James Poling

Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.

FKBP5 regulates the cortisol-binding affinity and nuclear translocation of the glucocorticoid receptor. Polymorphisms at the FKBP5 locus have been associated with increased recurrence risk of depressive episodes and rapid response to antidepressant treatment. A recent study showed that FKBP5 genotypes moderated the risk of post-traumatic stress disorder (PTSD) symptoms associated with childhood maltreatment. One thousand one hundred forty-three European Americans (EAs) and 1284 African Americans (AAs) recruited for studies of the genetics of substance dependence were also screened for lifetime PTSD. Four single-nucleotide polymorphisms (SNPs) in FKBP5, rs3800373, rs9296158, rs1360780, and rs9470080, were genotyped on the complete sample. Logistic regression analyses were performed to explore the interactive effect of FKBP5 polymorphisms and childhood adversity on the risk for PTSD. After correction for multiple testing, childhood adversity significantly increased the risk for PTSD. FKBP5 genotypes were not associated with the development of the disorder. In AAs, one of the SNPs, rs9470080, moderated the risk of PTSD that was associated with childhood abuse. Without childhood adverse experiences, participants with the TT genotype of this SNP had the lowest risk for PTSD, whereas they had the highest risk for PTSD after childhood adversity exposure. In addition, in EAs, alcohol dependence was observed to interact with childhood adverse experiences, and also FKBP5 polymorphisms, to increase the risk for PTSD. This study provides further evidence of a gene × environment effect of FKBP5 and childhood abuse on the risk for PTSD in AAs. Further study is required in other populations.

Personality, temperament, and character dimensions and the DSM-IV personality disorders in substance abusers.

The authors evaluated the relationship between P. T. Costa and R. R. McCraes (1992) NEO 5-factor model, C. R. Cloningers (1993) 7-factor Temperament and Character Inventory (TCI), and the American Psychiatric Associations (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed., personality disorders in 370 inpatient and outpatient alcohol, cocaine, and opiate abusers. NEO Neuroticism was associated with many disorders, and different patterns for Agreeableness, Conscientiousness, and Extraversion emerged for the different disorders. Several TCI scales were associated with different personality disorders, although not as strongly as the NEO dimensions. Results did not support most predictions made for the TCI. Normal personality dimensions contributed significantly to the prediction of personality disorder severity above and beyond substance abuse and depression symptoms.

Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone Maintained Patients: A Randomized Double-Blind Placebo-Controlled Efficacy Trial

CONTEXT Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy. OBJECTIVES To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence. DESIGN A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24. SETTING Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut. PARTICIPANTS One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%). INTERVENTION Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL. RESULTS The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 microg/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 microg/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths. CONCLUSIONS Attaining high (>or=43 microg/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Trial Registration clinicaltrials.gov Identifier: NCT00142857.

Vaccine Pharmacotherapy for the Treatment of Cocaine Dependence

BACKGROUND Cocaine abuse has no established pharmacotherapy, but active immunotherapy with a cocaine vaccine shows promise as a therapeutic intervention. METHODS An open label, fourteen week, dose-escalation study evaluated the safety, immunogenicity, and clinical efficacy of a novel human cocaine vaccine (TA-CD) in eighteen cocaine dependent subjects. Ten subjects (400 microg total dose group) received four-100 microg injections over the course of eight weeks. Subsequently, eight subjects (2000 microg total dose group) received five-400 microg vaccinations over twelve weeks. Intent to treat analysis of thrice weekly urine toxicologies and cocaine antibody titers were compared. RESULTS Sixteen of 18 subjects completed the study. There were no serious adverse reactions and the vaccine was well tolerated. The 2000 microg total dose group had a significantly higher mean antibody titer response (2000 units) as compared to the 400 microg total dose group (1000 units) (p = .05). The 2000 microg group was more likely to maintain cocaine free urines than those in the 400 microg group (Z = -3.12, p = .002). Despite relapse in both groups, most reported an attenuation of cocaines usual euphoric effects at the six month follow-up time points (63% in the 400 microg and 100% in the 2000 microg groups). CONCLUSIONS The conjugated cocaine vaccine was well tolerated and cocaine specific antibodies persisted at least six months. The likelihood of using cocaine decreased in subjects who received the more intense vaccination schedule.

Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders.

BACKGROUND Disulfiram and naltrexone are approved by the Food and Drug Administration (FDA) for the treatment of alcoholism, but these agents have not been rigorously evaluated in dually diagnosed individuals. METHOD Two-hundred and fifty-four patients with an Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at three Veterans Administration outpatient clinics. Randomization included assignment to one of four groups: 1) naltrexone alone; 2) placebo alone; 3) (open-label) disulfiram and (blinded) naltrexone; or 4) (open-label) disulfiram and (blinded) placebo. Medication compliance was evaluated using the Microelectric Events Monitoring System. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms, alcohol craving, g-GGT levels and adverse events. RESULTS There was a high rate of abstinence across groups. Subjects treated with an active medication had significantly more consecutive weeks of abstinence and less craving than those treated with placebo, but there were no significant group differences in other measures of alcohol consumption. There was no advantage of the combination of both medications. CONCLUSIONS These data suggest a modest advantage for the use of disulfiram and naltrexone for this group of dually diagnosed alcohol-dependent individuals but did not suggest an advantage in the combination.

PERSONALITY, SUBSTANCE OF CHOICE, AND POLYSUBSTANCE INVOLVEMENT AMONG SUBSTANCE DEPENDENT PATIENTS

The authors compared the association of several personality traits, drug of choice, and polysubstance involvement in 325 individuals (44% male) receiving treatment for substance dependence on heroin, cocaine, and/or alcohol. Measures included the Structured Clinical Interview for DSM-III-R, the MacAndrew Alcoholism Scale (MAC), the socialization scale of the California Psychological Inventory (CPI-Soc), the novelty seeking dimension of the Temperament and Character Inventory (TCI-NS), and the conscientiousness domain of the NEO Five-Factor Inventory (NEO-C). Analyses adjusted for demographic covariates, affective and antisocial personality disorder, and substance dependence severity. Although scant evidence supported the hypothesis that these personality traits were associated with substance choice, CPI-Soc and MAC were associated linearly with the extent of polysubstance involvement. Also, patients who were dependent on two or more substances displayed higher levels of TCI-NS, CPI-Soc, and MAC. Findings implicate an association between behavioral disinhibition and a continuum of addiction defined primarily in terms of polysubstance involvement.

The Effect of Cannabis Compared with Alcohol on Driving

The prevalence of both alcohol and cannabis use and the high morbidity associated with motor vehicle crashes has lead to a plethora of research on the link between the two. Drunk drivers are involved in 25% of motor vehicle fatalities, and many accidents involve drivers who test positive for cannabis. Cannabis and alcohol acutely impair several driving-related skills in a dose-related fashion, but the effects of cannabis vary more between individuals than they do with alcohol because of tolerance, differences in smoking technique, and different absorptions of Delta(9)-tetrahydrocannabinol (THC), the active ingredient in marijuana. Detrimental effects of cannabis use vary in a dose-related fashion, and are more pronounced with highly automatic driving functions than with more complex tasks that require conscious control, whereas alcohol produces an opposite pattern of impairment. Because of both this and an increased awareness that they are impaired, marijuana smokers tend to compensate effectively while driving by utilizing a variety of behavioral strategies. Combining marijuana with alcohol eliminates the ability to use such strategies effectively, however, and results in impairment even at doses which would be insignificant were they of either drug alone. Epidemiological studies have been inconclusive regarding whether cannabis use causes an increased risk of accidents; in contrast, unanimity exists that alcohol use increases crash risk. Furthermore, the risk from driving under the influence of both alcohol and cannabis is greater than the risk of driving under the influence of either alone. Future research should focus on resolving contradictions posed by previous studies, and patients who smoke cannabis should be counseled to wait several hours before driving, and avoid combining the two drugs.

Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia.

Risk for cocaine dependence (CD) is genetically influenced. We recruited a sample of small nuclear families (528 full and 155 half sibpairs) with at least one subject affected with CD. The sample was classified via Bayesian clustering as 45.5% European American (EA) and 54.5% African American (AA). Assessment, via the Semi‐Structured Assessment for Drug Dependence and Alcoholism, allowed for detailed evaluation of substance dependence‐related traits. To define subgroups with increased genetic homogeneity, consistent with our a priori analytic plan, we used cluster analytic methods to identify six cocaine‐related symptom clusters; membership was shown to be significantly heritable. We then completed a genomewide linkage scan (409 markers) for the CD diagnosis, cocaine‐induced paranoia (CIP; an outcome that occurs in some cocaine users) and the clusters (three of which contained >80% of the CD subjects). We observed a “suggestive” linkage signal on chromosome 10 for the trait of CD in the full sample; and two “suggestive” linkage signals at different locations on chromosome 3, in the EA part of the sample. We observed a genomewide‐significant lod score of 3.65 for the trait of CIP on chromosome 9, in the AA part of the sample only. Our strongest results were observed for the cluster membership traits, including a lod score of 4.66 for membership in the “Heavy Use, Cocaine Predominant” cluster on chromosome 12 (in EAs only) and a lod score of 3.35 for membership in the “Moderate Cocaine and Opioid Abuse” cluster on chromosome 18. These results provide a basis for the identification of specific genes contributing to risk for these traits.

Adverse childhood events as risk factors for substance dependence: Partial mediation by mood and anxiety disorders

AIMS Adverse childhood events (ACEs) are associated with negative health outcomes. We examined ACEs as risk factors for substance dependence (SD) and the mediating effects of mood and anxiety disorders on the relations between ACEs and SD risk. DESIGN We compared early life experiences in 2061 individuals with a lifetime diagnosis of alcohol, cocaine, or opioid dependence and 449 controls. MEASUREMENTS Diagnostic and ACE data were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. FINDINGS Childhood abuse or exposure to violent crime was positively related to the number of lifetime mood and anxiety disorders and to SD risk. Mood and anxiety disorders had their first onset a mean of nearly 3 years before the first SD diagnosis and partially mediated the effect of ACEs on SD risk. CONCLUSION ACEs appear to contribute additively to the risk of SD, with mood and anxiety disorders in the causal path for a portion of this risk. The identification and effective treatment of mood and anxiety disorders associated with ACEs could reduce the risk of developing SD.

Treatment Outcome Predictors for Cocaine Dependence

Over the past decade, a large number of potential medications have been examined in clinical trials for cocaine dependence. Unfortunately, no effective pharmacotherapies for cocaine dependence have been found to date. Although effective treatments for cocaine dependence are still being investigated, a few variables have been found to significantly predict cocaine treatment response. These variables include cocaine use variables, such as days of cocaine use in the month before treatment, baseline urine cocaine results, and cocaine withdrawal symptoms. Comorbid depression and alcohol use have also been shown to be risk factors for relapse. Among personality variables, impulsivity and similar personality traits may predict treatment response. Initial promising findings with genetic polymorphism, brain activation, and stress response have also been found and need to be replicated in future studies.