Kyle Valentino

Antidepressant medications variably affect weight and metabolic outcomes and pose risks related to obesity. The clinical relevance of these effects across randomized trials remains unclear. Understanding these effects can inform treatment selection for patients with obesity. Relevant studies were identified through searches of PubMed, MEDLINE, Cochrane Library, Web of Science, PsycINFO, Scopus, and Embase. Studies were included if they were randomized controlled trials reporting whether a Food and Drug Administration-approved antidepressant agent was associated with obesity-related measures as either a primary outcome, secondary outcome, or safety outcome. Of the 222 identified records, 19 eligible studies (all randomized controlled trials, comprising 24,256 participants) met the inclusion criteria. In trials that combined pharmacotherapy with behavioral/psychotherapeutic interventions, fluoxetine was associated with larger weight reductions (−7.89 kg with fluoxetine + metformin vs. −0.48 kg in a comparator group in one trial), and cognitive behavioral therapy + fluoxetine produced greater reductions in binge-eating disorder samples than fluoxetine alone (≈5.1 kg vs. ≈2.1 kg). Bupropion monotherapy produced modest but sustained weight loss in some studies (reductions up to 2.4 kg over 52 weeks), while the naltrexone–bupropion combination produced the largest and most reproducible benefits when delivered with structured behavioral modification (9.3% ± 0.4% vs. 5.1% ± 0.6% at 56 weeks). These findings support the use of intensive behavioral therapy alongside targeted pharmacologic antidepressants such as bupropion and naltrexone–bupropion to produce clinically meaningful weight loss in selected settings; however, findings for fluoxetine appear context-dependent. Because trials varied in populations, follow-up duration, and risk-of-bias domains, these findings should not be interpreted as prescriptive treatment recommendations.

The high prevalence and economic burden of injuries and deaths related to violence and aggression invite the need to further assess the biological mechanisms underlying their expression. Evidence implicates estrogen signaling as a mediator of aggressive behavior. In accordance with PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. The databases were searched from inception to October 3, 2025. Study screening and selection were performed by three reviewers (A.K., L.C., and A.A.). The included studies reported on the role of estrogen in aggressive and antisocial behavior. A total of 103 studies were included in this review. Preclinical and clinical studies have consistently demonstrated the role of estrogen in social dominance and antagonistic behaviors. Early-life stress and anxiety can counteract these effects. Similarly, extant data suggest that aromatase, an enzyme that synthesizes estrogen from testosterone, is involved in reported aggression. This convergence between human and animal data supports the role of estrogen in instinctive behavior and invites future studies to assess the role of estrogen antagonism in aggressive behavior.

Depression commonly coexists with cardiovascular disease (CVD) and worsens prognosis, yet uncertainty persists about the efficacy and cardiovascular safety of antidepressants in cardiac populations. Following PRISMA 2020 guidelines, we systematically reviewed randomized controlled trials (RCTs) in English that contained Food and Drug Administration-approved antidepressant with at least one cardiovascular outcome (primary, secondary, or safety). Dual screening, extraction, and outcome-level risk of bias (RoB 2) were performed, and certainty was graded with GRADE. Heterogeneity in outcomes precluded meta-analysis and was summarized qualitatively. Seven RCTs (N = 3,512; mean age 58–67 years) met criteria. Results showed that selective serotonin reuptake inhibitors (SSRI) were CVD-neutral versus placebo/usual care, no excess in major adverse cardiovascular events (MACE), arrhythmia, QTc prolongation, or mortality. Antidepressant efficacy results were mixed with sertraline not outperforming placebo in heart failure, whereas escitalopram prevented incident depression post-acute coronary syndrome. A head-to-head trial showed that nortriptyline had more cardiac adverse events than paroxetine, supporting avoidance of tricyclics in ischemic heart disease. Integrated models showed dual benefits where older adults markedly improved depression and tripled hypertension control and those without baseline CVD had reduced long-term myocardial infarction or stroke. Overall, GRADE certainty score was higher for SSRI cardiovascular safety than for antidepressant efficacy, limited by modest sample sizes, outcome heterogeneity, and short follow-up. SSRIs appear cardiologically safe in adults with CVD in short term, tricyclics should generally be avoided, and early, collaborative depression care may yield cardiometabolic benefits, especially before overt CVD. Finally, large, longer-term RCTs with prespecified MACE and bleeding/QTc endpoints are needed to refine efficacy estimates.

Suicide accounts for over 700,000 deaths per year globally and remains a public health priority. Evidence suggests that sleep-related interventions may be effective in reducing depressive symptom severity and suicidal thoughts in patients diagnosed with depression and comorbid insomnia. This study aims to systematically review the efficacy of sedative-hypnotics and/or cognitive behavioral therapy for insomnia (CBT-I) on measures of suicidality. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Medline, Cochrane Library, Embase, Scopus, and Web of Science were searched from inception to July 30, 2024. Studies were included if they (1) were randomized controlled trials (RCTs) and (2) reported on suicide-related measures associated with sleep interventions as a primary outcome, secondary outcome, or a safety measure. We endeavored to define and operationalize suicidality as suicidal ideation (SI), suicide attempts (SA), and suicide completion (SC). In cases where study authors failed to separate these three dimensions, the term “suicidality” was applied. Eighteen studies were identified meeting inclusion criteria, comprised of studies investigating benzodiazepines (n = 2), Z-drugs (n=4), orexin receptor antagonists (ORAs) (n=8), and CBT-I (n=4). Zolpidem reduces SI as well as insomnia (linear association = 0.12, pt = −3.35, p<0.05). Effectively treating insomnia is associated with reduced SI. Available evidence suggests that Food and Drug Administration (FDA)-approved sedative-hypnotics do not increase the risk of suicidality.

Major depressive disorder (MDD) is a chronic, highly prevalent, and debilitating mental disorder associated with significant illness and economic burden globally. Exposure to trauma (eg, physical, sexual, emotional abuse, and/or physical, and emotional neglect) is common among individuals with MDD. Persons with MDD and a history of trauma often exhibit an attenuated response to conventional serotonergic antidepressants compared to those with non-traumatized depression. Emerging evidence indicates that exposure to trauma is associated with increased inflammatory markers [eg, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)] as well as glutamatergic dysregulation in the central nervous system (CNS). It is hypothesized that individuals with MDD and a history of trauma may be conceptualized as a distinct bio-phenotype compared to non-traumatized depression. Furthermore, preliminary evidence positions select glutamatergic modulators as potential, novel, mechanistically-informed therapeutic strategies that may provide benefit to persons with elevated inflammation and glutamatergic dysregulation.