Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

New antipsychotic prescription and recurrent infections among adult sepsis survivors: A population-based cohort study.

PURPOSE: Antipsychotic agents, which may increase the risk of infection through dopaminergic dysregulation, are prescribed to a fraction of patients following critical illness. We compared the rate of recurrent sepsis among patients who filled a prescription for antipsychotics with high- or low-D2 affinity. METHODS: Population-based cohort with active comparator design. We included sepsis survivors older than 65 years with intensive care unit admission and new prescription of antipsychotics in Ontario 2008-2019. The primary outcome were recurrent sepsis episodes within 1 year of follow-up. Patients who filled a prescription within 30 days of hospital discharge for high-D2 affinity antipsychotics (e.g., haloperidol) were compared with patients who filled a prescription within 30 days of hospital discharge for low-D2 affinity antipsychotics (e.g., quetiapine). Multivariable zero-inflated Poisson regression models with robust standard errors adjusting for confounding at baseline were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: Overall, 1879 patients filled a prescription for a high-D2, and 1446 patients filled a prescription for a low-D2 affinity antipsychotic. Patients who filled a prescription for a high-D2 affinity antipsychotic did not present a higher rate of recurrent sepsis during 1 year of follow-up, compared with patients who filled a prescription for a low-D2 affinity antipsychotic (IRR: 1.12; 95% CI: 0.94, 1.35). CONCLUSIONS: We did not find conclusive evidence of a higher rate of recurrent sepsis associated with the prescription of high-D2 affinity antipsychotics (compared with low-D2 affinity antipsychotics) by 1 year of follow-up in adult sepsis survivors with intensive care unit admission.

Are all antidepressants the same? The consumer has a point.

BACKGROUND: Although a large variety of antidepressants agents (AD) with different mechanisms of action are available, no significant differences in efficacy and safety have been shown. However, there have been few attempts to incorporate data on subjective experiences under different AD. METHOD: We conducted a qualitative and quantitative analysis of the posts from the website www.askapatient.com from different AD. We reviewed a random sample of 1000 posts. RESULT: After applying the inclusion and exclusion criteria, we included a final sample of 450 posts, 50 on each of the most used AD: sertraline, citalopram, paroxetine, escitalopram, fluoxetine, venlafaxine, duloxetine, mirtazapine, and bupropion. Bupropion, citalopram, and venlafaxine had the higher overall satisfaction ratings. Sertraline, paroxetine, and fluoxetine had high reports of emotional blunting, while bupropion very few. Overall satisfaction with AD treatment was inversely associated with the presence of the following side-effects: suicidality, irritability, emotional blunting, cognitive disturbances, and withdrawal symptoms. After adjusting for confounders, only emotional blunting was shown to be more frequently reported by users of serotonergic agents, as compared to non-serotoninergic agents. CONCLUSION: This research points out that the subjective experience of patients under treatment should be taken into consideration when selecting an AD as differences between agents were evident. In contrast to the more frequent treatment decisions, users might prefer receiving a non-serotoninergic agent over a serotonergic one due to their lower propensity to produce emotional blunting.

Suicide Following the COVID-19 Pandemic Outbreak: Variation Across Place, Over Time, and Across Sociodemographic Groups. A Systematic Integrative Review.

PURPOSE OF REVIEW: To systematically examine changes in suicide trends following the initial COVID-19 outbreak, focusing on geographical and temporal heterogeneity and on differences across sociodemographic subgroups. RECENT FINDINGS: Of 46 studies, 26 had low risk of bias. In general, suicides remained stable or decreased following the initial outbreak - however, suicide increases were detected during spring 2020 in Mexico, Nepal, India, Spain, and Hungary; and after summer 2020 in Japan. Trends were heterogeneous across sociodemographic groups (i.e., there were increases among racially minoritized individuals in the US, young adults and females across ages in Japan, older males in Brazil and Germany, and older adults across sex in China and Taiwan). Variations may be explained by differences in risk of COVID-19 contagion and death and in socioeconomic vulnerability. Monitoring geographical, temporal, and sociodemographic differences in suicide trends during the COVID-19 pandemic is critical to guide suicide prevention efforts.

Manic morbidity and executive function impairment as determinants of long-term psychosocial dysfunction in bipolar disorder.

OBJECTIVE: In this study, we aimed to evaluate the role of cognitive performance and measures of clinical course-including both syndromal and subsyndromal symptomatology-as determinants of the functional outcome of patients with Bipolar Disorder (BD) during a mean follow-up period of more than 4 years. METHODS: Seventy patients with euthymic BD completed a neurocognitive battery at study entry. Clinical course was assessed prospectively for a period longer than 48 months by two measures: time spent ill (documented using a modified life charting technique) and density of affective episodes (defined as the number of depressive and hypo/manic episodes per year of follow-up). Psychosocial functioning was assessed during euthymia using the Functioning Assessment Short Test (FAST) total score at the end of follow-up period. RESULTS: Baseline deficits in phonological fluency, a measure of executive functions (ß = -2.49; 95% CI = -3.98, -0.99), and density of hypo/manic episodes during follow-up (ß = 6.54; 95% CI = 0.43, 12.65) were independently associated with FAST total score at the end of study. CONCLUSIONS: Although interrelated, manic morbidity and executive function impairments independently contribute to long-term psychosocial dysfunction in BD and could be potential targets of intervention.

Association of depressive symptoms with health care utilization in older adults: Longitudinal evidence from the Survey of Health, Aging, and Retirement in Europe.

OBJECTIVES: Many older adults with depression do not receive adequate treatment. Differences in treatment utilization may reflect the heterogeneous nature of depression, encompassing multiple distinct symptoms. We assessed whether depressive symptoms are differentially associated with subsequent health care utilization with respect to three outcomes as follows: (1) contact with a medical doctor (MD), (2) depression-specific treatment, and (3) inpatient psychiatric admission. METHODS/DESIGN: Longitudinal analyses were based on data from three follow-up cycles conducted between 2004 and 2013 among 53,139 participants from the Survey of Health, Aging, and Retirement in Europe. Depressive symptoms were self-reported at baseline of each follow-up cycle using the 12-item EURO-D scale. Health care utilization was self-reported at the end of each follow-up cycle. RESULTS: After adjustment for sex, age, country of interview, follow-up time, educational attainment, presence of a partner in household, body-mass index, the number of chronic diseases, disability, average/prior frequency of contact with an MD, and all other depressive symptoms, people with more frequent contact with an MD had most often reported sleep problems (IRR = 1.10) and fatigue (IRR = 1.10), followed by sad/depressed mood, tearfulness, concentration problems, guilt, irritability, and changes in appetite. Those treated for depression had most often reported sad/depressed mood (OR = 2.18) and suicidal ideation (OR = 1.72), but also sleep problems, changes in appetite, fatigue, concentration problems, hopelessness, and irritability. Sad/depressed mood (OR = 2.87) was also associated with psychiatric inpatient admission. Similarly to other outcomes, appetite change, fatigue, and sleep problems were associated with inpatient admission. CONCLUSIONS: Specific symptoms of depression may determine utilization of different types of health care among elderly.

Longitudinal analysis of cognitive performances in recent-onset and late-life Bipolar Disorder: A systematic review and meta-analysis.

OBJECTIVES: Neurocognitive deficits have been widely reported in euthymic Bipolar Disorder (BD) patients and contribute to functional disability. However, the longitudinal trajectory of these deficits remains a subject of debate. Although most research to this date shows that neurocognitive deficits tend to be stable among middle-age BD patients, it remains plausible that deterioration occurs at either early or late stages of this condition. METHODS: We conducted a comprehensive meta-analysis of studies that reported longitudinal neurocognitive performance among individuals with BD either within the year of their diagnosis or among late-life BD patients. Pooled effects of standardized mean differences (SMDs) for changes in neuropsychological scores over follow-up were estimated using random effects model. We also examined effect moderators, such as length of follow-up, mood state, or pharmacological load. RESULTS: Eight studies met inclusion criteria for recent-onset and four studies for late-life BD analysis. No evidence for a deterioration in neurocognitive functioning was observed among recent-onset BD patients (8 studies, 284 patients, SMD: 0.12, 95% CI -0.06 to 0.30, mean follow-up: 17 months) nor for late-life BD patients (4 studies, 153 patients, SMD: -0.35, 95% CI -0.84 to 0.15, mean follow-up: 33 months). None of the moderators were shown to be significant. CONCLUSIONS: These results, when appraised together with the findings in middle-life BD patients and individuals at genetic risk for BD, suggest that neurodevelopmental factors might play a significant role in cognitive deficits in BD and do not support the notion of progressive cognitive decline in most patients with BD.

Personality Disturbances in Melancholic and Nonmelancholic Unipolar Major Depression: A Systematic Review and Meta-Analysis.

Although melancholic depression has been associated with a more adequate premorbid personality style, the empirical evidence supporting this statement is inconclusive. We conducted a systematic review and meta-analyzed studies comparing the presence of personality disturbances in melancholic and nonmelancholic subtypes of major depressive disorder (MDD). We defined a) a continuous outcome, defining personality traits as a dimensional construct, and b) a dichotomous outcome, defined as the presence/absence of personality disorders (PD). We also evaluated the role of potential moderators. Our results showed significantly higher levels of neuroticism and interpersonal sensitivity, and a higher likelihood of presenting a PD in nonmelancholic depression. No significant differences were found for extraversion. The scarcity of studies and high heterogeneity were among our limitations. In conclusion, personality disturbances seem to be overrepresented in nonmelancholic MDD. The assessment of personality disturbances can be useful in clinical practice and in the study of MDD heterogeneity.

Episodic density, subsyndromic symptoms, and mood instability in late-life bipolar disorders: A 5-year follow-up study.

OBJECTIVES: Characterization of clinical course in old age bipolar disorder (OABD) is scarce and based solely on episode density (ED). The aim of this study was to explore mood instability (MI) and subsyndromal symptomatology (SS) in a prospective cohort of OABD. Further, we contrasted these measures with a cohort of young age bipolar disorder (YABD). METHODS: Life charts from weekly mood ratings were used to compute the number of weeks spent with subsyndromal symptoms (SD), the ED, and the MI during follow-up for a cohort of OABD (N = 38) that excluded late onset BD. Linear and logistic regression models were fitted to compare the clinical course of OABD with a cohort of YABD (N = 52) and to explore the relationship between these measures and functional outcomes. RESULTS: Median follow-up was 5 years (IQR: 3.6-7.9). OABD (61.6 years, SD: 8.3) spent 15%, 6%, and 3% of their follow-up with depressive, manic, and mixed symptoms, respectively, and suffered 4.2 mood changes per year (SD: 2.6). No significant differences between OABD and YABD regarding ED or MI emerged in multivariate analysis, while a higher subsyndromal manic symptom burden was observed in OABD (ß coefficient: 3.79, 95%CI: 0.4-7.2). Both SS and MI were associated with functional outcomes in OABD. CONCLUSIONS: The course of illness throughout OABD was similar to the one observed in YABD except for a higher subsyndromal manic burden. This study extended the association of MI and SD with global functioning to the late-life BD.

Melancholia: An Attempt at Definition Based on a Review of Empirical Data.

We sought to identify clinical features that best discriminate melancholia from nonmelancholic depressive conditions. An extensive review of studies using latent factor models that identified a melancholic depression dimension/factor was undertaken. Clinical variables extracted from these studies were analyzed in terms of their contribution to a diagnosis of melancholia and their consistency across studies. Psychomotor retardation and mood nonreactivity were the most relevant clinical features for the identification of melancholic depressions. Other clinical features commonly described as weighted to melancholia, such as anhedonia, psychomotor agitation, late insomnia, or appetite/weight loss, seemed less useful in distinguishing these subtypes of depression. Study results are considered in relation to the potential limitations of current operational definitions of melancholia, and how symptom sets could be modified.

Antipsychotic Use Among Adult Outpatients and Venous Thromboembolic Disease: A Retrospective Cohort Study.

BACKGROUND: Treatment with antipsychotic (AP) agents is associated with incident thromboembolic events. However, the underpinnings of this association remain unknown. We sought to evaluate the effect of AP agents-categorized by their metabolic/sedative and hyperprolactinemia adverse effect profile-on the risk of venous thromboembolic disease during long-term follow-up. METHODS: A retrospective cohort study of adult patients initiating AP treatment for the first time was conducted. Primary outcome was defined as the time to venous thromboembolism (VTE) (either deep venous thrombosis or acute pulmonary embolism). Antipsychotic agents were categorized by their risk (high vs low) of either drug-induced (a) sedation/metabolic adverse event or (b) hyperprolactinemia. We used a propensity score-adjusted Cox proportional hazards model to control for confounding. FINDINGS: One thousand eight patients (mean age, 72.4 y) were followed for a median of 36 months. Incident VTE occurred in 6.25% of patients, corresponding to an incidence rate of 184 cases per 10,000 person-years. We found no difference in the hazard of VTE during follow-up between high- and low-risk groups (hazard ratio, 1.23 [95% confidence interval, 0.74-2.04] for drug-induced sedation/metabolic adverse event risk categories, and hazard ratio 0.81 [95% confidence interval, 0.50-1.35] for high versus low hyperprolactinemia risk). CONCLUSIONS: These results suggest that the risk of thromboembolic events in older adults who started AP treatment for the first time does not seem to be related to these drugs' risk of either sedation/metabolic adverse events or hyperprolactinemia. However, VTE remains a common problem in this subgroup of patients.

[ATTENUATED PSYCHOSIS SYNDROME: A LITERATURE REVIEW]. / Sindrome de psicosis atenuada. Revisión bibliográfica.

Despite recent findings on the treatment of schizophrenia, it is an illness still associated with high morbidity and incapacity in social and work domains. There is a growing interest in examining the phases prior to the development of the illness so as to make early interventions that would potentially change its devastating course. The attenuated psychosis syndrome was included in the section III of the last version of the Diagnostic and Statistical Manual of Mental Disorders as a condition in which a patient exhibits mild psychotic symptoms, an intact reality testing and certain degree of social or occupational impairment. The present work is a review of the available literature on this subject. The main findings were: the risk of conversion to a psychotic disorder is relatively low and there are some variables (social withdrawal, negative symptoms, neurocognitive impairment, poor global functioning and certain neuroimaging findings) that increase this risk. Those people diagnosed with attenuated psychosis syndrome had one or more other current psychiatric comorbid conditions and these are the main reason to warrant medical attention. Regarding to the treatment of this condition, there are available evidence on atypical antipsychotics, cognitive-behavioral therapy and omega 3 fatty acid.

Making causal inferences from transactional data: A narrative review of opportunities and challenges when implementing the target trial framework.

The target trial framework has emerged as a powerful tool for addressing causal questions in clinical practice and in public health. In the healthcare sector, where decision-making is increasingly data-driven, transactional databases, such as electronic health records (EHR) and insurance claims, present an untapped potential for answering complex causal questions. This narrative review explores the potential of the integration of the target trial framework with real-world data to enhance healthcare decision-making processes. We outline essential elements of the target trial framework, and identify pertinent challenges in data quality, privacy concerns, and methodological limitations, proposing solutions to overcome these obstacles and optimize the framework's application.

Melancholic features and treatment outcome to selective serotonin reuptake inhibitors in major depressive disorder: A re-analysis of the STAR*D trial.

BACKGROUND: Melancholia has been positioned as a qualitatively different form of Major Depressive Disorder (MDD). Some studies have suggested that melancholic MDD patients may show lower remission when receiving treatment with Selective Serotonin Reuptake Inhibitors, but this has not yet been explored in large, representative samples of MDD. METHODS: We used data from the STAR*D, a multisite randomized controlled trial (n = 4041). We defined melancholia status through the BA Melancholia Empirical Index, constructed using items from the Inventory of Depressive Symptomatology (IDSC). The main outcome of interest was symptomatic remission defined as a Quick Inventory of Depressive Symptoms (Clinician version) (QIDS-C) below or equal to 5. Inverse probability weighting was used to control for confounding. RESULTS: 3827 patients were eligible for this study. Melancholic patients were more likely to be unemployed, never married, to self-report an African American race, and to have a higher depressive severity. The adjusted 4-month probability of remission was 26.9 % (22.0, 45.5) for melancholic and 53.8 % (53.2, 58.5), for nonmelancholic patients. Compared with nonmelancholic, the difference in 4-month probability of remission was -26.9 % (-37.0, -15.6). Results were consistent across sensitivity analyses. LIMITATIONS: Items from IDSC were used as a surrogate measure of the BA Melancholia Index, and extrapolation of the results to agents other than citalopram and to psychotic MDD patients requires caution. CONCLUSIONS: Melancholic MDD patients showed lower probabilities of remission at 4-months receiving treatment with citalopram. The results of this study show how validly subtyping episodes could contribute to the personalized treatment of depression.

Clinical characteristics and outcomes of people with severe mental disorders hospitalized due to COVID-19: A nationwide population-based study.

OBJETIVE: Hospitalized COVID-19 patients with severe mental illness (SMI) have worse outcomes than counterparts without SMI. Barriers in access to acute care medical procedures among SMI patients may partially explain this phenomenon. Here, we examined differences in critical care admission and in-hospital mortality between hospitalized COVID-19 patients with and without SMI. METHODS: This population-based study used Spain's nationwide electronic health records. Based on International Classification Diseases, Tenth Revision, ICD-10-CM codes, we identified all patients aged ≥15 years hospitalized due to COVID-19 between July 1st-December 31st, 2020, and compared patients with and without SMI in terms of (i) critical care admission and (ii) in-hospital mortality - overall and stratified by age. We used logistic regression models including sex, age, and comorbidity burden as measured by Charlson Comorbidity Index Score as covariates. RESULTS: Of 118,691 hospital admissions due to COVID-19 of people aged ≥15 years, 1512 (1.3%) included a diagnosis of SMI. Compared to non-SMI patients, SMI patients had higher in-hospital mortality (OR,95%CI: 1.63,1.42-1.88) and were less frequently admitted to critical care (OR,95%CI: 0.70,0.58-0.85). Admission to critical care in SMI patients was lower than for non-SMI counterparts only among individuals aged ≥60 years. The magnitude of the difference in in-hospital mortality between SMI and non-SMI patients decreased as age increased. CONCLUSIONS: Individuals with SMI had reduced critical care admission and increased in-hospital mortality compared non-SMI counterparts, suggesting that differences in delivery of acute care medical procedures may partially explain higher risk of negative outcomes among COVID-19 patients with SMI.

Emulating a Target Trial of Dynamic Treatment Strategies for Major Depressive Disorder Using Data From the STAR∗D Randomized Trial.

BACKGROUND: Clinical guidelines recommend adding a second drug for patients with major depressive disorder who have a partial response and switching antidepressants for those who show no response or intolerance. This guidelines-based strategy was compared with other strategies for the management of unresponsive depression. METHODS: A total of 1436 individuals experiencing treatment failure with citalopram and still requiring antidepressant therapy were identified in the STAR∗D (Sequenced Treatment Alternatives to Relieve Depression) trial. A (hypothetical) target trial was then designed and emulated. The following strategies for decision making were compared: sequential monotherapy, sequential dual non-selective serotonin reuptake inhibitor therapy (SD), and a guidelines-based strategy. The primary outcome was symptomatic remission defined as a Hamilton Depression Rating Scale score ≤7 or 2 consecutive scores ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated. Secondary outcomes were serious events (hospitalizations, suicide, and mortality). Inverse probability weighting was used to control for possible confounding. RESULTS: A total of 971 patients were eligible for our emulation. Patients initiating SD had the lowest levels of depression at baseline. The estimated 9-month probability of remission was 43.5% for the sequential monotherapy group, 47.6% for the SD group, and 53.2% for the guidelines-based strategy group. Compared with the sequential monotherapy group, the difference in 9-month probability of remission was -4.2% (95% CI, -15.6 to 4.6) for the SD group and -9.7% (-19.3 to 1.9) for the guidelines-based strategy group. The 9-month relative risks of remission were 1.09 (0.90 to 1.38) and 1.22 (0.96 to 1.46), respectively. Results were consistent across sensitivity analyses. The 9-month relative risks of serious events were 0.77 (0.38 to 1.40) and 0.62 (0.33 to 1.00), respectively. CONCLUSIONS: Using the guidelines-based strategy was associated with an increased probability of remission and a lower risk of serious adverse events. The potential implications are substantial given the large number of patients experiencing treatment failure to antidepressants.

Estimating the per-protocol effect of lithium on suicidality in a randomized trial of individuals with depression or bipolar disorder.

BACKGROUND: The CSP590 randomized trial was designed to estimate the effect of lithium on suicidality. After a third of the intended number of participants were enrolled, the hazard ratio of suicidality was 1.10 (95% CI: 0.77, 1.55). Based on this, the trial was stopped for futility. However, only 17% of patients adhered to the specified protocol. AIMS: The objective was to estimate the per-protocol effect of lithium on suicidality, that is, the effect of adhering to the treatment strategies as specified in the protocol. METHODS: We stopped individuals' follow-up if/when they showed evidence of nonadherence. We then conducted the analysis in the restricted sample, adjusting for prognostic factors that predict adherence via inverse probability weighting. The primary outcome was the 12-month risk of suicidality (including death from suicide, suicide attempt, interrupted attempt, hospitalization specifically to prevent suicide). RESULTS: The estimated 12-month risk of suicidality was 18.8% for lithium, and 24.3% for placebo. The risk ratio was 0.78 (95% CI: 0.43, 1.37) and the risk difference -5.5 percentage points (95% CI: -17.5, 5.5). Results were consistent across sensitivity analyses. CONCLUSIONS: With one-third of the targeted sample size, lithium effects (compared with placebo) ranging between a 17.5% reduction and a 5.5% increase in the risk of suicidality were highly compatible with the data. Thus, a protective effect of lithium on suicidality among patients with bipolar disorder or major depressive disorder cannot be ruled out. Trials should incorporate adequate per-protocol analyses into the decision-making processes for stopping trials for futility.

Risk of Overdose Associated With Co-prescription of Antipsychotics and Opioids: A Population-Based Cohort Study.

The US FDA issued a black-box warning against co-prescription of antipsychotic (AP) agents and opioids due to the risk of respiratory depression, but evidence on the comparative safety of sedating vs nonsedating APs is lacking. We classified APs as sedating (eg, quetiapine, olanzapine, and chlorpromazine) and nonsedating (eg, aripiprazole, haloperidol, and risperidone) based on their affinity to the histamine-1 neuroreceptor (Ki < or ≥20, respectively) and sought to compare the rate of overdose between patients using sedating vs nonsedating APs plus opioids. We constructed a population-based cohort nested in the IBM MarketScan database (2004-2017). Patients with concomitant use of sedating APs and prescription opioids ("exposed") were 1:1 matched to patients with concomitant use of nonsedating APs and prescription opioids ("referent") based on the propensity score (PS). The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days. The final cohort comprised 62 604 exposed and an equal number of PS-matched reference patients. Characteristics of matched exposed and reference patients were similar. There were 178 overdose events among the exposed (35.3 events per 1000 person-years [PY]) vs 133 among the reference group (26.4 events per 1000 PY), for an adjusted hazard ratio of 1.34 (95% CI: 1.07-1.68). This finding was consistent across sensitivity and subgroup analyses. Among patients receiving prescription opioids, concomitant use of sedating APs was associated with an increased risk of overdose compared with nonsedating APs. Caution is required when co-prescribing opioids and APs. If co-prescription is needed, choosing a nonsedating agent should be preferred whenever possible given the clinical context.