Report of the 2023-24 AACP Research and Graduate Affairs Committee.

The 2023-2024 American Association of Colleges of Pharmacy (AACP) Research and Graduate Affairs Committee (RGAC or the Committee) was charged with developing programs focused on career and professional development for researchers, new faculty, and graduate students in colleges and schools of pharmacy. After reviewing exiting resources available to pharmacy faculty for grant writing, the Committee recognized a need for more comprehensive, diverse, and tailored resources for pharmacy faculty. The Committee therefore focused its effort on creating an intensive grant writing course, intended for independent pharmacy researchers without prior major grant awards, that would support writing for both career development and research grant applications and cater to faculty in translational, clinical sciences, and pharmacy practice, along with fellows and residents. To implement this grant writing course and other programs to advance research progress by pharmacy faculty, the Committee proposes three recommendations for consideration by AACP and one suggestion for consideration by colleges and schools of pharmacy.

A systematic review of clozapine-associated inflammation and related monitoring.

Clozapine is an effective antipsychotic medication used for treatment-resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life-threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: (i) the impact of clozapine on inflammatory markers, (ii) monitoring cardiac and other organ function during clozapine-associated inflammatory processes, and (iii) monitoring non-specific signs and symptoms of inflammation. Elevated levels of C-reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4-8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine-associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence-based guidelines for the monitoring of clozapine-associated inflammation.

Depressive Symptoms Longitudinally Mediate the Effect of Hyperglycemia on Memory Decline in Type 2 Diabetes.

OBJECTIVE: We sought to examine the mediating role of changes in depressive symptoms in the association between chronic hyperglycemia and longitudinal cognition in a sample of older adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a longitudinal mediation analysis using structural equation modeling of observational data collected over 6 years from 2,155 participants with T2D (aged ≥51 years) in the U.S.-wide Health and Retirement Study. T2D was defined using self-reported diagnosis, and HbA1c was assessed at study baseline. Self-reported depressive symptoms were assessed at two time points 4 years apart. Episodic memory was measured using a list-learning test administered at three time points over 6 years. We adjusted for sociodemographics, chronic health comorbidities, medication adherence, study enrollment year, and prior years' depressive symptoms and memory scores. RESULTS: At baseline, participants' mean age was 69.4 (SD = 9.1), mean HbA1c was 7.2% (SD = 1.4%), 55.0% were women, 19.3% were non-Latinx Black, and 14.0% were Latinx. Higher baseline levels of HbA1c were associated with increases in depressive symptoms over 4 years, which, in turn, were associated with poorer memory 2 years later. Depressive symptoms accounted for 19% of the longitudinal effect of HbA1c on memory over the 6-year period. Sensitivity analyses ruled out alternative directions of associations. CONCLUSIONS: Incident elevations in depressive symptoms mediated the longitudinal association between hyperglycemia and 6-year episodic memory scores. For older adults with T2D, interventions to prevent HbA1c-related incident depressive symptoms may be beneficial in reducing the neurotoxic effects of chronic hyperglycemia on cognition.

Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: A pilot study.

Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained <5% to identify potential biomarkers of antipsychotic-induced weight gain. Minimally AP-exposed cases were distinguished from controls by six fatty acids when compared at baseline, namely reduced levels of palmitoleic acid, lauric acid, and heneicosylic acid, as well as elevated levels of behenic acid, arachidonic acid, and myristoleic acid (FDR < 0.05). Baseline levels of the fatty acid adrenic acid was increased in 11 individuals who experienced a clinically significant body weight gain (≥5%) following 12 weeks of AP exposure as compared to those who did not (FDR = 0.0408). Fatty acids may represent illness biomarkers of PSDs and early predictors of AP-induced weight gain. The findings may hold important clinical implications for early identification of individuals who could benefit from prevention strategies to reduce future cardiometabolic risk, and may lead to novel, targeted treatments to counteract metabolic dysfunction in PSDs.

Assessing the impact of pre-test education on patient knowledge, perceptions, and expectations of pharmacogenomic testing to guide antidepressant use.

Pharmacogenomic (PGx) testing is an increasingly utilized technology that offers the potential for precision drug selection to treat depression. Though PGx-guided therapy is associated with increased rates of remission of depression symptoms, for many patients, treatment will not change based on PGx testing results. Lack of consensus guidelines for pre-test counseling may hinder the communication of PGx testing limitations, and patients often have high expectations for test outcomes. To explore this issue, we created and evaluated the impact of a pre-test education video for patients with depression. Individuals in the education group (n = 198) viewed this brief video about PGx testing prior to completing a survey that explored knowledge, perception, and expectations of PGx testing developed using a theoretical framework to measure intention to test. Individuals in the survey-only group (n = 189) completed the same survey but were not provided with any PGx educational materials. Analyses demonstrate efficacy of the video in improving knowledge of PGx. The education group also reported more positive attitudes and greater perceived control over pursuing PGx testing compared to the survey-only group. Further analyses identified significant differences in expectations, attitudes, and intention to pursue PGx testing based on number of previous medication trials. Path analyses identified the best model for predicting PGx testing intention, specifically that social norms and ease of testing have a strong positive association, and knowledge has a strong negative association with patients' intentions to test across the full sample, the education group, and the survey-only group. The findings of this study serve as a foundation for future tailored educational initiatives in the PGx testing space.

Reimagining a summer research program during COVID: Strategies for enhancing research workforce diversity.

Well-designed, accessible short-term research training programs are needed to recruit and retain underrepresented persons into clinical and translational research training programs and diversify the workforce. The Michigan Institute for Clinical and Health Research developed a summer research program, training over 270 students in 15 years. In response to the 2020 COVID-19 pandemic, we pivoted swiftly from an in-person format to a fully remote format. We describe this process, focusing on factors of diversity, equity, and inclusion including enabling student participation in remote research activities. We collected data about students' learning experiences since the program's inception; therefore, we could evaluate the impact of remote vs. in-person formats. We examined data from five cohorts: three in-person (2017-2019; n = 57) and two remote (2020-2021; n = 45). While there was some concern about the value of participating in a remote format, overall students in both formats viewed the program favorably, with students in the remote cohorts rating some aspects of the program significantly more favorably. In addition, more students who identified as Black or African American participated in the remote format than in the in-person format. We describe lessons learned from this unprecedented challenge and future program directions.

Sexual Functioning in Adolescents With Major Depressive Disorder: A Prospective Study.

Objective: To examine the association between sexual functioning, depression and anxiety severity, and selective serotonin reuptake inhibitor (SSRI) use in adolescents.Methods: From September 2010 to December 2014, 15- to 20-year-old participants, either unmedicated or within a month of beginning SSRI treatment, completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Changes in Sexual Functioning Questionnaire (CSFQ) at baseline and every 4 months for up to 2 years. The DSM-IV-TR was used to determine presence of psychiatric disorders. Data regarding use of medications and hormonal contraception were collected. Polymorphisms of the HTR2A and ABCB1 genes were genotyped. Linear mixed-effects regression models examined the association between depression and anxiety symptom severity, SSRI use, and sexual functioning, accounting for relevant covariates.Results: A total of 263 participants (59% female, mean ± SD age = 18.9 ± 1.6 years, 70% with major depressive disorder) contributed to this analysis. After adjusting for age, sex, and duration in the study, depression severity, but not anxiety severity, was associated with lower CSFQ total scores (ß = -0.13, P < .0001) and lower arousal, orgasm, and pleasure subscale scores (all ß = -0.03, P < .003). Higher SSRI doses were associated with lower orgasm subscale scores (ß = -0.30, P < .03). Hormonal contraceptive use was associated with higher CSFQ total scores (ß = 0.97, P < .003) and higher arousal (ß = 0.25, P < .009), desire (ß = 0.24, P < .001), orgasm (ß = 0.27, P < .02), and pleasure (ß = 0.15, P < .004) subscale scores. No significant genetic moderating effect was found.Conclusions: In adolescents, depression is associated with lower sexual functioning while SSRI use impairs orgasm.

Genetic and Metabolite Variability in One-Carbon Metabolism Applied to an Insulin Resistance Model in Patients With Schizophrenia Receiving Atypical Antipsychotics.

Background: Patients with schizophrenia are at high risk of pre-mature mortality due to cardiovascular disease (CVD). Our group has completed studies in pharmacogenomics and metabolomics that have independently identified perturbations in one-carbon metabolism as associated with risk factors for CVD in this patient population. Therefore, this study aimed to use genetic and metabolomic data to determine the relationship between folate pharmacogenomics, one-carbon metabolites, and insulin resistance as measured using the homeostatic model assessment for insulin resistance (HOMA-IR) as a marker of CVD. Methods: Participants in this pilot analysis were on a stable atypical antipsychotic regimen for at least 6 months, with no diabetes diagnosis or use of antidiabetic medications. Participant samples were genotyped for MTHFR variants rs1801131 (MTHFR A1298C) and rs1801133 (MTHFR C677T). Serum metabolite concentrations were obtained with NMR. A least squares regression model was used to predict log(HOMA-IR) values based on the following independent variables: serum glutamate, glycine, betaine, serine, and threonine concentrations, and carrier status of the variant alleles for the selected genotypes. Results: A total of 67 participants were included, with a median age of 47 years old (IQR 42-52), 39% were female, and the median BMI was 30.3 (IQR 26.3-37.1). Overall, the model demonstrated an ability to predict log(HOMA-IR) values with an adjusted R 2 of 0.44 and a p-value of < 0.001. Glutamate, threonine, and carrier status of the MTHFR 1298 C or MTHFR 677 T allele were positively correlated with log(HOMA-IR), whereas glycine, serine, and betaine concentrations trended inversely with log(HOMA-IR). All factors included in this final model were considered as having a possible effect on predicting log(HOMA-IR) as measured with a p-value < 0.1. Conclusions: Presence of pharmacogenomic variants that decrease the functional capacity of the MTHFR enzyme are associated with increased risk for cardiovascular disease, as measured in this instance by log(HOMA-IR). Furthermore, serine, glycine, and betaine concentrations trended inversely with HOMA-IR, suggesting that increased presence of methyl-donating groups is associated with lower measures of insulin resistance. Ultimately, these results will need to be replicated in a significantly larger population.

Pharmacogenomic testing for mental health (Part I): documenting early adopter perceptions of use for eight scenarios.

Aim: We sought to understand how early adopters used pharmacogenomic (PGx) testing for treating depression and attention deficient hyperactivity disorder (ADHD). Patients & methods: We conducted a phone survey with prescribers who had previously ordered an Informed PGx (Progenity, Inc., MI, USA) test. Results: We identified 1037 prescribers in our sampling period. Respondents (n = 64) were predominantly female (61.5%) and in pediatrics (n = 42; 64.6%). PGx testing was used for multiple scenarios (mean 3.3 ± 1.6); the most common was after no response to medication was observed (80%; 51/64). Most respondents state that test results typically reveal an altered metabolizer status. Conclusion: PGx test results ordered by early adopters often reveal altered metabolizers which leads them to change the depression/ADHD medication regimen. Future work should evaluate the clinical utility of PGx testing for depression/ADHD treatment.

Pharmacogenomic testing for mental health (Part II): qualitative analysis of early adopter prescriber perceptions.

Aim: We sought to explore how early adopters use pharmacogenomic (PGx) testing for treating depression and attention-deficit/hyperactivity disorder. Patients & methods: Prescribers of the Informed PGx (Progenity, Inc., Ann Arbor, MI 48108, USA) test completed a phone survey assessing use of PGx testing for different scenarios. We conducted a qualitative thematic text analysis of transcribed audio recordings of open-ended responses (n = 62). Results: PGx testing was used when treating multiple comorbidities or resistant disease, and to ease patients' concerns with future therapy. Use of PGx testing is influenced by insurance coverage, interpretability of results and results turnaround time. Conclusion: Prescribers used PGx tests to modify medications for complex patients with depression, attention-deficit/hyperactivity disorder and other disorders to alleviate concerns related to adverse effects and lack of effectiveness.

Use of psychiatric medication by college students: A decade of data.

OBJECTIVES: Given the rising prevalence of psychiatric symptomatology among college students, this analysis aims to identify temporal trends in psychiatric medication usage. METHODS: This analysis used data from the Healthy Minds Study Survey administered between 2007 and 2019, yielding a sample of 320,817 university students. Survey data were examined via descriptive analyses. RESULTS: Over the last decade from 2007 to 2018-2019, there was an increase in use of nearly all classes of psychiatric medications, with reported antidepressant medication (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], etc.) use increasing from 8.0% to 15.3%, anti-anxiety medication (benzodiazepines, buspirone, etc.) from 3.0% to 7.6%, psychostimulants from 2.1% to 6.3%, antipsychotics from 0.38% to 0.92%, and mood stabilizers from 0.8% to 2.0% (all p < 0.0001), respectively. In addition, the use of more than one category of medication at a time has increased, from 28.2% in 2007 to 40.8% in 2018-2019 (p < 0.0001). The proportion of students who received their most recent prescription for psychiatric medication from primary care providers has risen from 49.1% in 2007 to 58.8% in 2018-2019 (p < 0.0001), while the proportion receiving these prescriptions from psychiatric providers did not increase significantly and stands at 36.1% in 2018-2019. The percentage of students taking psychiatric medication without a prescription varied from year to year, starting at 11.9% in 2007 and ending at 7.7% in 2018-2019 (p < 0.0001). The proportion of students who discussed their use of psychiatric medication with their doctor or other health professional three or more times in the previous year has increased from 39.2% in 2007 to 49.5% in 2018-2019 (p < 0.0001). CONCLUSIONS: The proportion of college students who have taken psychiatric medications of all categories has risen in the last decade; these students are increasingly likely to be on more than one kind of psychiatric medication and be treated by healthcare providers at a greater frequency. Despite the growing complexity of student treatment, the proportion of students receiving psychiatric medication management by psychiatric providers has not changed, while the proportion receiving services in primary care settings has increased.

Assessments of Research Competencies for Clinical Investigators: A Systematic Review.

Although there is extensive research literature on clinical skill competencies and the use of competency-based frameworks for clinical research, the appropriate methods to assess these competencies are not as well understood. Our goal in this systematic literature review is to identify, compare, and critique assessments of clinical research competencies. Articles were included in this review if they examined clinical investigators or clinical investigators in training, focused on research-based skills, and included some form of assessment of research-based competencies. A total of 76 articles were identified as part of the initial search; 16 met the criteria for inclusion. Two types of assessments of clinical research competence were identified: subjective self-assessments (n = 13) and objective tests (n = 6). These assessments covered a wide range of competencies, but there were no competency domains common to all. Most assessments had limited validation. Training was consistently associated with self-assessed competence but had little relationship to objective measures of competence. In contrast, experience was consistently associated with objectively assessed competence but not with self-assessed competence. These findings have important implications for those interested in assessing medical education programs. We describe a recommended standard for validity for assessments used for the purposes of summative program assessment.

The Research Objective Structured Clinical Exam (R-OSCE): An Innovative Tool to Assess Clinical and Translational Research Competencies.

This article was migrated. The article was marked as recommended. Introduction The Research Objective Structured Clinical Exam (R-OSCE) described in this paper was designed as part of a comprehensive program to assess competency in specific domains of clinical and translational research (CTR) for students enrolled in a 12-week introductory summer research program. Methods The program curriculum was mapped to core competencies developed by the National Center for Translational Science (NCATS) and used to develop R-OSCE stations. Twelve stations were developed, with five administered during orientation as a practice test and seven administered post-program. A scoring rubric using an anchored scale of 1-5 was developed and six qualified raters were trained in its use. The exam was self-paced and delivered through a secure online computer-based platform. Results Forty-seven students (three cohorts) completed the post-program R-OSCE. Most respondents scored at 3 (developing competence) or higher on most stations for both the practice and post-program exams, the exceptions being the stations involving writing research questions and engaging communities in research. Students indicated they liked demonstrating CTR skills through the R-OSCE. Most participants agreed that exam tasks were related to stated program competencies and that stations were realistic. Discussion The R-OSCE is best used as part of a comprehensive assessment program and may be useful in providing formative feedback to trainees that they can share with their mentors. Additionally, this study demonstrated that it could feasibly be used to evaluate the effectiveness of research education programs. However, additional time was needed to train raters and score the R-OSCE. Modifications were made to administer the exam through use of an online format with a modest budget. The computer-based format provides a solution to the current need for assessments that can be administered remotely.

The DIAMOND portal: An innovative platform for sharing translational research workforce training and assessment resources.

Although several initiatives have produced core competency domains for training the translational science workforce, training resources to help clinical research professionals advance these skills reside primarily within local departments or institutions. The Development, Implementation, and AssessMent of Novel Training in Domain (DIAMOND) project was designed to make this training more readily and publicly available. DIAMOND includes a digital portal to catalog publicly available educational resources and an ePortfolio to document professional development. DIAMOND is a nationally crowdsourced, federated, online catalog providing a platform for practitioners to find and share training and assessment materials. Contributors can share their own educational materials using a simple intake form that creates an electronic record; the portal enables users to browse or search this catalog of digital records and access the resources. Since September 2018, the portal has been visited more than 5,700 times and received over 280 contributions from professionals. The portal facilitates opportunities to connect and collaborate regarding future applications of these resources. Consequently, growing the collection and increasing numbers of both contributors and users remains a priority. Results from a small subset of users indicated over half accomplished their purpose for visiting the site, while qualitative results showed that users identified several benefits and helpful features of the ePortfolio.

Could Dietary Glutamate Play a Role in Psychiatric Distress?

Glutamate is an amino acid that functions as an excitatory neurotransmitter. It has also been associated with somatic and psychiatric distress and is implicated in the pathophysiology of psychiatric disorders such as schizophrenia. Ingestion of dietary glutamate, such as monosodium glutamate (MSG), has been mechanistically linked with greater distress among patients with chronic pain conditions, though findings have been equivocal. Preliminary research suggests that an MSG-restricted diet confers beneficial effects on somatic symptoms and well-being for some individuals with chronic pain conditions. In addition to associations with somatic distress, glutamate has been associated with the onset and progression of psychiatric symptoms. Thus, the role of dietary glutamate in psychiatric distress represents an underdeveloped and potentially important area for future research aimed at clarifying pathophysiological mechanisms and identifying targets for dietary intervention in psychiatric illnesses.

Indices of Clinical Research Coordinators' Competence.

INTRODUCTION: There is a clear need to educate and train the clinical research workforce to conduct scientifically sound clinical research. Meeting this need requires the creation of tools to assess both an individual's preparedness to function efficiently in the clinical research enterprise as well as tools to evaluate the quality and effectiveness of programs that are designed to educate and train clinical research professionals. Here we report the development and validation of a competency self-assessment entitled the Competency Index for Clinical Research Professionals, version II (CICRP-II). METHODS: CICRP-II was developed using data collected from clinical research coordinators (CRCs) participating in the "Development, Implementation and Assessment of Novel Training In Domain-Based Competencies" project at four clinical and translational science award (CTSA) hubs and partnering institutions. RESULTS: An exploratory factor analysis identified a two-factor structure: the first factor measures self-reported competence to perform routine clinical research functions while the second factor measures competence to perform advanced clinical functions. We demonstrate the between groups validity by comparing CRCs working in different research settings. DISCUSSION: The excellent psychometric properties of CICRP-II, its ability to distinguish between experienced CRCs at research intensive CTSA hubs and CRCs working in less intensive community-based sites coupled with the simplicity of alternative methods for scoring respondents make it a valuable tool for gauging an individual's perceived preparedness to function in the role of CRC as well as an equally valuable tool to evaluate the value and effectiveness of clinical research education and training programs.

Using Pharmacogenomic Testing in Primary Care: Protocol for a Pilot Randomized Controlled Study.

BACKGROUND: Antidepressants are used by primary care providers to treat a variety of conditions, including (but not limited to) depression and anxiety. A trial-and-error approach is typically used to identify effective therapy, as treatment efficacy and safety can vary based on the response, which is affected by certain gene types. Pharmacokinetic pharmacogenomic (PGx) testing provides phenotypic classification of individuals as poor, intermediate, extensive, and ultrarapid CYP450 metabolizers, providing information for optimal drug selection. OBJECTIVE: The objective of this pilot study is to examine the feasibility, acceptability, and preliminary effectiveness of PGx testing when used after starting a new antidepressant medication. METHODS: We are conducting a pilot study with physicians from 6 Department of Family Medicine clinics at the University of Michigan who are willing to use PGx test results to manage antidepressant medication use. From enrolled physicians, patients were recruited to participate in a 6-month randomized, wait-list controlled trial in which patient participants newly prescribed an antidepressant had PGx testing and were randomized equally to have the results released to their primary care physician as soon as results were available or after 3 months. Patients were excluded if they had been taking the antidepressant for more than 4 weeks or if they had undergone PGx testing in the past. Physician participants completed a baseline survey to assess demographics, as well as knowledge, feasibility, and acceptability of PGx testing for this population. At the conclusion of the study, physician participants will complete a survey to assess knowledge, satisfaction, feasibility, acceptability, perceived effectiveness, and barriers to widespread adoption of PGx testing. Patient participants will complete a baseline, 3-month, and 6-month assessment, and control patient participants will have an additional 9-month assessment. Data collected will include the reason for antidepressant use, self-reported medication adherence, side effects, patient health questionnaire 8-item depression scale, generalized anxiety disorder 7-item scale, 12-Item Short-Form Health Survey, work status or changes, and physician and emergency department visits. PGx knowledge and perceptions (including acceptability and feasibility) as well as demographic information will also be obtained. RESULTS: We recruited 23 physician participants between November 2017 and January 2019, and 52 patient participants between January 2018 and April 2019. Currently, all physician and patient participants have been recruited, and we expect data collection to conclude in January 2020. CONCLUSIONS: This study will examine the preliminary effectiveness of PGx testing after treatment initiation and determine the feasibility and acceptability of PGx testing for use in primary care. Through this study, we expect to demonstrate the benefit of PGx testing and lay the foundation for translating this approach into use within primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03270891; https://clinicaltrials.gov/ct2/show/NCT03270891. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/13848.

Metabolic syndrome is negatively associated with cognition among endothelial nitric oxide synthase (eNOS)- 786C carriers in schizophrenia-spectrum disorders.

Although metabolic syndrome and cognitive inefficiencies are well-described common complications of schizophrenia, their association remains inconsistent, potentially due to poorly understood mechanisms underlying their relationship. Variability in the endothelial nitric oxide synthase (eNOS) gene, specifically the T-786C variant, has been separately associated with cognition and metabolic syndrome, with worse outcomes for eNOS-786C carriers likely occurring via negative effects on blood vessel functioning. However, the interaction between eNOS and metabolic syndrome in cognition among adults with schizophrenia is unknown. This study aimed to test the main and interaction effects of the eNOS-786C allele in cognition using hierarchical regression analyses controlling for age, sex, education, race, and antipsychotic exposure. Metabolic syndrome, eNOS T-786C genotype, and cognitive performance were assessed in 226 community-dwelling participants with chronic schizophrenia-spectrum disorders. Results demonstrated a significant interaction between metabolic syndrome and the eNOS-786C allele. Specifically, among eNOS-786C carriers only, metabolic syndrome was independently associated with lower scores in processing speed and verbal fluency, and predicted 12.5% and 15.8% of variance in performance, respectively. These results suggest that the additive negative effects of eNOS-786C and metabolic syndrome on blood vessel functioning may be severe enough to negatively impact cognition. The finding that metabolic syndrome is associated with worse cognition only in the presence of the eNOS-786C allele may clarify extant inconsistencies in the literature. These findings provide preliminary evidence that may inform interventions to reduce cognitive morbidity among adults with schizophrenia.

The Fragile Brain: Stress Vulnerability, Negative Affect and GABAergic Neurocircuits in Psychosis.

Persons with schizophrenia exhibit sensitivity to stress and negative affect (NA), both strongly correlated with poor functional outcome. This theoretical review suggests that NA reflects a "fragile brain," ie, vulnerable to stress, including events not experienced as stressful by healthy individuals. Based on postmortem evidence of altered gamma-aminobutyric acid (GABA) function in parvalbumin positive interneurons (PVI), animal models of PVI abnormalities and neuroimaging data with GABAergic challenge, it is suggested that GABAergic disruptions weaken cortical regions, which leads to stress vulnerability and excessive NA. Neurocircuits that respond to stressful and salient environmental stimuli, such as the hypothalamic-pituitary-adrenal axis and the amygdala, are highly dysregulated in schizophrenia, exhibiting hypo- and hyper-activity. PVI abnormalities in lateral prefrontal cortex and hippocampus have been hypothesized to affect cognitive function and positive symptoms, respectively; in the medial frontal cortex (dorsal anterior cingulate cortex and dorsal medial prefrontal cortex), these abnormalities may lead to vulnerability to stress, NA and dysregulation of stress responsive systems. Given that postmortem PVI disruptions have been identified in other conditions, such as bipolar disorder and autism, stress vulnerability may reflect a transdiagnostic dimension of psychopathology.