A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay.

Executive functions (EF) are a complex set of neurodevelopmental, higher-ordered processes that are especially salient during adolescence. Disruptions to these processes are predictive of psychiatric problems in later adolescence and adulthood. The objectives of the current study were to characterize the latent structure of EF using bifactor analysis and to investigate the independent and interactive effects of genes and environments on EF during adolescence. Using a representative young adolescent sample, we tested the interaction of a polymorphism in the serotonin transporter gene (5-HTTLPR) and parental supervision for EF through hierarchical linear regression. To account for the possibility of a hierarchical factor structure for EF, a bifactor analysis was conducted on the eight subtests of the Delis-Kaplan Executive Functions System (D-KEFS). The bifactor analysis revealed the presence of a general EF construct and three EF subdomains (i.e., conceptual flexibility, inhibition, and fluency). A significant 5-HTTLPR by parental supervision interaction was found for conceptual flexibility, but not for general EF, fluency or inhibition. Specifically, youth with the L/L genotype had significantly lower conceptual flexibility scores compared to youth with S/S or S/L genotypes given low levels of parental supervision. Our findings indicate that adolescents with the L/L genotype were especially vulnerable to poor parental supervision on EF. This vulnerability may be amenable to preventive interventions.

Paradoxical Decrease in Striatal Activation on an fMRI Reward Task Following Treatment in Youth with Co-morbid Cannabis Dependence/Major Depression.

Reward behavior, including reward behavior involving drugs, has been shown to be mediated by the ventral striatum and related structures of the reward system. The aim of this study was to assess reward-related activity as shown by fMRI before and after treatment among youth with comorbid cannabis dependence and major depression. We hypothesized that the reward task (Delgado et al., 2003) would elicit activation in the reward system, and that the level of activation in response to reward would increase from the beginning to the end of the 12-week treatment study as levels of depressive symptoms and cannabis use decreased. Six subjects were recruited from a larger treatment study in which all received Cognitive Behavioral Therapy/Motivational Enhancement Therapy (CBT/MET), and also were randomized to receive either fluoxetine or placebo. Each of the six subjects completed an fMRI card- guessing/reward task both before and after the 12-week treatment study. As hypothesized, the expected activation was noted for the reward task in the insula, prefrontal, and striatal areas, both before and after treatment. However, the participants showed lower reward-related activation after treatment relative to pre-treatment, which is opposite of what would be expected in depressed subjects who did not demonstrate a comorbid substance use disorder. These paradoxical findings suggest that the expected increase in activity for reward associated with treatment for depression was overshadowed by a decrease in reward-related activation associated with treatment of pathological cannabis use in these comorbid youth. These findings emphasize the importance of comorbid disorders in fMRI studies.

Mirtazapine in Comorbid Major Depression and Alcohol Use Disorder: A Long-Term Follow-Up Study.

BACKGROUND/OBJECTIVE: To date, pharmacotherapy trials of depressed alcoholics (MDD/AUD) have focused on SSRI medications, with disappointing results, so effective treatments for that comorbid population are lacking. Mirtazapine is an FDA-approved medication for treating MDD with a unique pharmacological profile whose efficacy may exceed that of SSRIs. Results from our recent open label study suggest robust acute phase efficacy for mirtazapine for decreasing both the depression and the drinking of that population. However, to date, no studies have evaluated the longer-term efficacy of mirtazapine in that population. We now report findings from a first long-term (two-year) naturalistic follow-up evaluation involving subjects from the acute phase trial. We hypothesized that the improvements would persist at follow-up. METHODS: An eight-week open label study of mirtazapine and motivation therapy was conducted involving persons 18 to 55 years of age with DSM-IV diagnoses of comorbid MDD/AD. Two years after entry into the acute phase study, a long-term evaluation was conducted using the same instruments that had been used at baseline to assess whether the improvements seen during the acute phase trial had persisted. RESULTS: Ten of the twelve patients who entered the acute phase study participated in the follow-up study. The large magnitude improvements (p<.01) in depressive symptoms (BDI), drinking (TLFB), and sleep disturbance (HDRS) persisted at the follow-up evaluation. Two of the subjects demonstrated MDD on structured interview at follow-up, while all ten had demonstrated MDD at baseline. Six of the ten used antidepressants during the follow-up period. At baseline, three were employed, while at follow-up seven were employed. CONCLUSIONS: These findings suggest long-term efficacy for mirtazapine for decreasing the drinking and depression of depressed alcoholics. Double-blind, placebo-controlled studies are warranted to clarify the efficacy of mirtazapine in depressed alcoholics.

Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults.

OBJECTIVE: This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid major depression (MDD) and a cannabis use disorder (CUD) (cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid MDD/CUD. METHODS: We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. RESULTS: Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or cannabis-use related outcome variable over the 12-week study. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in number of DSM diagnostic criteria for a CUD. Large magnitude decreases in depressive symptoms were noted in both treatment groups, and end-of-study levels of depressive symptoms were low in both treatment groups. CONCLUSIONS: Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample of comorbid adolescents and young adults. The lack of a significant between-group difference in these symptoms may reflect limited medication efficacy, or may result from efficacy of the CBT/MET psychotherapy or from limited sample size.

Factor structure of the SOCRATES in a clinical sample of adolescents.

This study investigated the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES; W. R. Miller & J. S. Tonigan, 1996) in adolescents presenting for treatment of alcohol use disorder (AUD). The participants were 80 males and 43 females (mean age = 16.8 years) who presented for AUD treatment (95.1% outpatient, 4.9% inpatient). Participants completed assessments at baseline and 1 year and provided information on alcohol use and related variables monthly between these 2 assessments. Principal-components and confirmatory factor analyses of the baseline SOCRATES identified 2 factors, Taking Steps and Recognition, which showed good internal consistency and concurrent and predictive evidence of validity. The results were interpreted as supporting the use of the SOCRATES with clinical samples of adolescents.

Nonproblem drinking outcomes in adolescents treated for alcohol use disorders.

Change to nonproblem drinking was studied in 159 adolescents (70% male) presenting for alcohol use disorders (AUDs) treatment. A community sample (n = 148,47% male) also was assessed. Clinical participants had a current AUD at baseline; 1 year later, 17% remained abstinent, 60% had at least 1 AUD symptom (problem drinkers), and 23% were drinking but had no AUD symptoms (nonproblem drinkers). Drinking among the nonproblem drinkers decreased and was lower than in the problem drinkers. Nonproblem drinkers increased in psychosocial functioning and decreased in the number of illicit drugs used relative to problem drinkers and generally did not differ from the abstainers. The results suggest alternative views of treatment goals, relapse, and treatment outcome in adolescents.