Both intravenous (IV) racemic ketamine and intranasal (IN) esketamine have emerged as rapid-acting antidepressants for treatment-resistant depression (TRD) and are increasingly used in clinical settings. Relatively few s...Both intravenous (IV) racemic ketamine and intranasal (IN) esketamine have emerged as rapid-acting antidepressants for treatment-resistant depression (TRD) and are increasingly used in clinical settings. Relatively few studies, however, have compared these interventions in larger, naturalistic cohorts. This study was conducted to assess the comparative efficacy and rapidity of response observed with repeated IV ketamine versus IN esketamine in a psychiatric neurotherapeutics specialty service. Through retrospective chart review, we conducted what is, to the best of our knowledge, among the larger such comparisons to date. Data from 153 patients with severe TRD were reviewed (111 patients received IV ketamine and 42 patients received IN esketamine). In accordance with consensus criteria for TRD and validated objective criteria for illness severity, included patients failed a minimum of 2 adequate antidepressant treatment trials and demonstrated a preketamine treatment score of 16 or higher on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). Severity of depression was subsequently reassessed with the QIDS-SRprior to each ketamine and esketamine administration. A 2-way analysis of variance was used to compare changes in QIDS-SRscores between the IV ketamine and IN esketamine treatment groups. With equivalent depression severity measured by QIDS-SRat pretreatment baseline, the IV ketamine treatment group showed significantly greater decreases in QIDS-SRscores compared to the IN esketamine group, as measured immediately before each treatment from the third to the eighth session (all values < .05). Patients who received IV ketamine infusions demonstrated a 49.22% reduction in QIDS-SRscores by the eighth treatment, while patients who received IN esketamine over the same induction period showed a 39.55% reduction. As expected, both IV ketamine and IN esketamine treatments resulted in significant decreases in QIDS-SRscores. In the IV ketamine group, the decrease in QIDS-SRscores reached significance after 1 treatment, while in the IN esketamine treatment group, the decrease in QIDS-SRscores reached significance after the second treatment. In this naturalistic sample of patients with similarly severe TRD treated in a ketamine subspecialty service over a 4-5-week induction period, treatment with IV racemic ketamine was associated with a more rapid response and greater overall efficacy than treatment with IN esketamine.
Finasteride, widely prescribed for androgenetic alopecia, has long been suspected of causing severe neuropsychiatric reactions, including depression, anxiety, and suicidality, even after the drug is discontinued. This st...Finasteride, widely prescribed for androgenetic alopecia, has long been suspected of causing severe neuropsychiatric reactions, including depression, anxiety, and suicidality, even after the drug is discontinued. This study systematically reviews evidence that supports this suspicion and analyzes the reasons for this delayed recognition. Concerns about depression from finasteride were raised in several studies as early as 2002. Between the years 2017 and 2023, 4 independent analyses of adverse event reporting systems and 4 studies using data mining of healthcare records indicated a significant increase in the risk for depression, anxiety, and/or suicidal behavior with the use of finasteride. There has been, therefore, a two-decade delay in the realization of the incidences and the gravity of neuropsychiatric effects, allowing harm from a medicine prescribed for a cosmetic indication of hair loss. Over 20 years worldwide, hundreds of thousands may have endured depression, and hundreds may have died by suicide. According to the precautionary principle, such a risk from a cosmetic medication suggests a benefit-to-harm balance that justifies action to protect the public, and the burden of proving that the intervention is harmful falls on manufacturers. The long delay in recognizing the risks associated with finasteride exposure includes the manufacturer's failure to perform and publish simple pharmacovigilance studies using database analyses and regulators' failure to request such studies from the manufacturer or to perform them. Current evidence shows that finasteride use can cause depression and suicidality. A historical literature review discloses gaps between research evidence and regulatory steps. The lesson is that before approving a medication for the market, regulators should require manufacturers to commit to performing and disclosing ongoing postapproval analytical studies, and this requirement needs to be enforced.
Meyerson WU, Ross EL, Kennedy CJ
… +4 more, Hoyle RH, Chhatwal J, Wang PS, Smoller JW
J Clin Psychiatry
· 2025 Sep · PMID 41004167
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In treatment-resistant depression (TRD), augmentation with aripiprazole (A-ARI) or combination therapy by adding bupropion (C-BUP) has been reported as more effective than switching to bupropion (S-BUP), but C-BUP risks...In treatment-resistant depression (TRD), augmentation with aripiprazole (A-ARI) or combination therapy by adding bupropion (C-BUP) has been reported as more effective than switching to bupropion (S-BUP), but C-BUP risks falls in older adults, and A-ARI risks weight gain and tardive dyskinesia (TD). The aim of this study was to clarify whether the enhanced effectiveness outweighs such risks. In this risk-benefit decision analysis, lifetime quality-adjusted life-years (QALYs) following 1 year of A-ARI or C-BUP vs S-BUP treatment were simulated in a health-state transition model tracking depression remission, falls, weight gain, and TD, in age and baseline body mass index (BMI) subgroups, using data from the VAST-D and OPTIMUM trials and other literature. QALYs were converted to depression-free day-equivalents (DFDs), the QALYs gained from 1 day of remitted versus active depression. Simulated adults aged 18-64 years experienced a net benefit of C-BUP over S-BUP of 20.7 DFDs, equivalent to about 3 weeks of faster remission of depressive symptoms. In older adults, especially those aged 85+ years, this benefit over S-BUP was partially but not fully offset by a risk of falls. In adults aged 18-64 years, A-ARI was estimated to offer only 8.0 DFDs after subtracting the expected harms from TD, and this was further reduced to -22.8 DFDs once metabolic harms were considered, in those overweight at baseline. Overall, C-BUP was preferred over A-ARI in all subgroups except ages 85-89 years with BMI<25, in whom A-ARI was preferred. In our model, C-BUP better balanced efficacy and tolerability in TRD in adults under 85 years than did S-BUP or A-ARI. A-ARI was least-preferred in overweight adults. These results may inform shared decision-making and clinical guidelines.
This study examined the relationships between body fat mass percentage and mental health (depression and anxiety symptoms) during pregnancy, while assessing the moderating effects of physical activity and diet quality....This study examined the relationships between body fat mass percentage and mental health (depression and anxiety symptoms) during pregnancy, while assessing the moderating effects of physical activity and diet quality. A prospective cohort of 219 pregnant women was recruited for a longitudinal study of maternal health during pregnancy and offspring outcomes. Pregnant participants were assessed at ∼12 and ∼36 weeks of pregnancy. Body composition was measured using air displacement plethysmography, physical activity was measured with ActiGraph wearables, and diet was measured using the National Institute of Health Diet History Questionnaire-III. Depression and anxiety symptoms were also evaluated using the Beck Depression Inventory-II and State-Trait Anxiety Inventory, respectively, at each study visits. Multivariable mixed linear models adjusted for demographic and socioeconomic factors were used to analyze relationships among these parameters. The study period is from October 2019 to August 2024. Higher body fat mass percentage was significantly associated with increased depression (β= 0.246, =.014) and anxiety scores (β= 0.241, =.002). Physical activity moderated the effect of body fat on depression (interaction β=-0.001, =.017), while diet quality moderated the effect of body fat on anxiety (interaction β=-0.002, =.047). Higher body fat mass during pregnancy is associated with more symptoms of depression and anxiety. However, increased physical activity and adherence to high-quality diets can attenuate these effects, indicating that lifestyle interventions during pregnancy may improve mental health of pregnant women, particularly for those with obesity.
To compare the results of a proprietary online assessment of adult attention-deficit/hyperactivity disorder (ADHD) with the current standard of care, a clinical interview, among a real-world population of adults seeking...To compare the results of a proprietary online assessment of adult attention-deficit/hyperactivity disorder (ADHD) with the current standard of care, a clinical interview, among a real-world population of adults seeking online ADHD assessment. Participants recruited from a population of adults seeking online ADHD assessment completed a virtual clinical interview followed by the online self-report assessment between July and November 2024. Agreement was calculated using a 2×2 matrix, and disagreement was further examined: first, a licensed clinician reviewed both assessments and rendered a "full data" diagnosis using all available results, and then, factors associated with disagreement (eg, psychiatric comorbidities, ADHD presentation) were explored. The sample (N = 345) was predominantly female, with an approximate age of 35 years. The most common ADHD presentations were combined and inattentive. The agreement between assessments was 78% (positive predictive value: 94.9%, negative predictive value: 15.1%, sensitivity: 80.6%, specificity: 44.0%, and κ: 0.13). Over 80% of cases in which there was disagreement between the assessments were found to have ADHD on clinical interview, whereas the initial online assessment did not confirm a diagnosis of ADHD and recommended further assessment. This is the first study to validate an online asynchronous ADHD assessment relative to the current standard of care among individuals seeking online behavioral health care. The online assessment correctly identified over 80% of ADHD-positive cases. Compared with the clinical interview, the online assessment was more conservative in rendering ADHD-positive diagnoses, allaying possible concerns about overdiagnosis. Due to the high prevalence of ADHD in the study sample, these results are not yet generalized to a broader clinical setting.
Patarroyo-Rodriguez L, Pazdernik VK, Vande Voort JL
… +3 more, Kung S, Frye MA, Singh B
J Clin Psychiatry
· 2025 Sep · PMID 40965838
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Short-term studies have demonstrated antisuicidal effects of ketamine/esketamine for patients with treatment-resistant depression (TRD). However, long-term data and their impact in reducing suicidality-related health car...Short-term studies have demonstrated antisuicidal effects of ketamine/esketamine for patients with treatment-resistant depression (TRD). However, long-term data and their impact in reducing suicidality-related health care utilization are limited. This 6-month mirror-image study compares suicidality-associated emergency department (ED) visits before and after acute treatment with ketamine/esketamine in a TRD cohort. This study included adults with TRD evaluated at Mayo Clinic Depression Center (Rochester, Minnesota) from May 2018 to May 2024, who received an acute series of intravenous (IV) ketamine or intranasal (IN) esketamine treatments. The primary outcome measure was the number of suicidality-associated ED visits in the 6 months before and after treatment. Negative binomial mixed-effects model was utilized to analyze suicidality-associated ED visits per person, estimating incidence rate ratios (IRRs) and 95% confidence intervals for the change between pre-and posttreatment periods. Of 124 eligible individuals, 27 were excluded due to unavailable data, leaving 97 for analysis. The cohort was 69% female, with a median age of 48.9 years; 97% had major depressive disorder, and most (75%) received IV ketamine. After the acute treatment phase, ED visits for suicidal ideation decreased by 84% (IRR=0.16, 95% CI, 0.06-0.46, =.001), and total ED visits for suicidality decreased by 63% (IRR=0.37, 95% CI, 0.18-0.77, =.007). Ketamine and esketamine reduced long-term ED visits for suicidality in individuals with TRD. Further longer-term follow-up research is encouraged to ascertain if these benefits on suicidality reduction are mood state dependent or reflect an independent mechanism.
Posttraumatic stress disorder is a significant public health concern in the US, with military veterans disproportionately affected. Although younger veterans exhibit a higher prevalence of posttraumatic stress disorder (...Posttraumatic stress disorder is a significant public health concern in the US, with military veterans disproportionately affected. Although younger veterans exhibit a higher prevalence of posttraumatic stress disorder (PTSD) compared to their older counterparts, the mechanisms driving this age-related difference remain unclear. This study examined sociodemographic, trauma-specific, and psychosocial factors that may contribute to the elevated prevalence of PTSD in younger (age <50) vs older (age 50 and older) veterans. Data were analyzed from the National Health and Resilience in Veterans Study, which surveyed a nationally representative sample of US military veterans (n=4,069). Younger veterans were 3 times more likely to screen positive for PTSD compared to older veterans (weighted 14.7% vs 4.9%, <.001). Mediation analysis revealed that 90% of the association between younger age and PTSD was indirectly mediated by psychosocial and trauma-specific factors. Psychosocial difficulties contributed the most to accounting for this association (42.9%), followed by loneliness (23.6%), avoidance coping (9.7%), adverse childhood experiences (9.5%), and combat exposure severity (4.2%). Secondary analyses identified interpersonal relationship challenges, substance use and self-blame coping strategies, and childhood physical abuse as key mediators of this association. Psychosocial and trauma-specific factors may mediate the link between younger age and higher rates of PTSD among US military veterans. These findings underscore the importance of targeted interventions designed to address psychosocial challenges, strengthen social connections, and promote adaptive coping strategies among younger veterans who are at risk for or currently living with PTSD.
Ketamine, introduced as an anesthetic drug, is now used for many indications beyond anesthesia; it is also increasingly a drug of abuse. Long-term recreational use and abuse of ketamine are associated with urological ris...Ketamine, introduced as an anesthetic drug, is now used for many indications beyond anesthesia; it is also increasingly a drug of abuse. Long-term recreational use and abuse of ketamine are associated with urological risks. This article discusses ketamine-associated uropathy from the perspective of prevalence, clinical features, mechanisms, and strategies for risk reduction in patients who require long term maintenance therapy with the drug for psychiatric indications. A systematic review and meta-analysis of 37 studies of uropathy in recreational (ab)users obtained prevalences of 44% to 77% for lower urinary tract symptoms and 8% to 30% for upper urinary tract disease; for reasons explained, these findings are potentially misleading and cannot be extrapolated to therapeutic contexts. More recent studies, using different methods of case ascertainment, present lower risks (2% to 27%). A systematic review of 27 studies of ketamine used to treat psychiatric disorders, mainly depression, found urological symptoms in 0% to 24% of patients; however, in 14 randomized controlled trials, urological symptom prevalences differed little between ketamine and comparison arms. The review presented no convincing evidence of ketamine-associated uropathy arising in therapeutic contexts. The literature on ketamine-associated uropathy is critically examined; reasons for false positive uropathy findings are considered. Ketamine pharmacokinetics are described to assist the understanding of how ketamine and its metabolites may predispose to uropathy. Mechanisms of uropathy, arising from exposure to ketamine and its metabolites in urine (rather than in circulation), are summarized. A reasonable conclusion is that higher doses of ketamine, more frequent dosing with ketamine, longer duration of treatment with ketamine, and oral administration of ketamine are all potential risk factors for ketamine-associated uropathy during maintenance therapy. High hydration and frequent voiding of urine on treatment days can reduce exposure of the bladder to ketamine and its metabolites, reducing urological risks. Fortnightly or monthly urine testing is also advisable.
The objective of this study was to investigate potential associations between bariatric surgery and new onset mental health diagnoses and emergent psychiatric care utilization. This was an observational retrospective co...The objective of this study was to investigate potential associations between bariatric surgery and new onset mental health diagnoses and emergent psychiatric care utilization. This was an observational retrospective cohort study. Patients without a history of mental health diagnoses who underwent bariatric surgery between 2010-2016 were matched to patients who were eligible for but did not undergo bariatric surgery on demographic, body mass index (BMI), and comorbidity burden at baseline (date of surgery for cases and matching date for controls). Outcomes of new onset mental health diagnoses after baseline and emergent care utilization were measured in 2-year increments between baseline (ranged from 2010 to 2016) until the end of follow-up (December 31, 2021) to assess changes in risk over time. The surgical group had lower risk of a new onset mental health diagnosis in the first 2 years (hazard ratio [HR]: 0.82, 95% CI, 0.76-0.88) and approximately 20% higher risk in years 4-8 of follow-up than the control group (years 4-6 HR: 1.22, 95% CI, 1.09-1.36; years 6-8 HR: 1.19, 95% CI, 1.03-1.39). However, emergent psychiatric service utilization did not differ between the groups during follow-up. Utilization was associated with a higher BMI (HR: 1.03, 95% CI, 1.02-1.04) and higher comorbidity burden (HR: 1.43, 95% CI, 1.37-1.49) at baseline. Bariatric surgery may have a delayed impact on new onset mental health diagnoses, with surgical patients having higher risk of diagnoses than their nonsurgical counterparts 4-8 years following surgery. Despite these increases, there was no change in emergent psychiatric service utilization.
Electroconvulsive therapy (ECT) has potent antidepressant effects yet can lead to neurocognitive side effects. Ketamine is a rapid-acting antidepressant, which may be an alternative to ECT. Few have directly compared the...Electroconvulsive therapy (ECT) has potent antidepressant effects yet can lead to neurocognitive side effects. Ketamine is a rapid-acting antidepressant, which may be an alternative to ECT. Few have directly compared the cognitive effects of ECT and ketamine treatment. We compared cognitive effects of intravenous ketamine and ECT in patients with treatment-resistant depression (TRD), collected through a multisite, randomized trial conducted between April 2017 and November 2022 (the ELEKT-D study). Participants received 6 IV ketamine treatments or 9 ECT sessions. Cognitive functioning was assessed through 4 validated cognitive tasks at pre- and posttreatment visits. The Squire Memory Complaint Questionnaire (SMCQ) and Global Self-Evaluation of Memory (GSE-My) were used to measure changes in memory functioning. Responders (those who achieved ≥50% reduction in depressive symptoms) were evaluated again at 1-, 3-, and 6-month follow-up visits. In the intent-to-treat sample (N = 365), ECT recipients performed significantly worse than ketamine recipients on all cognitive tasks at end of treatment ( < .001), with no significant differences in task performance associated with response to either treatment. Among responders, we observed no significant group differences at 1-, 3-, and 6-month follow-up. Analyses of subjective memory questionnaires were mixed. SMCQ scores improved for both groups with ketamine recipients reporting greater functional gains; ketamine-treated patients reported improvements in GSE-My scores while ECT-treated patients reported a decline in GSE-My scores. Within-group analyses in the ketamine group found improvements in executive functioning and cognitive flexibility. This survived adjustments for changes in depression, suggesting partial independence of cognitive and mood effects. Patients treated with ketamine demonstrated superior cognitive functioning compared with those treated with ECT following a 3-week treatment course, with no differences between treatments observed among responders in follow-up. Findings support the short-term superiority of ketamine on cognitive functioning and the long-term cognitive safety of both treatments for TRD. ClinicalTrials.gov identifier: NCT03113968.
On October 7, 2023, Israel experienced a large-scale terrorist attack followed by a prolonged war, exposing civilians and military personnel to acute and sustained trauma. While prior studies have documented short-term p...On October 7, 2023, Israel experienced a large-scale terrorist attack followed by a prolonged war, exposing civilians and military personnel to acute and sustained trauma. While prior studies have documented short-term psychological effects of mass trauma, few have included baseline assessments or addressed long-term trajectories across distinct exposure groups. In this study, we aimed to examine changes over time in both probable diagnoses and symptom severity of posttraumatic stress disorder (PTSD), depression, anxiety, and suicidal ideation (SI), while accounting for preattack symptom levels among different exposed groups. A prospective, representative study assessed 614 Israeli participants (309 females; 50.3%) through an online survey conducted across 3 time points: prior to the attack (T1), 1 month after (T2), and 1 year later (T3). Participants were categorized into 4 mutually exclusive exposure groups based on a predefined hierarchy prioritizing the most impactful exposure: direct exposure, bereavement (loss of a close other), reserve-duty combatants, and indirect exposure. Probable diagnoses of PTSD (using the International Trauma Questionnaire), depression (Patient Health Questionnaire-2), and anxiety (Generalized Anxiety Disorder-2) were assessed along with symptom severity and SI (SI by the Columbia-Suicide Severity Rating Scale). Generalized estimating equations were used to examine main and interaction effects of exposure type and time (T2 to T3), controlling for baseline symptom levels (T1). Overall, prevalence and severity of psychiatric symptoms declined between T2 and T3. However, exposure group moderated these changes. Reserve-duty combatants exhibited the highest rates of probable diagnoses and symptoms at both time points, with minimal improvement over time. In contrast, indirectly exposed participants demonstrated significant symptom reduction. Uniquely, SI increased over time among reserve-duty participants, highlighting their vulnerability. Recovery following mass trauma such as the October 7th attack is not uniform. Exposure type and initial distress levels shape distinct psychological trajectories. Findings underscore the importance of differentiated, long-term, and trauma-informed interventions-especially for bereaved and reserve-duty individuals. Integration of baseline mental health data enhances risk identification and has critical implications for both clinical care and policy planning in the context of ongoing national crises.
To assess proof-of-concept (PoC) for efficacy, tolerability, and safety of TRPC4/5 inhibitor BI 1358894 vs placebo in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressants. In...To assess proof-of-concept (PoC) for efficacy, tolerability, and safety of TRPC4/5 inhibitor BI 1358894 vs placebo in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressants. In this phase 2, multicenter, randomized, double-blind, dose-finding trial (December 2020-February 2024), patients with MDD (per ) and current depressive episode of ≥8 weeks and ≤24 months were randomized (3.5:1:1:1:2:2) to receive placebo or BI 1358894 (5 mg, 25 mg, 75 mg, or 125 mg) or quetiapine 150-300 mg orally, once daily for 6 weeks. Primary end point was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. Secondary end points included ≥50% reduction from baseline in MADRS total score at Week 6, change from baseline in State-Trait Anxiety Inventory scores, Clinical Global Impression Severity Scale score, and Symptoms of Major Depressive Disorder Scale total score at Week 6. Of 940 enrolled patients, 389 were randomized, and 361 (93.0%) completed the trial. No differences were observed between BI 1358894 treatment groups and placebo for primary and secondary end points. Adverse events were slightly more frequent in the BI 1358894-total group (66.7%) vs placebo (53.9%). No worsening of Columbia-Suicide Severity Rating Scale was observed for most patients; serious adverse events of suicidal ideation were reported for 4.7% (placebo), 5.1% (BI 1358894 75 mg group), and 1.4% (quetiapine) of patients. Although this was a negative trial in MDD with PoC not established, BI 1358894 was well tolerated with no increase in self-harm or suicidality. ClinicalTrials.gov identifier: NCT04521478.