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.

Stimulant Diversion Risk Among College Students Treated for ADHD: Primary Care Provider Prevention Training.

OBJECTIVE: To address increasing rates of stimulant misuse in college students, this study developed an evidence-based, brief clinical practice intervention for primary care providers (PCPs) to reduce stimulant medication diversion among young adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: College students (N-114; 18-25 years; 68% attending universities; 24% attending community college) treated for ADHD with a stimulant and their PCPs across six practices participated in this initial, uncontrolled study of pre- to post-intervention change. An educational workshop providing strategies aimed at reducing stimulant diversion was developed and delivered to providers and staff across all practices (50% pediatric; 50% family medicine). Patients and providers completed baseline and post intervention surveys. RESULTS: Diversion was relatively infrequent, 16.7% at baseline and 14.9% post-intervention, respectively. Statistically significant decreases from baseline to post-intervention were found for three diversion risk factors: (1) number of times approached to divert, (2) intent to share, sell, or trade stimulants, and (3) disclosure of stimulant use. Providers and staff reported mostly high satisfaction with the training. CONCLUSIONS: This study provides initial evidence for a PCP-delivered intervention to reduce stimulant diversion. Research is needed on the efficacy of targeting college students directly, working with pharmacies and student health centers, and preventing misuse among teenagers.

Cannabis use and brain structural alterations in first episode schizophrenia--a region of interest, voxel based morphometric study.

Structural alterations of the brain in schizophrenia have been associated with genetic and environmental factors. Among the environmental factors, cannabis use has been associated with increased risk for patients with schizophrenia, but the effect of cannabis on their brain structure is unclear. We examined gray matter alterations in first episode schizophrenia patients (FES) with cannabis use (FES+C; n=15) compared to FES without cannabis use (FES-C; n=24) and 42 healthy controls who did not use cannabis. We conducted a voxel based morphometric analysis of a priori determined regions of interest consisting of the CB1 receptor rich brain regions. We observed a decrease in gray matter density in the right posterior cingulate cortex (PCC) in FES+C when compared with FES-C. The results suggest that cannabis use may be associated with altered brain structure, in particular regions rich in CB1 receptors. These findings need to be confirmed by larger, prospective studies.

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.

Comorbid symptomatology moderates response to risperidone, stimulant, and parent training in children with severe aggression, disruptive behavior disorder, and attention-deficit/hyperactivity disorder.

OBJECTIVE: In this study, we evaluated parent and child characteristics as predictors and moderators of response in the four-site Treatment of Severe Childhood Aggression (TOSCA) study. METHODS: A total of 168 children with severe aggression, disruptive behavior disorder, and attention-deficit/hyperactivity disorder (ADHD) were enrolled in a 9-week trial of basic treatment (n=84, stimulant+parent training+placebo) versus augmented treatment (n=84, stimulant+parent training+risperidone). In the initial report, augmented treatment surpassed basic treatment in reducing the primary outcome of disruptive behavior (D-Total) scores. In the current study, we evaluated parent (income, education, family functioning, employment) and child variables (intelligence quotient [IQ], aggression type, comorbid symptomatology) as predictors or moderators, using linear mixed models and the MacArthur guidelines. RESULTS: Higher scores on ADHD symptom severity and callous/unemotional traits predicted better outcome on D-Total regardless of treatment assignment. Two moderators of D-Total were found: Higher anger/irritability symptoms and lower mania scores were associated with faster response, although not better overall effect at endpoint, in the augmented but not the basic group. Several variables moderated response on secondary outcomes (ADHD severity and prosocial behavior), and were characterized by faster response, although not better outcome, in the augmented but not in the basic group. Maternal education moderated outcome on the measure of positive social behavior; children of mothers with less education benefited more from augmented treatment relative to basic than those with more education. CONCLUSION: Although these findings require validation, they tentatively suggest that augmented treatment works equally well across the entire sample. Nevertheless, certain child characteristics may be useful indicators for the speed of response to augmented treatment.

What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder?

OBJECTIVE: Although combination pharmacotherapy is common in child and adolescent psychiatry, there has been little research evaluating it. The value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression was tested. METHOD: One hundred sixty-eight children 6 to 12 years old (mean age 8.89 ± 2.01 years) with severe physical aggression were randomized to a 9-week trial of PT, stimulant (STIM), and placebo (Basic treatment; n = 84) or PT, STIM, and risperidone (Augmented treatment; n = 84). All had diagnoses of attention-deficit/hyperactivity disorder and oppositional-defiant disorder (n = 124) or conduct disorder (n = 44). Children received psychostimulant (usually Osmotic Release Oral System methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of week 3, placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (Disruptive-Total subscale was the primary outcome) and Antisocial Behavior Scale; blinded clinicians rated change on the Clinical Global Impressions scale. RESULTS: Compared with Basic treatment (PT + STIM [44.8 ± 14.6 mg/day] + placebo [1.88 mg/day ± 0.72]), Augmented treatment (PT + STIM [46.1 ± 16.8 mg/day] + risperidone [1.65 mg/day ± 0.75]) showed statistically significant improvement on the Nisonger Child Behavior Rating Form Disruptive-Total subscale (treatment-by-time interaction, p = .0016), the Nisonger Child Behavior Rating Form Social Competence subscale (p = .0049), and Antisocial Behavior Scale Reactive Aggression subscale (p = .01). Clinical Global Impressions scores were substantially improved for the 2 groups but did not discriminate between treatments (Clinical Global Impressions-Improvement score ≤2, 70% for Basic treatment versus 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented treatment; other adverse events differed modestly from Basic treatment; weight gain in the Augmented treatment group was minor. CONCLUSIONS: Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behaviors when added to PT and optimized stimulant treatment. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study), URL: http://clinicaltrials.gov, unique identifier: NCT00796302.

Risperidone added to parent training and stimulant medication: effects on attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and peer aggression.

OBJECTIVE: In this study, we aimed to expand on our prior research into the relative efficacy of combining parent training, stimulant medication, and placebo (Basic therapy) versus parent training, stimulant, and risperidone (Augmented therapy) by examining treatment effects for attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms and peer aggression, symptom-induced impairment, and informant discrepancy. METHOD: Children (6-12 years of age; N = 168) with severe physical aggression, ADHD, and co-occurring ODD/CD received an open trial of parent training and stimulant medication for 3 weeks. Participants failing to show optimal clinical response were randomly assigned to Basic or Augmented therapy for an additional 6 weeks. RESULTS: Compared with Basic therapy, children receiving Augmented therapy experienced greater reduction in parent-rated ODD severity (p = .002, Cohen's d = 0.27) and peer aggression (p = .02, Cohen's d = 0.32) but not ADHD or CD symptoms. Fewer children receiving Augmented (16%) than Basic (40%) therapy were rated by their parents as impaired by ODD symptoms at week 9/endpoint (p = .008). Teacher ratings indicated greater reduction in ADHD severity (p = .02, Cohen's d = 0.61) with Augmented therapy, but not for ODD or CD symptoms or peer aggression. Although both interventions were associated with marked symptom reduction, a relatively large percentage of children were rated as impaired for at least 1 targeted disorder at week 9/endpoint by parents (Basic 47%; Augmented 27%) and teachers (Basic 48%; Augmented 38%). CONCLUSION: Augmented therapy was superior to Basic therapy in reducing severity of ADHD and ODD symptoms, peer aggression, and symptom-induced impairment, but clinical improvement was generally context specific, and effect sizes ranged from small to moderate. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302.

Untreated illness duration correlates with gray matter loss in first-episode psychoses.

Frontolimbic neural circuit dysfunction has been thought to underlie schizophrenia. Prolonged duration of untreated illness (DUI) is associated with frontolimbic structural changes. We present data addressing this question in minimally treated first-episode patients with psychoses. To determine the relationship between DUI and gray matter changes in schizophrenia, we analyzed the structural magnetic resonance images of 82 minimally treated first-episode patients with psychotic disorder by using optimized voxel-based morphometry. DUI inversely correlated with gray matter in the left fusiform gyrus extending into the lingual gyrus, cerebellum, and the parahippocampal gyrus. The observed inverse relationship between DUI and temporal gray matter density is consistent with a progressive process during the early course of schizophrenia.

Do premorbid impairments predict emergent 'prodromal' symptoms in young relatives at risk for schizophrenia?

AIMS: Individuals at risk for developing schizophrenia (SZ) in the future frequently exhibit subtle behavioural and neurobiological abnormalities in their childhood. A better understanding of the role of these abnormalities in predicting later onset of 'prodromal' symptoms or psychosis may help in early identification of SZ. METHODS: In an ongoing prospective follow-up study of young genetically at-risk relatives of patients with SZ, we studied the prevalence of problems in premorbid social adjustment and childhood psychopathology and examined their relationship with the presence and progression of 'prodromal' symptoms of SZ. RESULTS: Growth curve analyses showed that 'prodromal' symptoms, as measured by the Scale of 'Prodromal' Symptoms, increased during follow-up. Premorbid maladjustment and childhood behavioural disturbances were cross-sectionally correlated broadly with 'prodromal' symptomatology scores. Longitudinal analyses revealed that behavioural disturbances, but not childhood maladjustment at baseline, significantly predicted increases in 'prodromal' symptomatology during the 2-year study period. CONCLUSION: Premorbid behavioural disturbance and maladjustment may predict the later emergence of 'prodromal' symptoms. 'Prodromal' symptoms in young at-risk relatives may define a subgroup worthy of follow-up into the age of risk for psychosis in order to cost-effectively characterize the predictors of psychotic symptoms and SZ.