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PubMed2026

Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.

BACKGROUND: Impaired cognitive functioning is a severe symptom in major depressive disorder (MDD). Recent evidence suggests it may be a central characteristic in its treatment resistant form (TRD), potentially constituting a clinical marker for treatment resistance and a target amenable to intervention. To date, cognitive functioning in TRD remains poorly understood and longitudinal investigations are scarce. METHODS: This observational prospective cohort study, including 320 patients diagnosed with MDD from the multicentre PROMPT study, examined differences in cognitive functioning between 118 TRD and 202 non-TRD patients over a period of twelve weeks in a real-world setting, using linear mixed modelling. Patients that failed to respond to at least two prior antidepressants trials at baseline were classified as TRD. RESULTS: TRD patients showed significantly poorer baseline performances than non-TRD patients in attention/processing speed (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) and verbal memory (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003). Significant time × group interactions were observed in motor speed and verbal fluency tasks. Post-hoc-analyses revealed stagnation in TRD patients and significant improvement in non-TRD patients. Across all other tasks improvement was observed in both groups, and random effects showed large heterogeneity between patients, indicating notable individual differences in cognitive performances. CONCLUSIONS: The results suggest distinct recovery patters between non-TRD and TRD patients, and diminished functioning in TRD patients at the domain level. However, intact and diminished performances likely occur in both groups, warranting further investigation of cognitive heterogeneity. These short-term findings highlight the need for more comprehensive longitudinal research on cognition in TRD.

Humans↗
PubMed2026

Esketamine multi-omic biomarker evaluation in major depressive disorder (EMBER-MDD): concept, objectives and methodologies of a non-clinical investigator-initiated study.

Treatment resistance (TR) in major depressive disorder (MDD) affects a substantial minority of patients and is hard to recognize early, delaying intensified care. The Esketamine multi-omic biomarker evaluation in MDD (EMBER-MDD) is a non-interventional, investigator-initiated, in-vitro study within the EU Psych-STRATA programme, analyzing biospecimens collected in the randomized INTENSIFY study and the mirror OBS-TR cohort after participants complete treatment. EMBER-MDD aims to discover individual-omic and integrated multi-omic (hypothesis-free) biomarkers and signatures associated with TR risk, and molecular correlates of clinical response to esketamine nasal spray versus treatment as usual (TAU). Biomaterials will derive from approximately 420 adults with MDD (estimated n = 210 esketamine; n = 210 TAU) and include whole blood, RNA-stabilized whole blood, plasma and serum, sampled at baseline and, when feasible, during and after treatment (up to ~ 5,040 aliquots stored at - 80 °C). Genomics will use baseline DNA genotyping on Illumina Infinium GSA v3.0+MD arrays; epigenomics will profile genome-wide DNA methylation across time points using MethylationEPIC v2.0; transcriptomics will employ mRNA-seq (NovaSeq X/ X Plus); and proteomics/ metabolomics will be generated using high-throughput Olink and/ or Biocrates platforms. Each layer will undergo state-of-the-art preprocessing and analyses (e.g., GWAS/ PRS, EWAS, differential expression, WGCNA, pathway and network analyses), followed by integrative strategies including QTL mapping (meQTL/ eQTL/ pQTL/ mQTL) and intermediate-fusion machine learning with nested cross-validation, explainable AI (SHAP/ LIME) and treatment-effect modelling. All outputs are research-only and will not support individual efficacy, tolerability, or clinical decision-making. The study will deliver robust biosignatures and mechanistic hypotheses to guide future validation and inform stratified, molecularly guided intervention strategies in subsequent prospective trials. Trial registration number: 2023-506617-21-00 and 2025-178-f-S.

Humans↗
PubMed2025

Exploring depression treatment response by using polygenic risk scoring across diverse populations.

Treatment-resistant depression (TRD), usually defined as limited or no response to at least two antidepressants, occurs in approximately one-third of individuals diagnosed with major depressive disorder (MDD). Studies of individuals of European ancestry highlight a genetic overlap between TRD and MDD. We analyzed two large and diverse biobanks, the UCLA ATLAS Community Health Study (ATLAS) and the All of Us Research Program (AoU), to test for associations between a polygenic score for major depression (MDD-PGS) and TRD. Compared to treatment responders, TRD individuals have higher MDD-PGS across all ancestries. MDD-PGS was significantly associated with response to selective serotonin reuptake inhibitors in individuals of European and Hispanic/Latin American genetic ancestries in both biobanks. In AoU, a decreased MDD-PGS was observed in response to tricyclics or serotonin modulators in individuals of European American ancestry and in response to serotonin and norepinephrine reuptake inhibitors in individuals of African American ancestry. ATLAS found that MDD-PGS showed lower odds of responding to atypical agents than did TRD in MDD-affected individuals belonging to the Hispanic/Latin American group, MDD-PGS was associated with atypical agents. Overall, by leveraging larger sample sizes from two diverse biobanks, we provide new insights into antidepressant response and treatment specificity for MDD in individuals of diverse genetic ancestries.

Adult↗
PubMed2026

Pilot randomized trial of intermittent theta-burst stimulation versus H-Coil transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Intermittent theta burst stimulation (figure-8-coil iTBS) and H7-coil repetitive transcranial magnetic stimulation (rTMS) are FDA-cleared treatments for major depression; yet their comparative effectiveness in treatment-resistant depression (TRD) has not been evaluated in randomized trials. This pilot randomized trial was designed to obtain preliminary comparative estimates and to explore whether baseline cognitive functioning relates to early remission. METHODS: Twenty-eight adults with TRD were randomized to six weeks of figure-8-coil iTBS delivered to the dorsolateral prefrontal cortex (DLPFC) (n = 15) or H7-coil rTMS delivered to the dorsomedial prefrontal cortex (DMPFC) (n = 13). The primary outcome was change in 17-item Hamilton Depression Rating Scale (HRSD-17) score from baseline to week 6, analyzed with ANCOVA. Additional outcomes included response, remission, and symptom trajectories through week 18. Exploratory analyses examined the association between baseline cognitive functioning, such as executive functions and memory, and remission. RESULTS: Twenty-five participants completed all 30 sessions. Adjusted week-6 HRSD-17 scores did not differ between groups (mean difference -0.40, 95% CI -5.23 to 4.43; p=.865). Response rates were 40.0% for figure-8-coil iTBS and 50.0% for H7-coil rTMS (p>.60), and remission rates were identical across groups (20.0%). Remitters showed higher baseline executive functioning than non-remitters in exploratory analyses, although these associations were not confirmed in adjusted models. CONCLUSION: In this pilot trial, figure-8-coil iTBS and H7-coil rTMS showed symptom improvement, with no clear between-group differences. Exploratory findings suggest a potential signal involving executive functioning that warrants further investigation. These results inform the feasibility and design of larger comparative trials. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05902312).

Adult↗
PubMed2026

Perceptions of Pharmacogenomic Testing Among People With Treatment Resistant Depression: Legitimization as a Facilitator of Acceptance.

Pharmacogenomic testing for psychiatric medications has been proposed as both an early intervention to optimize treatment response, and for use among patients who have tried multiple medications without symptom remission. Therefore, this testing may be particularly salient to the subset of individuals with major depressive disorder for whom depression has been labeled as "treatment resistant". Understanding the impact of this diagnostic label on illness identity and attitudes towards new therapies is important as genomic technology expands and rates of depression increase. We sought to explore perceptions and attitudes towards pharmacogenomic testing among individuals who had received a diagnosis of treatment resistant depression. We conducted a qualitative study with a constructivist orientation. Participants were recruited from a larger genomic research study and interviewed by phone or video call. We took an inductive approach to coding guided by reflexive thematic analysis. Themes were then organized into a relational framework following principles of interpretive description. Twelve individuals were interviewed. Key themes included internalized acceptance/hopelessness, and external validation/frustration, which were cyclically interconnected. These themes were situated within a larger framework illustrating the ways that illness identity and modifying factors such as relief of guilt, social support, pharmacogenomic testing and depressive symptoms can either facilitate acceptance and validation or contribute to feelings of hopelessness and frustration. Though participants expressed some skepticism around its effectiveness, pharmacogenomic testing may contribute to the shift towards acceptance and validation by legitimizing individuals' experiences with lack of treatment response. Genetic counselors and other healthcare providers should be aware of the complex balance between hope and frustration underlying conversations around pharmacogenomic testing, and factors that are more likely to foster self-acceptance.

Humans↗
PubMed2025

Treatment-resistant depression: role of genetic factors in the perspective of clinical stratification and treatment personalisation.

Treatment-resistant depression (TRD) is associated with chronic depression, suicidal behaviours, and reduced quality of life. TRD has a demonstrated genetic component, estimated around 8% based on common genetic variation in unrelated individuals. However, only six genome-wide association studies of TRD were published, and no replicated signals at locus or gene level have been identified; furthermore, apparently opposite results were reported in terms of genetic overlap between TRD and other traits. Other than limited power, an important issue of previous studies was the scarce consideration of TRD heterogeneity, as TRD likely comprises different groups and talking about TRDs could be more appropriate. This review points out important issues in the definition of TRD and differences across samples included in previous studies, which can be partly responsible for the inconsistency across results. Different definitions of TRD should not be expected to have similar genetic profiles, and the whole TRD group can partitioned into subgroups, based on clinical and biological features, to increase reproducibility, as exemplified by recent findings. This can be a key factor to develop/repurpose targeted treatments, or simply to aid a more personalised prescription of available medications compared to current clinical practice, that is largely concentrated on the prescription of a limited number of antidepressants compared to those available.

Humans↗
PubMed2026

Discovery of a potential novel pharmacogenomic biomarker on ANK3 gene for liafensine, a triple reuptake inhibitor for treatment-resistant depression.

Liafensine is a triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine for treatment-resistant depression (TRD). It did not exhibit efficacy in non-biomarker-selected TRD patients in two Phase 2b studies. We utilized the blood samples from the patients enrolled in these two studies and extracted genomic DNA to conduct a genome‑wide association study aiming to find a biomarker which can predict liafensine response. A single single-nucleotide polymorphism (SNP), rs12217173, at ANK3 gene was identified as strongly associated with treatment response to liafensine (p = 6.61 × 10-8) in the discovery set (n = 186) and was further confirmed in the replication sample set (n = 47, p = 0.05, combined p = 1.27 × 10-8). In addition, this SNP was not associated with the efficacy of the duloxetine or escitalopram, suggesting it is a liafensine-specific biomarker. This finding was subsequently confirmed in a prospective clinical study. Thus, this study represents a novel approach to translating precision medicine into psychiatric diseases.

Humans↗
PubMed2026

Novelty seeking and rapid symptom improvement across active and sham accelerated iTBS conditions: A pooled individual-patient data analysis.

INTRODUCTION: Major depressive disorder (MDD) is highly prevalent and often treatment-resistant. Accelerated intermittent theta burst stimulation (aiTBS) is a promising intervention for treatment-resistant depression (TRD), though outcomes vary. Personality traits have been examined in relation to rTMS outcomes, yet their role in aiTBS remains underexplored. This pooled individual-patient-data analysis of two randomized, sham-controlled trials examined associations between baseline Temperament and Character Inventory (TCI) traits and one-week symptom change, and whether they differed by condition. METHODS: The left dorsolateral prefrontal cortex was targeted for 20 sessions over 4 days. Personality was assessed with the TCI, depression severity with the 17-item Hamilton Depression Rating Scale (HDRS-17). TCI-symptom-change associations were examined with a robust linear mixed-effects model, adjusting for age, gender, repeated measurements, and study membership. RESULTS: 104 participants were included (M/F 45/59; mean age 40.9 ± 12.7; active/sham 50/54). The model yielded a Time × Novelty Seeking interaction (β = -1.70, p = 0.021): higher baseline Novelty Seeking was associated with faster symptom reduction, without a between-arm difference. However, the interaction did not survive Holm correction across 14 trait-interaction tests (adjusted p = 0.294) and is therefore exploratory. No other interaction reached the uncorrected threshold. CONCLUSIONS: Higher baseline Novelty Seeking showed a nominal association with faster symptom reduction, without a difference between active and sham conditions. Because it did not survive multiplicity correction and was not reproduced in within-arm analyses, it is preliminary and may reflect contextual or nonspecific processes. Independent replication is required before temperament assessment can be clinically informative.

Humans↗
PubMed2026

Neurophysiological signatures of Stanford Neuromodulation Therapy in treatment resistant depression.

Treatment-resistant depression (TRD) affects approximately 30% of patients with major depressive disorder. Stanford Neuromodulation Therapy (SNT), a high-dose intermittent theta-burst transcranial magnetic stimulation protocol, produces rapid antidepressant effects, but its neurophysiological mechanisms remain unclear. Here, we used longitudinal TMS-EEG to characterize the progressive neurophysiological changes induced by SNT, assess their site-specificity, and explore whether baseline neural markers are associated with clinical response. We conducted a double-blind, randomized, sham-controlled trial at Stanford University (2017-2018; analysis August 2024-October 2025) in 24 TMS-na&#xef;ve participants with TRD (Montgomery-&#xc5;sberg Depression Rating Scale &#x2265;20; &#x2265;1 failed antidepressant trial). Participants were randomized to active (n&#x2009;=&#x2009;12) or sham (n&#x2009;=&#x2009;12) SNT, consisting of 10 sessions per day over 5 consecutive days targeting the left dorsolateral prefrontal cortex (90,000 pulses). TMS-EEG was acquired at two baseline sessions, before and after each treatment session, and at 1-month follow-up (14 TMS-EEG sessions in total). Active SNT progressively reduced cortical excitability at the treatment site, with significant decreases by day 3 in the early window component (-27.9%; P&#x2009;<&#x2009;0.01), while no changes were observed at the vertex control site. Site-specific comparisons confirmed early window reductions only at the left dorsolateral prefrontal cortex (t&#x2082;&#x2082; = -3.82; P&#x2009;<&#x2009;0.001). SNT also selectively decreased estimated medial prefrontal source activity consistent with the subgenual anterior cingulate cortex (sgACC) across sessions (F&#x2081;&#x2083;,&#x2082;&#x2082;&#x2082; = 4.93; P&#x2009;<&#x2009;0.001), with effects persisting at 1-month follow-up. In an exploratory analysis in the active group (n&#x2009;=&#x2009;12), higher baseline estimated sgACC source activity was associated with greater clinical improvement (r = -0.67; P&#x2009;=&#x2009;0.023); although promising, the latter preliminary finding requires replication in larger, adequately powered samples before predictive utility can be established. These findings indicate that SNT induces progressive, site-specific cortical modulation and selective downstream effects on estimated sgACC source activity. Early cortical excitability changes represent candidate neurophysiological markers of SNT response, while the observed association between baseline sgACC activity and clinical outcome, while preliminary, motivates prospective investigation of subcortical source activity as a potential predictor of treatment response in larger trials. ClinicalTrials.gov Identifier: NCT03068715.

Journal Article↗
PubMed2026

Polygenic risk scores in major depressive disorder: A systematic review across diagnostic, treatment, course/severity, and subtype domains.

BACKGROUND: Major depressive disorder (MDD) is heterogeneous across diagnostic, treatment-related, course/severity, and subtype domains. Polygenic risk score (PRS) studies have examined these domains, but differences in PRS sources, samples, methods, and endpoint definitions have fragmented the evidence. We synthesised findings and examined potential contributors to heterogeneity. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science were searched for studies published from January 2016 through 25 November 2025. Result records were synthesised using SWiM, and certainty was assessed with an adapted GRADE framework. RESULTS: Sixty studies contributed 493 retained records; 450 were descriptively classified as positive, null, or reverse, although records were not independent. Positive findings accounted for 44/56 diagnostic, 61/273 treatment-related, 64/100 course/severity, and 14/21 subtype records. For MDD/depression-derived PRSs and case-control MDD status, all 10 contributing studies showed higher liability in cases (exploratory exact sign test p&#xa0;=&#xa0;0.002; FDR q&#xa0;=&#xa0;0.004). The same PRS group showed positive findings for overall depressive symptom severity (14/18), although the study-level test was imprecise (5/5 studies; p&#xa0;=&#xa0;0.063). Pharmacological response/remission findings for these PRSs were mostly null or directionally mixed (10 positive, 18 null, and 9 reverse). Treatment-resistant depression (TRD) findings differed by operational definition. Atypical and psychotic subtype signals arose mainly from single-study PRS and endpoint contrasts. CONCLUSIONS: PRS evidence was clearest for MDD diagnostic status and showed a tentative pattern for overall symptom burden. Treatment and subtype findings were less consistent or less replicated. Larger, ancestrally diverse studies with standardised endpoints and transparent PRS methods are needed.

Humans↗
PubMed1978

[Management of treatment-resistant depression (author's transl)].

An intensive course of drug treatment--combination of a major tranquilliser with two antidepressants--was used in 46 patients with endogenous depression and 31 with exhaustion depression, all of which had proved refractory to other forms of treatment. After one week intramuscular injection of the major tranquilliser, in order to relax the patient, intravenous infusion of the two antidepressants, clomipramine and maprotiline, was performed daily for 10-20 days, while the major tranquilliser was given orally during this period. Complete remission after 4-6 weeks was achieved in 70% of patients with endogenous depression and 48% with exhaustive depression. It is stressed that careful diagnosis and treatment by drug and psychotherapy are preconditions for the successful management of otherwise resistant depressions.

Administration, Oral↗
PubMed1979

Chlorimipramine therapy for obsessive-compulsive neurosis.

Twenty patients with a history of treatment-resistant obsessional neurosis underwent a 4-week clinical trial of chlorimipramine. Scores on the Psychiatric Questionnaire for Obsessive Compulsive Neurosis, the Leyton Obsessional Inventory, and 3 self-assessments indicated that although there was no significant change in obsessive ruminations, obsessive rituals, horrific temptations, or pervading doubt, there was a substantial significant improvement in the obsessive symptom item and severity of obsessions, as well as anxiety, depression, and phobia. Side effects were mild. The authors believe that chlorimipramine is the most promising treatment for obsessive-compulsive neurosis.

Adult↗