OBJECTIVE:To characterize the treatment burden of generalized anxiety disorder (GAD) using real-world data on pharmacotherapy use, treatment changes, and treatment progression. METHODS:This retrospective analysis used closed claims from the Komodo Healthcare Map (2021-2024) to identify U.S. adults (≥18 years) with newly diagnosed or established GAD. Treatment patterns were assessed at the drug level. RESULTS:Among the 259 158 newly diagnosed and 1 018 288 established GAD patients, GAD-related pharmacotherapy use during the 12 months post-index was 76% and 98%, respectively. Treatment patterns were further analyzed in 59 275 newly diagnosed and 86 920 established GAD patients with ≥1 pharmacy claim. Among newly diagnosed patients, 55% discontinued and 28% added or switched treatments; among established patients, 16% discontinued and 55% added or switched treatments. The median time to first treatment event varied by cohort and event type: discontinuation occurred at a median of 84 days in newly diagnosed and 119 days in established patients, combination therapy at 49 and 32 days, and switching at 31 and 42 days, respectively. Of those who discontinued, 57% of newly diagnosed and 26% of established GAD patients did not resume treatment; among those who restarted, the median treatment gap was 146 and 96 days, respectively. Overall, 75% of newly diagnosed and 94% of established GAD patients who underwent treatment modification experienced at least one additional therapy change during the study. CONCLUSION:This study underscores the significant unmet needs in the current treatment of GAD, evidenced by high rates of pharmacotherapy switching, discontinuation, and prolonged gaps in care.

Epidemiological and clinical research has confirmed a link between obesity and depressive symptoms, with inflammation as a potential common mechanism. Given that dietary components modulate inflammation and relate to both conditions, investigating dietary inflammation as a potential underlying pathway is necessary. Herein, we aimed to explore the potential role of the Energy-adjusted Dietary Inflammatory Index (E-DII) in explaining the relationship between obesity and depressive symptoms. We conducted a cross-sectional analysis of the 2007-2018 National Health and Nutrition Examination Survey cohort, enrolling 20 324 participants. Obesity and dietary inflammation were assessed by BMI and E-DII, respectively. Depressive symptoms were evaluated using the nine-item Patient Health Questionnaire-9. We found that obesity and inflammatory diets were positively associated with depressive symptoms (β = 0·50, 95 % CI 0·30, 0·69; β = 0·35, 95 % CI 0·19, 0·50; both P < 0·001), and variations in the association among obesity, pro-inflammatory diets and depressive symptoms were evident across various population subgroups (e.g. sex, age, chronic diseases and smoking status subgroups, Pfor interaction < 0·050). After adjusting for all covariates, E-DII accounted for 4 % of the obesity-depression association. Despite this modest proportion, the finding identifies dietary-induced inflammation as a statistically significant, modifiable pathway. In conclusion, obesity and pro-inflammatory diets are linked to an increased risk of depressive symptoms, with E-DII serving as a modest but significant modifiable pathway. These findings highlight dietary intervention as a potential strategy for mitigating depressive symptoms in individuals with obesity.

Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.

There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. To address circumstances warranting psychotropic medication deprescribing. The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.

BACKGROUND:Ketamine and esketamine produce rapid and sustained antidepressant effects in persons with treatment-resistant depression (TRD). Although it is posited that these effects are largely attributed to N-methyl-D-aspartate receptor antagonism, the potential involvement of the opioid system remains unclear. This systematic review investigates whether ketamine and esketamine antidepressant efficacy is mediated through the opioid system. METHODS:We conducted a systematic search of preclinical and clinical studies investigating the potential involvement of the opioid system in the antidepressant effects of ketamine and esketamine. Database searches on PubMed, Cochrane Library, Embase and PsycINFO occurred from inception to September 27, 2025. RESULTS:16 studies were identified: 12 clinical (n = 790) and 4 preclinical studies. Clinical designs included randomized controlled trials, case reports, pre-post studies and observational cohort studies. Preclinical studies utilized animal models of depression. Only one study examined esketamine. Naltrexone (nonselective opioid antagonist) attenuated ketamine's effects in three studies, while four reported no such effect and one reported mixed evidence. Genetic markers of opioid receptor subtypes (i.e., OPRM1 and OPRD1) were examined in three studies, but results were inconclusive, potentially due to limited evidence. Separately, opioid use was not associated with ketamine response. Few studies directly examined opioid receptor subtypes. CONCLUSIONS:The reported mixed findings suggest that the opioid system may exert a partial mediating effect of ketamine in TRD. However, given the inconsistent attenuation of ketamine's antidepressant effects by opioid receptor antagonists, the opioid system likely functions as a context-dependent modulator rather than a primary mediator, particularly at standard antidepressant doses.

Despite decades of effort, depression research has made limited progress in improving predictive models and treatment outcomes. Biomarker studies, in particular, have yielded few clinically translatable findings. This Review argues that such limitations stem not from a lack of research activity, but from fundamental conceptual issues in defining and measuring major depression, specifically its theoretical construct, diagnostic criteria, subtyping, measurement tools and staging frameworks. We highlight three major challenges: (1) the heterogeneity of depression measurement, (2) insufficient attention to longitudinal disease trajectories and (3) underrepresentation of lived-experience perspectives. Here, to advance precision psychiatry, we propose focusing on specific symptom domains (for example, anhedonia, cognitive impairment and insomnia), modeling trajectories across multiple timescales with dynamic symptom assessments and improved staging, and integrating patient-defined outcomes into research via a core outcome set. These strategies aim to resolve conceptual limitations and support the development of more targeted, person-centered approaches to understanding and treating depression. In this Review the authors discuss the reasons behind the limited advance in depression phenotyping and provide strategic points for addressing this gap.

Background and AimEmerging evidence suggests that weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be in part attributable to changes in lean mass, which has potential clinical implications. This study evaluates the disproportionate reporting of muscle atrophy in association with GLP-1 RA therapy using real-world global data.. MethodsWe analyzed reports of muscle atrophy submitted to the FDA Adverse Event Reporting System (FAERS) database from October 2003 to March 2024 using the validated pharmacovigilance tool OpenVigil 2.1. Disproportionality was assessed using reporting odds ratios (RORs) with 95 % confidence intervals (CIs), the standard metric for pharmacovigilance signal detection worldwide. To contextualize associations, disproportionality estimates were calculated using niacin, simvastatin, and the complete FAERS database (all other drugs) as comparators. ResultsA total of 142 cases of muscle atrophy were identified with GLP-1 RA therapy, the majority occurring in adults aged 18-64 years (43 % female, 57 % male). Disproportionality analysis showed pharmacovigilance signals for semaglutide (ROR = 2.39, 95 % CI = 1.63-3.52) and tirzepatide (ROR = 1.69, 95 % CI = 1.14-2.50), indicating increased reporting of muscle atrophy relative to all other drugs in FAERS. In contrast, exenatide (ROR = 0.26, 95 % CI = 0.12-0.55) and liraglutide (ROR = 0.27, 95 % CI = 0.09-0.83) were associated with significantly lower reporting odds. All significant signals satisfied thresholds of p < 0.05 and IC025 > 0.. ConclusionsCertain GLP-1 receptor agonists demonstrate a pharmacovigilance signal of disproportionate reporting of muscle atrophy. These findings should be interpreted as signal detection rather than evidence of causality and highlight the need for future studies incorporating objective measures of muscle mass and function..

BACKGROUND:Consensus exists that scalable point-of-care capabilities are required to improve the timeliness and accuracy of Major Depressive Disorder (MDD) during clinical encounters. Artificial intelligence (AI), through the integration of high-dimensional and multimodal data has emerged with the potential capability to improve the quality and accuracy of MDD diagnosis. While AI diagnostic algorithms are increasingly applied in medical and neurological domains, their role in MDD psychiatric care requires further evaluation. METHOD:We conducted a targeted narrative commentary of peer-reviewed literature evaluating AI and machine learning applications in MDD diagnosis. Relevant sources were identified through structured PubMed searches and manual reference screening of the neuroimaging, speech and language, digital phenotyping and clinical decision support studies. We further prioritized studies that demonstrated diagnostic classification, replication across cohorts, model interpretability and real-world application. FINDINGS:Across disparate AI modalities, several algorithms have demonstrated the capacity to identify diagnostic markers that can complement self-report and clinical assessments. Neuroimaging-based classifiers have achieved an accuracy in the diagnosis of MDD that is comparable to expert "ground truth" diagnosis. Notwithstanding, neuroimaging is neither scalable, cost-effective nor affordable. Separately, integrating other aspects of phenomenology and behavior also appears promising as enablers of more timely and accurate diagnoses of MDD. CONCLUSION:AI-supported diagnostic approaches offer scalable pathways to improve the accuracy and timeliness of MDD detection. Nonetheless, clinically-meaningful implementation requires prospective validation, transparent model reporting to patients and clinicians, as well as mitigation of demographic and algorithmic biases.

IMPORTANCE:Seltorexant, a selective orexin-2 receptor (OX2R) antagonist, has demonstrated antidepressant effects in major depressive disorder (MDD), particularly among patients with higher baseline insomnia symptoms. OBJECTIVE:To investigate flexibly dosed seltorexant vs flexibly dosed quetiapine extended release (quetiapine-XR) as adjunctive treatment to a selective serotonin (SSRI) or serotonin-norepinephrine (SNRI) reuptake inhibitor. SETTING:Outpatient. DESIGN:Randomized, active-controlled, multicenter, exploratory phase 2 study with screening (≤4 weeks), double-blind treatment (24 weeks), and post-treatment follow-up (2 weeks) phases. PARTICIPANTS:Patients with MDD and inadequate response to 1-3 SSRIs/SNRIs, including an ongoing SSRI/SNRI, in the current depressive episode. INTERVENTIONS:Flexibly dosed seltorexant (20 or 40 mg) or quetiapine-XR (150 or 300 mg, with 2-day initial dosing of 50 mg) once daily as adjunctive therapy to an SSRI/SNRI. Randomization (1:1) was stratified by baseline Insomnia Severity Index total score (≥15 vs <15). Safety, tolerability, and preliminary efficacy were evaluated. MAIN OUTCOMES AND MEASURES:Primary efficacy endpoint was time to all-cause study drug discontinuation. Secondary efficacy endpoints included change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Subgroup analyses included MADRS change by mode dose (MD; most frequent daily dose received by a patient during the study). Safety and tolerability also were assessed. RESULTS:Time to all-cause discontinuation (estimated 25th percentile [80% CI]: seltorexant, 62 [38, 83] days vs quetiapine-XR, 42 [35, 61] days; hazard ratio [80% CI]: 0.83 [0.6, 1.2]) and all-cause discontinuation (seltorexant, 41.2% vs quetiapine-XR, 47.1%; 2-sided P = .5355) did not differ significantly between treatment groups. For the seltorexant 20-mg MD group, MADRS total scores consistently improved over time and reductions were numerically greater at weeks 18 and 24 versus the seltorexant 40-mg MD and the combined quetiapine-XR groups, and patients with higher baseline insomnia symptoms had greater improvement in MADRS total score, consistent with prior studies showing efficacy at 20 but not 40 mg. Treatment-emergent adverse event rates were 65.4% for seltorexant and 80.8% for quetiapine-XR. CONCLUSIONS AND RELEVANCE:Results support the favorable tolerability and preliminary efficacy of seltorexant 20 mg daily as adjunctive treatment in patients with MDD, especially those with insomnia symptoms, and suggest potential approaches to differentiate seltorexant from quetiapine-XR in future adequately powered studies. TRIAL REGISTRATION:Clinicaltrials.gov  identifier: NCT03321526.

Importance:Consistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1 Rs) affects reward processes; however, to our knowledge, no study has previously evaluated whether a GLP-1 R agonist (GLP-1 RA) affects motivated behavior in individuals with major depressive disorder (MDD) in a randomized clinical trial. Objective:To assess the effects of a GLP-1 RA, semaglutide, on reward-related dysfunction in a population with MDD. Design, Setting, and Participants:This study was a 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial. A total of 72 participants with a diagnosis of MDD and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or higher were randomized to oral semaglutide (n = 35) or placebo (n = 37). Participants were recruited from the Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, a university-based mood disorders program. Participants were enrolled between March 14, 2022, and July 26, 2024. Data analysis was performed from January 7, 2025, through February 3, 2025. Intervention:Patients were randomized 1:1 to receive placebo or oral semaglutide, 14 mg (initiated at 4 mg and titrated using a 4-week dose-escalation regimen), adjunctive to their treatment as usual. Main Outcome and Measure:The preregistered outcome of this secondary analysis was performance on the Effort-Expenditure for Rewards Task (EEfRT). Results:A total of 72 participants were randomized to oral semaglutide (n = 35 [49.7%]; mean [SD] age, 38.17 [11.79] years; 18 female participants [51.4%]) or placebo (n = 37 [51.3%]; mean [SD] age, 40.27 [9.32] years; 19 female participants [51.3%]). Semaglutide-treated participants exhibited a pattern of increased willingness to exert physical efforts with higher expected values of reward (treatment × visit × expected value interaction: χ2 = 12.024; P = .02). Computational modeling indicated that semaglutide's effects on choice behavior were a result of reduced effort discounting. Sensitivity to effort was significantly reduced by treatment with semaglutide (β = -1.737; P = .03), whereas there was no treatment effect on sensitivity to probability (β = -0.776; P = .51). Conclusions and Relevance:In this secondary analysis of a double-blind randomized clinical trial, treatment with semaglutide significantly improved measures of motivation in patients with MDD. Semaglutide reduced the perceived cost of effort, relative to the monetary reward; the results of this trial have implications for the treatment of multiple neuropsychiatric disorders, which are characterized by varied reward dysfunctions. Trial Registration:ClinicalTrials.gov Identifier: NCT04466345.

Anhedonia, or the lack of interest and pleasure, is a transdiagnostic feature of mental health disorders with emerging links to physical health. This exploratory literature review investigated evidence of anhedonia's association with physical health and somatic diseases. A citation chaining approach was applied to 20 papers identified through targeted searches conducted from September to October 2024 on PubMed and Google/Google Scholar. Studies published in English and reporting outcomes in adults with anhedonia were included. Quality assessments were performed using the Centre for Evidence-Based Medicine critical appraisal tool for prognostic studies. Data on study characteristics, assessment and definition of anhedonia, and clinical outcomes were extracted. 41 publications on 40 unique studies were included. Most studies included patients with cardiac conditions, and 14 reported a psychiatric diagnosis, predominantly depression. Anhedonia was significantly associated with all-cause mortality, risk of major adverse cardiovascular events and worse physical health-related quality of life. Moreover, high positive affect was correlated with lower risk of functional decline, reduced inflammatory biomarkers and protective effects against conditions like diabetes and hypertension, compared with low positive affect. To our knowledge, this is the first exploratory review to gather evidence that anhedonia, whether occurring as a symptom of depression, another psychiatric disorder, or a somatic condition, may be associated with poorer health and somatic disease outcomes. Conversely, positive affect may confer protective benefits. These insights emphasise the need to prioritise development of treatment modalities that have proven impacts on hedonic tone.

Incretin receptor agonists (IRAs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual/triple receptor co-agonists, have transformed the treatment of obesity, type 2 diabetes mellitus, and cardiovascular disease. Given the extraordinary burden of cardiometabolic comorbidity and excess premature mortality in persons living with psychiatric disorders, IRAs represent a highly relevant and potentially transformative pharmacologic class for this population. Beyond their established metabolic indications, a triangulation of preclinical, neuroimaging, observational, and emerging controlled trial evidence suggests that IRAs may exert direct central nervous system effects — augmenting neurogenesis, neuroplasticity, and functional brain connectivity — that underpin putative psychiatric benefits. Replicated evidence supports effects on alcohol and substance use disorders, and preliminary data indicate benefits in mood and neurocognitive disorders. However, controlled trial evidence remains limited and mixed, and several clinical considerations specific to psychiatric populations — including suicidality surveillance, sarcopenia, constipation risk, drug-drug interactions, and aspiration risk with ketamine — require careful attention. Whether IRAs ultimately meet the evidentiary threshold to be classified as psychiatric drugs remains to be determined by ongoing phase III trials. In the interim, their use for cardiometabolic indications in psychiatric populations is well-justified and may confer meaningful mortality reduction.

OBJECTIVES:This systematic review aims to assess the efficacy and tolerability of ketamine in the treatment of obsessive-compulsive disorder. BACKGROUND:Obsessive-compulsive disorder is a chronic and severe disorder characterized by intrusive thoughts and repetitive behaviours that can cause significant distress. Notwithstanding current treatments and interventions for obsessive-compulsive disorder, some individuals still do not adequately respond to conventional pharmacotherapeutic and/or psychotherapeutic interventions. Emerging evidence indicates that ketamine, an N-methyl-D-aspartate receptor antagonist, could have potential rapid-acting and enduring efficacy in the treatment of obsessive-compulsive disorder. METHODS:A systematic search was conducted with OVID, PubMed, and Scopus from database inception to July 2025. Two independent reviewers (I.H. and M.C.S.) screened the studies, assessed methodological quality, and extracted pertinent data. Five studies (3 randomized controlled trials and 2 open-label trials) were deemed eligible for inclusion and included variable routes of administration (intravenous, intramuscular, and oral) and dosing frequencies. RESULTS:Across studies, ketamine consistently and significantly improved overall obsessive-compulsive disorder symptom severity, with reductions up to 50% to 60%; however, the duration of effects varied from a few hours postinfusion to 6 weeks. Overall, ketamine was generally well tolerated. CONCLUSIONS:Further research should focus on optimizing ketamine treatment (ie, dosing regimens, routes of administration) for sustained symptom reduction.

Atypical antipsychotics (AAs) are first-line treatments for bipolar I disorder (BP-I). While cariprazine is approved in the US for the treatment of both BP-I manic/mixed and depressive episodes, most other AAs are only approved for one affective pole but are utilized across the disease spectrum. For example, aripiprazole is only approved for BP-I manic/mixed episodes. This real-world analysis compared the rates of healthcare resource utilization (HRU)-defined manic and depressive events among patients treated with cariprazine versus aripiprazole. A retrospective observational cohort study was conducted using IQVIA® PharMetrics® Plus Database (5/28/2018–6/30/2022). Adults diagnosed with BP-I with ≥ 2 dispensings for cariprazine or aripiprazole were included. Cohorts were balanced via inverse probability of treatment weighting. Manic and depressive events were identified using a claims-based algorithm and reported per person-year (PPY) by setting of care [inpatient, emergency department (ED), and outpatient] and overall (any setting). Manic and depressive events during the ≥ 3-month on-treatment period were compared between cohorts via rate ratios (RRs) with P values and 95

Background: Whether glucagon-like peptide 1 receptor agonists influence the development of colorectal precursor lesions remains uncertain. Prior studies have largely focused on colorectal cancer and have not evaluated colonoscopically detected benign neoplasms under comparable surveillance. We conducted a colonoscopy-anchored target trial emulation to compare incident colorectal polyps and adenomas among new users of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) versus sodium glucose cotransporter 2 (SGLT2) inhibitors. Methods: Using de-identified electronic health records from the TriNetX network, we emulated a new-user, active-comparator target trial among adults initiating either therapy who subsequently underwent colonoscopy. Time zero was defined as the first colonoscopy after treatment initiation. Incident benign colorectal neoplasms were assessed after prespecified latency periods to reduce misclassification of prevalent lesions (primary ≥180 days; secondary ≥365 and ≥730 days). Propensity score matching and Cox proportional hazards models estimated hazard ratios. Results: Among 173,922 GLP-1 RA and 84,752 SGLT2 inhibitor initiators who underwent colonoscopy, initiation of GLP-1 RAs was associated with a lower hazard of incident benign colorectal neoplasms at 180 days (hazard ratio 0.96, 95% confidence interval 0.94–0.98). Similar estimates at 365 and 730 days demonstrated consistency. In sustained-exposure analyses requiring confirmed or persistent treatment, associations were stronger (hazard ratios 0.85–0.86). Findings were consistent in mutually exclusive exposure and temporal restriction analyses. Conclusions: In this colonoscopy-anchored target trial emulation, GLP-1 RA initiation was associated with a lower hazard of benign colorectal neoplasms compared with SGLT2 inhibitors, supporting prospective evaluation of potential effects on early colorectal carcinogenesis.