Psychostimulant Treatment and the Developing Cortex in Attention Deficit Hyperactivity Disorder

Philip Shaw, M.D., Ph.D., Wendy S. Sharp, M.S.W., Meaghan Morrison, B.S., Kristen Eckstrand, B.S., Deanna K. Greenstein, Ph.D., Liv S. Clasen, Ph.D., Alan C. Evans, Ph.D., and Judith L. Rapoport, M.D.

Objective: While there has been considerable concern over possible adverse effects of psychostimulants on brain development, this issue has not been examined in a prospective study. The authors sought to determine prospectively whether psychostimulant treatment for attention deficit hyperactivity disorder (ADHD) was associated with differences in the development of the cerebral cortex during adolescence. Method: Change in cortical thickness was estimated from two neuroanatomic MRI scans in 43 youths with ADHD. The mean age at the first scan was 12.5 years, and at the second scan, 16.4 years. Nineteen patients not treated with psychostimulants between the scans were compared with an age-matched group of 24 patients who were treated with psychostimulants. Further comparison was made against a template derived from 620 scans of 294 typically developing youths without ADHD. Results: Adolescents taking psychostimulants differed from those not taking psychostimulants in the rate of change of the cortical thickness in the right motor strip, the left middle/inferior frontal gyrus, and the right parieto-occipital region. The group difference was due to more rapid cortical thinning in the group not taking psychostimulants (mean cortical thinning of 0.16 mm/year [SD=0.17], compared with 0.03 mm/year [SD=0.11] in the group taking psychostimulants). Comparison against the typically developing cohort without ADHD showed that cortical thinning in the group not taking psychostimulants was in excess of age-appropriate rates. The treatment groups did not differ in clinical outcome, however. Conclusions: These findings show no evidence that psychostimulants were associated with slowing of overall growth of the cortical mantle.

Double-Blind Comparison of First- and Second-Generation Antipsychotics in Early-Onset Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) Study

Linmarie Sikich, M.D., Jean A. Frazier, M.D., Jon McClellan, M.D., Robert L. Findling, M.D., Benedetto Vitiello, M.D., Louise Ritz, M.B.A., Denisse Ambler, M.D., Madeline Puglia, B.A., Ann E. Maloney, M.D., Emily Michael, B.A., Sandra De Jong, M.D., Karen Slifka, R.N., C.S., Nancy Noyes, C.P.N.P., C.S., Stefanie Hlastala, Ph.D., Leslie Pierson, M.P.H., Nora K. McNamara, M.D., Denise Delporto-Bedoya, M.A., Robert Anderson, B.S., Robert M. Hamer, Ph.D., and Jeffrey A. Lieberman, M.D.

Objective: Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. Method: This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5–20 mg/day), risperidone (0.5–6 mg/day), or molindone (10–140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and 20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. Results: In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. Conclusions: Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders

Adjunctive Psychotherapy for Bipolar Disorder: State of the Evidence

David J. Miklowitz, Ph.D.

Objective: Psychotherapy has long been recommended as adjunctive to pharmacotherapy for bipolar disorder, but it is unclear which interventions are effective for which patients, over what intervals, and for what domains of outcome. This article reviews randomized trials of adjunctive psychotherapy for bipolar disorder. Method: Eighteen trials of individual and group psychoeducation, systematic care, family therapy, interpersonal therapy, and cognitive-behavioral therapy are described. Relevant outcome variables include time to recovery, recurrence, duration of episodes, symptom severity, and psychosocial functioning. Results: The effects of the treatment modalities varied according to the clinical condition of patients at the time of random assignment and the polarity of symptoms at follow-up. Family therapy, interpersonal therapy, and systematic care appeared to be most effective in preventing recurrences when initiated after an acute episode, whereas cognitive-behavioral therapy and group psychoeducation appeared to be most effective when initiated during a period of recovery. Individual psychoeducational and systematic care programs were more effective for manic than depressive symptoms, whereas family therapy and cognitive-behavioral therapy were more effective for depressive than manic symptoms. Conclusions: Adjunctive psychotherapy enhances the symptomatic and functional outcomes of bipolar disorder over 2-year periods. The various modalities differ in content, structure, and associated mediating mechanisms. Treatments that emphasize medication adherence and early recognition of mood symptoms have stronger effects on mania, whereas treatments that emphasize cognitive and interpersonal coping strategies have stronger effects on depression. The placement of psychotherapy within chronic care algorithms and its role as a preventative agent in the early stages of the disorder deserve investigation.