ABSTRACT
In a widely cited study, Mattay et al. reported that amphetamine (0.25 mg/kg oral, or 17 mg for a 68 kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5, 10, and 20 mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research.
Subject(s)
Catechol O-Methyltransferase/genetics , Central Nervous System Stimulants/pharmacology , Dextroamphetamine/pharmacology , Executive Function/drug effects , Genotype , Adult , Blood Pressure/drug effects , Case-Control Studies , Dextroamphetamine/administration & dosage , Female , Homozygote , Humans , Male , Mutation, MissenseABSTRACT
Sixty-five young adults with remitted major depressive disorder (MDD) were followed for 18 months. Recurrence of MDD was reported by 41.5% of the initial sample and 49.1% of those who completed the study (n = 53). Survival analyses were used to identify predictors of recurrence so that individuals at greatest risk could be targeted for intervention. Potential predictors included measures of comorbid psychopathology (Axis II pathology, and current and lifetime nonmood Axis I diagnoses), depression-specific clinical features (number of episodes, past treatment, and suicidality), and self-reported cognitive and interpersonal constructs (hope, dysfunctional attitudes, and interpersonal problems). Only personality pathology (specifically, the total dimensional and Cluster B dimensional scores on the International Personality Disorder Examination) significantly predicted hazard of recurrence.