Patterns of Substance Use During Cognitive Enhancement Therapy: An 18-Month Randomized Feasibility Study.

OBJECTIVE: Substance use problems are common among people with schizophrenia, as are significant cognitive impairments. Because of potential shared neurobiological pathways, it is possible that cognitive remediation interventions may be associated with improvements in both substance use and cognition. This study examined the impact of cognitive remediation on alcohol and cannabis use and the cognitive correlates of changes in substance use among outpatients with schizophrenia. METHODS: Individuals with schizophrenia who were receiving outpatient services at a psychiatric clinic and had moderate or higher addiction severity scores (N = 31) were randomized to 18 months of cognitive enhancement therapy (n = 22) or usual care (n = 9). Cognitive enhancement therapy is a cognitive remediation approach that integrates computer-based training in attention, memory, and problem solving with a group-based social cognition curriculum. Usual care was provided to all participants and consisted of routine psychiatric care. Primary outcomes included days of alcohol and cannabis use, assessed with the Timeline Followback method every six months and modeled using penalized quasi-likelihood growth curves. RESULTS: Participants were on average 38.23 (SD = 13.44) years of age, had been ill for 14.19 (SD = 11.28) years, and were mostly male (n = 22, 71%), and about half were Caucasian (n = 16, 52%). Temporal patterns of substance use days were highly variable and followed nonlinear trajectories. Intent-to-treat analyses indicated that, compared to patients only receiving usual care, those receiving cognitive enhancement therapy were significantly less likely to use alcohol (OR = .22; 95% CI: .05, .90; p = .036), but not cannabis (OR = 1.89; 95% CI: .02, 142.99; p = .774) over time, and they reduced their alcohol use at significantly accelerated rates (OR = 1.02; 95% CI: 1.01, 1.03; p = .003). Changes in cognition were variably associated with substance use outcomes, although improvements in visual learning and reasoning and problem solving were both consistently related to reduced alcohol and cannabis use. CONCLUSIONS: Cognitive remediation may be effective for improving some substance use problems in schizophrenia. Visual learning and problem-solving deficits may be particularly important targets of such interventions, given their association with reduced alcohol and cannabis use. This study is registered at clinicaltrials.gov under #NCT01292577.

Cognitive Enhancement Therapy Improves Frontolimbic Regulation of Emotion in Alcohol and/or Cannabis Misusing Schizophrenia: A Preliminary Study.

Individuals with schizophrenia who misuse substances are burdened with impairments in emotion regulation. Cognitive enhancement therapy (CET) may address these problems by enhancing prefrontal brain function. A small sample of outpatients with schizophrenia and alcohol and/or cannabis substance use problems participating in an 18-month randomized trial of CET (n = 10) or usual care (n = 4) completed posttreatment functional neuroimaging using an emotion regulation task. General linear models explored CET effects on brain activity in emotional neurocircuitry. Individuals treated with CET had significantly greater activation in broad regions of the prefrontal cortex, limbic, and striatal systems implicated in emotion regulation compared to usual care. Differential activation favoring CET in prefrontal regions and the insula mediated behavioral improvements in emotional processing. Our data lend preliminary support of CET effects on neuroplasticity in frontolimbic and striatal circuitries, which mediate emotion regulation in people with schizophrenia and comorbid substance misuse problems.

Cognitive Enhancement Therapy in substance misusing schizophrenia: results of an 18-month feasibility trial.

Substance use is a frequent problem in schizophrenia, and although many substance misusing patients with the disorder also experience considerable cognitive impairments, such individuals have been routinely excluded from clinical trials of cognitive remediation that could support their functional and addiction recoveries. This study conducted a small-scale feasibility trial of Cognitive Enhancement Therapy (CET) in substance misusing schizophrenia patients to assess the feasibility and efficacy of implementing comprehensive neurocognitive and social-cognitive remediation in this population. A total of 31 schizophrenia outpatients meeting addiction severity criteria for alcohol and/or cannabis use were randomized to 18months of CET or usual care. Feasibility findings indicated high degrees of satisfaction with CET, but also presented significant challenges in the recruitment and retention of substance misusing patients, with high levels of attrition (50%) over the study period, primarily due to positive symptom exacerbation. Intent-to-treat efficacy analyses showed large and significant improvements in neurocognition (d=.86), social cognition (d=1.13), and social adjustment (d=.92) favoring CET. Further, individuals treated with CET were more likely to reduce alcohol use (67% in CET vs. 25% in usual care) during treatment (p=.021). These results suggest that once engaged and stabilized, CET is a feasible and potentially effective treatment for cognitive impairments in patients with schizophrenia who misuse alcohol and/or cannabis. Substance misusing patients who are able to engage in treatment may be able to benefit from cognitive remediation, and the treatment of cognitive impairments may help improve substance use outcomes among this underserved population.

Serotonin Transporter Genotype Linked to Adolescent Substance Use Treatment Outcome through Externalizing Behavior.

Meta-analyses suggest that the serotonin transporter linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for alcohol dependence, particularly among individuals with early onset antisocial alcoholism. Youth in substance use treatment tend to show antisocial or externalizing behaviors, such as conduct problems, which predict worse treatment outcome. This study examined a pathway in which 5-HTTLPR genotype is associated with externalizing behavior, and the intermediate phenotype of externalizing behavior serves as a link between 5-HTTLPR genotype and substance use treatment outcome in youth. Adolescents (n = 142) who were recruited from addictions treatment were genotyped for 5-HTTLPR polymorphisms (S and LG carriers vs. LALA), assessed for externalizing and internalizing behaviors shortly after starting treatment, and followed over 6-months. 5-HTTLPR genotype was not associated with internalizing behaviors, and was not directly associated with 6-month substance use outcomes. However, 5-HTTLPR genotype was associated with externalizing behaviors (S and LG > LALA), and externalizing behaviors predicted alcohol and marijuana problem severity at 6-month follow-up. Results indicated an indirect (p < 0.05) and non-specific (i.e., both alcohol and marijuana severity) effect of 5-HTTLPR genotype on youth substance use treatment outcomes, with externalizing behaviors as an important linking factor. Adolescents in substance use treatment with low expressing (S and LG) 5-HTTLPR alleles and externalizing behavior might benefit from intervention that addresses serotonergic functioning, externalizing behaviors, and substance use to improve outcomes.

Assessing TLI as a Predictor of Treatment Seeking for SUD among Youth Transitioning to Young Adulthood.

BACKGROUND: To date, few studies have been conducted evaluating predictors of treatment seeking for substance use disorders as persons make the transition from preadolescence (a period of very low substance use) to young adulthood (a period of peak substance use). The few studies of this area which have been conducted to date have generally been limited by their use of a cross-sectional rather than a longitudinal study design. We have conducted a longitudinal etiology study (CEDAR) to assess whether an index of behavioral undercontrol called the Transmissible Liability Index (TLI) measured during preadolescence serves as a predictor of the development of substance use disorders (SUD) and of treatment utilization during young adulthood. Our recent work has focuses on subjects with cannabis use disorders (CUD), since CUD are the most common SUD. In recent analyses, we found that TLI serves as a predictor of the development of cannabis use disorder (CUD) among young adults (Kirisci et al., 2009). OBJECTIVE: In the current study, we hypothesized that TLI as assessed during preadolescence would predict treatment seeking a decade later when the subjects were young adults. METHOD: The 375 participants in this study were initially recruited when they were 10-12 years of age. TLI status was determined at baseline, and subsequent assessments were conducted at 12-14, 16, 19, and 22 years of age. Variables examined included TLI as well as demographic variables. Path analyses were conducted. RESULTS: Of the 375 subjects recruited at age 10-12, 92 subjects (24.5%) were diagnosed with a CUD by the age of 22. TLI as assessed during pre-adolescence (at age 10 to 12) was found to be associated with substance-related treatment during young adulthood (age 19 and at age 22). CONCLUSIONS: These findings confirmed our hypothesis that TLI assessed during preadolescent years serves as a predictor of treatment at age 19 and at age 22.

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.

TREATMENT TRIAL AND LONG-TERM FOLLOW-UP EVALUATION AMONG COMORBID YOUTH WITH MAJOR DEPRESSION AND A CANNABIS USE DISORDER.

OBJECTIVE: This study compared the acute phase (12-week) and the long-term (1 year) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of youth with comorbid major depressive disorder (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy in the acute phase trial and at the 1-year follow-up evaluation. Data is also provided regarding the prevalence of risky sexual behaviors in our study sample. METHODS: We recently completed the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. A total of 70 persons participated in the acute phase trial, and 68 of those persons (97%) also participated in the 1-year follow-up evaluation. Results of the acute phase study have already been presented (Cornelius, Bukstein, et al., 2010), but the results of the 1 year follow-up assessment have not been published previously. 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. The 1-year follow-up evaluation was conducted to assess whether the clinical improvements noted during the acute phase trial persisted long term. RESULTS: During the acute phase trial, subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in cannabis-related symptoms. However, no significant difference was noted between the floxetine group and the placebo group on any treatment outcome variable during the acute phase trial. End of study levels of depressive symptoms were low in both the fluoxetine group and the placebo group. Most of the clinical improvements in depressive symptoms and for cannabis-related symptoms persisted at the 1-year follow-up evaluation. CONCLUSIONS: Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample during the acute phase study or at the 1-year follow-up assessment. The lack of a significant treatment effect for fluoxetine may at least in part reflect efficacy of the CBT/MET psychotherapy. A persistence of the efficacy of the acute phase treatment was noted at the 1-year follow-up evaluation, suggesting long-term effectiveness for the CBT/MET psychotherapy.

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.

Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence.

Recently, reports have suggested that cannabis withdrawal occurs commonly in adults with cannabis dependence, though it is unclear whether this extends to those with comorbid depression or to comorbid adolescents. We hypothesized that cannabis withdrawal would be common among our sample of comorbid adolescents and young adults, and that the presence of cannabis withdrawal symptoms would be associated with a self-reported past history of rapid reinstatement of cannabis dependence symptoms (rapid relapse). The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in our sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal symptoms (in the N=170 sample) were reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggest that cannabis withdrawal should be included as a diagnosis in the upcoming DSM-V, and should be listed in the upcoming criteria list for the DSM-V diagnostic category of cannabis dependence.

Divalproex utility in bipolar disorder with co-occurring cocaine dependence: a pilot study.

OBJECTIVE: The aim of this open-label pilot study was to evaluate the utility of divalproex in decreasing cocaine use and stabilizing mood symptoms among patients with bipolar disorder with comorbid cocaine dependence. METHOD: Fifteen patients enrolled in the study and seven met final inclusion criteria of DSM-IV/SCID diagnoses of bipolar I disorder and comorbid cocaine dependence with active cocaine use. Patients were started on open-label divalproex. After stabilization on divalproex sodium, weekly assessments were undertaken for 8weeks. Subjects also attended dual recovery counseling. RESULTS: The results revealed significant improvement on % cocaine abstinent days, dollars spent on cocaine, ASI's drug use severity index, % alcohol abstinent days, drinks per drinking day, marijuana use and cigarettes smoking. They also had significant improvement on manic, depressive, and sleep symptoms and on functioning. There were no reported adverse events or increases in liver function tests. CONCLUSION: The results of this open-label study point to the potential utility of divalproex in patients with bipolar disorder and primary cocaine dependence. Double-blind, placebo-controlled studies to fully evaluate the efficacy of divalproex in this high risk clinical population are warranted.

Acute phase and five-year follow-up study of fluoxetine in adolescents with major depression and a comorbid substance use disorder: a review.

This paper reviews the results of an acute phase trial and a five-year follow-up study of fluoxetine in adolescents with major depression and a substance use disorder (SUD). This study included a 12-week open label acute phase study of 13 comorbid adolescents, followed by comprehensive assessments conducted 1, 3, and 5 years after entry into an acute phase fluoxetine trial. The results of the acute phase study and of the 1, 3, and 5-year follow-up assessments have already been published in four papers. The current paper was designed to cover the results of the study across the entire 5-year time spectrum of the study, and to summarize the clinical results across that entire time period. The data from this pilot study suggest that the long-term (5-year) clinical course for the Alcohol Dependence, Cannabis Dependence, and academic functioning of comorbid adolescents following acute phase treatment with SSRIs is generally good. However, the long-term clinical course for the Major Depression of that comorbid adolescent population is surprisingly poor.

Patient characteristics and treatment implications of marijuana abuse among bipolar alcoholics: results from a double blind, placebo-controlled study.

OBJECTIVE: Marijuana abuse, primarily a disorder of adolescents and young adults, is highly prevalent among patients with severely ill psychiatric population, especially those with bipolar disorder. Additional marijuana abuse may impact on the clinical presentation of bipolar illness and may potentially act as mediator of treatment response in this population. However, the characterization of bipolar disorder patients with additional marijuana abuse and the impact of such abuse on treatment outcome has been rarely examined. The aim of this study was to characterize bipolar alcoholic patients with comorbid marijuana abuse and test the impact of marijuana abuse on alcohol and mood outcome of patients with bipolar disorder and comorbid alcohol dependence. METHOD: We conducted secondary analyses of a randomized, double blind, placebo-controlled trial testing valproate in 52 bipolar alcoholics. Subjects had a comprehensive assessment at baseline using structured diagnostic assessments, and they were then assessed every 2 weeks for 24 weeks. RESULTS: Twenty-five subjects (48%) reported marijuana abuse. Those with co-occurring marijuana abuse were younger, had fewer years of education, and had significantly higher number of additional psychiatric comorbidity. They also had more severe alcohol and other drug use and were significantly more likely to present in the manic phase. The mixed model indicated that the placebo-treated marijuana abuse group had the worst alcohol use outcome. CONCLUSIONS: Marijuana abuse among patients with bipolar disorder and alcohol dependence is associated with higher degree of severity of alcohol and other drugs of abuse and may negatively impact on alcohol treatment outcome.

Rapid relapse generally follows treatment for substance use disorders among adolescents.

This prospective study involved 59 adolescents with drug and alcohol disorders who had just completed outpatient treatment. They participated in a comprehensive baseline assessment, and then participated in monthly telephone assessments of substance use and reasons for use. Despite their recent treatment, two-thirds (66%) of the participants in this study had relapsed to drug use within 6 months. The median time to drug relapse was only 54 days (+/-14 days), or slightly less than 2 months. The three most commonly given reasons for relapse were social pressure, withdrawal, and negative affect. These findings provide a first confirmation of the results of S.A. Brown [Recovery patterns in adolescent substance abuse. (1993). In J. S. Baer, G. A. Marlatt, & R. J. McMahon (Eds.), Addictive behaviors across the life span (pp. 160-183). London: SAGE.] in showing that most adolescents relapse quickly following treatment for substance use disorders.