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.

Twenty-eight children took part in a double-blind, placebo-controlled, crossover study of fenfluramine and methylphenidate. Fenfluramine dosage was gradually increased to a standardized dose of 1.5 mg/kg per day, whereas methylphenidate was given in doses of 0.4 mg/kg per day. The children were assessed on laboratory tests of selective and sustained attention, visual matching, and color matching, during which seat activity was monitored automatically. Results showed fenfluramine to be superior to placebo on the memory task, whereas methylphenidate reduced commission errors on a continuous performance test. Methylphenidate caused shorter response times, and fenfluramine caused increases, on two of the tests. Examiner behavior ratings indicated significant improvements with both drugs on the domains of attention, activity level, and mood. These findings, together with those from a companion clinical study, suggest that the drugs may have contrasting mechanisms of action, but both appear to have useful clinical effects in these children.

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