Using artificial intelligence to improve administrative process in Medicaid.

Administrative burden across state-federal benefits programs is unsustainable, and artificial intelligence (AI) and associated technologies have emerged and resulted in significant interest as possible solutions. While early in development, AI has significant potential to reduce administrative waste and increase efficiency, with many government agencies and state legislators eager to adopt the new technology. Turning to existing frameworks defining what functions are considered "inherently governmental" can help determine where more autonomous implementation could be not only appropriate but also provide unique advantages. Such areas could include eligibility and redetermination of Medicaid eligibility as well as preventing improper Medicaid payments. However, while AI is promising, this technology may not be ready for fully autonomous implementation and instead could be deployed to augment human capabilities with robust safeguards until it has proven to be more reliable. In the meantime, the Centers for Medicare and Medicaid Services should release clear guidance around the use of AI by state Medicaid programs, and policymakers must work together to harness AI technologies in order to improve the efficiency and effectiveness of the Medicaid program.

Longitudinal study of insomnia, suicidal ideation, and psychopathology in schizophrenia.

OBJECTIVE: Insomnia is a common comorbidity in schizophrenia. Increasing cross-sectional evidence suggests an association between insomnia and suicidal ideation (SI) and symptom severity in schizophrenia. We investigated longitudinal associations over 3 months between insomnia, suicidal ideation, and symptom severity in a group of patients with chronic schizophrenia. METHOD: We performed a secondary analysis of data from n = 305 participants from the Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy (PROACTIVE) schizophrenia trial using regression models. RESULTS: The prevalence of moderate-to-severe insomnia was 17.7 % at baseline and 13.6 % at 3 months, respectively. The prevalence of SI was 22 % at baseline and 22.5 % at 3 months. After controlling for potential confounders, improved SI from baseline to 3 months was associated with both baseline moderate-to-severe insomnia (OR = 3.81, 95 % CI 1.11-13.12, p = 0.034) and improvement in insomnia (OR = 3.50, 95 % CI 1.23-9.92, p = 0.013). Worsening SI from baseline to 3 months was associated with worsening insomnia (OR = 3.50, 95 % CI 1.23-9.92, p = 0.013), but not baseline insomnia. Improvement in BPRS total score from baseline to 3 months was associated with improvement in insomnia (ß = 0.17, p = 0.029), but not baseline insomnia. CONCLUSION: Insomnia is common in patients with chronic schizophrenia and insomnia showed significant associations with SI and psychopathology. Clinicians should consider insomnia when assessing suicide risk in patients with schizophrenia.

Integrated Devices: A New Regulatory Pathway to Promote Revolutionary Innovation.

Policy Points Current medical device regulatory frameworks date back half a century and are ill suited for the next generation of medical devices that involve a significant software component. Existing Food and Drug Administration efforts are insufficient because of a lack of statutory authority, whereas international examples offer lessons for improving and harmonizing domestic medical device regulatory policy. A voluntary alternative pathway built upon two-stage review with individual component review followed by holistic review for integrated devices would provide regulators with new tools to address a changing medical device marketplace.

Sleep Problems, Suicidal Ideation, and Psychopathology in First-Episode Psychosis.

BACKGROUND AND HYPOTHESIS: Insomnia occurs frequently in the clinical course of schizophrenia. A growing literature has found associations between insomnia, suicidal ideation and behavior, and psychopathology in schizophrenia. We explored associations between sleep problems, suicidal ideation, and psychopathology in a cohort of patients with first-episode psychosis. STUDY DESIGN: We performed a secondary analysis of data for n = 403 subjects with data from the Recovery After an Initial Schizophrenia Episode study using regression models. STUDY RESULTS: The prevalence of sleep problems and suicidal ideation at baseline was 57% and 15%, respectively. After controlling for potential confounders, in the study baseline sleep problems were associated with increased odds of suicidal ideation with evidence of a dose-dependent relationship (OR = 2.25, 95% CI 1.15-4.41, P = .018). Over 24 months, sleep problems at any time point were associated with an over 3-fold increased odds of concurrent suicidal ideation (OR = 3.21, 95% CI 1.45-7.14, P = .004). Subjects with persistent sleep problems were almost 14 times more likely to endorse suicidal ideation at least once over the study than those without sleep problems (OR = 13.8, 95% CI 6.5-53.4, P < .001). Sleep problems were also a predictor of higher Positive and Negative Syndrome Scale total (ß = 0.13-0.22), positive (ß = 0.14-0.25), and general (ß = 0.16-0.27) subscale scores at baseline and multiple follow-up visits (P < .01 for each). CONCLUSIONS: Sleep problems are highly prevalent and associated with suicidal ideation and greater psychopathology in first-episode psychosis. Formal assessment and treatment of insomnia appear relevant to the clinical care of patients with psychosis as a predictor of suicidal ideation and symptom severity.

Meta-analysis of a family history of diabetes in schizophrenia.

OBJECTIVE: Type 2 diabetes (T2DM) is common in patients with schizophrenia and non-affective psychosis. These patients also have an increased prevalence of a family history of T2DM. We performed a systematic review and meta-analysis of the association between a family history of T2DM and schizophrenia. METHOD: We searched electronic databases from inception until July 2022 for studies of a family history of T2DM or gestational diabetes in patients with schizophrenia and controls. We performed random effects meta-analysis, calculating odds ratios (ORs) and 95 % confidence intervals (CI) and meta-regression analyses. RESULTS: Nine studies were included, comprising 2953 patients with non-affective psychosis and 4484 controls. Schizophrenia was associated with an over two-fold increased odds of a family history of T2DM or gestational diabetes (OR = 2.18, 95 % CI 1.61-2.96, p < 0.01). In meta-regression analyses, age, sex, study quality score, and year of publication were all unrelated to the association. CONCLUSION: We found that patients with schizophrenia had a 2.2-fold increased odds of a family history of T2DM versus controls. This association may be relevant to both the pathophysiology of schizophrenia and the reported increased risk of development of diabetes with antipsychotic treatment.

Role of Patient Sorting in Avoidable Hospital Stays in Medicare Advantage vs Traditional Medicare.

Importance: Unlike traditional Medicare (TM), Medicare Advantage (MA) plans limit in-network care to a specific network of Medicare clinicians. MA plans thus play a role in sorting patients to a subset of clinicians. It is unknown whether the performance of physicians who treat MA and TM beneficiaries is different. Objective: To examine whether avoidable hospital stay differences between MA and TM can be explained by the primary care clinicians who treat MA and TM beneficiaries. Design, Setting, and Participants: This was a cross-sectional study of a nationally representative sample of MA and TM beneficiaries in 2019 with any of 5 chronic ambulatory care-sensitive conditions (ACSCs). The relative risk (RR) of avoidable hospital stays in MA compared with TM was estimated with inverse probability of treatment-weighted Poisson regression, both without and with clinician fixed effects. The degree to which the estimated MA vs TM difference could be explained by patient sorting was calculated by comparing the 2 RR estimates. Data were analyzed between February 2022 and April 2023. Exposure: Enrollment in MA. Main Outcome and Measures: Whether a beneficiary had avoidable hospital stays in 2019 due to any of the ACSCs. Avoidable hospital stays included both hospitalizations and observation stays. Results: The study sample comprised 1 323 481 MA beneficiaries (mean [SD] age, 75.4 [7.0] years; 56.9% women; 69.3% White) and 1 965 863 TM beneficiaries (mean [SD] age, 75.9 [7.4] years; 57.1% women; 82.5% White). When controlling for the primary care clinician, the RR of avoidable hospital stays in MA vs TM changed by 2.6 percentage points (95% CI, 1.72-3.50; P < .001), suggesting that compared with TM beneficiaries, MA beneficiaries saw clinicians with lower rates of avoidable hospital stays. This effect size was statistically significant to explain the 2% lower rate of avoidable hospital stays in MA than in TM. Conclusions and Relevance: In this cross-sectional study of MA and TM beneficiaries, the lower rate of avoidable hospital stays among MA beneficiaries than TM beneficiaries was attributable to MA beneficiaries visiting clinicians with lower rates of avoidable hospital stays. The patient sorting that occurs in MA plays a critical role in the lower rates of avoidable hospital stays compared with TM.

Applications of Artificial Intelligence in Health Care Delivery.

Health care costs now comprise nearly one-fifth of the United States' gross domestic product, with the last 25 years marked by rising administrative costs, a lack of labor productivity growth, and rising patient and physician dissatisfaction. Policy experts have responded with a series of reforms that have - ironically - increased patient and physician administrative burden with little meaningful effect on cost and quality. Artificial intelligence (AI), a topic of great consternation, can serve as the "wheat thresher" for health care delivery, empowering and freeing both patients and physicians by decreasing administrative burden and improving labor productivity. In this Viewpoint, we discuss three principal areas where AI poses an unprecedented opportunity to reduce cost, improve care, and markedly enhance the patient and physician experience: (1) automation of administrative process, (2) augmentation of clinical practice, and (3) automation of elements of clinical practice.

A review of clinical studies of electrodermal activity and transcranial magnetic stimulation.

There is a growing body of evidence indicative of changes in autonomic nervous system (ANS) activity in patients with disorders of the central nervous system (CNS). Non-invasive measures of the ANS, including heart rate variability (HRV), electrodermal activity (EDA), and pupillary light reflex (PLR) may have value as markers of symptom severity, subtype, risk profile, and/or treatment response. In this paper we provide an introduction into the anatomy and physiology of EDA and review the literature published after 2007 in which EDA was an outcome measure of cortical stimulation with transcranial magnetic stimulation (TMS). Eleven studies were included and considered regarding the potential of EDA as an outcome measure reflecting ANS activity in TMS research and treatment. These studies are summarized according to study population, experimental methodology, cortical region targeted, and correlation with other measures of ANS activity. Results indicate that EDA changes vary with the frequency and target of TMS. Inhibitory TMS to the dorsolateral prefrontal cortex (dlPFC) was the most common paradigm in these studies, consistently resulting in decreased EDA.

Improving Health Care Quality Measurement to Combat Clinician Burnout.

This Viewpoint explores a critical source of administrative burden and physician frustration­the explosive growth of health care quality metrics­and how improving these metrics could combat clinician burnout.

The Role of the Autonomic Nervous System in the Mediation of the Resolution of Suicidal Ideation With Electroconvulsive Therapy: A Hypothesis and Review of Heart Rate Variability Over a Course of Electroconvulsive Therapy.

ABSTRACT: Longitudinal observational studies have shown a meaningful decrease in suicidal thinking and suicidal behavior after receipt of electroconvulsive therapy (ECT). The antisuicide effect of ECT may be related to success in the global relief of the presenting syndrome such as depressive or psychotic illness. However, it is possible that the antisuicide effect is specific to ECT per se, over and above the relief of the clinical syndrome. Electroconvulsive therapy is associated with many observable neurochemical and physiologic effects, and some of these may plausibly be specifically linked to an antisuicide effect. The phenomenon of physiologic hyperarousal has been named as a candidate mechanism driving the risk for suicide. Hyperarousal is associated with decreased neuropsychological executive function responsible for response inhibition and can lead to impulsive action. The level of arousal within the autonomic nervous system (ANS) can be assayed with the pupillary light reflex, electrodermal activity, or with heart rate variability (HRV). This article summarizes the literature on the effects of ECT on HRV 24 to 72 hours after a course of ECT and finds evidence for increases in HRV, which indicates lower levels of arousal in the ANS. This finding suggests that ECT-related reductions in ANS arousal, presumably with corresponding improvements in response inhibition, may be one mechanism whereby ECT reduces risk for suicide.

The 510(k) Third Party Review Program: Promise and Potential.

Every year, the Food and Drug Administration (FDA) clears approximately 3,000 medical devices for marketing via the 510(k) pathway. These constitute 99% of all devices approved for human use and includes the premarket review of many devices incorporating newer technology such as artificial intelligence (AI), machine learning (ML), and other software. As the complexity of these novel technologies and the number of applications is expected to increase in the coming years, statutory changes such as the 2016 21st Century Cures Act, regulations, and guidance documents have increased both the volume and complexity of device review. Thus, the ability to streamline the review of less complex, low-to-moderate risk devices through the 510(k) pathway will maximize the FDA's capability to address other important, future-oriented regulatory questions. For over twenty five years, third party review organizations have served a defined function to assist with the review of 510(k) applications for a set of enumerated device classes. This paper reviews the history of FDA device regulation, the evolution of the 510(k) review pathway, and the recent history of the 510(k) third party review program. Finally, the paper addresses policy concerns from all stakeholders - including the FDA - along with policy suggestions to improve the third party review program and FDA device regulation writ large.

Predictors of successful anti-inflammatory drug trials in patients with schizophrenia: A meta-regression and critical commentary.

Given evidence pointing toward a role for immune dysregulation in the pathogenesis of schizophrenia, anti-inflammatory agents are promising adjunctive treatments that have potential to support a causal relationship for inflammation and psychopathology and lead to novel treatments for individuals. Indeed, previous meta-analyses have demonstrated small-to-medium effect sizes (ES) in favor of various anti-inflammatory agents, though there is significant heterogeneity and challenges in the interpretation of this literature. Identifying predictors, including sociodemographic variables, trial duration, and/or symptoms themselves, of successful anti-inflammatory trials may help identify which patients who might benefit from these compounds. We performed a meta-regression analysis of 63 adjunctive anti-inflammatory trial arms (2232 patients randomized to adjunctive anti-inflammatory agents and 2207 patients randomized to placebo).Potential predictors of effect size estimates for changes in psychopathology scores from baseline to endpoint included geography, trial duration, sample size, age, sex, race, smoking, body mass index, illness duration, age of onset of psychosis, study quality score and psychopathology scores (total and subscale) at baseline. Geography (ß = 0.31, p = 0.011), smaller sample size (ß = 0.33, p = 0.009), and higher study quality score (ß = 0.44, p < 0.001) were significant predictors of larger ES estimates for change in total psychopathology in favor of anti-inflammatory agents. Smaller sample size (ß = 0.37, p = 0.034) and higher study quality score (ß = 0.55, p = 0.003) were significant predictors of larger ES estimates for change in negative psychopathology in favor of anti-inflammatory agents. Higher study quality score (ß = 0.46, p = 0.019) was a significant predictor of larger ES estimates for change in general psychopathology in favor of anti-inflammatory agents. These findings should be interpreted with caution given concerns of publication bias regarding the geographic differences and small study effects. The lack of an association with other demographic variables should be seen as a primary limitation of the literature that needs to be considered in future studies. The association with study quality score suggests that future anti-inflammatory trials must consider demographic variables known to be associated with inflammation (e.g., BMI and smoking) and evidence of increased baseline inflammation should be incorporated in study design. Moreover, evidence of target engagement and endpoints thoughts to be associated with increased inflammation should be considered as well.

Daytime autonomic nervous system functions differ among adults with and without insomnia symptoms.

STUDY OBJECTIVES: We gathered data to determine whether daytime assays of the autonomic nervous system would differ between persons with no vs modest insomnia symptoms and would correlate with the severity of insomnia symptoms in patients. METHODS: This report is composed of 2 studies. Study 1 conducted pupillary light reflex (PLR) measurements in community volunteers who were not seeking medical care. Study 2 contrasted PLR and heart rate variability in a different sample of community volunteers and a comparison sample of adults seeking outpatient care for insomnia and psychiatric problems. All measurements were taken between 3 and 5 pm. RESULTS: In Study 1, volunteers with modest insomnia symptom severity had a more rapid PLR average constriction velocity compared with those with no symptoms. In Study 2, lower heart rate variability, indicating higher levels of physiologic arousal, generally were in agreement with faster PLR average constriction velocity, both of which indicate higher levels of arousal. Insomnia symptom severity was highly correlated with faster average constriction velocity in the patient sample. CONCLUSIONS: These studies suggest that (1) daytime measurements of the autonomic nervous system differ between persons with modest vs no insomnia symptoms and (2) insomnia symptom severity is highly correlated with PLR. Daytime measurement of autonomic nervous system activity might allow for daytime point-of-care measurement to characterize the level of physiologic arousal to define a hyperarousal subtype of insomnia disorder. CITATION: McCall WV, Looney SW, Zulfiqar M, et al. Daytime autonomic nervous system functions differ among adults with and without insomnia symptoms. J Clin Sleep Med. 2023;19(11):1885-1893.

Medicare Modernization-The Urgent Need for Fiscal Solvency.

This Viewpoint describes how reforms to Medicare built around a transition from volume to value may be helpful for improving fiscal solvency.

Reproducibility of the pupillary light reflex over short intervals in psychiatric patients and community volunteers.

The pupillary light reflex (PLR) is a method for measuring dynamic responses within the autonomic nervous system, and would have potential value as a point-of-care test in a psychiatry clinic if reproducible results could be obtained in a short period of time. We collected PLR from adult community volunteers and depressed outpatients with the purpose of demonstrating (1) that valid data could be obtained >90% of the time from both the community volunteers and the patients, and (2) that reproducible results could be obtained with repeated measurement over short periods of time. Valid data were captured for 90.3% of 76 participants, allowing for two attempts of the PLR per participant. Success rates were similar for depressed patients and community volunteers. Eighteen of these 76 participants provided repeated paired measurements after 5 and 10 min of dark adaptation, producing high correlations for maximum constriction velocity (MCV) between assay 1 and 2 (Pearson's r = 0.71, p < 0.001), but there was a significant 8% increase in velocity for MCV between assay 1 and 2 (∆ = 0.34 ± 0.59 mm/s, p < 0.05). In contrast, PLR measurements were stable when tested in a separate cohort of 21 additional participants at 10 and 15 min of dark adaptation with an MCV Pearson's correlation of r = 0.84, p < 0.001, with a nonsignificant 1% difference between the two time points. These findings indicate an acceptable rate of collecting valid and reproducible PLR data when contrasting two measurements of PLR after 10 or 15 min of dark adaptation in depressed and suicidal patients.

The Local Market of Major Teaching Hospitals.

OBJECTIVE: The purpose of this study was to describe the local communities served by major teaching hospitals. METHODS: Using a dataset of hospitals around the United States provided by the Association of American Medical Colleges, we identified major teaching hospitals (MTHs) using the Association of American Medical Colleges' definition of those with an intern-to-resident bed ratio above 0.25 and more than 100 beds. We defined the local geographic market surrounding these hospitals as the Dartmouth Atlas hospital service area (HSA). Using MATLAB R2020b software, data from each ZIP Code Tabulation Area from the US Census Bureau's 2019 American Community Survey 5-Year Estimate Data tables were grouped by HSA and attributed to each MTH. One-sample t tests were used to evaluate for statistical differences between the HSAs and the US average data. We further stratified the data into regions as defined by the US Census Bureau: West, Midwest, Northeast, and South. One-sample t tests were used to evaluate for statistical differences between MTH HSA regional populations with their respective US regional population. RESULTS: The local population surrounding 299 unique MTHs covered 180 HSAs and was 57% White, 51% female, 14% older than 65 years old, 37% with public insurance coverage, 12% with any disability, and 40% with at least a bachelor's degree. Compared with the overall US population, HSAs surrounding MTHs had higher percentages of female residents, Black/African American residents, and residents enrolled in Medicare. In contrast, these communities also showed higher average household and per capita income, higher percentages of bachelor's degree attainment, and lower rates of any disability or Medicaid insurance. CONCLUSIONS: Our analysis suggests that the local population surrounding MTHs is representative of the wide-ranging ethnic and economic diversity of the US population that is advantaged in some ways and disadvantaged in others. MTHs continue to play an important role in caring for a diverse population. To support and improve policy related to the reimbursement of uncompensated care and care of underserved populations, researchers and policy makers must work to better delineate and make transparent local hospital markets.

Long-Acting Injectable Antipsychotics and Infections in Schizophrenia.

PURPOSE: Antipsychotics, particularly long-acting injectable (LAI) agents, are associated with decreased all-cause mortality. Antipsychotics are also associated with an increased prevalence of infections. We performed a systematic review and meta-analysis of the risk of infections in patients with schizophrenia treated with LAIs versus placebo. METHODS: We systematically searched PubMed and Food and Drug Administration package inserts for placebo-controlled studies of LAI antipsychotic use in schizophrenia. Random effects meta-analysis calculating odds ratios and 95% confidence intervals for any and site-specific infections were performed. RESULTS: The total study sample consisted of 2559 subjects with schizophrenia, with 867 receiving placebo and 1692 LAI antipsychotics. Long-acting injectable antipsychotic use was associated with a significant 1.75-fold increased odds of any infection versus placebo (2.4% vs 1.5%; odds ratio, 1.75; 95% confidence interval, 1.16-2.66; P = 0.008), although findings for specific infections did not reach statistical significance. The association between LAIs and infection was unrelated to study duration, age, sex, body mass index, and total psychopathology. CONCLUSIONS: Our findings suggest that LAIs are associated with a small, but significant, increased risk of infections. This association may be due to immunomodulatory effects of antipsychotics.

Meta-analysis of insomnia, suicide, and psychopathology in schizophrenia.

PURPOSE OF REVIEW: Insomnia is common in schizophrenia. Insomnia has been associated with suicidal ideation and behavior, as well as greater severity of psychopathology, in schizophrenia. This review performs a meta-analysis of associations between insomnia, suicide, and psychopathology in patients with schizophrenia. RECENT FINDINGS: We searched major electronic databases from inception until November 2022 for studies of insomnia, suicide, and psychopathology in patients with schizophrenia. Random effects meta-analysis calculating odds ratios (ORs, for suicide) and effect sizes (ESs, for psychopathology) and 95% confidence intervals (CIs) were performed. Ten studies met the inclusion criteria, comprising 3428 patients with schizophrenia. Insomnia was associated with a significant increased odds of suicidal ideation (OR = 1.84, 95% CI 1.28-2.65, P  < 0.01) and suicide attempt or death (OR = 5.83, 95% CI 1.61-2.96, P  < 0.01). Insomnia was also associated with total (ES = 0.16, 95% CI 0.09-0.23, P  < 0.01), positive (ES = 0.14, 95% CI 0.08-0.20, P  = 0.02), and general (ES = 0.17, 95% CI 0.08-0.27, P  < 0.01) psychopathology. In meta-regression analyses, BMI was negatively associated with suicidal ideation. Otherwise, age, sex, and study year were all unrelated to the associations. SUMMARY: Insomnia is associated with suicide and psychopathology in schizophrenia. Formal assessment and treatment of insomnia appears relevant to the clinical care of schizophrenia.

Longitudinal study of inflammation and relapse in schizophrenia.

INTRODUCTION: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. METHODS: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. RESULTS: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. CONCLUSION: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

Meta-analysis of clozapine and insomnia in schizophrenia.

INTRODUCTION: Insomnia commonly occurs in schizophrenia, and insomnia is associated with suicide risk. Clozapine has anti-suicidal properties and beneficial effects on sleep. We performed a meta-analysis of insomnia in randomized controlled trials (RCTs) of patients with schizophrenia treated with clozapine. We hypothesized that compared to clozapine there is an increased odds of insomnia in patients treated with other antipsychotics. METHODS: We systematically searched PubMed, PsycINFO, and Web of Science databases. We included RCTs, in English, with data on insomnia in patients with schizophrenia treated with clozapine versus other antipsychotics. Data were pooled using a random effects model. RESULTS: Eight RCTs (1952 patients: 922 on clozapine and 1030 on other antipsychotics) met inclusion criteria. Patients treated with other antipsychotics versus clozapine had a significant increased odds of insomnia (22.3 % versus 12.4 %, OR = 2.20, 95 % CI = 1.64-2.94, p < 0.01). Olanzapine, quetiapine, risperidone, and ziprasidone were each associated with significant increased odds of insomnia compared to clozapine. In meta-regression analyses, clozapine dose, publication year, sex, trial duration, and study quality score were unrelated to the association; however, there was a significant association with age. The observed ORs for insomnia from RCTs were almost perfectly correlated with reported ORs from pharmacovigilance data. CONCLUSION: Clozapine is associated with significantly less insomnia compared to other antipsychotics. Findings provide additional evidence for improvement in sleep as a potential pathway underlying clozapine's anti-suicidal properties. A greater mechanistic understanding of this association is needed.