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Purpose Women have historically been underrepresented in second-generation antipsychotic (SGA) clinical trials, accounting for less than 35% of participants, which raises concerns about the generalizability of the safety profile for these medications. Methods The US adverse event reporting system was queried for the dates January 1, 2019, to July 8, 2024, to examine the following 6 SGAs: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Reports were excluded if patients were under 18 years old, contained an unknown age or gender, or were duplicated. Five adverse events were examined: Torsades de pointes (TdP), neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), agranulocytosis (AG), and cerebrovascular adverse events (CVAE). Counts of these events were noted, and reporting odds ratios (ROR) were calculated. Results The total study cohort was 87,356 reports, consisting of aripiprazole (n = 10,715, 12.2%), clozapine (n = 25,096, 28.7%), olanzapine (n = 11,587, 13.3%), quetiapine (n = 28,746, 32.9%), risperidone (n = 10,467, 12%), and ziprasidone (n = 745, 0.9%). The cohort's mean age was 48.6 ± 18.5 years and comprised 42,584 females (48.7%). Most cases were reported by healthcare professionals (74,836, 85.7%). A total of 3,754 reports contained at least 1 of the 5 adverse events. The RORs among females compared to males for TdP (5.55, 95% confidence interval [CI] = 3.78–8.47), NMS (0.59, 95% CI = 0.53–0.65), TD (0.88, 95% CI = 0.76–1.02), AG (0.59, 95% CI = 0.51–0.70), and CVAE (1.12, 95% CI = 0.89–1.41) were observed. Females had a significantly higher odds of hospitalization or death with TdP compared to males (ROR = 3.09, 95% CI = 1.36–7.01). Conclusions Our findings suggest higher odds of TdP and worse TdP-associated outcomes among females exposed to SGAs compared to males. Further studies are needed to confirm these preliminary findings.

Background This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features. Procedures Patients (18–75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)–defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters. Results Lumateperone met the primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], −5.7; 95% confidence interval [CI], −7.60,−3.84; effect size [ES], −0.64; P < 0.0001), MDD (LSMD, −5.9; 95% CI, −8.61,−3.29; ES, −0.67; P < 0.0001), and bipolar depression (LSMD, −5.7; 95% CI, −8.29,−3.05; ES, −0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (≥5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk. Conclusions Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.

Background The objective of this study was to examine the characteristics of adverse drug reactions of duloxetine and investigate the potential precautions that may exist beyond the drug label. Methods This study used data from the Food and Drug Administration Adverse Event Reporting System database 2004–2023 and the linked information of duloxetine. Four algorithms used to evaluate the correlation between duloxetine and adverse events include reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results Adverse reactions involving duloxetine were associated with 24 System Organ Classes. Among them, the three most frequent systems affected were psychiatric disorders (reporting odds ratio [ROR] 5.05), nervous system disorders (ROR 2.27), and general medical conditions and administration site conditions (ROR 0.83). Of particular note, the number of reported cases and the risk of occurrence of adverse events of drug withdrawal syndrome (n = 7498), nausea (n = 7942), and headache (n = 5732) were the highest, increasing each year and reached a peak submission in 2017. More importantly, the occurrence of reproductive system and breast disorders (chisq 317.85) was not mentioned in the drug leaflet. Conclusions Psychiatric and nervous system disorders are the most frequently reported adverse events associated with duloxetine, with drug withdrawal syndrome, nausea, and headache being especially common. The emergence of mood-related symptoms, such as agitation and irritability, underscores the need for vigilant monitoring of mental health. Additionally, potential risks affecting the reproductive system suggest areas for further attention. These findings highlight the importance of proactive monitoring to improve patient safety during duloxetine treatment.

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Background A subset of novel psychoactive substances (NPS), designer benzodiazepines, are rising in popularity. These compounds are more potent derivatives of prescription benzodiazepines and can lead to profound sedation. Therefore, clinicians are challenged with caring for patients who present with designer benzodiazepine intoxication or withdrawal. We conducted a systematic review of the literature for designer benzodiazepine overdoses with a focus on patient presentation and clinical management. Methods We conducted a systematic literature search in multiple databases using Medical Subject Headings (MeSH) terms “designer benzodiazepine(s)” and “case report” along with additional permutations of search terms. We used the PICOS search algorithm to enhance reporting of systematic reviews' findings. Results A total of 27 articles were selected for inclusion in our systematic review, comprising 35 patient cases. The average patient age was 27.14 years (SD = 9.86), and the male-to-female ratio was 3.38:1. More than half (54.29%) of cases involved designer benzodiazepines alone, whereas 45.71% of cases involved co-ingestions. The most frequent presenting sign was altered mental status. The most frequent abnormal vital sign was tachycardia. Discussion Management of patients presenting with acute designer benzodiazepine intoxication was highly variable, depending on the severity. We include practical clinical management guidance based on 3 designer benzodiazepine toxidromes including sedation-predominant, withdrawal-predominant, or mixed-sedation with rebound agitation. Conclusion Designer benzodiazepines are highly potent compounds that present a significant risk to patients and pose a clinical management challenge to clinicians. More research is needed to fully understand the effects of designer benzodiazepines in humans.

Purpose/Background The antipsychotic class of medications has a varying degree of peripheral alpha antagonism resulting vasodilation and potentially hypotension. These hemodynamic changes may require treatment with crystalloids and vasopressors. The primary aim of this study was to evaluate the occurrence of hypotension after antipsychotic overdose and characterize vasopressor use. Methods/Procedures A retrospective cohort study was conducted by chart review of electronic records from 2 regional poison centers from January 1, 2004, to December 31, 2020. Inclusion criteria were single acute antipsychotic exposures evaluated in a health care facility and age >15. Exclusion criteria included missing data, minor or no effect outcomes, and polypharmacy overdose. The primary outcome was hypotension, which was defined as systolic blood pressure <90 mm Hg and/or MAP <65. Findings/Results There were 4488 single acute antipsychotic overdoses that presented to a healthcare facility after the initial search was conducted. After exclusions, there were 2070 cases with moderate or severe outcomes. The mean age was 42 (SD = 16), and 70% were female. There were 169 cases with hypotension. Of the hypotensive cases, 92% involved atypical antipsychotics, with quetiapine being the most common (n = 128, 76%). Vasopressor therapy was administered in 16/169 cases (9.9%). In the cases where vasopressor use was recorded, norepinephrine was used 12 times, dopamine 3 times, and phenylephrine once. No deaths were reported. Implications/Conclusions In antipsychotic overdoses that presented to a healthcare facility, hypotension was present in n = 169 (3.8%). Conclusions Among patient reports to 2 regional poison centers, we found that hypotension following acute antipsychotic overdose was infrequent and vasopressors are rarely administered.

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Purpose/Background Clozapine-induced hypersalivation is one of the most common bothersome adverse reactions of clozapine. The management strategies for this condition remain inadequately studied and understood. The objective of the study is to compare the effectiveness and tolerability of (1) trihexyphenidyl 5 mg/d, (2) clonidine 0.15 mg/d, or (3) a reduction of clozapine dosage by 25 to 50 mg/d for managing clozapine-induced hypersalivation Methods/Procedures A randomized, open-label, non–placebo-controlled clinical trial was conducted from December 2023 to May 2024. Eligible patients were randomly assigned to 1 of 3 groups. Primary outcomes were assessed using the Drooling Severity and Frequency Scale (DSFS) and the Nocturnal Hypersalivation Rating Scale (NHRS) at baseline, week 4, and week 8. Quality of life assessed using the pharmaceutical therapy for quality of life short version and adverse drug reactions were recorded as secondary outcomes. Findings/Results A total of 67 patients were randomly assigned to 1 of 3 treatment groups. By week 8, significant reductions in DSFS and NHRS scores were observed in all groups, with clonidine showing the greatest improvement. Trihexyphenidyl was also effective, whereas reducing clozapine dose resulted in more modest improvements. Quality of life improved significantly across all groups, with the greatest improvement observed in the clonidine group. The most common adverse effects were dry mouth, constipation, drowsiness, and dizziness. Implications/Conclusions Clonidine and trihexyphenidyl appear to be more effective options for managing clozapine-induced hypersalivation compared to clozapine dose reduction.

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Purpose To evaluate the risk of bleeding associated with the simultaneous administration of antidepressants (ADs) and direct oral anticoagulants (DOACs). Methods PubMed, Embase, and Scopus databases were searched for papers that focused on the concomitant administration of ADs and DOACs and presented data on the bleeding outcomes. The comparator group of interest was subjects who received only DOACs. Besides the overall pooled analysis, irrespective of the primary disease condition, we were also interested in studies involving patients with atrial fibrillation (AF). We therefore included studies with relevant comparisons (AD with DOACs, compared to DOACs alone), regardless of the reported underlying condition. Thereafter, we conducted a sensitivity analysis to refine estimates specific to AF. Clinical trials and observational studies were eligible. Pooled effect sizes were reported as relative risk (RR) for studies with cohort design and as odds ratio (OR) for case-control studies. Results Ten studies were included. Overall pooled analysis showed that treatment with both DOAC and selective serotonin reuptake inhibitor and serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) was associated with significantly higher risk of major bleeding (cohort: RR 1.25, 95% CI: 1.07–1.47; case-control: OR 1.40, 95% CI: 1.15–1.69). The risk of intracranial bleeding was found to be increased when cohort studies were pooled (RR 1.44, 95% CI: 1.24–1.66), but not with pooling of case-control studies (OR 1.58, 95% CI: 0.43–5.75). The risk of gastrointestinal bleeding and transient ischemic attack (TIA)/ischemic stroke was comparable between the 2 groups (DOAC + SSRI/SNRI vs DOAC only group). Conclusions Our results indicate that combined SSRIs/SNRIs and DOAC treatment may be associated with increased incidence of major and intracranial bleeding, further emphasizing the importance of caution when considering their concomitant use.

Background Clozapine is effective for treatment-resistant schizophrenia and bipolar disorder but is often discontinued due to adverse effects. This study compared early clozapine discontinuation rates and reasons in patients with mood and psychotic disorders. Methods Data from all individuals with mood or psychotic disorders who initiated clozapine for the first time at the inpatient psychiatric unit of Mayo Clinic, Rochester, Minnesota, between 2014 and 2022 were retrospectively analyzed. Early clozapine discontinuation, defined as discontinuation within 90 days of initiation, was the primary outcome. Cox proportional hazards regression was used to assess factors associated with discontinuation. Results Of 83 patients (mood group n = 37, psychosis group n = 46), those in the mood group were older (P = 0.022) and more likely to be nonsmokers (P = 0.034). The overall 90-day clozapine discontinuation rate was 45.7%. Early discontinuation was significantly higher in the mood group than in the psychosis group (hazard ratio = 2.41, 95% confidence interval = 1.26–4.64, P = 0.008). Other factors associated with early discontinuation were female sex (P = 0.033), older age (P = 0.026), and nonsmoking (P = 0.001). In multivariable analysis, smoking status was the only factor significantly inversely associated with early clozapine discontinuation (hazard ratio = 0.47, 95% confidence interval = 0.22–0.99, P = 0.048), while diagnostic group, sex, and age did not show significant associations (all P > 0.05). Discontinuations were primarily due to adverse drug reactions in both groups. Conclusions Nearly half of the patients discontinued clozapine early, with higher rates in the mood group. Studies should further explore potential pharmacodynamic and pharmacokinetic factors associated with discontinuation, including the influence of smoking. Careful monitoring and personalized management of side effects are crucial for optimizing clozapine therapy and improving treatment outcomes.

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Background In recent years, there has been a significant focus on exploring the potential therapeutic impact of altered states of consciousness on treatment outcomes for mental illness, with the goal of enhancing therapeutic strategies and patient results. Methods This meta-analysis was designed to investigate the potential link between the psychomimetic effects of ketamine and clinical outcomes in mental health, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Eleven studies were selected for meta-analysis, and the main result did not find a significant correlation between the psychoactive effects of ketamine and clinical outcomes either in mental illness (n = 11; n's = 27; r = 0.06 [−0.05, 0.17]; P = 0.268) or depression exclusively (n = 10; n's = 25; r = 0.03 [−0.07, 0.13]; P = 0.561). High heterogeneity was found for general analysis (I2 = 80.78). Egger's regression did not indicate publication bias (intercept = 1.57; SE = 1.49, P = 0.30). No significant Kendall's rank correlation coefficient was observed (τ = 0.02, P = 0.88) indicating funnel plot symmetry. The sub-analyses, aimed at minimizing study variability by specifically examining factors such as patient disorders (limited to depression), methods of administration (exclusively intravenous), types of assessment instruments, and the timing of evaluations, also yielded no significant findings. Conclusion This meta-analysis suggests that the altered states of consciousness experienced during ketamine sessions are not directly linked to clinical outcomes. However, it is important to acknowledge that the limited number of studies and their heterogeneity render this conclusion preliminary, warranting further investigation over time.