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1.  The Gut Microbiome: A New Frontier in Autism Research 
Current psychiatry reports  2013;15(2):337.
The human gut harbors a complex community of microbes that profoundly influence many aspects of growth and development, including development of the nervous system. Advances in high-throughput DNA sequencing methods have led to rapidly expanding knowledge about this gut microbiome. Here, we review fundamental emerging data on the human gut microbiome, with a focus on potential interactions between the microbiome and autism spectrum disorders (ASD) and consider research on atypical patterns of feeding and nutrition in ASD and how they might interact with the microbiome. Finally we selectively survey results from studies in rodents on the impact of the microbiome on neurobehavioral development. The evidence reviewed here suggests that a deeper understanding of the gut microbiome could open up new avenues of research on ASD, including potential novel treatment strategies.
doi:10.1007/s11920-012-0337-0
PMCID: PMC3564498  PMID: 23307560
Gut microbiome; Nervous system; Behavior; Autism; Autism spectrum disorders; ASDs; Feeding; Nutrition; Dietary intake; Animal studies; Neurobehavioral development; Genetic disorders; Psychiatry
2.  Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations 
Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (p=0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (p=0.03). SNP rs174696 also showed nominal significance in additive models (p=0.02). We considered the 3 SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z=2.845; p=0.0044, global p=0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (p=0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (p=0.001 and p=0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine.
doi:10.1002/ajmg.b.31205
PMCID: PMC3864552  PMID: 21656904
COMT; cocaine-induced paranoia; family-based analysis; haplotype; SNP; positive selection
3.  Sex differences in cocaine-dependent individuals’ response to disulfiram treatment 
Addictive behaviors  2004;29(6):1123-1128.
The objective of this study is to evaluate differential response to disulfiram treatment of cocaine dependence by sex. Sex by treatment interactions from two pooled randomized clinical trials involving 191 cocaine-dependent subjects (36% female) were evaluated. Primary outcomes were days of abstinence and percentage of drug-free urine specimens. Significant sex by treatment interactions were found, where men treated with disulfiram had better outcomes than those who were not. Women had an intermediate outcome regardless of whether they received disulfiram. Sex differences in response to disulfiram treatment have important clinical and theoretical implications. Reasons for this apparent sex-based response are not clear, but possible mechanisms worthy of greater study include differences in alcohol use by sex as well as differences in dopamine-mediated responses to cocaine and disulfiram.
doi:10.1016/j.addbeh.2004.03.004
PMCID: PMC3680597  PMID: 15236812
4.  Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation 
Neuropsychopharmacology  2012;37(7):1683-1688.
Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22–0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted.
doi:10.1038/npp.2012.13
PMCID: PMC3358736  PMID: 22373943
nicotine; addiction; craving; pharmacogenetics; galanin receptor; behavioral science; neurogenetics; pharmacogenetics / pharmacogenomics; psychiatry & behavioral sciences; nicotine; addiction; craving; pharmacogenetics; galanin receptor 1
5.  DNA methylation in neonates born to women receiving psychiatric care 
Epigenetics  2012;7(4):409-414.
Prenatal exposure both to maternal psychiatric illness and psychiatric medication has been linked with adverse child outcomes that affect physiological, emotional and psychiatric development. Studies suggest that epigenetic mechanisms, such as DNA methylation, may facilitate these effects. In this report, we explore the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns in a prospectively-characterized clinical cohort of 201 dyads. Associations between the percent of umbilical cord blood DNA methylated at 27,578 CpG sites and maternal psychiatric diagnosis, symptoms and antidepressant use were evaluated by fitting a separate linear mixed effects model for each CpG site. There were no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. Exposure to an antidepressant medication was associated with differential methylation of CpG sites in TNFRSF21 and CHRNA2 (false discovery rate < 0.05), but the average difference in methylation for both CpG sites was less than 3% between each group. The results were not specific to type of antidepressant or duration of the exposure. This study suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation. Delineation of the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy.
doi:10.4161/epi.19551
PMCID: PMC3368823  PMID: 22419064
antidepressants; depressive symptoms; DNA Methylation; HumanMethylation27 BeadChip; Infinium; prenatal exposures
6.  Association of a Polymorphism in the Indoleamine-2,3-Dioxygenase Gene and Interferon-α-Induced Depression in Patients with Chronic Hepatitis C 
Molecular Psychiatry  2011;17(8):781-789.
Interferon (IFN)-α treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in IFN-α-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-α-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-α-induced depression were explored in 2 self-reported ethnic groups, Caucasians (n=800) and African Americans (n=232), participating in a clinical trial on the impact of three pegylated IFN-α treatment regimens on sustained viral response in patients with chronic hepatitis C. Prior to treatment, all subjects were free of psychotropic medications and had a score ≤20 on the Center for Epidemiologic Studies Depression Scale (CES-D), which was used to assess depressive symptom severity throughout the study. In Caucasians, a polymorphism (rs9657182) in the promoter region of the gene encoding indoleamine-2,3-dioxygenase (IDO1) was found to be associated with moderate or severe IFN-α-induced depressive symptoms (CES-D >20) at 12 weeks of IFN-α treatment (p=0.0012, p<0.05 corrected). Similar results were obtained for treatment weeks 24, 36 and 48. In subjects homozygous for the risk allele (CC, n=150), the odds ratio for developing moderate or severe depressive symptoms at treatment week 12 was 2.91 (CI: 1.48–5.73) compared to TT homozygotes (n=270). rs9657182 did not predict depression in African Americans, who exhibited a markedly lower frequency of the risk allele at this locus. The findings in Caucasians further support the notion that indoleamine-2,3-dioxygenase plays an important role in cytokine-induced behavioral changes.
doi:10.1038/mp.2011.67
PMCID: PMC3179823  PMID: 21691274
interferon-α; indoleamine-2; 3-dioxygenase; cytokines; depression; genes; single nucleotide polymorphism
7.  Catechol-O-Methyltransferase (COMT) Modulation of Cortisol Secretion in Psychiatrically At-risk and Healthy Adolescents 
Psychiatric genetics  2010;20(4):166-170.
Recent research implicates the COMT Val108/158Met polymorphism in stress-sensitivity, via modulation of hypothalamic-pituitary-adrenal (HPA) function. In healthy samples, Met-homozygosity has been associated with greater HPA activity (i.e., cortisol) and stress sensitivity, though findings are mixed among clinical samples. To date, there are no reports examining baseline or longitudinal changes in HPA activity as a function of COMT genotype in youth. This study examined the association of COMT with salivary cortisol across a one-year period in healthy and at-risk adolescents with DSM-IV-TR Axis II diagnoses. Results indicated higher cortisol levels for Met-homozygotes (compared to heterozygotes and Val homozygotes) at the one-year follow-up, and increased mean cortisol levels across a one-year period among Met-carriers, suggesting that COMT associates with differences in cortisol secretion during adolescence. Findings are discussed with respect to COMT genotype as a potential genetic indicator of psychiatric risk that modulates developmental changes in HPA activity.
doi:10.1097/YPG.0b013e32833a1ff3
PMCID: PMC3522124  PMID: 20421850
genetic; COMT; catechol-o-methyltransferase; psychosis; schizophrenia; stress; risk; cortisol; hypothalamic-pituitary-adrenal axis; HPA
8.  Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia 
Human genetics  2011;130(5):635-643.
Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.
doi:10.1007/s00439-011-0989-6
PMCID: PMC3193571  PMID: 21509519
9.  Predictors of neonatal hypothalamic–pituitary–adrenal axis activity at delivery 
Clinical endocrinology  2011;75(1):90-95.
Summary
Objective
Clinical and preclinical studies indicate that maternal stress during pregnancy may exert long-lasting adverse effects on offspring. This investigation sought to identify factors mediating the relationship between maternal and neonatal hypothalamic–pituitary–adrenal (HPA) axes in pregnant women with past or family psychiatric history.
Patients
Two hundred and five pairs of maternal and umbilical cord blood samples from a clinical population were collected at delivery.
Measurements
Maternal and neonatal HPA axis activity measures were plasma adrenocorticotrophic hormone (ACTH), total cortisol, free cortisol and cortisol-binding globulin concentrations. The effects of maternal race, age, body mass index, psychiatric diagnosis (DSM-IV), birth weight, delivery method and estimated gestational age (EGA) at delivery on both maternal and neonatal HPA axis measures were also examined. Incorporating these independent predictors as covariates where necessary, we evaluated whether neonatal HPA axis activity measures could be predicted by the same maternal measure using linear regression.
Results
Delivery method was associated with umbilical cord plasma ACTH and both total and free cord cortisol concentrations (T = 10·53–4·21; P < 0·0001–0·010). After accounting for method of delivery and EGA, we found that maternal plasma ACTH concentrations predicted 23·9% of the variance in foetal plasma ACTH concentrations (T = 6·76; P < 0·0001), and maternal free and total plasma cortisol concentrations predicted 39·8% and 32·3% of the variance in foetal plasma free and total cortisol concentrations (T = 5·37–6·90; P < 0·0001), respectively.
Conclusion
These data suggest that neonatal response is coupled with maternal HPA axis activity at delivery. Future investigations will scrutinize the potential long-term sequelae for the offspring.
doi:10.1111/j.1365-2265.2011.03998.x
PMCID: PMC3367094  PMID: 21521269
10.  Predictors of remission in depression to individual and combined treatments (PReDICT): study protocol for a randomized controlled trial 
Trials  2012;13:106.
Background
Limited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient’s treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition.
Methods/design
Treatment-naïve adults aged 18 to 65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: (1) cognitive behavior therapy (CBT, 16 sessions); (2) duloxetine (30–60 mg/d); or (3) escitalopram (10–20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin-releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occurs at an early time-point in treatment, and upon completion of 12-week treatment, when a second Dex/CRH test is also conducted. Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes.
Discussion
The PReDICT study’s evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness.
Trial registration
Clinicaltrials.gov Identifier: NCT00360399. Registered 02 AUG 2006. First patient randomized 09 FEB 2007.
doi:10.1186/1745-6215-13-106
PMCID: PMC3539869  PMID: 22776534
Antidepressive agents; Clinical research protocol; Cognitive behavior therapy; Depression; Genetic polymorphisms; HPA Axis; Inflammation; Magnetic resonance imaging; Personality disorders; Personalized medicine
11.  The Galanin Receptor 1 Gene Associates with Tobacco Craving in Smokers Seeking Cessation Treatment 
Neuropsychopharmacology  2011;36(7):1412-1420.
Craving for tobacco is a major challenge for people with nicotine dependence (ND) who try to quit smoking. Galanin (GAL) and its receptors (GALRs) can alter addiction-related behaviors and are therefore good candidates for modulators of behavioral parameters associated with smoking. We performed a genetic association study in 486 subjects (432 European American, EA) recruited for smoking cessation trials. Twenty-six candidate genes for ND-related phenotypes were selected based on the literature. Subjects were assessed using the Minnesota Withdrawal Scale (MWS), which included a specific item for craving, the Fagerström Scale of Nicotine Dependence (FTND), and other ND-related instruments. One single-nucleotide polymorphism (SNP) in GALR1, rs2717162, significantly associated with severity of craving in EA samples (p=6.48 × 10−6) and in the combined sample (p=9.23 × 10−6). Individuals with TT and TC genotypes had significantly higher craving scores than CC subjects. We also observed that SNPs in the CHRNA5 locus, rs16969968 and rs684513, which have been associated with ND-related phenotypes in previous studies, were nominally associated with FTND scores, although these results did not meet Bonferroni-adjusted criteria for experiment-wide significance. Our findings suggest that variation at GALR1 associates with differences in the severity of past craving for tobacco among smokers motivated to quit. Taken together with preclinical evidence, these results, if replicated, suggest that GAL and GALRs may be useful therapeutic targets for the pharmacological treatment of ND. Our results also confirm previously reported associations between variation at CHRNA5 and ND.
doi:10.1038/npp.2011.25
PMCID: PMC3096810  PMID: 21430647
craving; nicotine dependence; smoking; GALR1; Minnesota Withdrawal Scale; Fagerström Test for Nicotine Dependence; addiction & substance abuse; behavioral science; craving; GALR1; Minnesota Withdrawal Scale; neurogenetics; neurotransmitters; nicotine dependence; smoking
12.  Substance Use Disorders Assessed using the Kreek-McHugh-Schluger-Kellogg (KMSK) Scale in an Urban Low-Income and Predominantly African-American Sample of Primary Care Patients 
The Kreek–McHugh–Schluger–Kellogg (KMSK) scale was developed to quantify self-exposure to opiates, cocaine, alcohol, and tobacco. The original study was limited by a relatively small sample that was not representative of general clinical populations, and did not include marijuana exposure. For the current study, participants were recruited from primary-care outpatient clinics in an urban public hospital. The primary measure was the KMSK scale. The Structured Interview for Diagnosis for DSM-IV (SCID) was used as the “gold standard” for substance dependence diagnoses, and the results of KMSK assessments were evaluated using Receiver Operator Characteristic (ROC) analysis. The sample (N=439) was predominantly African-American (90.6%), with mean age (± SD) of 43.1±12.8 yrs. ROC analyses found that the optimal cutoff scores for alcohol dependence were the same as suggested previously (11), while they were lower for cocaine dependence (10 vs. 11) and opiate dependence (4 vs. 9). The analysis suggested a cutoff score for marijuana of 8. The KMSK performed well in the current study as a brief tool for evaluating dependence on alcohol, cocaine, marijuana and opiates in this nonpsychiatric clinic sample of predominantly poor urban African Americans.
doi:10.1111/j.1521-0391.2011.00121.x
PMCID: PMC3076102  PMID: 21477058
15.  Copy Number Variants: A New Molecular Frontier in Clinical Psychiatry 
Current psychiatry reports  2011;13(2):129-137.
Molecular genetic research, building on genetic epidemiology, has provided the field of psychiatry with a host of exciting advances. It is now clear beyond any reasonable doubt that genetic inheritance influences liability to develop almost every major psychiatric disorder. Rapid progress in identifying genes contributing to psychiatric liability, recently accelerated by the advent of approaches such as genome-wide association studies and chromosomal microarray analysis, raises a critical question for psychiatric practice and training: how will molecular genetics alter the practice of psychiatry for front-line clinicians? The premise of the present review is that our growing knowledge regarding the roles of copy number variants in behavioral disorders will soon require revision of standards of evaluation and care for psychiatric patients.
doi:10.1007/s11920-011-0183-5
PMCID: PMC3108149  PMID: 21253883
DNA copy number variants; Schizophrenia; Autism spectrum disorders; Segmental duplications
16.  Differential Immune System DNA Methylation and Cytokine Regulation in Post-Traumatic Stress Disorder 
American Journal of Medical Genetics  2011;156B(6):700-708.
DNA methylation may mediate persistent changes in gene function following chronic stress. To examine this hypothesis, we evaluated African American subjects matched by age and sex, and stratified into four groups by post-traumatic stress disorder (PTSD) diagnosis and history of child abuse. Total Life Stress (TLS) was also assessed in all subjects. We evaluated DNA extracted from peripheral blood using the HumanMethylation27 BeadChip and analyzed both global and site-specific methylation. Methylation levels were examined for association with PTSD, child abuse history, and TLS using a linear mixed model adjusted for age, sex, and chip effects. Global methylation was increased in subjects with PTSD. CpG sites in five genes (TPR, CLEC9A, APC5, ANXA2, and TLR8) were differentially methylated in subjects with PTSD. Additionally, a CpG site in NPFFR2 was associated with TLS after adjustment for multiple testing. Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and TLS. Together, these results suggest that psychosocial stress may alter global and gene-specific DNA methylation patterns potentially associated with peripheral immune dysregulation. Our results suggest the need for further research on the role of DNA methylation in stress-related illnesses.
doi:10.1002/ajmg.b.31212
PMCID: PMC3292872  PMID: 21714072
PTSD; epigenetic; total life stress; TPR; APC5; TLR8; NPFFR2
17.  Randomized, Double Blind, Placebo-Controlled Trial of Disulfiram for the Treatment of Cocaine Dependence in Methadone-Stabilized Patients1 
Drug and alcohol dependence  2010;113(2-3):184-191.
This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants.
Design
One hundred sixty-one cocaine-and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites.
Methods
Participants were stabilized on methadone during weeks 1–2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3–14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained.
Results
Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p<0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p=0.04).
Conclusions
Disulfiram may be contraindicated for cocaine dependence at doses less than 250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined.
doi:10.1016/j.drugalcdep.2010.07.022
PMCID: PMC3005977  PMID: 20828943
cocaine dependence; opioid dependence; disulfiram; clinical trial
18.  Genotype-controlled analysis of serum dopamine β-hydroxylase activity in civilian Post-traumatic Stress Disorder 
Background
Norepinephrine (NE) plays a central role in post-traumatic stress disorder (PTSD). Dopamine β-hydroxylase (DβH) converts dopamine (DA) to NE and its activity varies widely across individuals. Mustapic et al. (2007) reported a PTSD-associated deficit in serum DβH activity (sDβH) in a genotype-controlled analysis of combat veterans. We tested whether such a deficit would occur in a sample of civilians.
Methods
The severity of current adult PTSD symptoms and current DSM-IV diagnosis of PTSD were determined by the PTSD Symptom Scale (PSS). Adulthood trauma exposure was assessed using the Traumatic Experience Inventory (TEI). sDβH was assayed by HPLC with electrochemical detection and genotypes were determined using the Taqman® platform.
Results
Two hundred and twenty seven African American (AA) subjects were enrolled in this study, with a mean age (± SD) of 42.9 (±12.9) years. We found a strong association between rs1611115 genotype and sDβH (p<0.0001). After controlling for adulthood trauma exposure, there were no significant differences of sDβH between subjects who met a PTSD diagnosis and those who did not (p>0.05) in any genotype group. No significant correlations were found between sDβH and PTSD severity, but sDβH significantly associated with the status of comorbid depression based on the cutoff of HAMD (p=0.014) in subjects with PTSD.
Conclusions
We have replicated in this sample the prior finding that DBH rs1611115 genotype strongly associates with sDβH. No associations between sDβH and PTSD diagnosis or symptom severity in this civilian sample.
doi:10.1016/j.pnpbp.2010.07.002
PMCID: PMC2974949  PMID: 20621148
post-traumatic stress disorder; serum dopamine β-hydroxylase; genotype; depression; civilian trauma; association
19.  A serotonin transporter gene polymorphism predicts peripartum depressive symptoms in an at risk psychiatric cohort 
Journal of psychiatric research  2009;44(10):640-646.
Backgroud
Peripartum major depressive disorder (MDD) is a prevalent psychiatric disorder with potential detrimental consequences for both mother and child. Despite its enormous health care relevance, data regarding genetic predictors of peripartum depression are sparse. The aim of this study was to investigate associations of the serotonin-transporter linked polymorphic region (5-HTTLPR) genotype with peripartum MDD in an at-risk population.
Methods
274 women with a prior history of MDD were genotyped for 5-HTTLPR and serially evaluated in late pregnancy (gestational weeks 31-40), early postpartum (week 1-8) and late postpartum (week 9-24) for diagnosis of a current major depressive episode (MDE) and depressive symptom severity.
Results
5-HTTLPR S-allele carrier status predicted the occurrence of a MDE in the early postpartum period only (OR = 5.13, p = 0.017). This association persisted despite continued antidepressant treatment.
Conclusions
The 5-HTTLPR genotype may be a clinically relevant predictor of early postpartum depression in an at-risk population.
doi:10.1016/j.jpsychires.2009.12.001
PMCID: PMC2891911  PMID: 20045118
peripartum depression; pregnancy; serotonin transporter; 5-HTTLPR; polymorphism; at risk population
20.  Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms 
Background
Gene x environment (GxE) interactions mediating depressive symptoms have been separately identified in the stress-sensitive serotonergic (5-HTTLPR) and corticotropin-releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene x gene (GxG) interactions between CRHR1 and 5-HTTLPR polymorphisms.
Methods
We used an association study examining GxGxE interactions of CRHR1 and 5-HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology. The participant population (N=1392) was African-American, of low socioeconomic status (60% with <$1000/month family income), and with high rates of childhood and lifetime trauma. Depressive symptoms were measured with Beck Depression Inventory (BDI) and history of Major Depression by Structure Clinical Interview based on DSM-IV (SCID).
Results
We first replicated an interaction of child abuse and 5-HTTLPR on lifetime SCID diagnosis of major depression in a subsample (N= 236) of the study population – the largest African American 5-HTTLPR cohort reported to date. We then extended our previously reported interaction with both a CRHR1 SNP (rs110402) and TCA haplotype interacting with child abuse to predict current symptoms (N=1059; p = 0.0089). We found that the 5-HTTLPR S allele interacted with CRHR1 haplotypes and child abuse to predict current depressive symptoms (N = 856, p = 0.016).
Conclusions
These data suggest that GxE interactions predictive of depressive symptoms may be differentially sensitive to levels of childhood trauma, and the effects of child abuse are moderated by genetic variation at both the CRHR1 and 5-HTTLPR loci and by their GxG interaction.
doi:10.1002/ajmg.b.31052
PMCID: PMC2924813  PMID: 20029939
Child Abuse; Childhood Maltreatmet; Trauma; Depression; PTSD; Genetic; risk factor
21.  Sex Dependent Influence of a Functional Polymorphism in Steroid 5-α-Reductase Type 2 (SRD5A2) on Post-Traumatic Stress Symptoms 
A non-synonymous, single nucleotide polymorphism (SNP) in the gene coding for steroid 5-α-reductase type 2 (SRD5A2) is associated with reduced conversion of testosterone to dihydrotestosterone (DHT). Because SRD5A2 participates in the regulation of testosterone and cortisol metabolism, hormones shown to be dysregulated in patients with PTSD, we examined whether the V89L variant (rs523349) influences risk for post-traumatic stress disorder (PTSD). Study participants (N = 1,443) were traumatized African-American patients of low socioeconomic status with high rates of lifetime trauma exposure recruited from the primary care clinics of a large, urban hospital. PTSD symptoms were measured with the post-traumatic stress symptom scale (PSS). Subjects were genotyped for the V89L variant (rs523349) of SRD5A2. We initially found a significant sex-dependent effect of genotype in male but not female subjects on symptoms. Associations with PTSD symptoms were confirmed using a separate internal replication sample with identical methods of data analysis, followed by pooled analysis of the combined samples (N = 1,443, sex × genotype interaction P < 0.002; males: n = 536, P < 0.001). These data support the hypothesis that functional variation within SRD5A2 influences, in a sex-specific way, the severity of post-traumatic stress symptoms and risk for diagnosis of PTSD.
doi:10.1002/ajmg.b.32147
PMCID: PMC3770127  PMID: 23505265
trauma; African-American; genetic; testosterone; cortisol; male; civilian; human; PTSD
22.  Subtypes of Major Depression in Substance Dependence 
Addiction (Abingdon, England)  2009;104(10):1700-1709.
Aims
This study evaluated features that differentiate subtypes of major depressive episode (MDE) in the context of substance dependence (SD).
Design
Secondary data analysis using pooled data from family-based and case-control genetic studies of SD.
Setting
Community recruitment through academic medical centers.
Participants
1,929 unrelated subjects with alcohol and/or drug dependence.
Measurements
Demographics, diagnostic criteria for psychiatric and substance use disorders, and related clinical features were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We compared four groups: no lifetime MDE (no MDE), independent MDE only (I-MDE), substance-induced MDE only (SI-MDE), and both types of MDE.
Findings
Psychiatric measures were better predictors of MDE subtype than substance-related or sociodemographic ones. Subjects with both types of MDE reported more lifetime depressive symptoms and co-morbid anxiety disorders and were more likely to have attempted suicide than subjects with I-MDE or SI-MDE. Subjects with both types of MDE, like those with I-MDE, were also more likely than subjects with SI-MDE to be alcohol dependent only than either drug dependent only or both alcohol and drug dependent.
Conclusions
SD individuals with both types of MDE have greater psychiatric severity than those with I-MDE only or SI-MDE only. These and other features that distinguish among the MDE subtypes have important diagnostic and potential therapeutic implications.
doi:10.1111/j.1360-0443.2009.02672.x
PMCID: PMC2980795  PMID: 19681804
Major Depressive Episode; Substance Dependence; Mood Disorder
23.  Transient Cocaine-Associated Behavioral Symptoms Rated with a New Instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP) 
Chronic use of cocaine is associated with a variety of behavioral symptoms. The current report describes the assessment of cocaine-related behavioral symptoms (CRB) using the Scale for Assessment of Positive Symptoms of Cocaine-Induced Psychosis (SAPS-CIP). The CRB section, one of the three domains in the SAPS-CIP, consists of sub-domains, including Aggressive/Agitated Behavior, Repetitive/Stereotyped Behavior, Unusual Social or Sexual Behavior. Severity scores are assigned according to operational criteria, and range from 0 (not present) to 5 (severe). We interviewed 261 unrelated cocaine-abusing adults using the SAPS-CIP, and 243 of them met criteria for inclusion in the study. The proportion of subjects endorsing different classes of CRBs varied across categories, with 109 of 243 (44.9%) subjects reporting aggressive and agitated behaviors, 180 subjects (74.1%) repetitive/stereotyped behaviors, and 192 (79.0%) unusual social/sexual behaviors. A substantial minority of the subjects (10.3-25.1%) reported that they experienced marked-to-severe behavioral symptoms associated with cocaine use. The proportions of subjects endorsing CRB did not differ by ethnic/racial group or by sex. Correlations among the different domains of CRB were strong, but behaviors rated in the CRB section were less well correlated with psychotic symptoms, which were rated in the hallucination and delusion sections of the instrument. A variety of CRBs are common in cocaine-dependent subjects, and many of these are highly intercorrelated. CRBs also correlate with hallucinations and delusions induced by cocaine, but to a lesser degree. Our findings suggest that there may be some common vulnerability factors that contribute to both cocaine-induced psychosis and CRBs.
doi:10.3109/10550490903077937
PMCID: PMC2878659  PMID: 19874151
24.  Trauma Exposure and Stress-Related Disorders in Inner City Primary Care Patients 
General hospital psychiatry  2009;31(6):505-514.
Objective:
This study was undertaken to increase understanding of environmental risk factors for PTSD and MDD within an urban, impoverished, population.
Method:
This study examined the demographic characteristics, patterns of trauma exposure, prevalence of PTSD and MDD, and predictors of post-traumatic stress and depressive symptomatology using a verbally-presented survey and structured clinical interviews administered to low-income, primarily African-American (>93%), women and men seeking care in the primary care and obstetrics-gynecology clinics of an urban public hospital.
Results:
87.8% (N=1256) of the sample reported some form of significant trauma in their lifetime. Accidents were the most common form of trauma exposure followed by interpersonal violence and sexual assault. Childhood level of trauma and adult level of trauma separately, and in combination, predicted level of adult PTSD and depressive symptomatology. The lifetime prevalence of PTSD was 46.2% and the lifetime prevalence of MDD was 36.7%.
Conclusions:
These data document high levels of childhood and adult trauma exposure, principally interpersonal violence, in a large sample of an inner-city primary care population. Within this group of subjects, PTSD and depression are highly prevalent conditions.
doi:10.1016/j.genhosppsych.2009.05.003
PMCID: PMC2785858  PMID: 19892208
Post-traumatic Stress Disorder; Depression; African-American; Minority; Trauma; Child Abuse; Childhood Maltreatment; Psychiatry
25.  Association of Variants in MANEA With Cocaine-Related Behaviors 
Archives of general psychiatry  2009;66(3):267-274.
Context
Cocaine dependence (CD) and related behaviors are highly heritable, but no genetic association has been consistently demonstrated. A recent genome-wide study of drug dependence identified an association between cocaine-induced paranoia (CIP) and a single-nucleotide polymorphism (SNP) in the α-endomannosidase (MANEA) locus in a family-based sample of European Americans and African Americans.
Objective
To conduct a comprehensive genetic association study of the MANEA locus with CD and CIP.
Design
Genome-wide association study.
Setting
Four university hospitals.
Participants
A total of 3992 individuals from 2 family-based and 2 case-control samples.
Intervention
Participants were classified as having CD or CIP or as a control using the Semi-Structured Assessment for Drug Dependence and Alcoholism. They were genotyped for 11 SNPs spanning MANEA and its surrounding region.
Main Outcome Measure
Association of CD and CIP with individual SNPs and haplotypes.
Results
Cocaine-induced paranoia was associated with 6 SNPs in the European American families and 9 SNPs in the African American families. The strongest evidence in the total sample of families was observed in 3 markers located in the promoter and 3′ untranslated regions (P < .001). The association of MANEA SNPs with CD in both family samples was much weaker. In the African American case-control sample, multiple markers were significantly associated with CIP and CD; CIP and CD were also significantly associated with a 2-SNP haplotype in the European American case-control sample. The A allele of the 3′ untranslated region SNP rs9387522 was associated with increased risk of CIP in all 4 data sets.
Conclusions
Our findings suggest that CD and associated behaviors may involve biological pathways not typically thought to be associated with brain metabolism.
doi:10.1001/archgenpsychiatry.2008.538
PMCID: PMC2758158  PMID: 19255376

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