October 2025

Lithium is a classic, primary treatment for bipolar disorder that has paradoxically been used less over time, especially in North America, which goes against the accumulating evidence for its efficacy. Bipolar disorder is increasingly conceptualised as a chronic, potentially progressive condition worsened and accelerated by each mood episode, which might resemble multiple sclerosis or rheumatoid arthritis as a condition that requires disease-modifying treatments to change illness trajectory. In this Personal View, we argue that lithium acts like a disease-modifying drug in bipolar disorder. Although the pathophysiology of bipolar disorder remains unclear, many of the mechanisms implicated in bipolar disorder, and the surrogate markers associated with this condition, are uniquely affected by lithium treatment from the DNA and cellular levels to the structure and function of the brain and other body systems. Clinical trial and cohort study evidence shows that lithium is effective and probably superior to other medications used to treat bipolar disorder, and that long-term outcomes are better with lithium than non-lithium regimens. Conceptualisation of lithium as a disease-modifying agent might help to increase clinical use by doctors, especially early in the disease course to better serve our patients.

This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal damage and lasting cognitive deficits, especially in perinatal animals. Infrequently administered relatively low and moderate subanesthetic doses (<1 mg/kg approximate human intravenous equivalent) do not yield overt histopathology in rat and nonhuman primate models. In humans, observational studies in frequent high-dose (>1 g/day) ketamine users show memory and executive function impairments. In contrast, a large clinical trial found that intranasal esketamine at doses up to 84 mg, administered weekly or every other week for several years, is associated with maintained or slightly improved cognitive function in adults with major depression. Lower cognitive function (attention, processing speed) showed some potential worsening among elderly patients; the clinical significance of this is unknown. Direct comparisons of esketamine and off-label racemic ketamine at higher doses have not been done. These studies underscore the potential for neurotoxic effects when ketamine is used at doses or frequencies beyond those utilized in clinical trials, highlighting a critical need for robust longitudinal research. Clinicians are advised to exercise caution, particularly when prescribing ketamine off-label at doses significantly higher than those used in clinical trials. When deviating from this in clinical practice, strong consideration should be given to conducting repeated cognitive assessments. Funding agencies should incentivize preclinical researchers to conduct studies that further elucidate the threshold of ketamine's neurotoxicity.

Background: Hallucinations and delusions are often grouped together as positive symptoms of psychosis. However, recent evidence suggests that they may be driven by distinct computational and neural mechanisms. Examining the time course of their emergence may provide insights into the relationship between these underlying mechanisms. Methods: Participants from the second (N = 719) and third (N = 699) iterations of the North American Prodrome Longitudinal Study (NAPLS 2 and 3) were assessed for timing of clinical high risk for psychosis (CHR-P)-level delusion and hallucination onset. Pre-onset symptom patterns in patients with first-episode psychosis from the Prevention and Early Intervention Program for Psychosis (PEPP-Montréal) (N = 694) were also assessed. Symptom onset was determined at the baseline assessment, and the evolution of symptom patterns was examined over 24 months. Results: In all 3 samples, participants were more likely to report the onset of attenuated/subthreshold delusions prior to attenuated/subthreshold hallucinations (odds ratios [ORs]: NAPLS 2 = 4.09; NAPLS 3 = 4.14; PEPP, z = 7.01, p < .001) and to present with only attenuated/subthreshold delusions compared with only attenuated/subthreshold hallucinations (ORs: NAPLS 2 = 5.6; NAPLS 3 = 11.11; PEPP = 42.75). The reemergence of attenuated/subthreshold delusions after remission was also more common than reemergence of attenuated/subthreshold hallucinations (ps < .05), which more often resolved first (ps < .001). In both CHR-P samples, ratings of delusional ideation decreased with the onset of attenuated hallucinations (p = .007). Conclusions: Attenuated/subthreshold delusions tend to emerge before attenuated/subthreshold hallucinations and may play a role in their development. Future work should examine the relationship between the mechanisms that drive these symptoms and its utility for diagnosis and treatment.

Insomnia is ubiquitous, is comorbid with all major mental disorders, increases the risk of depression, and contributes to inflammatory morbidity and all-cause mortality. This review examines the relationships between insomnia and inflammation in the pathophysiology of depression. The unique role of insomnia on depression risk is examined with interrogation of what aspects of sleep disturbance contribute to depressed mood. Furthermore, the influence of insomnia and its specific aspects (i.e., short sleep duration, disturbance of sleep maintenance) on affective mechanisms are considered, with a focus on reward activation and emotion processing. Given that inflammation contributes to some types of depression, the bidirectional interactions between sleep and inflammation are examined with consideration of how sleep deprivation induces activation of systemic, cellular, and genomic inflammatory outcomes and the causal role of inflammation in precipitating depressed mood and depressive symptoms. Key gaps in the literature linking insomnia and inflammation to depression risk are identified, and maps for future research are proposed. In particular, this review considers how the components of insomnia and inflammation conspire together to exaggerate deficits in reward activation and recognition of emotion, which underlie depression risk and adverse depression outcomes. Finally, informed by this two-hit model of insomnia and inflammation on depression risk, this review examines the efficacy of behavioral interventions that target insomnia and reverse related inflammation and discusses their potential to refine therapeutic approaches for depression treatment and prevention in individuals with insomnia.

Background and objectives: Concomitant use of tramadol and antidepressants with potent inhibition of the cytochrome P450 2D6 (CYP2D6) enzyme is postulated to increase risk of seizures in older adults; yet, such an association has not been empirically tested in populations. We aimed to examine the association of concomitant tramadol and CYP2D6-inhibiting vs CYP2D6-neutral antidepressant use and the risk of seizures among older nursing home (NH) residents. Methods: This population-based cohort study was conducted using a 100% Medicare NH sample from January 2010 to December 2021. We included long-term residents aged 65 years or older who initiated antidepressants on existing tramadol use (tramadol-antidepressant users) or initiated tramadol on existing antidepressant use (antidepressant-tramadol users). Patients were followed up until the end of 1 year, NH discharge, death, or study end. The key exposure was concomitant use of tramadol with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants. The key outcome was incident rates of medical encounters with a diagnosis of seizure and analyzed using negative binomial or Poisson regression models adjusted for baseline covariates (e.g., pain status and depressive, physical, and cognitive function) through the inverse probability of treatment weighting. Results: We identified 11,162 concomitant tramadol-antidepressant users (mean [SD] age, 86.2 [8.5] years; 9,077 [81.3%] female) and 58,994 concomitant antidepressant-tramadol users (mean [SD] age, 85.3 [8.4] years; 47,053 [79.8%] female). The incidence rate of seizures was 16.10 and 20.17 per 100 patient-years, respectively, for the tramadol-antidepressant and antidepressant-tramadol group. In both subgroups, co-use of tramadol with CYP2D6-inhibiting (vs with CYP2D6-neutral) antidepressants was associated with higher adjusted incidence rate ratios of seizures (1.09 [95% CI 1.02-1.18] and 1.06 [95% CI 1.03-1.10]). Findings were corroborated by a negative control exposure analysis in which co-use of hydrocodone with CYPD2D6-inhibiting (vs CYP2D6-neutral) antidepressants was not associated with risk of seizures. Discussion: Concomitant use of tramadol with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants was associated with increased risk of seizures. Findings are only generalizable to long-term NH populations and are subject to residual confounding. Clinicians should be mindful of seizure risk in older patients who use tramadol concomitantly with antidepressants, particularly CYP2D6-inhibiting antidepressants. Classification of evidence: This study provides Class II evidence that the combination of tramadol and CYP2D6-inhibiting antidepressants is associated with a higher risk of seizures compared with the combination of tramadol and CYP2D6-neutral antidepressants.

Background: Depressive symptoms are common in neuropsychiatric disorders, significantly affecting quality of life and posing challenges to treatment. While pharmacological and psychological therapies remain standard, many patients show limited response. Fecal microbiota transplantation (FMT), which aims to restore gut microbial balance, has emerged as a novel approach for alleviating depressive symptoms by modulating the gut-brain axis. This study aims to conduct a comprehensive synthesis and quantitative evaluation of current evidence to elucidate the therapeutic potential of FMT in the management of depressive symptomatology. Methods: Following PRISMA guidelines, we conducted a systematic search across PubMed, Embase, Web of Science, the Cochrane Library, and CINAHL from January 1, 2000, to December 31, 2024. 12 randomized controlled trials (RCTs) with 681 participants were included. The standardized mean difference (SMD) was calculated to evaluate FMT's effect on depressive symptoms. Subgroup analyses examined effects by delivery routes, follow-up duration, and clinical population. Results: FMT significantly reduced depressive symptoms (SMD = -1.21; 95% CI: -1.87 to -0.55; p = 0.0003). Sensitivity analysis confirmed statistical significance (SMD = -0.56; 95% CI: -0.86 to -0.26; p = 0.001). Both oral capsule and direct gastrointestinal administration were effective, with greater effects seen in direct gastrointestinal delivery (SMD = -1.06 vs. -1.29). Improvements were most notable in the short- to mid-term; effects diminished by 6 months. Subgroup analysis showed stronger effects in patients with irritable bowel syndrome (IBS) (SMD = -1.06) than in those with neurological/psychiatric-related conditions (SMD = -0.67), with moderate heterogeneity (I² = 47%). Conclusions: This meta-analysis supports FMT as an effective adjunctive therapy for depressive symptoms, especially in individuals with IBS. Endoscopic or enema routes appear more efficacious than oral capsules. While short- and mid-term benefits are evident, sustained effects require further investigation through long-term, high-quality RCTs.

Importance: The criterion-standard treatment for opioid use disorder (OUD) is medications for OUD (MOUD). However, less than a quarter of people with OUD receive MOUD. The collaborative care model (CCM) is an evidence-based practice that integrates mental and physical health treatment in primary care settings. Expanding CCM to include patients with OUD could improve MOUD initiation. Objective: To compare the effectiveness of CCM for OUD and co-occurring mental health symptoms (intervention) with CCM for mental health symptoms only (active control). Design, setting, and participants: This hybrid type 2a trial cluster-randomized 24 US primary care clinics to intervention or control. Participants included patients with OUD and mental health symptoms who were not receiving specialty mental health care or specialty substance use treatment. Study data were analyzed from February 2024 to January 2025. Interventions: The control care team included primary care practitioners, care managers, and psychiatric consultants. Primary care practitioners prescribed psychotropic medications with psychiatric consultation. Care manager activities included patient education, engagement and self-management, shared decision-making, measurement-based care for mental health symptoms, and brief psychotherapy for mental health. The intervention had the same components as the control, with additional MOUD training and psychiatric consultation for primary care practitioners, measurement-based care for OUD, and brief psychotherapy for OUD. Main outcomes and measures: Participants completed research assessments at baseline, 3 months, and 6 months. The multiple primary outcomes were past-month number of days of using opioids and the Veterans RAND 12 Mental Health Component Summary score. Results: A total of 254 patients (mean [SD] age, 40.9 [12.4] years; 139 women [59.9%]) participated in the trial. Most participants (172 of 212 [81.1%]) were taking MOUD at baseline. Days using opioids decreased in both the control and intervention groups. The intervention significantly reduced opioid use more than the control with a medium effect size (adjusted ratio of odds ratio, 0.10; 95% CI, 0.03-0.38; Cohen d = -0.44; P < .001). Mental Health Component Summary scores improved slightly in both the control and intervention groups. The intervention did not significantly improve scores more than control (adjusted difference in change, -1.20; 95% CI, -4.97 to 2.57; Cohen d = -0.09; P = .53). Conclusions and relevance: Findings of this cluster randomized clinical trial indicate that OUD can be successfully managed in primary care with CCM, especially CCM for OUD and mental health symptoms. Primary care clinics with MOUD prescribers should consider implementing CCM for OUD and mental health.

mportance: Antipsychotic drug (AP)-induced glucose homeostasis changes are often attributed to AP-induced weight gain. Nevertheless, dysregulated glucose control can occur independently of weight gain. Objective: To examine the association between AP use and glucose homeostasis while considering weight gain propensity, medication type, and treatment duration. Data sources: MEDLINE, Embase, PsychINFO, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through February 3, 2025. Study selection: Blinded randomized clinical trials (RCTs) comparing changes in glucose homeostasis-related parameters between patients with severe mental illness or healthy volunteers assigned to AP or control (placebo or no intervention) groups were included. Studies were limited to English-language human studies without restrictions on study length, AP type, or previous AP exposure. Of 22 773 unique citations, 163 RCTs met inclusion criteria, with 127 studies included in the meta-analysis. Data extraction and synthesis: Each article was screened independently by 2 authors using predefined inclusion and exclusion criteria. Data extraction and risk of bias assessment were completed using a standardized spreadsheet. Data were analyzed via random-effects meta-analysis, with subgroup analyses for diagnosis, study length, AP type, age, concomitant medication use, and previous AP exposure. Metaregressions identified covariate effects. Data analysis was completed from October 2023 to February 2025. Main outcomes and measures: Primary study outcomes were changes in fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c) following AP treatment. Secondary outcomes included any other glucose metabolism-related parameters including, but not limited to, insulin resistance and hyperglycemia. Results: A total of 35 952 AP-treated patients and 19 010 placebo-treated patients were included in the qualitative synthesis, while 28 975 AP-treated and 15 101 placebo-treated patients were included in the meta-analysis. AP use was associated with significantly increased fasting glucose (mean difference [MD], 0.72 mg/dL; 95% CI, 0.54-1.08 [to convert to millimoles per liter, multiply by 0.0555]; P < .001), fasting insulin (MD, 1.94 μIU/mL; 95% CI, 1.28-2.61 [to convert to picomoles per liter, multiply by 6]; P < .001), glycated hemoglobin (MD, 0.04%; 95% CI, 0.02%-0.05% [to convert to proportion of total hemoglobin, multiply by 0.01]; P < .001), and hyperglycemia (odds ratio, 1.29; 95% CI, 1.04-1.59; P = .02) vs placebo. Findings were corroborated in healthy volunteers. Subgroup analyses suggested that AP type, diagnosis, age, concomitant medication use, and previous AP exposure do not consistently affect dysglycemia risk. In metaregression analyses, AP-associated dysregulations in glucose homeostasis were independent of study length and AP dose. Conclusions and relevance: In this systematic review and meta-analysis, results indicate that AP exposure significantly disrupts glucose homeostasis independent of exposure time, dose, diagnosis, and weight gain propensity. Increased awareness of AP-induced dysregulations in glucose homeostasis alongside ongoing metabolic monitoring and potential treatment is warranted.

Importance: Energy homeostatic dysregulation may constitute 1 module of the heterogeneous pathophysiology of major depressive disorder (MDD), potentially manifesting as a distinctive symptom profile. Objective: To test whether the shared genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with the expression of specific MDD symptoms. Design, setting, and participants: This study used summary-level data from large genome-wide association studies and individual-level data from 2 prospective psychiatric cohorts, the CoLaus|PsyCoLaus (population-based) and Netherlands Study of Depression and Anxiety (NESDA; clinically enriched) cohorts. Data were retrieved and analyzed from May 2023 through November 2024. A lifetime diagnosis of MDD was ascertained with semistructured diagnostic interviews. The sample comprised 1407 MDD cases and 2020 controls from CoLaus|PsyCoLaus and 1803 MDD cases and 266 controls from NESDA. Exposures: Genomic structural equation modeling was applied to model a unique underlying factor capturing the common genetic liability shared among metabolic and interoceptive signals (body mass index, triglycerides, fasting glucose, C-reactive protein, leptin) and motivational (anhedonia) processes. From this underlying factor, a polygenic score (PGS) was derived, indexing the shared genetic liability of traits potentially involved in energy homeostasis regulation. Main outcomes and measures: A total of 15 depressive symptoms endorsed by participants during MDD. Results: Among 1407 MDD cases (66.2% female; median year of birth [YOB], 1956) and 2020 controls (44.3% female; median YOB, 1955) from CoLaus|PsyCoLaus and 1803 MDD cases (68.3% female; median YOB, 1962) and 266 controls (56.0% female; median YOB, 1960) from NESDA, multiple significant bidirectional mendelian randomization estimates and genetic correlations (r = 0.11-0.81) indicated a shared genetic basis between the selected traits, which was modeled as a latent homeostatic factor with genomic structural equation modeling. In cohort data, the PGS indexing the latent homeostatic factor was significantly (false discovery rate, <5%) higher in MDD cases endorsing appetite increase and hypersomnia when contrasted with both controls (appetite increase odds ratio [OR], 2.25 [95% CI, 2.00-2.53]; P = 9.03 × 10-41; hypersomnia OR, 1.22 [95% CI, 1.10-1.35]; P = 1.15 × 10-04) and other MDD cases (appetite increase OR, 1.88 [95% CI, 1.63-2.18]; P = 2.38 × 10-17; hypersomnia OR, 1.18 [95% CI, 1.05-1.33]; P = 5.80 × 10-03). Conclusions and relevance: This study identified a module of depression pathophysiology characterized by altered energy homeostasis and associated with the expression of specific symptoms reflecting energy saving and intake responses. These findings could be used to identify patients with depression at higher metabolic risk and could pave the way for the development of targeted treatments.

Objective: The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States. Methods: U.S. safety data from patient monitoring forms submitted to the esketamine Risk Evaluation and Mitigation Strategy (REMS) program and reports submitted to the Janssen U.S. Global Medical Safety (US-GMS) database were evaluated (March 5, 2019, to January 5, 2024). Patient characteristics, use and dosage patterns, adverse events of interest (actively solicited reports of sedation, dissociation, and increased blood pressure), and serious adverse events following esketamine administration were described. The incidence of suicidality and drug abuse/misuse was also evaluated. Results: Most patients were 26-55 years of age (64.3%) and female (61.1%). A total of 1,486,213 outpatient treatment sessions were completed by 58,483 patients who had at least one esketamine treatment session. Sedation, dissociation, and increased blood pressure were reported in 34.7%, 41.0%, and 0.9% of sessions, respectively. Serious adverse events were reported in <0.1% and 0.18% of treatment sessions in REMS and US-GMS, respectively; suicide rates were lower than background rates; and 210 incidences of all-cause abuse/misuse were reported. Conclusions: Analysis of almost 5 years of real-world use of esketamine in the United States remains consistent with the established safety profile from clinical studies and current product labeling. No new safety signals were identified.

Objective: The authors previously demonstrated that symptoms of premenstrual dysphoric disorder (PMDD) remit during ovarian hormone suppression and recur after estradiol or progesterone is reintroduced (addback). In this study, using a substantially expanded sample, they aimed to 1) evaluate the specific contributions of estradiol and progesterone to symptom development, 2) analyze physical symptoms related to ovarian hormones, 3) identify differences between women with PMDD who experienced continued symptom remission and those who experienced symptom recurrence during hormone addback, and 4) determine whether change in hormone levels from baseline to addback is associated with PMDD symptom severity. Methods: Thirty-four women with PMDD (10 from the original cohort) and 76 healthy participants (15 from the original cohort) completed a daily rating form during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide, leuprolide+estradiol addback, and leuprolide+progesterone addback. Affective and somatic symptom scores during the last 8 of 12 weeks of leuprolide alone were compared with scores during the first 4 weeks of estradiol addback and the first 4 weeks of progesterone addback. Results: For affective symptoms (anxiety, sadness, irritability, mood swings), there were significant main effects of diagnosis and diagnosis-by-hormone interactions, reflecting a significant increase in symptom severity scores during estradiol addback and progesterone addback compared with leuprolide treatment alone. Compared to healthy comparison participants, women with PMDD had significantly higher symptom scores during each addback. With regard to physical symptoms, bloating and food cravings showed greater severity in women with PMDD regardless of hormone conditions, whereas breast pain increased in severity during estradiol addback compared with leuprolide alone and progesterone. Conclusions: The study confirmed that ovarian suppression in women with PMDD eliminated symptom cyclicity, and that symptoms emerged during ovarian steroid addback in women with PMDD but not in healthy comparison women. In PMDD, irritability and mood swings are tied more closely to progesterone than estradiol. Despite the replication of this hormone-related behavioral phenotype in PMDD, the mechanisms underlying the presumed alteration in steroid signaling require further characterization.

Importance: Dose reduction or discontinuation (DRD) early after remission from first-episode psychosis (FEP) increases short-term relapse risk. Controversy remains regarding potential benefits in functioning over the longer term because studies with long-term outcomes show conflicting findings. Objective: To compare short- and long-term effects between DRD and maintenance medication over a 4-year period in a large sample of patients with FEP. Design, setting, and participants: The Handling Antipsychotic Medication Long-Term Evaluation of Targeted Treatment (HAMLETT) study is a single-blind pragmatic randomized (1:1) clinical trial conducted in 26 specialized psychosis units in the Netherlands from September 2017 to March 2023. Patients remitted for FEP from in- and outpatient services were included. Interventions: DRD within 12 months after remission compared with 12 months maintenance treatment. Main outcomes and measures: The primary outcome was patient-rated functioning, measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2). Secondary outcomes were researcher-rated global assessment of functioning (GAF), quality of life, relapse, symptom severity (measured by the Positive and Negative Syndrome Scale [PANSS]), serious adverse events, and adverse effects. Results: A total of 347 patients (241 male [69.5%]; mean [SD] age, 27.9 [8.7] years) were included, with 168 randomized to early DRD and 179 to maintenance. WHODAS-2 showed no time × condition interaction. In the first year, DRD was associated with higher risk of relapse (odds ratio, 2.84; 95% CI, 1.08 to 7.66; P = .04) and lower quality of life (β = -3.31; 95% CI, -6.34 to -0.29; P = .03). At 3 years (β = 3.61; 95% CI, 0.28 to 6.95; P = .03) and 4 years (β = 6.13; 95% CI, 2.03 to 10.22; P = .003), a nonlinear effect of time occurred, showing significantly better GAF for patients in the DRD condition, with a similar trend for PANSS at 4 years (P for trend = .06). Although SAEs and adverse effects were similar between groups, 3 confirmed deaths by suicide occurred in the DRD group, against 1 death by suicide in the maintenance group. Conclusions and relevance: This randomized clinical trial found that DRD posed risks of relapse and worse quality of life over the first year but yielded better researcher-rated functioning at the third and fourth year, with a similar trend for symptom severity; because antipsychotic medication doses were comparable in the 2 groups from 1 year onwards, this finding is not a direct result of lower medication but may reflect a learning experience to use antipsychotics to better handle psychotic vulnerability. These findings suggest that the potential learning and empowering element of DRD needs to be weighed carefully against short-term risks.

Background: Antidepressants induce physiological alterations; however, the degree to which these occur in treatment with various antidepressants is unclear. We aimed to compare and rank antidepressants based on physiological side-effects by synthesising data from randomised controlled trials (RCTs). Methods: We searched MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and the US Food and Drug Administration (FDA) website from database inception to April 21, 2025. We included single-blinded and double-blinded RCTs comparing antidepressants and placebo in acute monotherapy of any psychiatric disorder. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in weight; total cholesterol; glucose; heart rate; systolic and diastolic blood pressure; corrected QT interval (QTc); sodium; potassium; aspartate transferase (AST); alanine transaminase (ALT); alkaline phosphatase (ALP); bilirubin; urea; and creatinine. We did meta-regressions to examine study-level associations between physiological change and age, sex, and baseline weight. We estimated the correlation between depressive symptom severity change and metabolic parameter change. Findings: Of 26 252 citations, 151 studies and 17 FDA reports met inclusion criteria. The overall sample included 58 534 participants, comparing 30 antidepressants with placebo. Median treatment duration was 8 weeks (IQR 6·0-8·5). We observed clinically significant differences between antidepressants in terms of metabolic and haemodynamic effects, including an approximate 4 kg difference in weight-change between agomelatine and maprotiline, over 21 beats-per-minute difference in heart rate change between fluvoxamine and nortriptyline, and over 11 mmHg difference in systolic blood pressure between nortriptyline and doxepin. Paroxetine, duloxetine, desvenlafaxine, and venlafaxine were associated with increases in total cholesterol and, for duloxetine, glucose concentrations, despite all drugs reducing bodyweight. There was strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP concentrations, although the magnitudes of these alterations were not considered clinically significant. We did not find strong evidence of any antidepressant affecting QTc, or concentrations of sodium, potassium, urea, and creatinine to a clinically significant extent. Higher baseline bodyweight was associated with larger antidepressant-induced increases in systolic blood pressure, ALT, and AST, and higher baseline age was associated with larger antidepressant-induced increases in glucose. We did not observe an association between changes in depressive symptoms and metabolic disturbance. Interpretation: We found strong evidence that antidepressants differ markedly in their physiological effects, particularly for cardiometabolic parameters. Treatment guidelines should be updated to reflect differences in physiological risk, but choice of antidepressant should be made on an individual basis, considering clinical presentation and preferences of patients, carers, and clinicians.

Background: Borderline personality disorder (BPD) typically onsets in adolescence and predicts later functional disability in adulthood. Highly structured evidence-based psychotherapeutic programs, including mentalization-based treatment (MBT), are first choice treatment. The efficacy of MBT for BPD has mainly been tested with adults, and no RCT has examined the effectiveness of MBT in groups (MBT-G) for adolescent BPD. Method: A total of 112 adolescents (111 females) with BPD (106) or BPD symptoms ≥4 DSM-5 criteria (5) referred to child and adolescent psychiatric outpatient clinics were randomized to a 1-year MBT-G, consisting of three introductory, psychoeducative sessions, 37 weekly group sessions, five individual case formulation sessions, and six group sessions for caregivers, or treatment as usual (TAU) with at least 12 monthly individual sessions. The primary outcome was the score on the borderline personality features scale for children (BPFS-C); secondary outcomes included self-harm, depression, externalizing and internalizing symptoms (all self-report), caregiver reports, social functioning, and borderline symptoms rated by blinded clinicians. Outcome assessments were made at baseline, after 10, 20, and 30 weeks, and at end of treatment (EOT). The ClinicalTrials.gov identifier is NCT02068326. Results: At EOT, the primary outcome was 71.3 (SD = 15.0) in the MBT-G group and 71.3 (SD = 15.2) in the TAU group (adjusted mean difference 0.4 BPFS-C units in favor of MBT-G, 95% confidence interval -6.3 to 7.1, p = .91). No significant group differences were found in the secondary outcomes. 29% in both groups remitted. 29% of the MBT group completed less than half of the sessions compared with 7% of the control group. Conclusions: There is no indication for superiority of either therapy method. The low remission rate points to the importance of continued research into early intervention. Specifically, retention problems need to be addressed.

Chronic pain (CP) is closely related with major depressive disorder (MDD) and anxiety disorders (ANX), with high comorbidity and shared risk factors. Prior studies have demonstrated common neural correlates across the three disorders, but their neuroanatomic basis is not fully clear. Hence, the preregistered meta-analysis (CRD42019119709) intended to explore common alterations in cortical thickness among CP, MDD, and ANX, a widely used parameter for quantitatively assessing various cerebral conditions with high sensitivity to pathology in neuropsychology. A total of 68 studies comprising 3072 patients and 3427 healthy controls were finally included. Across the disorders, four common clusters with a significant reduction in cortical thickness were identified, including right insula, left anterior cingulate (AC), triangular part of the left inferior gyrus (IFG), and left middle temporal gyrus (MTG). Our findings suggested the shared cortical deficits involving ACC-insula/IFG circuit and left MTG in CP, MDD and ANX, revealing common neural correlates for cognitive and emotional processing in these highly comorbid disorders.