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Objective: A consumer-oriented efficacy assessment in clinical trials should measure changes in chief complaint and consumer request (symptoms of most concern to patient/caregiver), which may be diluted in change scores of multisymptom scales., Method: In the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network 8-week double-blind trial of risperidone versus placebo, the chief concerns of parents were collected at 0, 4, and 8 weeks (endpoint), in addition to standardized primary measures. Blinded clinical judges rated change from baseline to 4 and 8 weeks on a 9-point scale (1 = normalized, 5 = unchanged, 9 = disastrous); 94 participants had usable data., Results: The most common symptoms identified by parents were tantrums, aggression, and hyperactivity. Interrater reliability was excellent. Mean ratings at endpoint were 2.8 +/- 1.2 on risperidone and 4.5 +/- 1.3 on placebo (p <.001). Ratings were collinear with Clinical Global Impression-Improvement and Aberrant Behavior Checklist Irritability subscale (primary dimensional measure). Effect size d was 1.4, compared to 1.2 on the Aberrant Behavior Checklist Irritability subscale. Effect sizes varied twofold by symptom category, largest for self-injury (2.11) and tantrums (1.95)., Conclusions: Risperidone was superior to placebo in reducing symptoms of most concern to parents of autistic children with irritable behavior. Rating individualized participant-chosen target symptoms seems a reliable, sensitive, efficient, and consumer-friendly way to assess treatment effect and might have clinical application.

Objective: To describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism., Methods: Review the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size., Results: We undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder. This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment., Conclusions: In the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

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.

Indoleamine 2,3-dioxygenase (IDO) activity as determined by increases in serum kynurenine was measured in a group of hepatitis C patients treated with consensus interferon (IFN-con1). Kynurenine levels increased significantly within 2 days of initiation of treatment but returned to normal values by week 4 after treatment. Although IDO is normally induced by IFN-gamma, no such IFN was detected by ELISA or biologic assays. Thus, consensus IFN induces low levels of IDO in vivo without an IFN-gamma intermediate.

There are no medications that are specifically marketed for the treatment of autism. There does exist, however, an extensive body of literature describing both open-label and controlled studies of medications in the treatment of both children and adults with autism. Some of the better-studied medications (including haloperidol and risperidone) are often efficacious in treating associated symptoms of autism but can also cause unacceptable adverse effects. Early studies of serotonin re-uptake inhibitors appear promising but may not be indicated for all age groups. Small, controlled studies of methylphenidate and clonidine indicate a possible role for these medications in the treatment of hyperactivity in autism. No medications have been proven to be efficacious in the treatment of the core social or communication impairment seen in autism. Current pharmacological management is best aimed at target symptoms that have been demonstrated to respond to medication in treatment studies.

Antipsychotics are frequently used in the treatment of a variety of neuropsychiatric conditions in children and adolescents. Atypical antipsychotics have come to the forefront in child psychiatry due largely to their tolerability profiles as well as their efficacy. Potential treatment options include clozapine, risperidone, olanzapine, quetiapine and ziprasidone. A number of studies investigating the use of clozapine have been published in children; however, owing to the frequent monitoring required for agranulocytosis, the use of clozapine may be restricted to patients with treatment-refractory disease. With accumulating data on the development of glucose intolerance in adults receiving clozapine, closer monitoring of bodyweight and fasting blood glucose is imperative. Clozapine also has an increased seizure risk, therefore a baseline electroencephalogram should be performed, as well as continued vigilance for this adverse effect. Risperidone is an atypical antipsychotic that is generally well tolerated and numerous studies have been published investigating this drug in children. Unlike clozapine, its receptor interaction profile lends itself toward increased risk of extrapyramidal symptoms (EPS) and hyperprolactinaemia. Bodyweight gain is a common adverse effect, although somewhat less than that reported with olanzapine. Baseline liver function studies prior to initiation of this medication are recommended. Risperidone-induced mania has been reported in adults and, therefore, increased caution should be used when deciding to treat children and adolescents with risperidone, particularly in those with a predisposition toward mania. Olanzapine, like risperidone, has also been associated with onset of mania in adults. Olanzapine has a receptor profile that results in significant risk for bodyweight gain and sedation. Furthermore, this drug has been linked to the development of glucose intolerance; thus, it is important to monitor bodyweight and fasting blood glucose on a frequent basis. Less information is known about quetiapine in children and adolescents. Reports about its efficacy and tolerability vary. Quetiapine appears to have increased risk for sedation and bodyweight gain, albeit less than that of olanzapine. The compound appears to be less likely to induce EPS. Finally, ziprasidone has recently been approved for use in the adult population. This compound, in terms of its receptor profile, has more in common with risperidone. This suggests a potential for increased risk of EPS and hyperprolactinaemia. It also has an increased risk of QTc prolongation; thus, a baseline electrocardiogram is suggested, particularly in those patients with a history of cardiovascular illness. Lack of evidence for bodyweight gain with ziprasidone is a considerable advantage.

Trichotillomania (TTM) is an impulse disorder, in which patients chronically pull hair from the scalp and/or other sites. Very early onset of hair pulling in children under the age of 6 may be more benign and self-limiting than the more common syndrome of late childhood onset hair pulling. While far more women and adolescent girls appear for treatment, survey studies suggest chronic hair pulling also occurs in males. Diagnosis may be complicated by patient and family denial or ignorance of the hair pulling; accurate scalp examination and biopsy can be critical. Classic scalp biopsies for TTM feature trichomalacia, pigment clumps, peribulbar hemorrhage and hair canal pigment casts, and lack lymphocytic infiltrates seen in alopecia areata. Treatment is difficult: the tricyclic antidepressant clomipramine is the most promising agent, although many patients find it difficult to tolerate at adequate dosages, and treatment response may not be maintained over the long term. More benign medications have not demonstrated efficacy in controlled studies. Augmentation with topical preparations or psychotropic medications may be helpful for patients experiencing limited efficacy or relapse. Specialized psychotherapy, known as habit reversal training, is highly recommended; however, the treatment is intensive and highly specialized. Skilled therapists are difficult to locate.

Repetitive thoughts and behavior are considered integral and core components of autistic disorder. Results from recent studies suggest that the types of repetitive thoughts and behavior of adults with autism and those with obsessive-compulsive disorder (OCD) may be different. Serotonin reuptake inhibitors (SRIs), the primary drug treatment for patients with OCD, may reduce the repetitive phenomena of some autistic patients. Two controlled studies of the nonselective SRI clomipramine have shown the drug to be more efficacious than the relatively selective norepinephrine reuptake inhibitor desipramine and placebo in children with autism. One controlled study of the selective SRI fluvoxamine found it to be significantly better than placebo for reducing repetitive phenomena and aggression in adults with autistic disorder. Additional research is needed.

Background: To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone., Methods: Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition., Results: For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personalty disorder. Other than mild, transient sedation, risperidone was well tolerated., Conclusion: These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy.

Research into the pharmacotherapy of autistic disorder has steadily increased over the past two decades. Several psychoactive medications have shown efficacy for selected symptoms of autistic disorder and can be used to augment critical educational and behavioral interventions that are the mainstays of treatment. A comprehensive review of medication trials conducted in individuals with autistic disorder and other pervasive developmental disorders is presented. The typical antipsychotic haloperidol is the best-studied medication in autistic disorder but is associated with a high rate of dyskinesias. Investigations to date suggest that the atypical antipsychotics such as risperidone have efficacy for certain symptoms of autistic disorder and may be better tolerated than typical antipsychotics. Preliminary results from trials with serotonin-reuptake inhibitors are favorable, although efficacy has not been demonstrated in younger age groups. Recent controlled studies of nalfrexone suggest that the drug has minimal efficacy. In two small controlled investigations, clonidine was more effective than placebo for a variety of symptoms, including hyperactivity and irritability; in one of these studies, however, the majority of patients relapsed within several months. Psychostimulants reduced hyperactivity and irritability in one small double-blind crossover study in children with autistic disorder, although these agents are frequently reported to exacerbate irritability, insomnia, and aggression in clinical populations. Recent controlled trials of secretin have not shown efficacy compared to placebo. Several other medications, including buspirone, mood stabilizers, and beta-blockers, have produced symptom reduction in some open-label studies and may warrant controlled investigation.

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.

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.

The authors examined the efficacy of ketoconazole in 16 adults with treatment-refractory major depressive disorder. Subjects participated in a 6-week, double-blind, placebo-controlled trial. Assessments of mood were made using the Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory (BDI), and the Clinical Global Impression Scale (CGI). Results showed that none of eight patients randomly assigned to receive placebo and two of eight patients randomly assigned to receive ketoconazole met criteria for response. As a group, patients assigned to receive ketoconazole showed no significant reductions in HAM-D, BDI, or CGI scores during the 6-week trial compared with those receiving placebo. These findings suggest a limited efficacy for ketoconazole in patients with treatment-refractory major depression.

Background: Several lines of evidence suggest that brain dopamine function may contribute to some obsessive-compulsive (OC) phenomena. The effects of catecholamine depletion were examined in drug-free patients with obsessive-compulsive disorder (OCD)., Methods: The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT) and diphenhydramine hydrochloride (placebo) were administered for three consecutive days, one week apart, to 6 drug-free adult OCD patients without a personal or family history of chronic tics, in a double-blind, randomized design. The effects of AMPT and placebo on OC, depression, anxiety and global clinical symptoms were assessed., Results: AMPT produced no clinically or statistically significant change in any behavioral ratings, including OC symptom severity, compared with placebo., Conclusions: Acute reduction of catecholamine levels does not seem to affect OC symptoms in drug-free patients with OCD. Studies of catecholamine depletion with AMPT in patients with comorbid OCD and chronic tics may be of considerable neurobiological and clinical interest.

Background: Despite the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder, a significant number of patients show no or only partial remission of symptoms. Some evidence exists to suggest that risperidone augmentation can be helpful in treating this refractory group. The efficacy of other atypical antipsychotic agents, such as olanzapine, in augmenting SSRIs in refractory obsessive-compulsive patients has yet to be systematically investigated., Method: A series of 10 patients with DSM-IV obsessive-compulsive disorder showing significant residual symptoms following an adequate SSRI trial (12 weeks) were given open-label olanzapine augmentation for a minimum of an additional 8 weeks. Treatment response was assessed using the Yale-Brown Obsessive Compulsive Scale and the Clinical Global Impressions scale., Results: Nine of the 10 patients in this series treated with olanzapine and an SSRI completed the 8-week augmentation trial. Of these, 4 demonstrated a complete remission or major improvement in obsessive-compulsive symptoms, 3 had partial remission, and 2 experienced no benefit. Nine patients experienced minimal adverse effects, primarily sedation, which did not interfere with continuing treatment. One patient discontinued olanzapine owing to excessive sedation., Conclusion: The results of this preliminary, open-label trial suggest that olanzapine may be effective in augmenting ongoing SSRI treatment for a portion of patients with obsessive-compulsive disorder refractory to SSRI treatment. Larger, placebo-controlled trials appear warranted to investigate the clinical efficacy and tolerability of olanzapine augmentation of SSRI treatment in SSRI-refractory obsessive-compulsive disorder.

This pilot study examined the efficacy and tolerability of olanzapine in the treatment of children, adolescents, and adults with pervasive developmental disorders (PDDs). Eight patients with principal diagnoses (DSM-IV) of autistic disorder (N = 5) or PDD not otherwise specified (N = 3) were given olanzapine in an open-label, prospective fashion for 12 weeks. Clinical ratings were obtained at baseline and at the end of weeks (EOWs) 4, 8, and 12. Seven of eight patients completed the 12-week trial, and six of the completers were deemed clinical responders as measured by ratings at the EOW 12 of "much improved" or "very much improved" on the global improvement item of the Clinical Global Impression Scale. Significant improvements in overall symptoms of autism, motor restlessness or hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, self-injurious behavior, aggression, irritability or anger, anxiety, and depression were observed. Significant changes in repetitive behaviors were not observed for the group. The EOW 12 mean +/- SD daily dose of olanzapine was 7.8 +/- 4.7 mg/day. The drug was well tolerated with the most significant adverse effects noted to be increased appetite and weight gain in six patients and sedation in three. With respect to weight gain, the mean +/- SD weight for the group increased from 137.50 +/- 55.81 pounds (62.50 +/- 25.37 kilograms) at baseline to 155.94 +/- 55.13 pounds (70.88 +/- 25.06 kilograms) at EOW 12. No evidence of extrapyramidal side effects or liver function abnormalities was seen. These preliminary results suggest that olanzapine may be an effective and well tolerated drug in targeting core and related symptoms of PDDs in children, adolescents, and adults. Further studies, particularly those that are placebo-controlled and double-blinded, are indicated to better define the clinical use of olanzapine in these patient populations.

Open-label addition of a low-dose typical (pimozide) neuroleptic was shown to be beneficial in some patients with serotonin reuptake inhibitor (SRI)-refractory trichotillomania (TTM). Risperidone's potentially more benign acute and long-term side effect profile makes it a candidate for investigation in the treatment of TTM. We report our experience with the systematic addition of open-label risperidone 0.5 to 3 mg/day in three patients with SRI-refractory TTM. All three patients had a robust decrease in hair pulling as measured by clinician-rated instruments. These results suggest that risperidone addition to ongoing treatment with SRIs may be an effective treatment strategy for patients with SRI-refractory TTM.

This report describes the use of risperidone in the treatment of two very young children with autistic disorder, a 29-month-old boy and a 23-month-old boy, respectively. These children presented with severe and persistent symptoms of aggression and irritability that had not responded to previous treatment. In both cases, risperidone significantly reduced aggression and improved social relatedness. One patient's treatment with risperidone was complicated by persistent tachycardia and QTc interval prolongation that was dose-related. Consideration should be given to the appropriate use of medication in the treatment of very young children with autism when other interventions do not prove helpful.

Background: Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism., Methods: Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone., Results: For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures., Conclusion: Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults.

The tryptophan (TRP) depletion paradigm has been employed to investigate mood and behavioral effects of acutely lowering plasma TRP, and presumably brain serotonin (5-hydroxytryptamine [5-HT]) levels through administration of a special diet and/or amino acid drink. Our goal was to test the assumption that a corresponding fall in central levels of TRP and 5-HT (measured by its major metabolite, 5-hydroxyindoleacetic acid [5-HIAA]) occurs during the standard execution of this method in healthy adult subjects. Three males and two females completed the protocol, which included a one-day low-TRP diet and a TRP-free amino acid drink. Lumbar puncture was performed, with placement of an indwelling catheter connected to a peristaltic pump and fraction collector. Cerebrospinal fluid (CSF) was sampled continuously for a 13.5-hour period (before, during, and after the drink), with fractions removed every 15 minutes. Plasma samples were simultaneously obtained. CSF TRP levels and plasma TRP levels were highly correlated, falling a mean of 92% and 85% from baseline, respectively. CSF nadirs were reached several hours after plasma nadirs. CSF 5-HIAA decreased modestly (24% to 40%, mean 31% change from baseline), with lowest concentrations observed 8-12 hours after the amino acid drink. These data suggest that TRP depletion results in substantial declines in central 5-HT turnover.

A chart review was conducted to compare the social, occupational, and daily functioning of 17 inpatients with obsessive-compulsive disorder, 17 with major depression, and 17 with schizophrenia. Current Global Assessment of Functioning (GAF) scores of patients with schizophrenia were significantly lower than those of patients with depression and with obsessive-compulsive disorder. However, on work performance, daily living skills, and past-year GAF scores, patients with obsessive-compulsive disorder and those with schizophrenia did not differ significantly, and both groups were significantly more impaired than patients with depression. Results show that inpatients with obsessive-compulsive disorder may exhibit severe and chronic functional impairments requiring extensive supportive and rehabilitative services.

The short-term efficacy and tolerability of sertraline for adults with pervasive developmental disorders (PDDs) were assessed in this investigation. Forty-two adults with PDDs (autistic disorder, N = 22; Asperger's disorder, N = 6; and PDD not otherwise specified [NOS], N = 14) participated in a 12-week, open-label, systematic trial of sertraline. Behavioral ratings of repetitive symptoms, aggression, and social relatedness were obtained at baseline and after 4, 8, and 12 weeks of sertraline administration. Twenty-four (57%) of 42 patients showed significant improvement, primarily in repetitive and aggressive symptoms. Statistically significant changes in measures of social relatedness did not occur. Patients with autistic disorder and PDD NOS did significantly better than those with Asperger's disorder. Based on global improvement item criteria from the Clinical Global Impression Scale, 15 of 22 (68%) patients with autistic disorder, none of six (0%) patients with Asperger's disorder, and 9 of 14 (64%) patients with PDD NOS were categorized as treatment responders. Sertraline was well tolerated; no adverse cardiovascular effects, extrapyramidal symptoms, or seizures were identified. These findings suggested that sertraline may be an effective treatment for interfering repetitive and aggressive symptoms in adults with PDDs. Definitive statements about the efficacy and tolerability of sertraline for treating adults with PDDs must await results from double-blind, placebo-controlled trials. These preliminary results should not be generalized to include children and adolescents with PDDs.

This study utilized neuroendocrine and mood responses to intravenous (i.v.) infusion of the serotonin (5-HT) agonist m-chlorophenylpiperazine (mCPP) to evaluate central 5-HT function in depressed patients undergoing acute tryptophan (TRP) depletion. Twenty-two drug-free patients with DSM-III-R major depression participated. Each patient underwent two randomized, double-blind TRP depletion tests, one sham and one active. At the estimated time of maximum TRP depletion, each patient received an i.v. infusion of mCPP 0.1 mg/kg. Blood was obtained for serum cortisol, prolactin, and growth hormone. Multiple rating scales were used to assess mood. The cortisol response to i.v. mCPP was significantly greater during TRP depletion than during sham depletion, and free plasma TRP was negatively correlated with the cortisol response during TRP depletion. These findings are consistent with the hypothesis that acute TRP depletion in drug-free depressed patients induces a compensatory up-regulation of postsynaptic 5-HT receptors, most likely of the 5-HT2A/2C subtype. Such changes suggest a mechanism by which acute and potent manipulations of 5-HT function in depressed patients could be used to effect rapid clinical improvement.

Clinical studies suggest that 5-HT1A receptor function may be blunted in depression, while 5-HT1A agonists may possess antidepressant activity. Preclinical findings implicate changes in 5-HT1A receptor sensitivity in the mechanism of antidepressant action. The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression could be related to those observations, since 5-HT1A receptors are inhibited by glucocorticoids. To evaluate the interaction of the HPA and 5-HT1A systems, we pretreated 15 unipolar depressed patients and 12 healthy control subjects with the antiglucocorticoid ketoconazole (KTCZ) prior to administration of a test dose of the 5-HT1A agonist ipsapirone (IPS). Neuroendocrine (ACTH, cortisol, growth hormone), physiological (hypothermia), and behavioral responses to IPS were assessed. As expected, KTCZ inhibited cortisol biosynthesis, but non-HPA responses to IPS were not enhanced. This study failed to show that glucocorticoid modulation of 5-HT1A receptor function is altered in depression.

Objective: The purpose of this study was to determine whether combined treatment with a selective serotonin reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor, desipramine, effectively reduces obsessive-compulsive symptoms in patients who do not respond to SSRIs., Method: In a double-blind study, desipramine or placebo was added for 6 or 10 weeks to the treatment of 30 patients with obsessive-compulsive disorder whose symptoms were refractory to SSRI treatment (fluvoxamine, fluoxetine, or sertraline) alone., Results: There were no significant differences between the adjunctive desipramine and placebo groups in obsessive-compulsive or depressive symptoms., Conclusions: These data suggest that clomipramine's possibly superior efficacy in the treatment of obsessive-compulsive symptoms may not stem from its capacity to inhibit reuptake of norepinephrine.

Objective: Obsessive-compulsive disorder encompasses a broad range of symptoms that represent multiple psychological domains, including perception, cognition, emotion, social relatedness, and diverse motor behaviors. The purpose of these analyses was to evaluate the correlational relationships of the symptoms of obsessive-compulsive disorder., Method: This study examined the 13 a priori categories used to group types of obsessions and compulsions in the Yale-Brown Obsessive Compulsive Scale symptom checklist in two independent groups of patients with obsessive-compulsive disorder (N = 208 and N = 98). A principal-components factor analysis with varimax rotation was performed, followed by a series of other exploratory analyses., Results: The two data sets yielded nearly identical results. Four factors--obsessions and checking, symmetry and ordering, cleanliness and washing, and boarding--emerged in each data set, in total accounting for more than 60% of the variance., Conclusions: Obsessive-compulsive disorder is a multidimensional and etiologically heterogeneous condition. The four symptom dimensions identified in this study are largely congruent with those identified in earlier reports. These factors may be of value in future genetic, neurobiological, and treatment response studies.

The purpose of this investigation was to determine the short-term efficacy and tolerability of clomipramine in a consecutive series of adults with pervasive developmental disorders (PDDs). Thirty-five adults with PDDs (DSM-IV), 16 of whom were nonverbal, entered a 12-week prospective open-label trial of clomipramine. The initial sample included 18 patients with autistic disorder, 6 patients with Asperger's disorder, and 11 patients with pervasive developmental disorder not otherwise specified (PDDNOS). Behavioral ratings were obtained at baseline and after 4, 8, and 12 weeks of clomipramine. Eighteen (55%) of the 33 patients who completed the trial were categorized as treatment responders based on scores of "much improved" or "very much improved" on the Clinical Global Impression (CGI) global improvement item (p < 0.001). Ten (63%) of 16 patients with autistic disorder, 2 (33%) of 6 patients with Asperger's disorder, and 6 (55%) of 11 patients with PDDNOS were considered responders to clomipramine treatment. In those 18 patients, clomipramine significantly reduced total repetitive thoughts and behavior (p < 0.001) and also aggression (p < 0.001), and improved some aspects of social relatedness, such as eye contact and verbal responsiveness (p < 0.001). Change in these specific symptom clusters over time was not related to DSM-IV subtype of PDD. The level of autistic behavior, as measured by the Autism Behavior Checklist (ABC) score, and full-scale intelligence quotient (IQ) were not significantly associated with global treatment response. Whereas clomipramine was well tolerated by most patients, 13 had clinically significant adverse effects. Three patients had seizures during clomipramine treatment, including 2 who had prior seizure disorders and were taking anticonvulsants. Of the 32 patients who had no history of prior seizures, only 1 had a seizure during clomipramine treatment. There were no adverse cardiovascular or extrapyramidal effects. All responders continued on clomipramine after completion of the study. The results of this open-label trial suggest that clomipramine may be an effective drug for reducing repetitive thoughts and actions and aggressive behavior and for improving some elements of social behavior, such as eye contact and verbal responsivity in adults with PDDs. Careful monitoring of adverse effects, particularly seizures, is warranted. Although an electroencephalogram (EEG) is not mandatory in patients with PDD prior to clomipramine treatment, we recommend that patients with PDD and a history of seizures be treated initially with a selective serotonin uptake inhibitor rather than with clomipramine. The findings of this study require replication in a double-blind placebo-controlled investigation before definitive statements of efficacy and tolerability can be made.

Objective: To investigate the short-term safety and efficacy of risperidone in the treatment of children and adolescents with pervasive developmental disorders., Method: This was a 12-week, prospective, systematic, open-label trial that included 18 subjects (15 boys and 3 girls) with a mean age of 10.2 +/- 3.7 years. The sample included 11 subjects with autistic disorder, 3 with Asperger's disorder, 1 with childhood disintegrative disorder, and 3 with pervasive developmental disorder not otherwise specified. Fourteen subjects had comorbid mental retardation. Behavioral ratings were obtained during two baseline visits and again after 12 weeks of risperidone treatment., Results: The optimal dose of risperidone for the 18 subjects was 1.8 +/- 1.0 mg/day. On the basis of the global improvement item of the Clinical Global Impression Scale, 12 of 18 subjects were considered responders. Significant improvement was seen in measures of interfering repetitive behavior, aggression and impulsivity, and some elements of impaired social relatedness. The most common side effect was weight gain (range 10 to 35 lb)., Conclusions: These preliminary results suggest that risperidone may be effective for improving interfering behavioral symptoms in some children and adolescents with pervasive developmental disorders. Double-blind, placebo-controlled studies are needed before definitive statements of safety and efficacy can be made.

A preponderance of patients with obsessive-compulsive disorder (OCD) experience little or no improvement in their symptoms when treated with serotonin reuptake inhibitors (SRIs). It is hypothesized that SRI-refractory patients may have altered serotonin neurotransmission different from patients responsive to SRIs, or that they may have abnormalities in their dopamine function. When drugs affecting serotonin function (e.g., tryptophan, fenfluramine, lithium, buspirone) are added to SRI therapy in SRI-refractory patients, results are mixed and not consistently encouraging. However, when drugs affecting dopamine function (e.g., pimozide, haloperidol, risperidone) are added to SRI therapy in SRI-refractory OCD patients, individuals with either a personal history or family history of tics experience a reduction in their symptoms.

Seasonality of mood disorders might involve alterations in the rhythmicity of serotonin [5-HT] function. We examined seasonal effects on the neuroendocrine and mood responses to L-tryptophan (L-TRP) in depressed patients and healthy subjects. In this study, 126 drug-free patients with DSM-III-R major depression and 58 healthy subjects received in i.v. infusion of L-TRP. Serum prolactin (PRL) and plasma tryptophan levels were measured. Mood was assessed with visual analogue scales. Cosinor analysis revealed seasonal variation in peak change (delta) PRL and baseline tryptophan levels in the combined depressed and in unipolar, nonmelancholic, and nonpsychotic patients. Peak delta PRL and tryptophan levels were inversely correlated in combined depressed and unipolar patients. Seasonality was more evident in female than in male patients. These data support previous evidence that 5-HT function is abnormal in depression and further suggest a seasonal variability of such abnormalities that is absent in healthy subjects.

Background: Autistic disorder is characterized by a fundamental disturbance in social interaction, impairments in communication, and a markedly restricted repertoire of activities and interests. Abnormalities in the serotonin neurotransmitter system have been identified in some persons with autism. No consistently effective and safe drugs have been developed for treating the symptoms of autism., Methods: Thirty adults with autistic disorder completed a 12-week double-blind, placebo-controlled trial of the potent and selective serotonin uptake inhibitor fluvoxamine maleate. Behavioral ratings were obtained at baseline and after 4, 8, and 12 weeks of treatment., Results: Eight (53%) of 15 patients in the fluvoxamine-treated group were categorized as responders compared with none of 15 in the placebo group (P = .001). Fluvoxamine was superior to placebo in reducing repetitive thoughts and behavior (P < .001), maladaptive behavior (P < .001), and aggression (P < .03), and in improving some aspects of social relatedness (P < .04), especially language usage (P < .008). Treatment response was not correlated with age level of autistic behavior, or full-scale IQ. Other than mild sedation and nausea in a few patients, fluvoxamine was well tolerated. No dyskinesias, adverse cardiovascular events, or seizures occurred., Conclusions: Fluvoxamine is more effective than placebo in the short-term treatment of the symptoms of autistic disorder in adults. Controlled studies of fluvoxamine and other potent and selective serotonin uptake inhibitors seem warranted in children and adolescents with autism.

Background: The primary objective of this study was to investigate the behavioral and biochemical responses to acute tryptophan depletion in drug-free adult patients with autistic disorder., Methods: Twenty drug-free adults with autistic disorder (16 men and 4 women) (mean [+/- SD] age, 30.5 +/- 8.5 years) underwent short-term tryptophan depletion in a double-blind, placebo-controlled, randomized crossover design. Patients received a 24-hour, low-tryptophan diet followed the next morning by an amino acid drink. Behavioral ratings were obtained on the morning of the amino acid drink (baseline) and 180, 300, and 420 minutes after the drink. Plasma free and total tryptophan levels were obtained at baseline and 5 hours after the drink. The active and sham testing sessions were separated by 7 days., Results: Eleven (65%) of the 17 patients who completed both test days showed a significant global worsening of behavioral symptoms with short-term tryptophan depletion, but none of the 17 patients showed any significant change in clinical status from baseline after sham depletion (P = .001). Tryptophan depletion led to a significant increase in behaviors such as whirling, flapping, pacing, banging and hitting self, rocking, and toe walking (P < .05). In addition, patients were significantly less calm and happy and more anxious. No significant change was observed in social relatedness or repetitive thoughts and behavior. Plasma total and free tryptophan levels were reduced 86% and 69%, respectively, 5 hours after the tryptophan-deficient amino acid drink. Patients who had a significant global exacerbation of symptoms had significantly higher baseline plasma total tryptophan levels (P < .001) and Autism Behavior Checklist scores (P = .005) than did patients who showed no significant change in symptoms after tryptophan depletion., Conclusions: The results of this study are consistent with previous research that has implicated a dysregulation in serotonin function in some patients with autism. These data suggest that the short-term reduction of serotonin precursor availability may exacerbate some symptoms characteristic of autism in some patients. Continued investigation into the role of serotonin in the pathogenesis and treatment of autistic disorder is warranted.

Established efficacy and tolerability in large multicentre controlled studies have made serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SRIs) the mainstay of monotherapy for adult obsessive-compulsive disorder (OCD). When compared with the selective serotonin reuptake inhibitors (SSRIs), the tricyclic compound clomipramine has a higher incidence of adverse effects but is well tolerated by most OCD patients and may confer the best overall antiobsessional effects. Consideration of specific adverse effect profiles, special patient population characteristics, drug interactions and relative cost of the various agents may direct clinicians in choosing the most appropriate first-line drug. Alternative agents as monotherapies have been explored, but none has consistently proven effective to date. Investigations of SRI augmentation with serotonin-enhancing agents have also failed to demonstrate substantial benefits for treatment-refractory OCD. Combination treatment with SRIs and dopamine receptor antagonist drugs appears to provide an improved response for the subpopulation of OCD patients who have comorbid 'tic-spectrum' disorders, though large-scale studies of the efficacy and tolerability of these regimens are not yet available.

There is considerable interest in the possible antidepressant properties of antiglucocorticoids. Studies of the hypothalamic-pituitary-adrenal (HPA) axis in depression, coupled with increasing recognition of the importance of glucocorticoids in brain function, strongly support such interest.Psychiatric symptomatology in Cushing's syndrome (a disorder involving hypersecretion of cortisol), the adverse cognitive effects of glucocorticoids, and the suppressive effects of conventional antidepressants on HPA function all suggest that HPA abnormalities could cause or contribute to depression. However, the psychiatrie effects of glucocortieoids and glucocorticoid withdrawal suggest that HPA hyperactivity compensates for some other defect. While preliminary clinical studies suggest that both glucocorticoids and antiglucocorticoids may have efficacy in depression, the toxicity and loss of efficacy of available drugs during long term administration will probably necessitate the development of new agents to advance this field.

Objective: The authors assessed the efficacy of clozapine monotherapy for adults with treatment-resistant obsessive-compulsive disorder., Method: Twelve adults with refractory obsessive-compulsive disorder participated in a 10-week, open-label, systematic trial of clozapine. They were assessed with the Yale-Brown Obsessive Compulsive Scale, the Hamilton Depression Rating Scale, and the global improvement item of the Clinical Global Impression (CGI) scale., Results: None of the 10 patients who completed the trial was a responder. No significant change was observed in obsessive-compulsive or depressive symptoms or in scores on the CGI global improvement item., Conclusions: These findings suggest that clozapine monotherapy is not effective for most adult patients with treatment-resistant obsessive-compulsive disorder.

Background: Forty percent to 60% of patients with obsessive-compulsive disorder (OCD) remain unimproved after adequate treatment with serotonin uptake inhibitors (SUIs). The addition of low-dose haloperidol and pimozide to ongoing SUI treatment has been shown to be effective in up to 65% of SUI-refractory OCD patients, particularly in those with comorbid chronic tic disorder. Because OCD patients typically require prolonged pharmacotherapy, they are subject to the development of tardive dyskinesia during neuroleptic treatment. Risperidone is a highly potent and selective serotonin2 and dopamine2 receptor antagonist with a side effect profile that appears to be much more tolerable and safer than that of typical neuroleptics., Method: We report our experience with three OCD patients who were unimproved after a minimum of 12 weeks of treatment with the potent and selective SUI fluvoxamine, in whom we added risperidone in an open-label manner., Results: All three patients showed significant improvement in their obsessive-compulsive symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after risperidone 1 mg/day was added to ongoing fluvoxamine (250-300 mg/day). Within 4 weeks of adding risperidone, the three patients' Y-BOCS scores had decreased by 65%, 56%, and 43%, respectively. Other than mild or moderate sedation, no side effects were observed., Conclusion: These results suggest that risperidone addition to ongoing SUIs may be an effective treatment strategy for refractory OCD.

Objective: The purpose of this trial was to investigate the short-term safety and efficacy of risperidone in the treatment of chronic tic disorders in children and adolescents., Method: This was an 11-week open-label trial and included seven subjects (five boys and two girls) with a mean age of 12.9 +/- 1.9 years. The sample included five patients with Tourette's syndrome and two with chronic motor tic disorder. The children were seen at baseline and for two follow-up visits. Three children had a comorbid diagnosis of obsessive-compulsive disorder (OCD)., Results: Clinical response, as measured by the Yale Global Tic Severity Scale and the Children's version of the Yale-Brown Obsessive Compulsive Scale, revealed a statistically significant reduction in tic scores ranging from 26% [corrected] to 66%. One of three children with comorbid OCD showed substantial improvement; the other two subjects showed no change. The most frequent side effect was weight gain, which ranged from 8 to 14 lb., Conclusions: Risperidone, a neuroleptic with both serotonin- and dopamine-blocking properties, appears to be effective in reducing tic frequency and intensity in children and adolescents with chronic tic disorders.

Objective: The authors examined whether subjects with Tourette's disorder have greater than normal striatal dopamine transporter densities, as suggested by previous post-mortem findings., Method: Single photon emission computed tomography (SPECT) and [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT) were used to assess dopamine transporter levels in five adult patients with Tourette's disorder and five age- and gender-matched healthy comparison subjects., Results: Striatal [123I]beta-CIT binding was a mean of 37% (range = 6%-79%) higher in the subjects with Tourette's disorder than in the comparison subjects, and each Tourette's disorder patient had a higher level than his or her paired comparison subject., Conclusions: These findings corroborate post-mortem results and support the hypothesis of a dysregulation in presynaptic dopamine function in Tourette's disorder.

The objective of this study was to investigate the role of serotonin (5-HT) in mediating the effects of cocaine in humans. To accomplish this, 12 subjects each participated in two randomized, double-blind test sessions separated by 1 week. In one session, subjects underwent acute depletion of the 5-HT amino acid precursor tryptophan (TRP), followed by a test dose of intranasal cocaine. In the other session, the cocaine test dose was preceded by sham depletion. Subject ratings of cocaine "high" were significantly lower following active TRP depletion than after the sham procedure. Subjects also showed an earlier but less sustained rise in self-rated nervousness during active TRP depletion. These findings are consistent with the hypothesis that 5-HT may be involved in mediating the euphorigenic and modulating the anxiogenic effects of cocaine in humans, either directly or through actions on other (e.g., dopaminergic) systems.

Objective: The purpose of this study was to investigate the types of repetitive thoughts and behavior demonstrated by adults with autistic disorder and compare them with those of age- and sex-matched adults with obsessive-compulsive disorder., Method: Fifty consecutive patients admitted to the Yale Adult Pervasive Developmental Disorders (Autism) Clinic with a primary diagnosis of autistic disorder (DSM-III-R and DSM-IV) completed the symptom checklist of the Yale-Brown Obsessive Compulsive Scale. Types of current obsessions and compulsions were evaluated. The comparison group consisted of 50 age- and sex-matched adults with obsessive-compulsive disorder (without tics) (DSM-III-R and DSM-IV)., Results: Direct discriminant function analysis showed that the patients with autistic disorder could be distinguished from those with obsessive-compulsive disorder on the basis of the types of current repetitive thoughts and behavior that they demonstrated. Compared to the obsessive-compulsive group, the autistic patients were significantly less likely to experience thoughts with aggressive, contamination, sexual, religious, symmetry, and somatic content. Repetitive ordering; hoarding; telling or asking (trend); touching, tapping, or rubbing; and self-damaging or self-mutilating behavior occurred significantly more frequently in the autistic patients, whereas cleaning, checking, and counting behavior was less common in the autistic group than in the patients with obsessive-compulsive disorder. In addition, a specific subset of seven obsessive-compulsive variables from the Yale-Brown Obsessive Compulsive Scale symptom checklist was identified that reliably predicted membership in the autistic group., Conclusions: These results suggest that the repetitive thoughts and behavior characteristics of autism differ significantly from the obsessive-compulsive symptoms displayed by patients with obsessive-compulsive disorder. Future studies are warranted to assess the treatment response and neurobiological underpinnings of repetitive thoughts and behavior in patients with autism and obsessive-compulsive disorder.

Objective: Family accommodation of patients with obsessive-compulsive disorder, i.e., participation in symptoms and modification of personal and family routines, was assessed in relation to family stress, functioning, and attitudes toward the patient., Method: Primary caretakers for 34 patients with obsessive-compulsive disorder were interviewed to assess the nature and frequency of accommodating behaviors. The caretakers also completed several measures of family functioning., Results: Of the 34 spouses or parents, 30 (88.2%) reported accommodating the patient. Family accommodation correlated with poor family functioning, rejecting attitudes toward the patient, and several types of family stress., Conclusions: Family accommodation of patients with obsessive-compulsive disorder was associated with global family dysfunction and stress. This study suggests that families' efforts to accommodate patients may be intended to reduce patient anxiety or anger directed at relatives.

The effects of oral administration of ethanol [1.1 ml/kg 95% ethanol administered as a 20% (by volume) solution] and intravenous administration of the alpha 2 adrenergic receptor antagonist yohimbine hydrochloride (0.4 mg/kg), alone and in combination, were compared using a double-blind, placebo-controlled design. Twelve healthy subjects completed 4 test days during which drug effects on subjective measures of intoxication and anxiety, plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and cortisol, and cardiovascular indices were assessed. Acutely administered oral ethanol significantly increased the subjective measures of intoxication and anxiety, plasma MHPG, and sitting systolic blood pressure compared with placebo. Intravenous yohimbine significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and blood pressure relative to placebo. The ethanol-induced increase in plasma MHPG was significantly greater than that following yohimbine, whereas yohimbine resulted in significantly greater increases in anxiety, plasma cortisol, and blood pressure measurements than ethanol. The combined administration of ethanol and yohimbine had a clear additive effect of increasing the severity of acute intoxication compared with ethanol or yohimbine alone, and resulted in a significantly greater plasma MHPG response compared with either drug given alone. Although the pharmacokinetic effects of ethanol administration on NE metabolism must be considered, these findings suggest that the intoxicating and anxiogenic effects of acute ethanol administration may be associated with increased NE turnover, as measured by plasma MHPG, in healthy human subjects. In addition, these results indicate that ethanol and yohimbine may act additively to increase ethanol intoxication and that they may increase NE turnover through different physiological mechanisms.