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.

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.

Patient perspectives on medication self-management in rural Kenya: a cross-sectional survey.

OBJECTIVES: The presence of HIV, tuberculosis and non-communicable diseases result in a double burden of disease in the East African community. Most studies have focused on urban Nairobi and western Kenya, leading to a lack of information on rural regions that make up 75% of the population. This study determined baseline rates and barriers to medication self-management in rural Meru County. DESIGN: A cross-sectional, descriptive community survey focused on Meru, Kenya. SETTING: Participants were surveyed at a local Kithoka dispensary and the government operated Meru Level 5 Hospital. PARTICIPANTS: Seventy-five chronic illness patients between June 2016 and July 2016. INTERVENTION: Twelve-question Measures of Drug Self-Management Scale (MeDS). MAIN OUTCOME MEASURE: Baseline rates of medication self-management. A score of 10 or more defined 'adequate' medication drug self-management. RESULTS: The average MeDS score was 8.16 ± 2.4, indicating inadequate medication self-management. There was no significant difference across age (P = 0.75), and between the scores of males and females (8.1 ± 2.4 and 8.2 ± 2.5, respectively, P = 0.89). Minor side effects and the idea that taking medicines disrupt life were highly associated with inadequate drug self-management (r = 0.58). Forgetfulness and non-adherence had the highest correlation (r = 0.64). Cost is a large barrier, with 64% agreeing that they have a hard time paying for their medicines. CONCLUSIONS: All questions on the MeDS survey had statistically significant correlations with the overall score, while gender and age did not. The MeDS questionnaire showed to be an effective tool to evaluate risk of long-term non-adherence globally in rural populations.

Germline genetic variants with implications for disease risk and therapeutic outcomes.

Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care.

Gene-specific DNA methylation may mediate atypical antipsychotic-induced insulin resistance.

OBJECTIVES: Atypical antipsychotics (AAPs) carry a significant risk of cardiometabolic side effects, including insulin resistance. It is thought that the insulin resistance resulting from the use of AAPs may be associated with changes in DNA methylation. We aimed to identify and validate a candidate gene associated with AAP-induced insulin resistance by using a multi-step approach that included an epigenome-wide association study (EWAS) and validation with site-specific methylation and metabolomics data. METHODS: Subjects with bipolar disorder treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze peripheral blood DNA methylation and insulin resistance. Epigenome-wide DNA methylation was analyzed in a discovery sample (n = 48) using the Illumina 450K BeadChip. Validation analyses of the epigenome-wide findings occurred in a separate sample (n = 72) using site-specific methylation with pyrosequencing and untargeted metabolomics data. Regression analyses were conducted controlling for known confounders in all analyses and a mediation analysis was performed to investigate if AAP-induced insulin resistance occurs through changes in DNA methylation. RESULTS: A differentially methylated probe associated with insulin resistance was discovered and validated in the fatty acyl CoA reductase 2 (FAR2) gene of chromosome 12. Functional associations of this DNA methylation site with untargeted phospholipid-related metabolites were also detected. Our results identified a mediating effect of this FAR2 methylation site on AAP-induced insulin resistance. CONCLUSIONS: Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance.

Identification of non-reported bupropion metabolites in human plasma.

Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non-reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non-reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet. Plasma samples were collected and analysed by LC-MS/MS at 0, 6 and 24 h. Two non-reported metabolites (M1 and M3) were identified with mass-to-charge (m/z) ratios of 276 (M1, hydration of bupropion) and 258 (M3, hydroxylation of threo/erythrohydrobupropion) from human plasma in addition to the known hydroxybupropion, threo/erythrohydrobupropion and the glucuronidation products of the major metabolites (M2 and M4-M7). These new metabolites may provide new insight and broaden the understanding of bupropion's variability in clinical pharmacokinetics. © 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd.

Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population.

OBJECTIVE: Since a poor diet is often cited as a contributor to metabolic syndrome for subjects diagnosed with bipolar disorder and schizophrenia, we sought to examine dietary intake, cigarette smoking, and physical activity in these populations and compare them with those for the general population. METHODS: Individuals diagnosed with bipolar disorder (n = 116) and schizophrenia (n = 143) were assessed for dietary intake, lifestyle habits, and metabolic syndrome and compared to age-, gender-, and race-matched subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Additionally, matched subgroups within the patient populations were compared to elicit any differences. RESULTS: As expected, the metabolic syndrome rate was higher in the samples with bipolar disorder (33%) and schizophrenia (47%) compared to matched NHANES controls (17% and 11%, respectively), and not different between the patient groups. Surprisingly, both subjects with bipolar disorder and those with schizophrenia consumed fewer total calories, carbohydrates and fats, as well as more fiber (p < 0.03), compared to NHANES controls. No dietary or activity differences between patient participants with and without metabolic syndrome were found. Subjects with schizophrenia had significantly lower total and low-density cholesterol levels (p < 0.0001) compared to NHANES controls. Subjects with bipolar disorder smoked less (p = 0.001), exercised more (p = 0.004), and had lower body mass indexes (p = 0.009) compared to subjects with schizophrenia. CONCLUSIONS: Counter to predictions, few dietary differences could be discerned between schizophrenia, bipolar disorder, and NHANES control groups. The subjects with bipolar disorder exhibited healthier behaviors than the patients with schizophrenia. Additional research regarding metabolic syndrome mechanisms, focusing on non-dietary contributions, is needed.

Report of the 2023-2024 AACP Research and Graduate Affairs Committee.

The 2023-2024 American Association of Colleges of Pharmacy Research and Graduate Affairs Committee ("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 previous major grant awards that would support writing for 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 3 recommendations for consideration by the American Association of Colleges of Pharmacy and 1 suggestion for consideration by colleges and schools of pharmacy.

Can Machine Learning Overcome the 95% Failure Rate and Reality that Only 30% of Approved Cancer Drugs Meaningfully Extend Patient Survival?

Despite implementing hundreds of strategies, cancer drug development suffers from a 95% failure rate over 30 years, with only 30% of approved cancer drugs extending patient survival beyond 2.5 months. Adding more criteria without eliminating nonessential ones is impractical and may fall into the "survivorship bias" trap. Machine learning (ML) models may enhance efficiency by saving time and cost. Yet, they may not improve success rate without identifying the root causes of failure. We propose a "STAR-guided ML system" (structure-tissue/cell selectivity-activity relationship) to enhance success rate and efficiency by addressing three overlooked interdependent factors: potency/specificity to the on/off-targets determining efficacy in tumors at clinical doses, on/off-target-driven tissue/cell selectivity influencing adverse effects in the normal organs at clinical doses, and optimal clinical doses balancing efficacy/safety as determined by potency/specificity and tissue/cell selectivity. STAR-guided ML models can directly predict clinical dose/efficacy/safety from five features to design/select the best drugs, enhancing success and efficiency of cancer drug development.

A pilot study investigating tumor necrosis factor-α as a potential intervening variable of atypical antipsychotic-associated metabolic syndrome in bipolar disorder.

BACKGROUND: Strong associations exist between tumor necrosis factor-α (TNF-α) and metabolic syndrome (MetS). Although TNF-α is associated with bipolar depression (BD), its role in atypical antipsychotic (AAP)-associated MetS in BD is unclear. Here, we investigate the potential intervening role of TNF-α in the indirect relationship between AAP treatment and MetS in BD. MATERIALS AND METHODS: Using a cross-sectional design, 99 euthymic BD volunteers were stratified by the presence or the absence of MetS (National Cholesterol Education Program Adult Treatment Panel III). Serum TNF-α concentration, determined via chemiluminescent immunometric assays, was compared between groups (ie, MetS or no MetS). We investigated the intervening effect of TNF-α on the relation between AAP treatment and MetS in BD using regression techniques. RESULTS: Treatment with those antipsychotics believed associated with a higher risk for MetS (ie, AAPs: olanzapine, quetiapine, risperidone, paliperidone, clozapine) was found to be associated with significantly greater TNF-α (F 1,88 = 11.2, P = 0.001, mean difference of 1.7 ± 0.51) and a higher likelihood of MetS (F 1,88 = 4.5, P = 0.036) than in those not receiving treatment with an AAP. Additionally, TNF-α was greater (trending toward significance; T 52 = 2.0, P = 0.05) in BD volunteers with MetS and was found to have a statistically significant effect on the indirect relationship between AAP treatment and elevated waist circumference in these BD volunteers. DISCUSSION: These results identify TNF-α as a potential intervening variable of AAP-associated MetS in BD, not previously identified in this population. Future prospective studies could assess the predictive potential of TNF-α in determining risk of AAP-associated MetS in BD. Given previous evidence relating TNF-α and mood state in BD, this study increases the importance in understanding the role of TNF-α in "mind-body" interactions and renews discussions of the utility of research into the clinical efficacy of TNF-α antagonist treatment in mood disorders.

P-glycoprotein (PGP) polymorphisms and sexual dysfunction in female patients with depression and SSRI-associated sexual side effects.

Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18-40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 ± 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 ± 6.3) or CC genotypes (46.6 ± 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men.

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.

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.

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.

Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics.

Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject's mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (χ = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (χ = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate's role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.

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.

Association of DRD2 and ANKK1 polymorphisms with prolactin increase in olanzapine-treated women.

UNLABELLED: Dopamine D2 receptors, encoded by DRD2, play a role in regulating serum prolactin concentration. Single nucleotide polymorphisms (SNPs), rs2734842(C), rs6275(T), and rs6279(C) located within DRD2, have been shown to be associated with prolactin increase in olanzapine/fluoxetine combination (OFC)-treated women. The present analyses seek to replicate these results and test other SNPs in DRD2 and neighboring gene ANKK1 for associations with prolactin increase in women, using data from 3 pooled studies of olanzapine, and 2 previously examined studies OFC. An ANCOVA was used to test whether change from baseline in the natural log of prolactin concentration (ln[prolactin]) was associated with SNPs in the pooled olanzapine studies. A meta-analysis was also performed using the inverse chi-square method, pooling p-values from the 2 previously examined studies and the 3 olanzapine studies. Negative strand alleles rs2734842(C), rs6275(T), and rs6279(C) were significantly associated with increased prolactin in olanzapine-treated women, replicating previous results. These SNPs also showed moderate association with increased prolactin in olanzapine-treated and OFC-treated women in the meta-analysis, as did rs4938016, rs2734848, rs2734841, rs1124493, and rs1076562. Five of these SNPs fall in or are adjacent to an LD block spanning DRD2 intron 7, exon 7, 5' untranslated region and ANKK1. CLINICAL TRIAL REGISTRATION: www.clinicaltrial.gov.

Association between type-three metabotropic glutamate receptor gene (GRM3) variants and symptom presentation in treatment refractory schizophrenia.

OBJECTIVE: Positive associations between polymorphisms in the type-three metabotropic glutamate receptor gene (GRM3) and the pathogenesis of schizophrenia as well as response to antipsychotic treatment have been reported. The objective of this study was to determine whether refractory psychiatric symptoms in antipsychotic non-responders are related to polymorphisms in GRM3. METHODS: Ninety-five treatment refractory schizophrenia participants were enrolled. Prior to a medication switch, global psychopathology and negative symptoms were rated. These participants were genotyped for seven markers in GRM3. Genotype associations with symptoms were assessed. RESULTS: Two markers in GRM3 (rs1989796 and rs1476455), were associated with the presence of refractory global symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) Total scores. Participants with an rs1476455_CC genotype had significantly higher BPRS scores than A-carriers (55.1±10.4 vs. 48.3±9.2; F=7.6, p=0.0071). Additionally, participants with the rs1989796_CC genotype had significantly higher BPRS scores than T-carriers (50.1±5.7 vs. 55.8±10.5, F=7.1, p=0.0091). No evidence for significant associations with negative symptoms was observed. CONCLUSIONS: Polymorphisms in the GRM3 gene may be associated with refractory global psychosis symptoms but not negative symptoms in persons with schizophrenia.

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.

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.