Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.

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.

Compulsive shopping: A review and update.

The author comprehensively reviews compulsive shopping (CS), a disorder characterized by excessive shopping and/or spending that leads to subjective distress and impaired functioning. CS has been linked to substance use disorders, mood, and anxiety disorders, and to the obsessive-compulsive spectrum. More recently, CS has been considered a behavioral addiction. Most CS experts consider CS an independent disorder. CS has an estimated prevalence of 5% in the United States general population with an onset in the late teens/early 20s. Psychiatric comorbidity is common, including mood, anxiety, substance use, and personality disorders. Little is known about its neurobiology and genetics. There are no standard treatments, but cognitive-behavioral group therapy appears promising. Future research should focus on validating the disorder and developing effective treatments.

Factor structure of borderline personality disorder and response to Systems Training for Emotional Predictability and Problem Solving.

Differential response to the Systems Training for Emotional Predictability and Problem Solving (STEPPS) program was compared in subgroups identified through latent class analysis (LCA). STEPPS is an evidence-based group treatment program for patients with borderline personality disorder (BPD). A reanalysis of data was conducted using data from a 20-week randomized controlled trial and 1-year follow-up. Subjects (n = 164) with DSM-IV BPD were assessed for comorbid Axis I and II disorders and selected clinical variables. Severity was assessed using the Zanarini Rating Scale for BPD (ZAN-BPD) and the Borderline Evaluation of Severity Over Time (BEST). Three- and four-class models were identified with the four-class model having the better fit. The latter included a high severity (HS) class (26%), an affective instability/substance abuse (AISA) class (16%), an empty/dissociation/identity disturbance (EDID) class (27%), and a low severity (LS) class (30%). High impulsiveness predicted membership in the HS class. Improvement was determined using a linear mixed-effects model. Those most likely to benefit were those in the HS group characterized by high symptom severity, Axis I and II comorbidity, problem relationships, abandonment fears, and intense anger. This work should help further efforts to match patients with treatments based on sociodemographic, diagnostic, and other illness characteristics.

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.

Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

STEPPS for Borderline Personality Disorder: A Pragmatic Trial and Naturalistic Comparison With Noncompleters.

Systems Training for Emotional Predictability and Problem Solving (STEPPS) is a group psychotherapy approach that is effective for patients with borderline personality disorder (BPD) in a public health care setting. The sample in this study comprised 118 outpatients with BPD who were asked to participate in a Spanish-adapted version of STEPPS for 18 months, a psychotherapy program that could be added to their usual psychiatric intervention. They were divided into an experimental group who participated in STEPPS, and a control group, who received treatment as usual. Several variables were collected and the Borderline Evaluation of Severity Over Time (BEST) scale was administered at pretest, Months 3 and 6, posttest (Month 18), and 2-year follow-up (Month 42), after which a post hoc data analysis was carried out. The STEPPS program improved the as-usual treatment provided previously, and the results were cost-effective. A higher educational level and good patient collaboration predicted better outcome.

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.

Attitudes of Mental Health Staff Toward Patients With Borderline Personality Disorder: An Italian Cross-Sectional Multisite Study.

Negative attitudes toward borderline personality disorder (BPD) can present a barrier to those seeking care. We explored caring attitudes toward BPD among 860 mental health professionals, including psychiatrists, psychologists, social health educators, nurses, and social workers. The results showed that social workers and nurses scored significantly lower on caring attitudes than psychiatrists, social health educators, and psychologists. Our analysis showed that the more BPD patients treated in the past year, more years of experience in mental health, and having prior BPD training were positively associated with caring attitudes scores. For all professional subgroups, except for social health educators, the caring attitudes score is higher in those who have had prior BPD training, and for professionals with low and medium level of experience in mental health. This result shows that training on BPD should target less experienced clinicians and those professional groups who had less opportunity to receive such education.

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

OBJECTIVE: Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS: In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS: At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS: In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

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.

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.

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.