Purpose/Background This phase 2a randomized, double-blind, placebo-controlled, 8-week trial assessed the efficacy and safety of navacaprant, a highly selective kappa opioid receptor antagonist, in adults with major depressive disorder (MDD). Methods/Procedures Participants with 17-Item Hamilton Depression Rating Scale (HAMD-17) scores of 14 to 30 were randomized 1:1 to once-daily navacaprant 80 mg or placebo (n = 102 each). The primary endpoint was HAMD-17 change from baseline (CFB) to week 8. Secondary endpoints included CFB in Snaith-Hamilton Pleasure Scale (SHAPS). No adjustment for multiple comparisons was made. Findings/Results At week 8, HAMD-17 CFB was not statistically significantly improved with navacaprant vs placebo (least squares mean difference −1.7 [standard error, 1.08], P = 0.121; mixed-models repeated-measures) in the efficacy population. In a prespecified sensitivity analysis using last-observation-carried-forward, navacaprant statistically significantly improved HAMD-17 CFB (−2.9 [0.88], P = 0.002; −2.2 [0.98], P = 0.024) and SHAPS CFB (−2.8 [0.96], P = 0.004; −3.4 [1.10], P = 0.002) vs placebo at weeks 4 and 8. In the prespecified subgroup with moderate-to-severe MDD (baseline HAMD-17 score ≥22; n = 100), navacaprant statistically significantly improved HAMD-17 CFB at both timepoints (−3.0 [1.20], P = 0.015; −2.8 [1.33], P = 0.037) and SHAPS CFB at week 8 (−4.8 [1.35], P = 0.001) vs placebo. Most frequently reported adverse events (AEs) included headache (4.9% both) and nausea (4.9% navacaprant, 1.0% placebo); no serious AEs were reported with navacaprant. Implications/Conclusions Although the primary endpoint was not met in the efficacy population, which included participants with mild depression, statistically significant improvements with navacaprant on depressive symptoms including anhedonia in the moderate-to-severe MDD subgroup, along with a favorable safety profile, support further study of navacaprant for the treatment of MDD.

Purpose/Background Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Purpose/Background This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). Methods US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. Implications/Conclusions To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.

Background Aripiprazole, a prolactin-sparing antipsychotic, is considered relatively safe during pregnancy and has a better metabolic profile compared to other antipsychotics. However, its impact on lactation has not been adequately studied. This study aimed to assess the relationship between aripiprazole use during pregnancy and the postpartum period with lactation outcomes. Methods Clinical charts of women attending perinatal psychiatry services between January 2016 and December 2021 were reviewed for details of aripiprazole prescription, clinical information, and lactation outcomes. Lactation failure was defined as the total absence of milk flow or secretion of minimal amounts for at least 7 days. Results Among the 398 women attending perinatal psychiatry services, 60 were prescribed aripiprazole during pregnancy, with lactation data available for 35 women who continued the drug during the postpartum period. The mean age of women in years was 29 (±4.4) years. The most common diagnosis for aripiprazole prescription was schizophrenia (60%). Approximately 54.2% of the women were primiparous. Of the 35 women with available lactation data, 26 (74%) experienced complete lactation failure, and 4 (11%) had insufficient milk production while on aripiprazole. The mean dose of aripiprazole was 16.4 mg/day, with a mean duration of use of 20 months. Conclusions In this study, most women who continued aripiprazole through pregnancy and postpartum experienced either lactation failure or insufficient milk production. It is important to discuss lactation issues associated with the use of aripiprazole with women during pregnancy and the postpartum period.

No abstract available

Background Antibacterials are among the most frequently prescribed medications. Antibacterial drugs have the unintended consequence of destroying healthy gut flora, which can lead to known adverse events such as Clostridium difficile infection. Given emerging research concerning the role of these microorganisms in the gut-brain axis and some limited epidemiological studies, the objective of this study was to determine if antimicrobial exposure is associated with increased risk for depression. Methods National Veterans Health Administration administrative data were used to identify 878,405 veteran patients prescribed an incident antimicrobial during calendar year 2018. Sequence symmetry analysis was used to compare the incidence of a depressive disorder in the 6 months before and after antibacterial exposure, with additional analyses conducted with other antimicrobial classes as negative controls including antifungals, antivirals, and nonsystemic antibacterials. Results Antibacterial initiation was associated with a small but significant increase in the risk of incident depression (symmetry ratio [SR] = 1.04, 95% confidence interval [CI]: 1.03, 1.05), which was limited to the first 8 weeks following exposure. The strength of association varied with categories of antibacterial spectrum, from SR = 0.98 (95% CI: 0.95, 1.01) with the narrowest spectrum regimens, to SR = 1.12 (95% CI: 1.09, 1.15) with the broadest regimens. No significant association with incident depression was observed for antifungals, antivirals, and nonsystemic antibacterials. Conclusions Antibacterial exposure was associated with increased risk for a depressive disorder. These findings are consistent with emerging literature and support the need for further research investigating a causal relationship between antibacterial exposure and risk for adverse mental health outcomes.

No abstract available

Purpose/Background Clozapine requires careful monitoring to minimize adverse reactions and optimize response. Because of variable pharmacokinetics and interpatient variability, guidelines recommend therapeutic drug monitoring (TDM), although practical guidance is limited. This study aims to characterize patient factors associated with TDM, rates of TDM use over time, turnaround times of TDM results, and influence of institutional initiatives aimed to improve TDM. Methods/Procedures A retrospective chart review was conducted at a large 2000-bed academic medical center from August 1, 2015, to November 26, 2023. Adult patients who were administered clozapine during medical or psychiatric inpatient hospitalizations were included. Data collected included patient demographics, clozapine TDM ordering, and clozapine TDM turnaround time. Yearly TDM rates were analyzed to evaluate the impact of various institutional clozapine-related initiatives on TDM practices. Results There were 679 encounters involving 334 patients; 62.7 % were men, and 84.4% were White. Younger patients were less likely to have levels drawn (odds ratio 0.98, confidence interval 0.97–0.99), while self-identified Asian patients more likely (odds ratio 7.54, confidence interval 1.60–35.42). TDM rates increased significantly over time for both medical (P = 0.002) and psychiatric (P < 0.001) admission types, with turnaround times improving from 66.07 hours in 2016 to 28.65 hours in 2022. Overall, TDM annual rates increased from 46.2% in 2015 to 69.6% in 2023. The time-period before and after an institutional initiative, which improved TDM turnaround time, was associated with improvements of TDM rates (36.2% vs 67.9%, P < 0.001) Conclusions This study highlights an increase in clozapine TDM use during the study period, but use remained suboptimal. Improvement of turnaround time was associated with increased TDM rates.

Background At least 50% of patients with treatment-resistant depression (TRD) fail to respond to antidepressant augmentation with aripiprazole (AA), currently the augmentation strategy with the best evidence of efficacy. The present observational study investigated whether pramipexole augmentation (PA) might be useful for patients who failed AA. Methods We compared the short- and long-term effectiveness and safety of PA in 81 consecutively recruited unipolar patients with TRD, 58 (71.6%) not previously treated with AA (UAA) and 23 (28.4%) who previously failed AA (FAA). Results The FAA and UAA groups did not differ significantly in terms of remission, response, improvement, and general functioning at 12 and 24 weeks and in terms of freedom from relapse at 12 and 24 months. The response rates at 24 weeks were 69.6% (n = 16) and 77.6% (n = 45), and the remission rates were 60.9% (n = 14) and 74.1% (n = 43), respectively. The rates of sustained response at 24 months were 72.7% (n = 8) and 84.2% (n = 16), respectively. The 2 groups did not differ significantly on safety outcomes (acceptability, tolerability, suicidality and suicide attempts) in the short and long term. Conclusions Our study showed that the off-label use of PA may be a promising treatment for patients with unipolar TRD who had previously failed respond to AA. The present findings are preliminary and should be interpreted with caution due to study limitations, including the flexibility of the add-on schedule and the small sample size of patients followed up for 12 and 24 months, and need to be confirmed in larger studies.

No abstract available

Background There are significant interindividual and interethnic variations in serum clozapine levels achieved for a particular dose of clozapine. Therapeutic drug monitoring (TDM) helps optimize the clozapine dosing. We studied the impact of TDM on clozapine dosing and clinical outcomes in subjects with treatment-resistant schizophrenia. Methods We compared clozapine dose and clinical outcomes before and after the TDM service implementation in our center, a tertiary care psychiatric facility in India. A retrospective file review of inpatients diagnosed with treatment-resistant schizophrenia and started on clozapine between 2016–2017 (pre-TDM arm; n = 45) and 2021–23 (post-TDM arm; n = 45) was conducted. Clozapine dose in milligrams per day (mg/d), Clinical Global Impression-Improvement scores, and adverse event profile were compared between these groups after 3 months of therapeutic clozapine dose. Results The median clozapine dose reduced by 100 mg/day after introducing TDM (mean ± SD [median] mg, pre-TDM arm: 276.66 ± 118 [250] mg vs post-TDM arm: 167.22 ± 68 [150] mg, P ≤ 0.0001). However, there was no significant difference in Clinical Global Impression-Improvement score between the 2 groups (pre-TDM arm = median 2; post-TDM arm = median 2, P = 0.33). The incidence of hypersalivation (P = 0.026, odds ratio (95% confidence interval) = 3.06 [1.2–7.6]) and weight gain (P = 0.04, odds ratio [95% CI] = 4.5 [1.1–17.5]) were higher in the pre-TDM group. The median serum clozapine concentration/dose (C/D) ratio was 3 ng/mL/mg in our post-TDM sample of 35, where serum clozapine levels were done. Conclusions After introducing TDM, there was a significant reduction in clozapine dosage while the magnitude of clinical improvement was comparable.

No abstract available

No abstract available

No abstract available

Purpose/Background Rates of prescriptions of psychotropic medications to youth have increased, a significant proportion of which are recipients of psychiatric polypharmacy. Polypharmacy can increase the risk of multiple negative outcomes. Prior studies attempting to identify predictors/correlates of polypharmacy have been heterogeneous. This study aimed to examine factors associated with polypharmacy among psychiatrically hospitalized youth, and measure changes in polypharmacy over time throughout the COVID-19 pandemic. Methods/Procedures The medical records of 1101 patients were reviewed. Sociodemographic and clinical information was collected and analyzed using SPSS. Findings/Results About one-third of patients received psychotropic polypharmacy; this group contained a higher percentage of males, White patients, and fewer Asian/South Asian patients. They had on average more hospitalizations, a longer hospitalization period, and were more likely to be diagnosed with an impulsive/behavioral disorder, developmental disorder, or bipolar spectrum disorder. They were twice as likely to receive medication for agitation while hospitalized. A regression model identified positive predictors of polypharmacy as having a history of violence and a higher number of psychiatric hospitalizations. Negative predictors included non-White race. The rate of polypharmacy was relatively stable throughout the study time period, and no impact of the COVID-19 pandemic was found. Implications/Conclusions Pediatric psychiatric polypharmacy is relatively common and may be associated with poorer outcomes. Certain sociodemographic and clinical characteristics may aid clinicians in predicting which youth may be at risk for polypharmacy. Longitudinal studies are indicated to examine outcomes of polypharmacy so that providers can effectively implement judicious prescribing practices in the community.

No abstract available

No abstract available

No abstract available

Background Acute drug-induced dystonia (DID) is an extrapyramidal side effect triggered by certain medications, primarily antipsychotics. It presents as acute involuntary muscle contractions, causing twisting, repetitive movements, or abnormal postures. Pyramidal signs, typically from upper motor neuron damage, are characterized by positive pathological reflexes, increased muscle tone, and hyperactive tendon reflexes. Procedures This study describes 2 cases of acute DID following antipsychotic treatment, both presenting with positive pyramidal sign. A literature review was conducted to find reports of abnormal pyramidal signs in acute DID cases, focusing on medical tests for differential diagnosis and neurological assessments related to DID. Results After reviewing the detailed medication history and conducting comprehensive tests, it was concluded that risperidone and haloperidol caused DID. Adjusting the medication and providing symptomatic treatment led to significant improvement. Conclusions These cases highlight the importance of being alert to the possibility of acute DID when using antipsychotics and pyramidal signs appear, providing insights for future research into the mechanisms of these unusual symptoms.

No abstract available

No abstract available

No abstract available

Purpose/Background Clozapine and norclozapine are highly protein bound. Currently, clozapine is increasingly prescribed once daily (QD). Higher (once daily) doses may theoretically lead to saturation of protein binding of (nor)clozapine, resulting in increased unbound fractions. This study investigated whether protein binding of clozapine and norclozapine becomes saturated at higher concentrations. Secondly, the correlation between unbound (nor)clozapine fractions and alpha-1 acid glycoprotein (AGP) concentrations was studied. Methods/Procedures From 44 patients taking clozapine QD or twice daily a total of 319 blood samples were collected at different time points within a dose interval. AGP concentrations were measured in samples drawn just before clozapine intake. A validated liquid chromatography-tandem mass spectrometry method was used for quantification of the (nor)clozapine concentrations. Ultrafiltration was used to separate the bound and unbound molecules. The relation between total concentrations and fractions, and between unbound fractions and AGP concentrations were investigated using linear mixed model analysis. Findings/Results There was no significant correlation between total clozapine (P = 0.270) and norclozapine (P = 0.678) concentrations and its unbound fractions with total clozapine concentrations up to 1500 μg/L. A statistically significant (negative) correlation between AGP concentrations and clozapine (P = 0.000) and norclozapine (P = 0.028) unbound fractions was found. Implications/Conclusions In general, total concentrations remain suitable for therapeutic drug monitoring if clozapine is used once daily. Future research is needed to define if higher total concentrations are warranted in case of lower unbound fractions due to increased AGP concentrations.

Background Williams syndrome (WS) is a genetic disorder that results from a microdeletion of 25 to 27 genes on chromosome 7q11.23. Individuals with WS often exhibit comorbid neuropsychiatric symptoms, especially anxiety. To our knowledge, nonsuicidal self-injurious behavior (NSSIB) has not been reported in WS. N-acetylcysteine (NAC) is a safe and readily available drug that may modulate glutamate activity in the brain. NAC is effective for treating various neuropsychiatric symptoms and disorders. There are limited reports in the literature where NAC has been used to treat NSSIB effectively, but none in WS. Methods This report describes using NAC to treat NSSIB in 3 adults with WS. Findings Nonsuicidal self-injurious behavior was successfully treated in 3 adults with WS using NAC in doses ranging from 2400 to 3600 mg a day, resulting in significant improvement in their daily functioning. Additionally, NAC was well tolerated. Conclusions NAC was effective for treating NSSIB in 3 adults with WS. By addressing these challenging behaviors, NAC offers a promising pharmacological intervention that can significantly improve the quality of life for patients with WS who engage in NSSIB. Further research and clinical trials are necessary.