Richard P. Malone

Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review

OBJECTIVES To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents. METHOD and searches (1990-present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking. RESULTS Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, beta-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric populations. Atypical antipsychotics are generally associated with fewer extrapyramidal symptoms than are typical antipsychotics. CONCLUSIONS Psychosocial interventions and atypical antipsychotics are promising treatments for aggression in youth. Double-blind studies should examine the safety and efficacy of atypical antipsychotics compared to each other and to medications from other classes, the efficacy of specific medications for different subtypes of aggression, combining various psychotropic medications, optimal dosages, and long-term safety.

Neuroleptic-Related Dyskinesias in Autistic Children: A Prospective, Longitudinal Study

OBJECTIVE To report results from a long-term prospective study of safety of haloperidol treatment and prevalence of haloperidol-related dyskinesias. METHOD Subjects were children with autism requiring pharmacotherapy for target symptoms. After baseline assessments, children received haloperidol treatment; responders requiring further treatment were considered for enrollment into the present study. Six-month haloperidol treatment periods were followed by a 4-week placebo period. The procedure was repeated if further haloperidol treatment was required. At specified times children were evaluated by using multiple instruments. RESULTS Between 1979 and 1994, 118 children aged 2.3 to 8.2 years participated in the study. The mean dose of haloperidol was 1.75 mg/day. Mainly withdrawal dyskinesias (WD) developed in 40 (33.9%) children; 20 had more than one dyskinetic episode. A subgroup that remained significantly longer in the study and had a significantly higher cumulative dose of haloperidol evidenced a significantly higher incidence of WD. Occurrence rates of tardive dyskinesia (TD) and multiple episodes of TD/WD were higher among girls. CONCLUSION Female gender and pre- and perinatal complications may be involved in susceptibility to dyskinesias; greater cumulative haloperidol dose and/or longer exposure to haloperidol may increase the risk.

Olanzapine versus haloperidol in children with autistic disorder : An open pilot study

OBJECTIVES Conventional neuroleptics ameliorate symptoms in children with autistic disorder; however, they are known to cause dyskinesias. Atypical neuroleptics, including olanzapine, may have less risk for dyskinesia, but their efficacy in autistic disorder is not established. This study was designed to investigate the safety and effectiveness of open-label olanzapine as a treatment for children with autistic disorder by using haloperidol as a standard comparator treatment. METHOD In a parallel groups design, 12 children with DSM-IV autistic disorder (mean age 7.8+/-2.1 years) were randomized to 6 weeks of open treatment with olanzapine or haloperidol. Mean final dosages were 7.9+/-2.5 mg/day for olanzapine and 1.4+/-0.7 mg/day for haloperidol. Outcome measures included the Clinical Global Impressions (CGI) and the Childrens Psychiatric Rating Scale (CPRS). RESULTS Both groups had symptom reduction. Five of six in the olanzapine group and three of six in the haloperidol group were rated as responders according to the CGI Improvement item. Subjects showed improvement on the CPRS Autism Factor (F1,9 = 24.4, p = .0008). Side effects included drowsiness and weight gain. CONCLUSIONS The findings suggest that olanzapine is a promising treatment for children with autistic disorder. Further placebo-controlled and long-term studies of olanzapine in autistic disorder are required.

Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness.

OBJECTIVE Atypical neuroleptics, including risperidone, are used to treat children with autism, despite limited efficacy and safety data. Many clinicians believe that risperidone will not induce dyskinesias in children. The authors investigated open risperidone treatment in children with autism and included findings on dyskinesias. METHOD The sample included 22 outpatients (mean age = 7.1 years) diagnosed with autism (DSM-IV). Treatment consisted of a 1-month short-term phase followed by a 6-month long-term phase. At the end of the long-term phase, drug was discontinued, and the need for further drug treatment and the occurrence of withdrawal dyskinesias were assessed. Measures included the Clinical Global Impressions (CGI), Childrens Psychiatric Rating Scale (CPRS), and the Abnormal Involuntary Movement Scale. RESULTS The mean risperidone dosage was 1.2 mg/day. Overall, the children had significant clinical improvement as assessed by the CPRS and CGI. Untoward effects included sedation, increased appetite, and weight gain. Two of 13 (15.4%) children treated long-term developed mild, reversible withdrawal dyskinesias when risperidone was discontinued. No child developed dyskinesias on risperidone. CONCLUSIONS Risperidone shows promise as a treatment in autism. However, withdrawal dyskinesias were noted. Further assessment of the risk of risperidone-related dyskinesias is indicated.

Ziprasidone in Adolescents with Autism: An Open-Label Pilot Study

INTRODUCTION The antipsychotic drugs are the best-studied agents shown to reduce symptoms in autism, including hyperactivity, aggression, self-abusive behavior, temper tantrums, lability, irritability, social withdrawal, and stereotypical behaviors. However, significant weight gain has been associated with use of many atypical agents. Ziprasidone has been weight neutral in adult populations, but data from adolescents and patients with autism are sparse. However, ziprasidone administration has been associated with increases in the QTc. The purpose of this study was to collect pilot data on the efficacy and safety of ziprasidone in adolescents with autism, focusing on safety issues of weight gain and QTc. METHODS Twelve adolescents with autism (mean age 14.5 +/- 1.8 years) were treated in a 6-week open pilot study. Ziprasidone dosage ranged from 20 to 160 mg/day (mean, 98.3 +/- 40.4 mg/day). The primary efficacy measure was the Clinical Global Impressions-Improvement item (CGI-I); other efficacy measures included the Aberrant Behavior Checklist and the Childrens Psychiatric Rating Scale. RESULTS Based on the CGI-I, 9 of 12 (75%) patients were treatment responders. Ziprasidone was weight neutral, and the QTc increased by a mean of 14.7 msec. Two subjects had acute dystonic reactions. Cholesterol decreased and prolactin remained the same. CONCLUSIONS Ziprasidone shows promise as a treatment for adolescents with autism. More definitive trials are needed.

Pharmacokinetics of lithium carbonate in children

The pharmacokinetics in both serum and saliva of a single oral dose of lithium carbonate 300 mg was investigated in nine children aged 9 to 12 years. The serum and saliva concentration-time curves were parallel and biexponential, with a fast distribution phase after the peak at the second hour and a slow elimination phase starting from the 12th hour. The fast phase half-life was 6.0 +/- 1.8 hour in the serum, and 5.8 +/- 1.9 hour in the saliva. The slow phase half-life was 17.9 +/- 7.4 hour in the serum and 15.6 +/- 8.2 hour in the saliva. Lithium was 2.84 +/- 0.86 times higher in the saliva than in the serum, with a saliva/serum r coefficient of correlation of 0.93. A relatively large error was found in predicting serum levels from saliva. There were significant intersubject differences in the saliva/serum ratio, which point to the need for individual ratios in clinical use. On the whole, the pharmacokinetics of lithium in children had the same features as in adults, with a trend toward a shorter elimination half-life and higher total clearance.

Nonpharmacological Response in Hospitalized Children With Conduct Disorder

OBJECTIVE There is a paucity of research regarding the effects of hospitalization and/or the response to placebo in children with conduct disorder who are hospitalized for chronic and severe aggression. However, many children with this problem are hospitalized and immediately begin pharmacotherapy. In this report, the effects of hospitalization and placebo administration were examined. METHOD Subjects were forty-four children (37 males, 7 females) with conduct disorder, aged 9.83 to 17.14 years, who were hospitalized for chronic and severe aggression. This was a 4-week double-blind and placebo-controlled study with a 2-week single-blind placebo lead-in period. During the 2-week placebo baseline period, aggression was measured on a 24-hour basis, using the Overt Aggression Scale. Only subjects meeting a specific aggression criterion were randomized to the treatment period of the trial. RESULTS Of the 44 subjects enrolled, 23 (52.3%) met the aggression criteria for entering the treatment period (baseline nonresponders), while 21 (47.7%) did not (baseline responders). Thus, almost half of the subjects, while taking no active medication, benefited from the inpatient milieu/structure and/or placebo. CONCLUSION This finding has important treatment and research implications. Medication to treat aggression should not be initiated immediately upon hospitalization because improvements associated with hospitalization may be attributed inaccurately to pharmacotherapy, resulting in unnecessarily medicating children. A placebo baseline period is essential to decrease the risk of a type II error in pharmacological research concerning aggression.

Advances in Drug Treatments for Children and Adolescents with Autism and Other Pervasive Developmental Disorders

Autism is a disorder characterised by abnormalities in language and social development, and repetitive behaviours. Antipsychotics, including haloperidol and risperidone, are the most widely studied drugs for reducing symptoms in children and adolescents with autism. When administered at relatively low dosages, antipsychotics have been shown to reduce repetitive behaviours (stereotypies) and social withdrawal, as well as a number of related symptoms, such as hyperactivity, aggression, self-abusive behaviour, temper tantrums, lability of mood and irritability. Adverse effects of antipsychotics include sedation, dizziness, increased appetite, weight gain, changes in the electrocardiogram parameters, drooling, hyperprolactinemia and a risk of drug-related dyskinesias.Other agents have been less well studied for the treatment of autism, but there are suggestive data regarding their safety and efficacy. Of these agents, a number have been investigated, based on theories about the aetiology of autism, including SSRIs and naltrexone, although the efficacy of these agents has been limited. Stimulant drugs have been shown to reduce hyperactivity and improve focus, but they may cause behavioural worsening, weight loss and stereotypies de novo. Secretin is a treatment that has received much media attention after reports of efficacy from small open studies, but all controlled studies have failed to show any benefit. In autism, alternative treatments have also been used, but none have shown benefit in well-designed studies.

The Role of Antipsychotics in the Management of Behavioural Symptoms in Children and Adolescents with Autism

Autistic disorder or autism is a serious childhood-onset disorder that affects all areas of development, particularly in the areas of language, communication and reciprocal social interaction. Patients with autistic disorder typically demonstrate repetitiveness and a restricted repertoire of behaviour. Additionally, they also have a number of disruptive symptoms that may be reduced by drug treatment, including severe tantrums, hyperactivity and lability.Antipsychotic drugs are the agents that are the most critically studied as treatments for reducing symptoms. Both first- and second-generation antipsychotics have shown safety and efficacy in short- and long-term studies in autism. The most studied antipsychotic drugs include haloperidol and risperidone, although studies of other antipsychotic drugs are underway. Safety concerns associated with treatment include the risk of drug-related dyskinesias, which is greater with the first-generation drugs, and the risk of weight gain and associated metabolic problems (i.e. increases in glucose and lipids), which is greater with second-generation agents. Prescription of antipsychotic drugs requires careful monitoring because of these safety risks and the likelihood of long-term use. Drug administration should be initiated at low dosages and subsequent dosage changes should be based on tolerability and clinical response.

Noncompliance in the treatment of endocarditis the medical staff as co-conspirators

Intravenous drug abusers with endocarditis present difficult problems in both medical and psychiatric management. A retrospective chart survey revealed that eight of nine such patients with endocarditis signed out against medical advice before antibiotic therapy was completed. Reasons for premature discharge included the patients underlying psychopathology as well as the emotional response of the staff to these patients. Understanding both of these factors may help to prevent these premature discharges.