Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

OBJECTIVE: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

Mood stabilizers in the treatment of juvenile bipolar disorder. Advances and controversies.

Controlled studies of mood stabilizer (mono and combination) therapy are needed in children and adolescents to develop safe and effective treatment strategies for a disorder that now has a cohort and that carries a high human and economic cost. Through the use of a variety of diagnostic instruments and novel outcome measures, we may continue to refine DSM categories into more sensitive and specific diagnostic constructs. In addition, identification of neurobiologic and genetic markers for early-onset BPD, ADHD, CD, and IED could provide powerful tools in the process of breaking down phenotypes and establishing biologic predictors of targeted pharmacologic interventions in the face of new drug developments.

Nimodipine treatment of an adolescent with ultradian cycling bipolar affective illness.

This is a single case report of an open trial of nimodipine, a dihydropyridine-type calcium antagonist, in the treatment of a 13-year-old boy with refractory, ultradian rapid cycling, bipolar disorder type I. Prior clinical trials with calcium channel blockers in adults with ultrarapid cycling affective disorder supported an empirical trial of nimodipine for treatment of ultradian rapid cycling in this adolescent. Severity of mania and depression were rated before and after nimodipine therapy. A marked decrease in rapid, repeated, and significant mood changes was clinically observed and measured by standardized scales after 9 days of nimodipine 180 mg daily. No adverse effects were noticed. Remission persisted with continued treatment at 36-month follow-up. Medication response was partially attributed to adjunctive therapy with levothyroxine. Implications of treatment benefit are discussed in the context of novel pharmacotherapies for refractory bipolar disorder. These findings are preliminary and do not provide sufficient basis to recommend nimodipine as the treatment of choice in adolescents with ultradian cycling bipolar disorder, but suggest that controlled studies may be indicated.

Paroxetine treatment of aggression and self-injury in persons with mental retardation.

An open, prospective assessment of the treatment of severe aggression and self-injurious behavior (SIB) with paroxetine, a serotonin re-uptake inhibitor, in 15 institutionalized persons with mental retardation was undertaken. Frequency and severity of aggression and SIB were charted by trained staff members. Only aggression severity was reduced over the entire 4-month follow-up period. Within the limits of an open trial, this effect was significant at one month but did not remain significant subsequently. The apparent diminution of effectiveness after 4 weeks of treatment may suggest adaptive changes warranting further study.

Open trial lamotrigine in the treatment of self-injurious behavior in an adolescent with profound mental retardation.

This single case reports an open trial of lamotrigine in the treatment of self-injurious behavior (SIB) and epilepsy in an 18-year-old female diagnosed with generalized seizure disorder, stereotypic movement disorder, and compulsive SIB in the context of profound mental retardation. Animal models of SIB suggest that the glutamate neurotransmitter systems, involved in the generation of epileptic seizures, may also have a role in the pathophysiology of SIB. Data suggesting that lamotrigine may decrease glutamate release encouraged an empirical trial of lamotrigine for treatment of SIB. After 4 weeks of treatment of lamotrigine 200 mg daily, decreases in agitation and fearfulness were clinically observed, along with a 50% reduction in the frequency of SIB as measured by standardized scales. Good seizure control was maintained throughout the trial. No significant adverse effects were observed. Positive effects persisted at 1-year follow-up. Symptoms of stereotypic movement disorder appeared unchanged. Because these findings are preliminary, no clinical recommendations for the treatment of SIB with lamotrigine can be made until controlled studies have been completed.