This post hoc analysis assessed the benefit-risk of aripiprazole once-monthly 400 mg (AOM 400) as acute and long-term maintenance treatment for patients diagnosed with schizophrenia, based on number needed to treat (NNT)...This post hoc analysis assessed the benefit-risk of aripiprazole once-monthly 400 mg (AOM 400) as acute and long-term maintenance treatment for patients diagnosed with schizophrenia, based on number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Data were derived from 2 studies that evaluated efficacy and safety/tolerability of AOM 400 versus placebo in an acute or maintenance setting. Main efficacy outcomes were ≥30% reduction in Positive and Negative Syndrome Scale (PANSS) total score (acute treatment) and patients free from impending relapse (maintenance treatment); main safety/tolerability outcome was incidence of patient discontinuation due to treatment-emergent adverse events (TEAEs). NNT, NNH, and LHH were calculated using standard methods. In the acute study, 60/167 AOM 400 recipients (37.0%) versus 24/168 placebo recipients (14.4%) had a ≥30% reduction in PANSS total score at week 10 (NNT=5 [95% confidence interval (CI), 4-8]). Corresponding values for avoidance of impending relapse in the maintenance study (median observation time: 113 days) were 242/269 (90.0%) versus 81/134 (60.4%) (NNT=4 [95% CI, 3-5]). Discontinuations due to TEAEs were lower with AOM 400 versus placebo in both studies, resulting in negative NNH values. Calculated LHH values were 200 (acute treatment) and 250 (maintenance treatment), indicating a higher likelihood to be helped than harmed with AOM 400. Data demonstrate a favorable benefit-risk profile for AOM 400 versus placebo in the acute and maintenance treatment of schizophrenia. ClinicalTrials.gov identifiers: NCT01663532 and NCT00705783.
Tardive dyskinesia (TD) is a persistent, potentially disabling, medication-induced movement disorder that has been underrecognized. Involuntary movements in TD have a substantial impact beyond movement on individuals wit...Tardive dyskinesia (TD) is a persistent, potentially disabling, medication-induced movement disorder that has been underrecognized. Involuntary movements in TD have a substantial impact beyond movement on individuals with TD. To quantify TD impact and burden, the Tardive Dyskinesia Impact Scale (TDIS), a new, TD-specific, fit-for-purpose patient-reported outcome (PRO) measure, was developed. Objectives were to examine how TDIS contributes to understanding of TD burden and use of clinician-reported outcomes (ClinROs) and other PROs in clinical trials assessing effects of vesicular monoamine transporter 2 inhibitors on TD. TDIS analyses included assessment of correlations between TDIS and other clinical outcome assessments (PROs and ClinROs), estimation of the minimal clinically importance difference (MCID), and description of the change in TDIS individual items longitudinally and via item response theory. In KINECT trials, TDIS followed a similar trajectory to Abnormal Involuntary Movement Scale. An MCID of 4 points in TDIS was considered clinically meaningful. Item-level analyses showed that TDIS is reliable and precise for individual items. Most improved items in longitudinal analyses were self-consciousness (mean change: -1.24), embarrassment (-1.19), unwanted attention (-1.00), and mouth noises (-1.05), which exceeded the empirically derived item-level threshold for meaningful change (≥0.8). TDIS showed moderate correlation with treatment response as measured by Patient's Global Impression of Change (=0.30) and Clinician's Global Impression of Change (=0.34) scores. TDIS is the only disease-specific PRO that has been validated in individuals with TD and complements ClinROs and other PROs by providing a comprehensive picture of TD impact beyond movement symptoms and can measure potential benefit of TD treatments.
Suicide is a public health crisis in the US, with limited evidence demonstrating efficacy of treatments for high-risk patients due in part to their exclusion from most clinical trials. This clinical trial evaluates the f...Suicide is a public health crisis in the US, with limited evidence demonstrating efficacy of treatments for high-risk patients due in part to their exclusion from most clinical trials. This clinical trial evaluates the feasibility and efficacy of adjunctive cognitive behavioral therapy (CBT) with esketamine in patients with major depression and suicidal ideation (MDSI). Treatment-seeking patients (57 inpatients; 36 outpatients) with major depressive disorder ( criteria) and suicidal ideation were randomized (1:1) to receive esketamine plus a 16-week course of CBT or esketamine plus treatment as usual (TAU) alone. The starting dose of esketamine was 84 mg in both groups. The primary outcome was feasibility, with a key secondary outcome being improvement in suicidal ideation. CBT consisted of traditional one-on-one therapy sessions and a computer-assisted program to facilitate psychoeducation and attainment of skills. Enrollment occurred between March 2021 and May 2025. Ninety-three subjects were randomized with a 72% study completion rate, demonstrating feasibility (primary outcome) by meeting recruitment goals of 80% of the targeted enrollment and 70% of retention through study end point. Change in suicidal ideation from baseline through week 18 (a key secondary outcome), based on the Beck Scale for Suicidal Ideation (BSSI), Clinician Global Improvement Scale for Suicide Severity (CGI-S), and Montgomery-Åsberg Depression Rating Scale (MADRS), favored the CBT group over the TAU group (BSSI mean difference of -1.91, 95% CI -3.57 to -0.24, =.025; CGI-S mean difference of -0.33, 95% CI -0.58 to -0.08, =.011; MADRS mean difference of -3.77, 95% CI -6.62 to -0.93, =.009). No difference between groups was observed in the Columbia-Suicide Severity Rating Scale score, MADRS-SI score, or suicide-related events. This study demonstrates the feasibility and the effectiveness of combining CBT with esketamine to reduce SI and prevent relapse in patients with MDSI. ClinicalTrials.gov identifier: NCT04760652.
Posttraumatic stress disorder (PTSD) is a common psychiatric condition, especially among US Veterans. Individuals diagnosed with PTSD have higher likelihoods of experiencing suicidal thoughts, attempting suicide, and dyi...Posttraumatic stress disorder (PTSD) is a common psychiatric condition, especially among US Veterans. Individuals diagnosed with PTSD have higher likelihoods of experiencing suicidal thoughts, attempting suicide, and dying by suicide compared to those without PTSD diagnoses. Although the US Department of Veterans Affairs (VA) emphasizes psychotherapy as a leading treatment for PTSD and associated suicide risk, there is limited understanding about how these treatments are used by VA patients who did and did not die by suicide. To better assess these patients' psychotherapy usage differences, we used Latent Dirichlet Allocation, a natural language processing topic modeling methodology, to study patients' unstructured electronic health record (EHR) note corpus. We evaluated VA suicide-risk-stratified patients (high-, moderate-, and low-suicide-risk) who died by suicide in 2017-2018 (cases) and suicide-risk-matched patients with similar demographics, diagnoses, and care who did not die by suicide (controls). After collecting all psychotherapy EHR notes within 1 year of case death and completing corpus preprocessing, we derived topics and used a binomial logistic regression model to evaluate topic differences, calculate odds ratios and values, and examine topic clinical relevance. We identified 5 topics: Risk, Treatment Planning, Evaluation, Psychosocial, and Medication. Cases and controls had several significantly different topic patterns, including Risk differences for moderate-risk patients, Treatment Planning differences for moderate- and high-risk patients, Evaluation differences for high-risk patients, Psychosocial differences for low- and moderate-risk patients, and Medication differences for all patient subgroups. Topic differences help distinguish closely matched cases and controls, aiding understanding of psychotherapy utilization and risk monitoring. Our findings suggest divergent care priorities, such that evaluation and risk monitoring are more central for high-risk cases while collaborative treatment planning and medication management are more central for high-risk controls.
Alacreu-Crespo A, de Granda-Beltrán AM, Abances-Utrilla E
… +7 more, Grijalba S, Jiménez-Muñoz L, Barrigón ML, Courtet P, López-Castromán J, Porras-Segovia A, Baca-García E
The desire to self-harm (DSH) is a key predictor of nonsuicidal self-injury (NSSI), which is also linked to negative affect, suicidal ideation (SI), and interpersonal difficulties. However, studies on these relationships...The desire to self-harm (DSH) is a key predictor of nonsuicidal self-injury (NSSI), which is also linked to negative affect, suicidal ideation (SI), and interpersonal difficulties. However, studies on these relationships are scarce and often limited by short follow-up periods. The aim of this study was to explore the relationship between DSH and NSSI during a 12-month follow-up and to test whether SI, negative affect, and negative interpersonal experiences are risk factors for NSSI. Adult outpatients were recruited in hospitals in Spain for presenting SI and/or a suicide attempt. The variables were registered by ecological momentary assessment (EMA) through a mobile application during a 12-month follow-up. Mixed models were used to test the association between variables. A total of 106 patients were analyzed. We found a statistically significant positive relationship between mean DSH and the occurrence of NSSI episodes (OR=1.026, 95% CI=1.005-1.046). Furthermore, higher negative affect (=.009) and negative interpersonal experience (<.001) were related with NSSI but showed a negative slope. Thus, NSSI patients had higher negative affect and negative interpersonal experience that decreased across the follow-up. With regard to specific emotions, restlessness, sadness, and hopelessness behaved similarly to the general variable of negative affect. By contrast, passive SI and anxiety showed a positive slope across the follow-up. Finally, intraindividual variability of SI was positively related with intraindividual mean of DSH (<.001). These results highlight the relevance of DSH in understanding NSSI. They also show the variation in the levels of SI, negative affect, and negative interpersonal experiences and their associations with NSSI. Future research should explore how to translate EMA-based monitoring into actionable suicide prevention programs implemented in routine care.
Proton pump inhibitors (PPIs) are the most prescribed gastric acid suppressant drugs; the category includes omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. In 2015, a study suggest...Proton pump inhibitors (PPIs) are the most prescribed gastric acid suppressant drugs; the category includes omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. In 2015, a study suggested that PPI use was associated with an increased risk of dementia. An early meta-analysis confirmed this concern, but the findings were inconsistent in subsequent meta-analyses. Also problematic is that these meta-analyses used questionable approaches, and their findings were characterized by very high heterogeneity. Notably, the high heterogeneity appeared to be driven by large studies with widely different outcomes. Nonetheless, one finding stands out in the body of research examined: older subjects who initiated and continued PPIs (implying chronic use) were at a significantly increased risk of dementia and mild cognitive impairment. Although there are causal and non-causal pathways that associate PPI use with dementia, for reasons that are explained in this article, a cause-effect relationship cannot at present be presumed; so, PPI use is best considered to be a marker of future dementia risk. However, because chronic use of PPIs has been associated with many adverse medical outcomes (eg, disturbances of the gut microbiome, orthopedic complications), and because some PPIs are associated with pharmacokinetic drug interactions (mainly inhibition of CYP2C19), it would be wise to limit the use of PPIs to the shortest duration necessary and to deprescribe PPIs when there does not appear to be need for their continuation.
To examine how Veterans Health Administration (VHA) utilization and suicide outcomes differ for those with and without a suicide attempt prior to separating from the military. Suicide attempts are frequently described a...To examine how Veterans Health Administration (VHA) utilization and suicide outcomes differ for those with and without a suicide attempt prior to separating from the military. Suicide attempts are frequently described as an important risk factor for future suicide behaviors. Additionally, Veterans who have recently transitioned out of military service have been identified as an at-risk group. We evaluated whether a suicide attempt prior to transition out of military service is an important risk factor among US Veterans. This retrospective study included 1,030,599 service members who separated from the active US military from 2015 to 2020. VHA utilization, VHA documented suicide behaviors, suicide mortality, and all-cause mortality in the 2 years following separation were examined, comparing those with and without a documented suicide attempt in their last 2 years of active duty service. Service members with a documented suicide attempt prior to military separation were significantly more likely to initiate VHA care (hazard ratio [HR]=1.91 [95% CI, 1.84-1.98]) and VHA mental health care (HR =2.20 [95% CI, 2.13-2.28]) compared with those without an attempt. Among those who initiated VHA care, 90% of those with a recent military suicide attempt accessed VHA mental health services. Still, 39% of those with a suicide attempt prior to separation did not utilize VHA care. Those with a history of suicide attempt prior to transition were also more likely to have a suicide attempt (relative risk=7.78 [95% CI, 7.10-8.52]) or die from suicide (standardized mortality ratio= 9.94 [95% CI, 7.37-13.10]) after separation than those without. Results indicate that most Veterans in this group receive VHA services after separation, but a significant minority of high-risk Veterans remain unengaged.
Cognitive impairment associated with schizophrenia (CIAS) is a key driver of functional deficits in patients with this disorder. CIAS may involve deficient NMDA receptor-dependent neurotransmission. Negative allosteric m...Cognitive impairment associated with schizophrenia (CIAS) is a key driver of functional deficits in patients with this disorder. CIAS may involve deficient NMDA receptor-dependent neurotransmission. Negative allosteric modulators (NAMs) of γ-aminobutyric acid (GABA) type A (GABA) α5 receptors enhance their activity and improve cognition in rodents and nonhuman primates. We tested whether prolonged treatment with basmisanil-a selective GABAα5 NAM-improved CIAS. This 24-week placebo-controlled phase 2b study in patients with CIAS diagnosed according to was conducted between November 2016 and December 2019. Two hundred thirteen patients were randomized to 80 mg of basmisanil, 240 mg of basmisanil, or placebo twice a day. Recruitment into the 80 mg group was stopped after a planned futility analysis. The primary outcome was the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score evaluated in the efficacy analysis population (EAP) in the placebo (n=76) and basmisanil 240 mg arms only (n=77, total EAP n=153). Secondary outcome measures included specific hippocampal and prefrontal-dependent cognitive tasks, functional outcomes, and symptoms. Novel study design features addressing potential sources of heterogeneity in drug response and learning and practice effects included stratification by cognitive trajectories and age as well as repeated administration of the MCCB test battery during screening. Twenty-four weeks of treatment with basmisanil was well tolerated without improving cognitive or functional measures overall or in any of the stratified subgroups. Practice and learning effects were not observed at week 12. Basmisanil did not improve cognitive deficits. Although unsuccessful, some results offer insight into important factors that should facilitate the design of more informative trials. ClinicalTrials.gov identifier: NCT02953639.
Addressing negative symptoms of schizophrenia can be a treatment challenge. This 56-week post hoc analysis examined effects of combined olanzapine and samidorphan (OLZ/SAM) on negative symptoms. Adults with acute schizo...Addressing negative symptoms of schizophrenia can be a treatment challenge. This 56-week post hoc analysis examined effects of combined olanzapine and samidorphan (OLZ/SAM) on negative symptoms. Adults with acute schizophrenia who received 4 weeks of OLZ/SAM, olanzapine, or placebo and initiated a subsequent 52-week open-label OLZ/SAM extension study (conducted 1/2016-6/2018) were included. Data were pooled across lead-in study (conducted 12/2015- 6/2017) treatment arms. Negative symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) Marder Negative Factor score. Changes from baseline were evaluated overall, in patients with prominent negative symptoms (defined as baseline Marder Negative Factor score ≥24), and in patients with predominant negative symptoms/low positive symptoms (baseline Marder Negative Factor score ≥24 and PANSS Mohr Positive Factor score ≤19). Patients (n=281) had mean (SD) PANSS Total and Marder Negative Factor scores of 101.7 (11.1) and 25.2 (4.6), respectively, at baseline. Least squares (LS) mean (SE) change from baseline in Marder Negative Factor score at week 56 was -8.2 (0.35). Among patients with prominent negative symptoms (baseline mean, 27.8; n=186), LS mean (SE) change in Marder Negative Factor score was -9.6 (0.44) at week 56. Similar improvement at week 56 was observed for patients with predominant negative symptoms (n=48; LS mean [SE] change, -8.9 [0.78]). In this 56-week post hoc analysis of patients initially experiencing an acute exacerbation of schizophrenia, OLZ/SAM was associated with significant and durable improvement in negative symptoms of schizophrenia, overall and among both patients with prominent and predominant negative symptoms. ClinicalTrials.gov identifiers NCT02634346 (https:// clinicaltrials.gov/study/NCT02634346) and NCT02669758 (https://clinicaltrials. gov/study/NCT02669758).
This exploratory post hoc analysis examined the safety/efficacy of the aripiprazole once-monthly 400 mg (AOM 400) long-acting injectable (LAI) in Black/African American patients diagnosed with bipolar I disorder (BP-I)....This exploratory post hoc analysis examined the safety/efficacy of the aripiprazole once-monthly 400 mg (AOM 400) long-acting injectable (LAI) in Black/African American patients diagnosed with bipolar I disorder (BP-I). Data were from a 52-week, open-label trial of AOM 400 maintenance treatment in patients diagnosed with -defined BP-I. Outcomes included treatment-emergent adverse events (TEAEs), clinician-rated extrapyramidal symptoms (EPS), patient stability, Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression-Bipolar Version-Severity (CGI-BP-S) scores, functioning, and quality of life (QoL). Data analyses comprised descriptive statistics and a mixed model for repeated measures. Outcomes were analyzed in 464 patients (Black/African American, n=104; White, n=255; Asian, n=94; other racial groups, n=11). No notable increase in TEAEs, serious TEAEs, or TEAEs leading to discontinuation were observed in Black/African American patients vs those in other racial groups. Rates of akathisia, tremor, increased weight, or hypertension were lower/similar in Black/African American patients vs other racial groups; changes in EPS scores were minimal in all groups. At last visit, 90.1% of Black/African American patients were stable, similar to other racial groups. Small changes in YMRS total score occurred in all groups, with MADRS total score and CGI-BP-S scores largely unchanged. Functioning and QoL improved in Black/African American patients, to a similar/greater degree than other racial groups. Limitations include the open-label design, prior aripiprazole stabilization, and sparse metabolic laboratory data, constraining causal inference and metabolic conclusions. The safety and efficacy of AOM 400 is comparable between Black/African American and non-Black/African American patients with BP-I. The data provide valuable evidence supporting second-generation LAI antipsychotic use in these patients. ClinicalTrials.gov identifier: NCT01710709.
Because limited research has evaluated criminal legal involvement (CLI) during a first episode of psychosis (FEP), we explored rates, correlates, and predictors of CLI among people with FEP. We conducted a secondary ana...Because limited research has evaluated criminal legal involvement (CLI) during a first episode of psychosis (FEP), we explored rates, correlates, and predictors of CLI among people with FEP. We conducted a secondary analysis on the Recovery After an Initial Schizophrenia Episode-Early Treatment Program (RAISE-ETP) study, a cluster randomized controlled trial conducted from 2010 to 2012 with people experiencing FEP in the US. We explored rates of recent CLI prior to baseline and over the 2-year follow-up and evaluated predictors of CLI at baseline and over the follow-up period (N = 381). At baseline, 11% of the sample reported CLI within the past month, which was significantly associated with lower education, longer duration of untreated psychosis, lifetime alcohol or any drug use disorder (other than cannabis), and more severe excitement factor symptoms on the Positive and Negative Syndrome Scale (PANSS). Over the 2-year follow-up, 13.6% of the sample reported CLI which, controlling for baseline CLI, was predicted by longer duration of untreated psychosis, schizophrenia diagnosis, lifetime alcohol or any other drug use disorder, alcohol or cannabis use in the 30 days prior to baseline, and more severe positive and excitement symptoms on the PANSS at baseline. Those with CLI at baseline were nearly 3 times more likely to have subsequent CLI over the follow-up. Baseline CLI was associated with dropping out of treatment due to incarceration. The findings suggest that CLI in people with FEP could be reduced by earlier detection and more effective treatment of psychotic symptoms, substance use, and criminogenic risk factors. Data used in this secondary analysis are from ClinicalTrials.gov identifier: NCT01321177.