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.

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.

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.

Electronic nicotine delivery systems: the need for continued regulatory innovation.

The recent surge in electronic nicotine delivery systems (ENDS) or electronic cigarette use among both adolescents and adults challenged tobacco regulatory frameworks worldwide. In this article, we review recent US Food and Drug Administration regulatory approaches to tobacco products, including attempts to regulate nicotine concentration and address youth use. We examine recent drives to promote a harm reduction approach in other product markets such as opioids, where the use of methadone and related therapies promote the public health. We describe the potential of a harm reduction framework for ENDS regulation based on tiered nicotine exposure standards coupled with risk-based product distribution controls that would enable ENDS products to meet the 'Appropriate for the Protection of the Public Health' standard required for tobacco product market entry. A harm reduction approach to ENDS regulation could help countries achieve the laudable public health goals of transitioning existing combustion cigarette users to ENDS products while preventing adolescent ENDS use and subsequent nicotine addiction.

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.

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.

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.

Recurrent antimicrobial exposure and acute psychosis.

BACKGROUND: There is an increased prevalence of recent antimicrobial exposure in patients with acute psychosis. We previously found recurrent urinary tract infections (UTIs) in some patients with psychosis. We evaluated the prevalence of recurrent antimicrobial exposure in acutely ill inpatients with psychosis. METHODS: We performed a retrospective chart review of 85 patients age 18 to 65 with multiple hospitalizations for acute psychosis. Antimicrobial exposure was defined as occurring within 3 days of each psychiatric hospitalization. Recurrent infections were defined as antimicrobial exposure during ≥2 separate hospitalizations for acute psychosis. RESULTS: The prevalence of recurrent antimicrobial exposure was 26% (22/85), including 25% (13/51) in patients with schizophrenia and 26% (9/34) in patients with psychotic mood disorders. Patients with schizophrenia and recurrent antimicrobial exposure were significantly more likely to have visual hallucinations in admissions with infection vs without (31% vs 14%, respectively, P = .04). CONCLUSIONS: We found that a subset of patients with schizophrenia and psychotic mood disorders has recurrent infections at the time of hospitalization for acute psychosis. Findings replicate an association between recurrent UTIs and acute psychosis. Although the mechanism of this association remains unclear, findings provide additional evidence that infections may be relevant to illness relapse in some patients with psychosis.

Development of Autonomic Nervous System Assays as Point-of-Care Tests to Supplement Clinical Judgment in Risk Assessment for Suicidal Behavior: A Review.

PURPOSE OF REVIEW: A biomarker point-of-care (POC) test that supplements the psychiatric interview and improves detection of patients at risk for suicide would be of value, and assays of autonomic nervous system (ANS) activity would satisfy the logistical requirements for a POC test. We performed a selective review of the available literature of ANS assays related to risk for suicide. RECENT FINDINGS: We searched PubMed and Web of Science with the strategy: "suicide OR suicidal" AND "electrodermal OR heart rate variability OR pupillometry OR pupillography." The search produced 119 items, 21 of which provided original data regarding ANS methods and suicide. These 21 studies included 6 for electrodermal activity, 14 for heart rate variability, and 1 for the pupillary light reflex. The 21 papers showed associations between ANS assays and suicide risk in a direction suggesting underlying hyperarousal in patients at risk for suicide. ANS assays show promise for future development as POC tests to supplement clinical decision making in estimating risk for suicide.

Prenatal exposure to viral infection and neuropsychiatric disorders in offspring: A review of the literature and recommendations for the COVID-19 pandemic.

The SARS-CoV-2 virus has emerged as a striking 21st century pandemic. Communities across the globe have experienced significant infection rates and widespread psychosocial stress and trauma, leading to calls for increased allocation of resources for mental health screening and treatment. In addition to the burden of psychosocial stress, there is increasing evidence of direct viral neuroinvasion of the central nervous system through physical contact with the nasal mucosa. In a parallel fashion, there is a significant body of ongoing research related to the risk of in utero viral transmission and the resulting neurodevelopmental impact in the fetus. Aberrant neurodevelopment secondary to viral transmission has previously been related to the later development of psychosis, schizophrenia, and schizophrenia spectrum disorders, generating the hypothesis that this population of individuals exposed to SARS-CoV-2 may see an increased incidence in future decades. We discuss the current understanding of the possible neurotropism and vertical transmission of SARS-CoV-2, and relate this to the history of viral pandemics to better understand the relationship of viral infection, aberrant immune response and neurodevelopment, and the risk for schizophrenia disorder.

Monitoring for myocarditis during treatment initiation with clozapine.

OBJECTIVE: Clozapine use is associated with myocarditis. In this study, we investigated what clinical signs and symptoms, and/or laboratory test(s), alert clinicians to presumptive myocarditis (PrMy) most accurately and at the earliest time point. We also investigated the incidence of PrMy during the initial exposure to clozapine versus in patients restarted on clozapine after extended interruption of prior prolonged treatment. METHODS: 100 patients admitted to state psychiatric hospital started on clozapine were recruited into the study. 76 patients were treated with clozapine for the first time and 24 patients were restarts. Creatine kinase (CK), troponin I (TROP), eosinophil count (EOS), and C-reactive protein (CRP) were obtained at baseline and weeks 1, 2, 3, and 4. Descriptive statistics were calculated for demographic and clinical variables. Student's t test and chi-squared test were used to compare means and proportions between initial exposure and restart groups. RESULTS: Clinical features and laboratory tests suggestive of PrMy were seen in 4 patients (5.3%) in initial exposure group and none in restart group. 3.5% of TROP levels were abnormal in initial exposure group and no abnormal levels were found in the restart group. 30% and 46% of CK, 23% and 39% of CRP, and 14% and 23% of EOS were abnormal in initial exposure group and restart groups, respectively. CONCLUSIONS: PrMy was common (5.3%) during clozapine initiation. Prospective management through serial laboratory monitoring with weekly TROP levels was sensitive enough to allow for timely clozapine discontinuation.

Inflammation, hippocampal volume, and cognition in schizophrenia: results from the Northern Finland Birth Cohort 1966.

Increased blood interleukin-6 (IL-6) levels are a replicated abnormality in schizophrenia, and may be associated with smaller hippocampal volumes and greater cognitive impairment. These findings have not been investigated in a population-based birth cohort. The general population Northern Finland Birth Cohort 1966 was followed until age 43. Subjects with schizophrenia were identified through the national Finnish Care Register. Blood IL-6 levels were measured in n = 82 subjects with schizophrenia and n = 5373 controls at age 31. Additionally, 31 patients with schizophrenia and 63 healthy controls underwent brain structural MRI at age 34, and cognitive testing at ages 34 and 43. Patients with schizophrenia had significantly higher median (interquartile range) blood IL-6 levels than controls (5.31, 0.85-17.20, versus 2.42, 0.54-9.36, p = 0.02) after controlling for potential confounding factors. In both schizophrenia and controls, higher blood IL-6 levels were predictors of smaller hippocampal volumes, but not cognitive performance at age 34. We found evidence for increased IL-6 levels in patients with midlife schizophrenia from a population-based birth cohort, and replicated associations between IL-6 levels and hippocampal volumes. Our results complement and extend the previous findings, providing additional evidence that IL-6 may play a role in the pathophysiology of schizophrenia and associated brain alterations.

Meta-analysis of total and differential white blood cell counts in schizophrenia.

OBJECTIVE: Schizophrenia is associated with alterations in blood inflammatory markers, including cytokines. Total white blood cell (WBC) count is a marker of low-grade inflammation. We conducted a meta-analysis of total and differential WBC counts in patients with schizophrenia. METHOD: Articles were identified through a systematic search of PsycINFO, Pub Med, Web of Science, and the associated references. Data were analyzed using a random effects approach. RESULTS: Twenty-four studies met the inclusion criteria. Blood total WBC, monocytes, and neutrophils were significantly higher in schizophrenia vs. controls with small-to-medium effect sizes (standardized mean difference [SMD] = 0.39-0.53, P < 0.01 for each). In first-episode psychosis compared with controls, neutrophils and monocytes were significantly increased with similar effect sizes (SMD = 0.40-0.41, P ≤ 0.01 for each), and there was a trend for higher total WBC (SMD = 0.46, P = 0.05). CONCLUSIONS: Consistent with studies of other inflammatory markers, we found evidence for increased total and differential WBC counts in schizophrenia. Our results complement other studies of WBC counts in schizophrenia. These findings are relevant to the pathophysiology and potentially the treatment of schizophrenia.

Acutely ill psychiatric inpatients and antimicrobial exposure.

BACKGROUND: Patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD) have increased infections. We explored the association between recent antimicrobial exposure and acute psychiatric illness. METHODS: We performed a retrospective chart review of 267 acutely ill patients age 18 to 65. There were 92 patients with schizophrenia, 42 with bipolar disorder, 61 with MDD, and 72 with alcohol use disorders (hospitalized controls). Recent antimicrobial exposure was defined as occurring within 3 days of psychiatric hospitalization. RESULTS: The prevalence of recent antimicrobial exposure was significantly increased in acutely ill patients with schizophrenia (16%), bipolar disorder (21%), and MDD (18%) compared with patients who had alcohol use disorders (4%, P ≤ .01 for each). After controlling for potential confounders, participants with schizophrenia or mood disorders were 5 to 7 times more likely to have recent antimicrobial exposure than participants with alcohol use disorders (schizophrenia: odds ratio [OR] = 4.5, 95% confidence interval [CI] 1.0-21.0, P = .053; bipolar disorder: OR = 6.9, 95% CI 1.3-35.7, P = .022; MDD: OR = 5.7, 95% CI 1.2-28.3, P = .032). Among participants with mood disorders, the association was stronger for participants with depression and affective psychosis compared with participants with alcohol use disorders. CONCLUSIONS: We found an increased prevalence of recent antimicrobial exposure in acutely ill patients with schizophrenia and mood disorders. The findings provide additional evidence that infections are relevant to acute psychiatric illness.

Association of C-reactive protein and metabolic risk with cognitive effects of lurasidone in patients with schizophrenia.

BACKGROUND: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. METHODS: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. RESULTS: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p < .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. CONCLUSIONS: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia.

Price Transparency: Empowering Patient Choice and Promoting Provider Competition.

In light of recent health policy efforts to promote price transparency, this perspective reviews the challenges and benefits of price transparency. These price transparency efforts include the recent executive order and associated rulemaking directing providers to disclose negotiated and out-of-pocket costs for "shoppable" healthcare services. First, we explore the previous efforts of states and health plans targeted at price transparency, reviewing lessons for future implementation. Second, we address the value of price transparency in light of various policy concerns and objections. Finally, we jointly hypothesize potential effects of and opportunities presented by price transparency for patients, physicians, and other healthcare industry stakeholders.

Psychosis as an adverse effect of monoclonal antibody immunotherapy.

Immunotherapy is a "hot" area in schizophrenia research. Monoclonal antibodies (mAbs) target specific immune molecules, and therefore offer an unparalleled opportunity to directly test the hypothesis that immune dysfunction plays a causal role in psychopathology in schizophrenia. Cytokine-based immunotherapy for other disorders has been associated with a range of neuropsychiatric adverse effects, including psychosis. The purpose of the present study was to investigate the prevalence of spontaneously-reported adverse drug reactions of psychotic symptoms for mAbs, and to calculate odds of psychosis for individual mAbs, compared to bevacizumab, which does not directly target the immune system. We searched the publicly available VigiBase, a World Health Organization global individual case safety report database from inception through February 2019 for which a mAb was the suspected agent of an adverse drug reaction (ADR). We investigated 43 different mAbs, comprising 1,298,185 case reports and 2025 psychosis ADRs. For individual mAbs, the prevalence of psychosis ADRs ranged from 0.1 to 0.4%. Seven mAbs were associated with a significantly increased odds of psychosis (OR = 1.42-2.22), including two agents that target CD25. Eight mAbs were associated with a significantly decreased odds of psychosis (OR = 0.28-0.75), including 4 anti-TNF-α agents. Our results suggest that psychosis is a relatively rare adverse effect of mAb treatment, but risks vary by specific agents. Findings indicate that modulating the immune system may sometimes lead to the development of psychosis. Ongoing clinical trials of adjunctive mAb immunotherapy in schizophrenia will provide valuable insights into the role of the immune system in psychosis.

Urinary tract infection, inflammation, and cognition in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study.

BACKGROUND: Schizophrenia is associated with an increased prevalence of infections throughout the life span. Previous studies have found an association between urinary tract infection (UTI) and acute psychosis. We investigated the prevalence and correlates of UTI in a large cohort of patients with schizophrenia. METHODS: We estimated the prevalence of UTI at the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. We then investigated associations between UTI and inflammatory markers, psychopathology, and cognition, controlling for potential confounding factors. RESULTS: The prevalence of probable UTI at baseline in the CATIE trial was 1.2% (n = 13 of 1,061 participants). Compared with participants with a normal urinalysis (n = 387), after controlling for potential confounders, UTI was a significant predictor of greater impairments (approximately 1 standard deviation difference) in the cognition composite score (beta = -0.153, P = .002), and poorer working memory (beta = -0.190, P < .001). There were no differences in psychopathology scores between participants with probable UTI and those with a normal urinalysis. CONCLUSIONS: Urinary tract infections in patients with schizophrenia may have an impact on cognition. Findings provide additional evidence regarding infectious disease comorbidity, which may be clinically relevant in the treatment of patients with schizophrenia.

Total and Differential White Blood Cell Counts, Cocaine, and Marijuana Use in Patients With Schizophrenia.

Schizophrenia is associated with blood inflammatory marker abnormalities. Illicit drug use, which is common in schizophrenia, may modulate inflammatory marker levels. We examined effects of marijuana and cocaine use on white blood cell (WBC) counts in acutely ill, hospitalized patients with schizophrenia using a within-subjects and between-groups design. Mean total and differential WBC counts were first compared in acutely ill patients with schizophrenia for hospitalizations with and without either marijuana (n = 18) or cocaine (n = 24) use. Mean total and differential WBC counts were then compared between patients with schizophrenia with either marijuana or cocaine use and patients with a negative urine drug screen (UDS; n = 43). Patients with schizophrenia had significantly higher total WBC, lymphocytes, and monocytes during hospitalizations with (vs. without) cocaine use. Patients with cocaine use also had significantly higher monocytes and eosinophils than those with a negative UDS. Our findings suggest that substance use, particularly of cocaine, may modulate inflammatory marker levels in acutely ill, hospitalized patients with schizophrenia.