Stefanie A. Hlastala

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

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 >or=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.

Premorbid functioning in early-onset psychotic disorders.

OBJECTIVE To examine the premorbid characteristics of youths with early-onset psychotic disorders. METHOD Subjects with early-onset psychotic disorders received an extensive diagnostic evaluation upon entry into the study, including a historic review of premorbid functioning using the Premorbid Adjustment Scale. RESULTS Youths with schizophrenia (n = 27), bipolar disorder (n = 22), and psychosis not otherwise specified (NOS) (n = 20) were included. High rates of premorbid behavioral problems and academic difficulties were noted across all subjects. Youths with schizophrenia had higher rates of premorbid social withdrawal and global impairment. They also tended to have fewer friends. The psychosis NOS group had significantly higher rates of abuse histories and posttraumatic stress disorder. CONCLUSIONS Premorbid abnormalities are common features of early-onset psychotic disorders. The social withdrawal and peer problems specific to youths with schizophrenia likely represent early manifestations of negative symptoms. The abuse histories in the psychosis NOS group may explain the atypical nature of their reported psychotic symptoms, which in many cases are likely posttraumatic phenomena.

Double-Blind Maintenance Safety and Effectiveness Findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) Study.

OBJECTIVE To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. METHOD Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. RESULTS Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. CONCLUSIONS Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.

Adapting interpersonal and social rhythm therapy to the developmental needs of adolescents with bipolar disorder

Interpersonal and social rhythm therapy (IPSRT) is a manual-based adjunctive psychotherapy specific to the treatment of bipolar disorder. This paper reviews the theoretical rationale and empirical evidence for the efficacy of IPSRT in combination with pharmacotherapy for adults with bipolar I disorder. We then provide an overview of the developmental modifications being made to IPSRT to increase its relevance to adolescents with bipolar disorder.

The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation

BackgroundLithium is a benchmark treatment for bipolar illness in adults. However, there has been relatively little methodologically stringent research regarding the use of lithium in youth suffering from bipolarity.MethodsUnder the auspices of the Best Pharmaceuticals for Children Act (BPCA), a Written Request (WR) pertaining to the study of lithium in pediatric mania was issued by the United States Food and Drug Administration (FDA) to the National Institute of Child Health and Human Development (NICHD) in 2004. Accordingly, the NICHD issued a Request for Proposals (RFP) soliciting submissions to pursue this research. Subsequently, the NICHD awarded a contract to a group of investigators in order to conduct these studies.ResultsThe Collaborative Lithium Trials (CoLT) investigators, the BPCA-Coordinating Center, and the NICHD developed protocols to provide data that will: (1) establish evidence-based dosing strategies for lithium; (2) characterize the pharmacokinetics and biodisposition of lithium; (3) examine the acute efficacy of lithium in pediatric bipolarity; (4) investigate the long-term effectiveness of lithium treatment; and (5) characterize the short- and long-term safety of lithium. By undertaking two multi-phase trials rather than multiple single-phase studies (as was described in the WR), the feasibility of the research to be undertaken was enhanced while ensuring all the data outlined in the WR would be obtained. The first study consists of: (1) an 8-week open-label, randomized, escalating dose Pharmacokinetic Phase; (2) a 16-week Long-Term Effectiveness Phase; (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. The second study consists of: (1) an 8-week, double-blind, parallel-group, placebo-controlled Efficacy Phase; (2) an open-label Long-Term Effectiveness lasting either 16 or 24 weeks (depending upon blinded treatment assignment during the Efficacy Phase); (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. In December of 2006, enrollment into the first of these studies began across seven sites.ConclusionThese innovative studies will not only provide data to inform the labeling of lithium in children and adolescents with bipolar disorder, but will also enhance clinical decision-making regarding the use of lithium treatment in pediatric bipolar illness.Trial RegistrationNCT00442039

An evidence map of psychosocial interventions for the earliest stages of bipolar disorder

Depression, schizophrenia, and bipolar disorder are three of the four most burdensome problems in people aged under 25 years. In psychosis and depression, psychological interventions are effective, low-risk, and high-benefit approaches for patients at high risk of first-episode or early-onset disorders. We review the use of psychological interventions for early-stage bipolar disorder in patients aged 15-25 years. Because previous systematic reviews had struggled to identify information about this emerging sphere of research, we used evidence mapping to help us identify the extent, distribution, and methodological quality of evidence because the gold standard approaches were only slightly informative or appropriate. This strategy identified 29 studies in three target groups: ten studies in populations at high risk for bipolar disorder, five studies in patients with a first episode, and 14 studies in patients with early-onset bipolar disorder. Of the 20 completed studies, eight studies were randomised trials, but only two had sample sizes of more than 100 individuals. The main interventions used were family, cognitive behavioural, and interpersonal therapies. Only behavioural family therapies were tested across all of our three target groups. Although the available interventions were well adapted to the level of maturity and social environment of young people, few interventions target specific developmental psychological or physiological processes (eg, ruminative response style or delayed sleep phase), or offer detailed strategies for the management of substance use or physical health.

Interpersonal Psychotherapy for Adolescents With Mood and Behavior Dysregulation: Evidence-Based Case Study

ABSTRACT Interpersonal psychotherapy for depressed adolescents, an evidence-based psychotherapy, has been adapted for youth with chronic irritability and excessive reactivity (i.e., temper outbursts), to create Interpersonal Psychotherapy for Mood and Behavior Dysregulation (IPT-MBD). Youth with chronic irritability and excessive reactivity were originally conceptualized as severe mood dysregulation (SMD) and in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) as disruptive mood dysregulation disorder. Because outbursts are the most prominent symptom, behavioral management strategies are typically a common focus of treatment. These outbursts, along with other mood symptoms, result in significant impairment in multiple domains, with a particularly adverse impact on interpersonal functioning. For this reason improving relationships is an important target for treatment. We present an evidence-based case study of an adolescent who met research criteria for SMD and who received the IPT-MBD intervention as part of a research study. Monthly ratings assessing severity and improvement of SMD symptoms were conducted by an independent evaluator. This adolescent had an overall improvement in SMD symptoms, attended all scheduled therapy sessions, and parent and teen reported satisfaction with the treatment. We discuss factors that may influence the effectiveness of this treatment.