Novelty seeking mediates the effect of DRD3 variation on onset age of amphetamine dependence in Han Chinese population.

The dopamine receptor D3 (DRD3) gene, one of the candidate genes for amphetamine dependence (AD), is involved in the mesolimbic dopaminergic system, implicated as the underlying mechanism of addiction. Our case-control study aimed to investigate whether the DRD3 gene is associated with the susceptibility to AD and specific personality traits in AD patients. A total of 1060 unrelated Han Chinese subjects (559 AD patients and 501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. All patients met the DSM-IV-TR criteria for AD, and personality traits of 539 were assessed using a Tridimensional Personality Questionnaire. Furthermore, AD individuals were divided into four clinical subgroups based on gender and psychosis status, to reduce the clinical heterogeneity. We found that the ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total AD patients (p = 0.0003 after 10,000 permutations). Similar results were observed in the both male and non-psychosis subgroup but not in other subgroups. In addition, DRD3 rs9825563 may influence onset age of drug use, partially mediated by novelty seeking in the non-psychosis AD group. In conclusion, DRD3 is a potential genetic factor in the susceptibility to AD and is associated with onset age of drug use through interaction with novelty seeking in a specific patient group in the Han Chinese population.

PTSD risk associated with a functional DRD2 polymorphism in heroin-dependent cases and controls is limited to amphetamine-dependent individuals.

Posttraumatic stress disorder (PTSD), a pathologic response to severe stress, is a common co-morbid disorder in substance-dependent individuals. Evidence from twin studies suggests that PTSD is moderately heritable. Genetic association studies to date have reported a limited number of replicated findings. We conducted a candidate gene association study in trauma-exposed individuals within the Comorbidity and Trauma Study's sample (1343 heroin-dependent cases and 406 controls from economically disadvantaged neighborhoods). After data cleaning, the 1430 single nucleotide polymorphisms (SNPs) retained for analyses provided coverage of 72 candidate genes and included additional SNPs for which association was previously reported as well as 30 ancestry-informative markers. We found a functional DRD2 promoter polymorphism (rs12364283) to be most highly associated with PTSD liability [odds ratio (OR) 1.65 (1.27-2.15); P = 1.58 × 10(-4) ]; however, this association was not significant, with a stringent Bonferroni correction for multiple comparisons. The top hits include SNPs from other dopaminergic system genes: DRD2 DRD3, TH and DBH. Additional analyses revealed that the association involving rs12364283 is largely limited to amphetamine-dependent individuals. Substantial risk is observed in amphetamine-dependent individuals, with at least one copy of this SNP [OR 2.86 (1.92-4.27); P = 2.6 × 10(-7) ]. Further analyses do not support extensive mediation of PTSD risk via self-reported impulsivity (BIS total score). These findings suggest roles for impairment in inhibitory control in the pathophysiology of PTSD and raise questions about stimulant use in certain populations (e.g. those in combat).

A mechanistic overview of approaches for the treatment of psychostimulant dependence.

Psychostimulant use disorder is a major health issue around the world with enormous individual, family-related and societal consequences, yet there are no effective pharmacological treatments available. In this review, a target-based overview of pharmacological treatments toward psychostimulant addiction will be presented. We will go through therapeutic approaches targeting different aspects of psychostimulant addiction with focus on three major areas; 1) drugs targeting signalling, and metabolism of the dopamine system, 2) drugs targeting either AMPA receptors or metabotropic glutamate receptors of the glutamate system and 3) drugs targeting the severe side-effects of quitting long-term psychostimulant use. For each of these major modes of intervention, findings from pre-clinical studies in rodents to clinical trials in humans will be listed, and future perspectives of the different treatment strategies as well as their potential side-effects will be discussed. Pharmaceuticals modulating the dopamine system, such as antipsychotics, DAT-inhibitors, and disulfiram, have shown some promising results. Cognitive enhancers have been found to increase aspects of behavioural control, and drugs targeting the glutamate system such as modulators of metabotropic glutamate receptors and AMPA receptors have provided interesting changes in relapse behaviour. Furthermore, CRF-antagonists directed toward alleviating the symptoms of the withdrawal stage have been examined with interesting resulting changes in behaviour. There are promising results investigating therapeutics for psychostimulant addiction, but further preclinical work and additional human studies with a more stratified patient selection are needed to prove sufficient evidence of efficacy and tolerability.

Differential effect of the DRD3 genotype on inflammatory cytokine responses during abstinence in amphetamine-dependent women.

Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune-cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1ß) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down-regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1ß levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence.

Validation of the Substance Use Risk Profile Scale (SURPS) With Bulgarian Substance Dependent Individuals.

Background: The Substance Use Risk Profile Scale (SURPS) is a 23-item self-report questionnaire that assesses four well-validated personality risk factors for substance misuse (Impulsivity, Sensation Seeking, Anxiety Sensitivity, and Hopelessness). While the SURPS has been used extensively with adolescents at risk for substance dependence, its properties with adult substance-dependent populations have been understudied. Further, the validity of the Bulgarian version of the SURPS has not been evaluated. The aims of the present study were to examine the factor structure of the Bulgarian version of the SURPS, its psychometric properties, and its ability to distinguish individuals with substance dependence from healthy controls. Methods: Participants included 238 individuals ages 18 to 50 (45% female): 36 "pure" (i.e., mono-substance dependent) heroin users, 34 "pure" amphetamine users, 32 polysubstance users, 64 controls with no history of substance dependence, 43 unaffected siblings of heroin users, and 29 unaffected siblings of amphetamine users. We explored the factor structure of the Bulgarian version of the SURPS with confirmatory factor analyses, examined its reliability and validity, and tested for group differences between substance dependent and non-dependent groups. Results: Confirmatory factor analyses (CFA) replicated the original four-factor model of the SURPS. The four subscales of the SURPS demonstrated good internal consistency (Cronbach's alphas ranged from 0.71 to 0.85) and adequate concurrent validity. Significant group differences were found on the Impulsivity and Sensation Seeking subscales, with the three substance dependent groups scoring higher than controls. Conclusions: The SURPS is a valid instrument for measuring personality risk for substance use disorders in the Bulgarian population. The Bulgarian version of the SURPS demonstrates adequate to good reliability, concurrent validity, and predictive validity. Its ability to distinguish between groups with and without a history of substance dependence was specific to externalizing traits such as Impulsivity and Sensation Seeking, on which opiate, stimulant, and polysubstance dependent individuals scored higher than non-dependent controls.

Cue reactivity and opioid blockade in amphetamine dependence: A randomized, controlled fMRI study.

BACKGROUND: The opioid antagonist, naltrexone, has been shown to reduce the risk of relapse in amphetamine dependence, but the mechanisms behind this effect are not well understood. We aimed to investigate if naltrexone attenuates cue reactivity and craving in amphetamine dependence. METHODS: Forty men with severe, intravenous amphetamine dependence were randomized to one dose of naltrexone (50 mg) or placebo. In a BOLD fMRI cue reactivity paradigm, they were exposed to drug-related and neutral films and gave subjective ratings of craving after each film. Twenty-nine patients left data of sufficient quality to be included in the final analysis. RESULTS: The drug-related films elicited strong subjective craving and BOLD activations of the striatum, cingulate cortex, and occipito-temporal visual attention networks. Longer history of amphetamine use was associated with greater activations of the prefrontal cortex. Naltrexone as compared to placebo had no significant effects on brain activations or subjective ratings. CONCLUSION: Patients with severe stimulant use disorder exhibit strong neural cue reactivity, the patterns of which are modulated by duration of drug use. In this sample, we found no evidence for any effects of naltrexone on cue reactivity.

The dopamine transporter gene may not contribute to susceptibility and the specific personality traits of amphetamine dependence.

BACKGROUND: A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. METHODS: Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. RESULTS: A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. CONCLUSIONS: This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men.

Diagnostic Interview for Genetic Studies (DIGS): validity, inter-rater and test-retest reliability of the Thai version (Th-DIGS)

Objective: To study the diagnostic validity, inter-rater reliability, and test-retest reliability of the Th-DIGS. Methods: The DIGS was translated into Thai. The accuracy and understandability was assured by back translation, consensus review and a pilot interview. The studied subjects were recruited from three major referral mental health centers in central Thailand. We recruited a total of 170 subjects with clinical psychiatric diagnoses and 33 controls. The referral psychiatric diagnoses were schizophrenia (n=33), major depressive disorder (n=31), bipolar I disorder (n=32), alcohol dependence (n=39), amphetamine dependence (n=35). To study validity and inter-rater reliability, we interviewed the subjects with the Th-DIGS by a trained interviewer in the presence of a co-rater who simultaneously completed the Th-DIGS. Approximately four weeks later, we re-interviewed the subjects using the Th-DIGS by a third independent interviewer to study the test-retest reliability. We then calculated the diagnosis concurrent validity, inter-rater and test-retest reliability of the Th-DIGS. Results: The overall kappa of concurrent validity was 0.82 with 93.6% sensitivity and 95.0% specificity. The overall kappa coefficients of inter-rater reliability and the test-retest reliability were 0.89 and 0.78, respectively. The excellent validity and reliability are robust to most diagnoses. The concurrent validity of alcohol dependence and the test-retest reliability of controls, major depressive disorder and alcohol dependence were in fair-to-good range. Moreover, the Th-DIGS also reliably discriminated normal controls from subjects with psychiatric disorders. Conclusion: The Th-DIGS has been developed. The study in Thai subjects demonstrated a good-toexcellent validity, inter-rater and test-retest reliability. This indicates that the Th-DIGS is a highly valid and reliable instrument for use in psychiatric studies, and studies of a variety of psychiatric disorders including alcohol dependence and amphetamine dependence.

Diagnostic Interview for Genetic Studies (DIGS): validity, inter-rater and test-retest reliability of the Thai version (Th-DIGS)

Objective: To study the diagnostic validity, inter-rater reliability, and test-retest reliability of the Th-DIGS. Methods: The DIGS was translated into Thai. The accuracy and understandability was assured by back translation, consensus review and a pilot interview. The studied subjects were recruited from three major referral mental health centers in central Thailand. We recruited a total of 170 subjects with clinical psychiatric diagnoses and 33 controls. The referral psychiatric diagnoses were schizophrenia (n=33), major depressive disorder (n=31), bipolar I disorder (n=32), alcohol dependence (n=39), amphetamine dependence (n=35). To study validity and inter-rater reliability, we interviewed the subjects with the Th-DIGS by a trained interviewer in the presence of a co-rater who simultaneously completed the Th-DIGS. Approximately four weeks later, we re-interviewed the subjects using the Th-DIGS by a third independent interviewer to study the test-retest reliability. We then calculated the diagnosis concurrent validity, inter-rater and test-retest reliability of the Th-DIGS. Results: The overall kappa of concurrent validity was 0.82 with 93.6% sensitivity and 95.0% specificity. The overall kappa coefficients of inter-rater reliability and the test-retest reliability were 0.89 and 0.78, respectively. The excellent validity and reliability are robust to most diagnoses. The concurrent validity of alcohol dependence and the test-retest reliability of controls, major depressive disorder and alcohol dependence were in fair-to-good range. Moreover, the Th-DIGS also reliably discriminated normal controls from subjects with psychiatric disorders. Conclusion: The Th-DIGS has been developed. The study in Thai subjects demonstrated a good-toexcellent validity, inter-rater and test-retest reliability. This indicates that the Th-DIGS is a highly valid and reliable instrument for use in psychiatric studies, and studies of a variety of psychiatric disorders including alcohol dependence and amphetamine dependence.