ABSTRACT
OBJECTIVE: The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs). METHODS: Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger's disorder, 1 with Rett's disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects' primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist. RESULTS: Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders ("much improved" or "very much improved" on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation. CONCLUSIONS: Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs.
Subject(s)
Antidepressive Agents, Tricyclic/therapeutic use , Autistic Disorder/drug therapy , Child Development Disorders, Pervasive/drug therapy , Mianserin/analogs & derivatives , Mianserin/therapeutic use , Adolescent , Adult , Aggression/drug effects , Antidepressive Agents, Tricyclic/adverse effects , Anxiety Disorders/drug therapy , Anxiety Disorders/etiology , Appetite/drug effects , Autistic Disorder/complications , Child , Child Development Disorders, Pervasive/complications , Child, Preschool , Depressive Disorder/drug therapy , Depressive Disorder/etiology , Disorders of Excessive Somnolence/chemically induced , Female , Humans , Irritable Mood/drug effects , Male , Mianserin/adverse effects , Mirtazapine , Self-Injurious Behavior/drug therapy , Self-Injurious Behavior/etiology , Severity of Illness Index , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep Initiation and Maintenance Disorders/etiology , Weight Gain/drug effectsABSTRACT
Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.
Subject(s)
Antipsychotic Agents/therapeutic use , Autistic Disorder/drug therapy , Risperidone/therapeutic use , Antipsychotic Agents/adverse effects , Autistic Disorder/diagnosis , Child , Humans , Neuropsychological Tests/statistics & numerical data , Reproducibility of Results , Risperidone/adverse effects , Treatment OutcomeABSTRACT
This article has reviewed the background and rationale for the choice of risperidone as the first drug to be studied by the RUPP Autism Network. Risperidone has potent effects on 5-HT and DA neuronal systems, both of which have been implicated in the pathophysiology of autism. Unlike the typical antipsychotics, haloperidol and pimozide, which have been shown to be effective for reducing many of the maladaptive behaviors associated with autism, risperidone's 5-HT2A/DA D2 ratio of receptor blockade appears to produce a lower risk of acute and chronic extrapyramidal side effects, as well as enhanced efficacy for the "negative" symptoms of autism. Indirect clinical and preclinical evidence supports the use of risperidone to treat impaired social behavior, interfering repetitive phenomena, and aggression, targets of pharmacotherapy for many patients with autism. Numerous published open-label trials in children and adolescents with autism and related PDDs and one double-blind, placebo-controlled study in adults suggest that risperidone has promise for the treatment of children and adolescents with autism. Because most of these studies have been short-term, open-label trials in small samples, however, a large-scale controlled study of risperidone in children and adolescents with autism is needed to confirm these results. Finally, because it is likely that children who demonstrate short-term benefit from risperidone will remain on the medication indefinitely, the longer-term effectiveness and safety of risperidone in this population also needs to be determined. The design of this study and the assessments used are described separately.
Subject(s)
Antipsychotic Agents/therapeutic use , Autistic Disorder/drug therapy , Risperidone/therapeutic use , Adolescent , Adult , Antipsychotic Agents/adverse effects , Autistic Disorder/diagnosis , Autistic Disorder/psychology , Brain/drug effects , Child , Clinical Trials as Topic , Humans , Receptors, Dopamine/drug effects , Receptors, Serotonin/drug effects , Risperidone/adverse effectsABSTRACT
Sixty-five mildly to moderately mentally retarded adults from institutional and community placements in Louisiana and Texas with DSM diagnoses of schizophrenia, depression, or no psychopathology were recruited. The primary goal was to establish the validity of the PIMRA's schizophrenic subscale for diagnosing mentally retarded adults. In addition, validity of the depression subscale was replicated. Assessment measures included the informant version of the Psychopathology Instrument for the Mentally Retarded (PIMRA), DSM-III-R checklists for schizophrenia and depression, and a drug response rating. Univariate and multivariate analyses were conducted, as were interrater reliability on all measures. The schizophrenia and depression subscale of the PIMRA were validated. Implications of the research and directions for future study are presented.
