but the trial is underpowered for definitive conclusions; regulatory and cost-effectiveness implications remain to be established.","value_numeric":null}],"summaries":{"what_studied":"This randomized, blinded clinical trial (n=40 adults, ages 22–80) compared connectivity-based vs. scalp-based (Beam F3) targeting of accelerated TMS (aTMS) for treatment-resistant major depressive disorder, with the primary outcome of MADRS score at 1 month post-treatment and follow-up for 1 year.","key_result":"Connectivity-based targeting produced a median MADRS score reduction of 24 points vs. 18 points with scalp-based targeting (P=.02), with an effect size (Cohen d analog) of 0.8 (95% CI, 0.26–1.54) and a number needed to scan of 5.","limitations":"Very small sample (n=40), limiting generalizability and power for subgroup analyses; single academic center; results described as hypothesis-generating, with authors calling for a confirmatory efficacy trial.","practice_takeaway":"When aTMS is planned for treatment-resistant depression, a single resting-state fMRI scan to individualize the DLPFC target to the convergent depression circuit may meaningfully boost antidepressant response — roughly 1 extra scan per 5 patients could improve outcomes. These results support conducting a larger confirmatory trial before adopting this as standard practice."}},{"doi":"10.1038/s41593-026-02301-4","pmid":"42225897","title":"Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks","journal_title":"Nature Neuroscience","journal_issn":"1097-6256","published_at":"2026-06-01T00:00:00.000Z","url":"https://doi.org/10.1038/s41593-026-02301-4","source_score":109,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-11T13:42:53.826Z","updated_at":"2026-06-11T13:42:53.826Z","tags":[{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"condition","value":"Neurological Disorders","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"modality","value":"Deep Brain Stimulation","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"study_design","value":"Controlled Animal Study","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"warning","value":"Full page text was not extractable from the PDF; sample sizes, exact statistical results, and stimulation parameters could not be confirmed and are not included in the summary.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"warning","value":"Level of evidence set to 5 (animal/experimental study) given the preclinical macaque model design.","value_numeric":null},{"paper_doi":"10.1038/s41593-026-02301-4","tag_type":"warning","value":"Study was conducted in macaques — generalizability to human clinical DBS practice should be interpreted with caution.","value_numeric":null}],"summaries":{"what_studied":"This study examined the anatomical and functional effects of subcallosal anterior cingulate cortex deep brain stimulation (SCC-DBS) in macaques, modeling the white matter-targeted approach used in treatment-resistant depression in humans. Outcomes included white matter microstructure (fractional anisotropy), cellular changes (myelination, oligodendrocytes), and brain-wide functional connectivity.","key_result":"SCC-DBS selectively increased fractional anisotropy in the cingulum bundle, associated with increased myelinated oligodendrocytes and greater myelination in the mid-cingulum. Functional connectivity was also altered brain-wide, with notable changes in interactions between the SCC and the default mode network.","limitations":"- Animal model only (macaques); direct translation to human DBS outcomes is uncertain.\n- Full text pages were not extractable, so sample sizes, stimulation parameters, and statistical details could not be verified from the source.\n- Causal link between white matter remodeling and clinical antidepressant efficacy remains inferred, not directly tested.","practice_takeaway":"SCC-DBS may work partly by remodeling white matter and reshaping default mode network connectivity — not just by acute neuromodulation. Clinicians should consider that structural brain changes may be part of DBS's therapeutic mechanism in depression."}},{"doi":"10.1001/jamapsychiatry.2026.1053","pmid":"42160062","title":"Interleukin 6 as a Treatment Target for Depression","journal_title":"JAMA Psychiatry","journal_issn":"2168-622X","published_at":"2026-05-20T00:00:00.000Z","url":"https://doi.org/10.1001/jamapsychiatry.2026.1053","source_score":91,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-24T13:23:05.251Z","updated_at":"2026-05-24T13:23:05.251Z","tags":[{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"brand","value":"Actemra","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"condition","value":"Major Depressive Disorder","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"generic","value":"tocilizumab","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"modality","value":"IL-6 Receptor Antagonist","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"sample_size","value":"n=30","value_numeric":30},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"warning","value":"Proof-of-concept trial only (n=30); all results are underpowered and exploratory — no efficacy conclusions should be drawn.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"warning","value":"Publication date (2026-05-20) is in the future relative to most training data; content is taken at face value from the abstract provided.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"warning","value":"Sample was 80% female, limiting generalizability to male patients.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1053","tag_type":"warning","value":"The 'level of evidence 2' rating reflects the RCT design, but the very small sample and single proof-of-concept nature make it functionally closer to preliminary evidence.","value_numeric":null}],"summaries":{"what_studied":"A 4-week, double-blind, placebo-controlled proof-of-concept RCT evaluated a single IV infusion of tocilizumab (IL-6R antagonist, 8 mg/kg) vs. placebo in 30 adults with moderate-to-severe treatment-resistant depression, low-grade systemic inflammation (hs-CRP ≥0.3 mg/dL), and prominent somatic symptoms, followed over 28 days.","key_result":"No results reached statistical significance. At day 28, remission favored tocilizumab (53.9% vs. 31.3%; NNT=5) and response rates also favored tocilizumab (46.2% vs. 18.8%; NNT=4). Clinically meaningful effect sizes were seen for depression severity, fatigue, anxiety, and quality of life. The primary endpoint (somatic symptoms at day 14) showed minimal difference (adjusted mean difference: −0.12; 95% CI, −2.51 to 2.28).","limitations":"- Very small sample (n=30); massively underpowered for statistical significance — all findings are exploratory only.\n- Single infusion design limits conclusions about optimal dosing duration or frequency.\n- 80% female sample may limit generalizability to male patients.","practice_takeaway":"Tocilizumab is not ready for routine use in depression, but this trial supports selecting patients by hs-CRP (≥0.3 mg/dL) rather than IL-6 levels when designing future immunotherapy trials. Clinicians should watch for a larger efficacy trial, as day-28 remission and response rates show a signal worth pursuing."}},{"doi":"10.1001/jamapsychiatry.2026.0096","pmid":"41879760","title":"GH001 vs Placebo in Patients With Treatment-Resistant Depression","journal_title":"JAMA Psychiatry","journal_issn":"2168-622X","published_at":"2026-03-25T00:00:00.000Z","url":"https://doi.org/10.1001/jamapsychiatry.2026.0096","source_score":202,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-10T14:23:49.907Z","updated_at":"2026-06-10T14:23:49.907Z","tags":[{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"brand","value":"GH001","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"generic","value":"mebufotenin","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"modality","value":"Inhaled Psychedelic / Serotonergic Agent","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"sample_size","value":"n=81","value_numeric":81},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"warning","value":"GH001 (mebufotenin) is not currently approved; the brand name 'GH001' is a clinical program identifier, not a confirmed proprietary name.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"warning","value":"Older adults (≥65) were excluded; generalizability to that population is unknown.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"warning","value":"Phase 2b trial — results are promising but not yet confirmed in a larger phase 3 study; the large effect size (−2.0) should be interpreted cautiously given the small sample.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.0096","tag_type":"warning","value":"The 6-month open-label extension is uncontrolled, so long-term efficacy and safety beyond the 7-day placebo-controlled window cannot be reliably assessed from this paper alone.","value_numeric":null}],"summaries":{"what_studied":"A 7-day randomized, double-blind, placebo-controlled phase 2b trial evaluated a single-day individualized dosing regimen of inhaled mebufotenin (GH001; up to 3 escalating doses: 6, 12, 18 mg) vs placebo in 81 adults aged 18–64 with treatment-resistant depression (nonresponse to 2–5 prior antidepressants), conducted across 16 European sites (May 2023–March 2025).","key_result":"At day 8, GH001 produced a significantly greater reduction in MADRS score vs placebo (LS mean difference −15.5 [SE 1.7]; P < .001; effect size −2.0), with remission rates of 57.5% (23/40) vs 0% (0/41); no severe or serious adverse events occurred during the placebo-controlled period.","limitations":"- Small sample size (n=81) limits generalizability.\n- Only a 7-day placebo-controlled period; durability of response relies solely on the 6-month open-label extension (uncontrolled).\n- Single-session treatment design and inhaled route may limit applicability in routine clinical settings.","practice_takeaway":"A single-day inhaled mebufotenin regimen showed a large effect size and 57.5% remission rate at day 8 in treatment-resistant depression with no serious adverse events — a striking early signal worth watching as phase 3 data emerge. Clinicians should note this is phase 2b evidence; the treatment is not yet approved."}},{"doi":"10.1001/jamapsychiatry.2026.0132","pmid":"41848690","title":"Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression","journal_title":"JAMA Psychiatry","journal_issn":"2168-622X","published_at":"2026-03-18T00:00:00.000Z","url":"https://doi.org/10.1001/jamapsychiatry.2026.0132","source_score":532,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-05-11","doi":"10.1001/jamapsychiatry.2026.0132","days":"7","issn":"2168-622X","rank":"1","field":"Clinical Medicine","score":"532","category":"Psychiatry","categories":["Psychiatry"],"_categories":["Psychiatry"]},"pubmed":{"doi":"10.1001/jamapsychiatry.2026.0132","title":"Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.","journal":"JAMA psychiatry","methods":"","results":"$30","abstract":"$31","keywords":[],"pubmed_id":"41848690","conclusions":"","publication_date":"2026-03-18T00:00:00"},"crossref":{"DOI":"10.1001/jamapsychiatry.2026.0132","URL":"https://doi.org/10.1001/jamapsychiatry.2026.0132","ISSN":["2168-622X"],"link":[{"URL":"https://jamanetwork.com/journals/jamapsychiatry/articlepdf/2846478/jamapsychiatry_mertens_2026_oi_260007_1777052914.3703.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"448","type":"journal-article","issue":"5","score":1,"title":["Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression"],"author":[{"given":"Lea J.","family":"Mertens","sequence":"first","affiliation":[{"name":"Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"German Center for Mental Health, partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany"}]},{"given":"Michael","family":"Koslowski","sequence":"additional","affiliation":[{"name":"Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany"},{"name":"German Center for Mental Health, partner site Berlin-Potsdam, Berlin, Germany"}]},{"given":"Felix","family":"Betzler","sequence":"additional","affiliation":[{"name":"Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany"},{"name":"German Center for Mental Health, partner site Berlin-Potsdam, Berlin, Germany"}]},{"given":"Manuela","family":"Brand","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"German Center for Mental Health, partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany"}]},{"given":"Ricarda","family":"Evens","sequence":"additional","affiliation":[{"name":"Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany"},{"name":"Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany"}]},{"given":"Laura","family":"Kärtner","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"German Center for Mental Health, partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany"}]},{"given":"Andrea","family":"Jungaberle","sequence":"additional","affiliation":[{"name":"Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany"},{"name":"MIND Foundation, Berlin, Germany"},{"name":"OVID Health Systems GmbH, Berlin, Germany"}]},{"given":"Henrik","family":"Jungaberle","sequence":"additional","affiliation":[{"name":"MIND Foundation, Berlin, Germany"},{"name":"OVID Health Systems GmbH, Berlin, Germany"}]},{"given":"Tomislav","family":"Majić","sequence":"additional","affiliation":[{"name":"Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany"},{"name":"German Center for Mental Health, partner site Berlin-Potsdam, Berlin, Germany"}]},{"given":"Christian N.","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"German Center for Mental Health, partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany"},{"name":"Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}]},{"given":"Andreas","family":"Ströhle","sequence":"additional","affiliation":[{"name":"Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, Germany"}]},{"given":"Dennis","family":"Scharf","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"},{"name":"German Center for Mental Health, partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany"},{"name":"Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, 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Outcomes included depressive symptoms (3 scales), daily function, quality of life, a tripartite composite, and CGI‑I; concomitant medications and interventional therapies were tracked.","key_result":"Among those with substantial benefit at 12 months, the median proportion maintaining benefit was 78.8% at 18 months and 79.0% at 24 months (across 5 measures). For participants with at least meaningful benefit at 12 months, medians were 83.1% at 18 months and 81.3% at 24 months (across 7 measures); among those without meaningful benefit at 12 months, 30.6% at 18 months and 37.8% at 24 months achieved it. Maintenance was not explained by changes in psychotropic medications or interventional modalities.","limitations":"Open‑label, single‑arm extension without a control group limits causal inference. Concomitant treatments were allowed, posing potential confounding despite analyses suggesting they did not account for maintenance. Findings apply to a highly refractory MDD population and may not generalize to less resistant cases.","practice_takeaway":"In markedly treatment‑resistant MDD continuing adjunctive VNS, benefits at 12 months commonly persist to 24 months (~80% by median across measures), and a meaningful share of 12‑month non‑responders gain benefit by 18–24 months. Durability did not appear driven by changes in medications or other interventional therapies."}}],"initialOffset":10,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Treatment-Resistant Depression"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Treatment-Resistant Depression"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Treatment-Resistant Depression"}}}]]

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