Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

Testing the Validity of the Pathways Model: A Latent Class Analysis of Potential Pathological Gambling Subtypes in a Non-Treatment Sample.

Latent class analysis (LCA) was used to test the validity of the Pathways Model in 285 subjects with DSM-IV pathological gambling (PG). In addition to identifying three subtypes that roughly correspond with those described in the model (Behaviorally Conditioned, or BC, Emotionally Vulnerable, or EV, Antisocial-Impulsivist, or AI), LCA identified a fourth class, termed the Antisocial Drinker, or AD, characterized by high rates of antisociality, conduct disorder, and alcohol use disorder. BC gamblers comprised 45% of the sample, followed by EV (24%), AD (22%), and AI (9%) gamblers. Women were more likely to be EV gamblers (OR = 1.89) and less likely to be AD gamblers (OR = 0.46). Those who had attempted suicide were more likely to be EV (OR = 3.06) or AI (OR = 3.05) gamblers and less likely to be BC (OR = 0.37) or AD gamblers (OR = 0.50). Greater childhood maltreatment was associated with AD (standardized OR = 1.81) and AI (standardized OR = 1.43) gamblers. Individuals with later PG onset were less likely to be AI gamblers (standardized OR = 0.48). Individuals who preferred slots were more likely to be EV gamblers (OR = 1.83) and less likely to be AD gamblers (OR = 0.33). The BC subtype was associated with better health outcomes, better social functioning, less childhood maltreatment, and less severe PG. The AI subtype was associated with worse health outcomes, worse social functioning, and higher PG severity. The findings provide a better understanding PG heterogeneity that could be relevant to clinical management.

Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition.

ABSTRACT: Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.

An Exploratory Analysis of Predictors of Course in Older and Younger Adults with Pathological Gambling: A Non-Treatment Sample.

We examined the association of baseline social, demographic, and clinical predictor variables with course in 48 older (≥ 60 years) and 57 younger (< 40 years) subjects with pathological gambling (PG) in a prospective follow-up study. Weekly gambling activity was tracked and used to categorize PG course. Generalized estimating equation models were used to examine predictors of disordered (i.e., level 2 or 3) gambling. Interaction tests were used to test for differential relationships for older and younger subjects. Predictors of disordered gambling during follow-up included greater severity of PG symptoms, greater severity of depressive symptoms, self-reported childhood neglect, cognitive distortions related to games of chance, and more role limitations due to physical health. Interaction tests showed that the relationships between some risk factors and disordered gambling varied for older and younger adults. Understanding these interrelationships could allow clinicians to more effectively monitor and manage their patients with PG.

Are Comorbid Disorders Associated with Changes in Gambling Activity? A Longitudinal Study of Younger and Older Subjects with DSM-IV Pathological Gambling.

This study investigates the association of comorbid disorders with gambling activity in a longitudinal follow-up study of younger and older adult subjects with DSM-IV pathological gambling (PG). The subjects included 57 younger adults with PG (≥ 18/ < 40 years) and 48 older adults with PG (≥ 60 years). Subjects were assessed at baseline and every 6 months for a mean (SD) of 31.4 (13.1) months. Comorbidity was assessed using a modification of the Longitudinal Interval Follow-up Evaluation (LIFE). During follow-up, rates of problem severity were highest for anxiety disorders, mood disorders, and impulse control disorders. Among all subjects with PG, greater severity of depression or posttraumatic stress disorder was associated with increased gambling activity. In older subjects, greater severity of agoraphobia and social phobia were associated with lowered gambling activity. In younger subjects, greater severity of any substance use disorder, an alcohol use disorder, or compulsive computer use were associated with lowered gambling activity. The latter findings provide presumptive evidence for the substitute addiction hypothesis. We conclude that increased severity of several comorbid disorders could serve as triggers for increased gambling or predict lowered gambling activity. On the other hand, certain comorbid disorders could be triggered by increased gambling activity. Knowing these interrelationships is important to gaining a better understanding of PG and its clinical management.

Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib.

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.

Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). METHODS: The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. RESULTS: Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. CONCLUSIONS: Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

Bipolar Disorder and Suicide: a Review.

PURPOSE OF REVIEW: Bipolar disorder has the highest rate of suicide of all psychiatric conditions and is approximately 20-30 times that of the general population. The purpose of this review is to discuss findings relevant to bipolar disorder and suicide. RECENT FINDINGS: Risk factors include male gender, living alone, divorced, no children, Caucasian, younger age (< 35 years), elderly age (> 75 years), unemployment, and a personal history of suicide attempt and family history of suicide attempt or suicide completion, as well as predominant depressive polarity. Suicide is associated with the depressed or mixed subtypes, not mania. Although there are emerging treatments for bipolar depression, such as ketamine and TMS, lithium remains the only medication associated with lowered suicide rates in bipolar disorder. Understanding clinical and demographic risk factors for suicide in bipolar disorder remains the best way to prevent suicidal behavior. Early intervention and treatment with anti-suicidal medications, such as lithium, along with close observation and follow-up is the best way to mitigate suicide in patients with bipolar disorder.

Schizoaffective disorder: A review.

BACKGROUND: Schizoaffective disorder (SAD) is a chronic, potentially disabling psychotic disorder common in clinical settings. SAD often has been used as a diagnosis for individuals having an admixture of mood and psychotic symptoms whose diagnosis is uncertain. Its hallmark is the presence of symptoms of a major mood episode (either a depressive or manic episode) concurrent with symptoms characteristic of schizophrenia, such as delusions, hallucinations, or disorganized speech. METHODS: A literature search in PubMed and Google Scholar was conducted to identify articles on SAD. We also reviewed major textbooks and DSM-5 to identify pertinent information. RESULTS: This review begins with the history and classification of SAD. Debate continues to swirl around the concept, as some experts view SAD as an independent disorder, while others see SAD as either a form of schizophrenia or a mood disorder. The disorder is more common in women and its course follows the middle ground between schizophrenia and bipolar disorder. SAD appears to have high heritability. Most patients appear to benefit from antipsychotics plus antidepressants and/or mood stabilizers, depending on whether the patient has the depressive or bipolar subtype. Electroconvulsive therapy can also be effective. CONCLUSIONS: SAD is a chronic psychotic disorder that continues to be controversial. There has been inadequate research regarding its epidemiology, course, etiologic factors, and treatment.

Religiosity and Chance Beliefs in Persons with DSM-IV Pathological Gambling Enrolled in a Longitudinal Follow-Up Study.

This study investigates the association of public, private and intrinsic religiosity and chance beliefs (superstition, illusion of control) with gambling behavior in a longitudinal follow-up study of younger and older adult subjects with DSM-IV pathological gambling (PG) and an older adult comparison group without PG. One-hundred sixty-three subjects were enrolled including 60 younger adults with PG (≥ 18/< 40 years), 53 older adults with PG (≥ 60 years), and 50 older adults without PG (≥ 60). Subjects were assessed at baseline and every 6 months thereafter. The Duke University Religion Index for Religious Assessment and the Drake Beliefs About Chance scales were administered at baseline. Follow-up was a mean (SD) of 2.6 (1.4) years. Older adults with PG scored lower on measures of public and intrinsic aspects of religiosity than older adults without PG, and scored higher on superstition and illusion of control. Older adults with PG also scored higher than younger adults with PG on private and intrinsic religiosity, but not public religiosity. Superstition predicted intrinsic, but not other aspects of religiosity. Importantly, during follow-up, higher levels of public and intrinsic religiosity were protective against problematic (levels 2, 3) gambling; were protective against chronic PG; and were predictive of PG remission status. Lower illusion of control ratings were protective against problematic gambling and chronic PG; lower superstition ratings were predictive of remission. We conclude that higher levels of public and intrinsic religiosity and lower levels of chance beliefs are associated with a more benign PG course.

A Four Marker Digital PCR Toolkit for Detecting Heavy Alcohol Consumption and the Effectiveness of Its Treatment.

Background.-Heavy alcohol consumption (HAC) is a shared concern of the forensic, medical and insurance underwriting communities. Unfortunately, there is a relative lack of clinically employable tools for detecting HAC and monitoring treatment response. Building on the results of 3 genome wide methylation studies, we have previously shown in a small group of samples that methylation sensitive digital PCR assays (MSdPCR) have the potential to accurately classify individuals with respect to HAC in a small set of individuals. Objective.-We now expand on those earlier findings using data and biomaterials from 143 participants with current HAC and 200 abstinent controls. Results.-We show that a set of 4 digital PCR assays that have a receiver operating characteristic (ROC) area under the curve (AUC) of 0.96 for detecting those with HAC. After a mean of 21 days of inpatient enforced abstinence, methylation status at one of these markers, cg04987734, began to revert to baseline values. Re-examination of methylation data from our smaller 2014 study with respect to this locus demonstrated a similarly significant reversion pattern at cg04987734 in association with treatment enforced abstinence. Conclusions.-We conclude that clinically implementable dPCR tools can sensitively detect the presence of HAC and that they show promise for monitoring alcohol treatment results. These dPCR tools could be useful to clinicians and researchers in monitoring those enrolled in substance use disorder treatment, employee wellness programs and insurance underwriting.

Does response to the STEPPS program differ by sex, age, or race in offenders with borderline personality disorder?

Systems Training for Emotional Predictability and Problem Solving (STEPPS) is an evidence-based group treatment program for ambulatory patients with borderline personality disorder (BPD). The program was introduced to the Iowa correctional system in 2005, and groups have been ongoing ever since. In this analysis, we examine whether response to the STEPPS program differs based on sex, age (<40/≥40 years), or race/ethnicity (minority/non-minority) using data collected in Iowa prisons and in community corrections. Subjects were recruited and assessed by correctional staff. Offenders with BPD were offered the opportunity to participate in the STEPPS program. The presence of BPD was assessed using a module from the Structured Interview for DSM-IV Personality. Efficacy assessments included the Borderline Evaluation of Severity Over Time Scale, the Beck Depression Inventory, and the Positive and Negative Affectivity Scale. The Client Satisfaction Questionnaire-8 assessed program satisfaction. Data on 77 offenders were analyzed. All participated in the STEPPS program and 53% completed all 20 weeks. The analysis showed that there were no significant differences in response to STEPPS in terms of sex, age, or race/ethnicity on any of the three efficacy measures. Women expressed greater satisfaction than men, but there were no differences with regard to age or race/ethnicity. The implications of the findings are discussed.

Genome-wide and digital polymerase chain reaction epigenetic assessments of alcohol consumption.

The lack of readily employable biomarkers of alcohol consumption is a problem for clinicians and researchers. In 2014, we published a preliminary DNA methylation signature of heavy alcohol consumption that remits as a function of abstinence. Herein, we present new genome-wide methylation findings from a cohort of additional subjects and a meta-analysis of the data. Using DNA from 47 consecutive heavy drinkers admitted for alcohol detoxification in the context of alcohol treatment and 47 abstinent controls, we replicate the 2014 results and show that 21,221 CpG residues are differentially methylated in active heavy drinkers. Meta-analysis of all data from the 448,058 probes common to the two methylation platforms shows a similarly profound signature with confirmation of findings from other groups. Principal components analyses show that genome-wide methylation changes in response to alcohol consumption load on two major factors with one component accounting at least 50% of the total variance in both smokers and nonsmoking alcoholics. Using data from the arrays, we derive a panel of five methylation probes that classifies use status with a receiver operator characteristic area under the curve (AUC) of 0.97. Finally, using droplet digital polymerase chain reaction (PCR), we convert these array-based findings to two marker assays with an AUC of 0.95 and a four marker set AUC of 0.98. We conclude that DNA methylation assessments are capable of quantifying alcohol use status and suggest that readily employable digital PCR approaches for substance consumption may find widespread use in alcohol-related research and patient care.

Quetiapine's effect on the SCL-90-R domains in patients with borderline personality disorder.

BACKGROUND: This study aimed to examine the impact of quetiapine on the symptom and distress domains measured by the Symptom Checklist-90-Revised (SCL-90-R) in patients with borderline personality disorder (BPD). METHODS: Ninety-five participants meeting DSM-IV diagnostic criteria for BPD were randomly assigned to low-dosage (quetiapine, 150 mg/d; n = 33), moderate-dosage (quetiapine, 300 mg/d; n = 33), or placebo (n = 29). SCL-90-R was administered weekly over the course of an 8-week double-blind treatment phase. We used a mixed-effects model to analyze subscale scores of the SCL-90-R. RESULTS: Results showed that both dosages of quetiapine were effective in reducing levels of overall psychological distress, interpersonal sensitivity, depression, and hostility compared with those who received placebo. CONCLUSIONS: SCL-90-R can be a useful tool that would allow clinicians to collect information in addition to the DSM symptoms to better understand the diagnostic heterogeneity found in patients diagnosed with BPD.

Five-year follow-up of people diagnosed with compulsive shopping disorder.

BACKGROUND: The authors assessed clinical symptoms and self-reported shopping and spending behavior in people diagnosed with compulsive shopping (CS) at a 5-year follow-up interview. METHODS: All met the criteria of McElroy et al. for lifetime CS and had the disorder for >1year. Structured and semistructured instruments and self-report questionnaires were used to collect data. RESULTS: Of the original 26 subjects, 17 (65%) were interviewed and are the focus of this report. At follow-up, their ages ranged from 23 to 67years (mean=44years). Lifetime psychiatric comorbidity was common, but few had current psychiatric disorders at follow-up. Interest in shopping and spending decreased for eight (47%), stayed the same for five (29%), and increased for four (24%) subjects. Eleven subjects (65%) reported having attempted to quit their CS and three (18%) reported successfully doing so. Triggers for returning to CS included feelings of pressure/excitement/tension to shop; boredom; negative feelings such as sadness, depression, frustration, or anger; and the desire for positive feelings like happiness, power, or elation. Mean scores on the Compulsive Buying Scale (CBS) and the shopping version of the Yale-Brown Obsessive-Compulsive Scale showed overall improvement in CS symptoms (d=1.16 and d=-1.19, respectively); subjects were also less impulsive (d=-0.48). At baseline and follow-up, those with a lifetime mood disorder tended to have greater CS severity. CONCLUSIONS: While the subjects showed overall improvement, most had ongoing symptoms of CS. The implications of the findings are discussed.

Intergenerational Childhood Maltreatment in Persons with DSM-IV Pathological Gambling and Their First-Degree Relatives.

This study investigates the characteristics of individuals with DSM-IV pathological gambling (PG) who experienced childhood maltreatment and rates of maltreatment occurring in their first-degree relatives (FDRs). 94 subjects with DSM-IV PG, 91 controls, and 312 FDRs were assessed for childhood maltreatment as part of a family study of PG. Maltreatment was evaluated using the Revised Childhood Experiences Questionnaire. The Family Assessment Device was used to evaluate the functionality of the PG subject's (or control's) family of origin. Data were analyzed using logistic regression by the method of generalized estimating equations. Rates of maltreatment were significantly higher in subjects with PG than controls (61 vs. 25 %, P < 0.001). Subjects with PG who experienced maltreatment were more likely to be female, had more severe PG symptoms, had co-occurring mood and anxiety disorders, and reported greater early family life dysfunction than those with PG who did not experience maltreatment. Rates of maltreatment were higher in FDRs of PG subjects than controls (41 vs. 24 %, P = .002). Rates in FDRs of individuals with PG who experienced maltreatment themselves were still higher that in FDRs of those with PG who did not experience maltreatment (50 vs. 28 %, P = .009). The former were also more likely to have anxiety disorders, substance use disorders, and suicide attempts. The results suggest that childhood maltreatment in persons with PG is common and intergenerational. Rates of maltreatment in FDRs of PG subjects are high, particularly among those who experienced abuse. The implications of the findings are discussed.

Common variants on chromosome 6p22.1 are associated with schizophrenia.

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.