Siefen and Remschmidt (1986) administered clozapine to 21 inpatients, 12 of whom were younger than 18 years (average age, 18.1 years). Their patients had an average of 2.4 inpatient hospitalizations and had been tried on an average of 2.8 different antipsychotics without adequate therapeutic response or with severe extrapyramidal effects. In addition, the authors considered it a risk that their patients’ psychotic symptoms would become chronic if clozapine was not administered.

Clozapine was administered over an average of 133 days. The average maximum dose was 415 mg/day (range, 225 to 800 mg/day) and the average maintenance dose was 363 mg/day (range, 150 to 800 mg/day). In addition, 11 of the 21 subjects were administered one or more other unidentified drugs for about half of the time they were receiving clozapine.

Approximately 67% of symptoms that had been relatively resistant to previous treatment with antipsychotics disappeared or improved markedly in 11 (52%) of the patients, and an additional 6 (29%) patients showed at least slight improvement in the same number of symptoms. Four patients, however, had no changes or worsening of more than half of their psychopathologic symptoms during clozapine therapy. Positive symptoms of schizophrenia improved more than negative symptoms. Specifically, improvements in incoherent/dissociative thinking, aggressiveness, hallucinations, agitation, ideas of reference, anxiety, inability to make decisions, psychomotor agitation, motivation toward achievement, impoverished and restricted thinking, and ambivalent behavior were reported. Symptoms such as lack of self-confidence, fear of failure, psychomotor retardation, irritability, slowed thinking, blunted affect, and unhappiness showed no improvement or deteriorated during treatment with clozapine (Siefen and Remschmidt, 1986).

The most frequent untoward effects observed early in treatment with clozapine were daytime sedation, dizziness, tachycardia, orthostatic hypotension, sleepiness, and increased salivation. No patients developed agranulocytosis, and the hematologic changes that occurred in approximately 25% of patients were clinically insignificant and normalized during continued maintenance on clozapine (Siefen and Remschmidt, 1986).

Schmidt et al. (1990) reported a total of 57 cases of children and adolescents (age range, 9.8 to 21.3 years; mean, 16.8 years; 30 males and 27 females) who were treated with clozapine. Forty-eight patients were diagnosed with a schizophrenic disorder, five with schizoaffective disorder, two with monopolar manic disorder, and two with pervasive developmental disorders (PDDs). These patients had a mean duration of illness of 19.4 months (range, 0 to 74 months) before this hospitalization, which was the first for 16 patients, the second for 16 patients, and the third or more for the remaining 25 patients. Clozapine was begun on an average approximately 3 months after hospitalization following treatment failures with other antipsychotic drugs and concern about chronicity, intolerable untoward effects, or uncontrolled excitation. Average dose during the length of hospitalization was 318 mg/day (range, 50 to 800 mg/day); average dose at discharge was somewhat lower, 290 mg/day (range, 75 to 800 mg/day). Thirty-five patients received only clozapine. In 22 cases, one or more additional other neuroleptics, primarily phenothiazines, were administered simultaneously, but in about one-half of these cases the additional drugs were tapered off and discontinued so that eventually 80% of the patients were on clozapine only. Mean duration on clozapine during hospitalization was 78 days (range, 7 to 355 days), and 17 (31%) patients were discharged on clozapine.

Clozapine was discontinued in 15 (28%) of the patients between the 8th and 132nd days of treatment (average, 50th day) when they were taking a mean dose of 143 mg/day (range, 25 to 350 mg/day) for the following reasons: insufficient antipsychotic effect in 7 cases; poor compliance and a change to
depot medication in 5 cases; and severe untoward effects in 3 cases (cholinergic delirium, seizure, and questionable clinically significant decrease of erythrocytes to 2.3 million).

The authors reported that two-thirds of the patients significantly improved in the whole range of symptoms. Paranoid-hallucinatory symptoms and excitation responded best, followed by a reduction in aggressivity. Clozapine was less effective in decreasing agitation and improving negative symptoms, and these symptoms sometimes worsened. Untoward effects were noted in all subjects. These included increased heart rates (during the first 8 weeks only) from 94 to 109 beats per minute in 37 (65%) patients, daytime sedation in 29 (51%) patients, hypersalivation in 20 (35%) patients, orthostatic hypotension in 20 (35%) patients, and an unspecified rise in temperature in 15 (26%) patients. Abnormal movements were observed in nine patients, including tremor (six cases), akathisia (one case), and unspecified EPS in two cases. During the first 16 weeks of clozapine therapy, a significant decrease of various hematologic parameters, including number of erythrocytes, was observed, but did not reach pathologic values; a relative shift from lymphocytes to neutrophils was seen in the differential during the first 2 weeks. There was a reversible increase in liver enzymes, which peaked during the third and fourth weeks. On EEGs, there was evidence that clozapine induced increased neuronal disinhibition (e.g., spike discharges) and a shift in background activity to lower frequencies. Pathologic EEG changes were present in 30 (55%) patients on clozapine compared with 17 (30%) patients before its administration (P < .01). One patient developed a seizure (Schmidt et al., 1990). The authors later noted that they considered EEG monitoring before and during treatment with clozapine to be mandatory (Blanz and Schmidt, 1993).

Birmaher et al. (1992) treated three inpatient adolescents (an 18-year-old female and two 17-year-old males) with clozapine; they were diagnosed with schizophrenia that was chronic and resistant to treatment with standard antipsychotics. Clozapine was titrated upward, resulting in markedly better symptom control than was achieved in previous drug trials. Doses at discharge were 100 mg/day for the female and 300 mg/day for the two males. The female patient experienced a reexacerbation of symptoms after approximately 1 year despite good compliance, and rehospitalization was required. She was discharged in 2 weeks, but it was necessary to increase clozapine to 400 mg/day; her functioning was described as satisfactory, but some auditory hallucinations remained.

The only untoward effects that these three patients complained about were sedation and increased salivation, and these gradually remitted. The buccolingual dyskinesia, which one of the males had developed during treatment with standard antipsychotics, disappeared while on clozapine (Birmaher et al., 1992).

Mandoki (1993) administered clozapine to two hospitalized males of age 14 and 16 years, diagnosed with schizophrenia, who had unsatisfactory responses to trials of many medications, including antipsychotics. The younger patient had predominantly severe negative symptoms and the older one predominantly severe positive symptoms. Clozapine in doses of 300 to 400 mg/day resulted in significant improvements. The 14-year-old was discharged on 300 mg/day of clozapine 11 weeks after clozapine treatment began. At follow-up, he was attending school. Clozapine had been increased to 200 mg every morning and 400 mg at bedtime. Untoward effects were significant weight gain, mild hypersalivation, and severe drowsiness. The 16-year-old was discharged on 300 mg/day of clozapine 2 months after beginning clozapine. Dose was increased to 400 mg/day after 2 months because inappropriate touching behaviors recurred. No untoward effects were reported. At follow-up, both adolescents were continuing to experience gradual clinical improvement.

Remschmidt et al. (1994) reported a retrospective study of 36 adolescent inpatients aged 14 to 22 years, diagnosed with schizophrenia, who were treated on
an open basis with clozapine following treatment failures with at least two other antipsychotic drugs. Doses ranged from 50 to 800 mg/day (mean, 330 mg/day), and the mean duration of clozapine administration was 154 ± 93 days. Twentyseven patients (75%) had clinically significant improvement; four (11%) had complete remissions. Three patients (8%) showed no improvement. Six (17%) developed untoward effects necessitating the discontinuation of clozapine: leukopenia without agranulocytosis (two patients); hypertension, tachycardia, and ECG abnormalities (two); elevations in liver transaminases to 10 times normal values without other signs of hepatitis (one); and worsening of symptoms and development of stupor when given in combination with carbamazepine 400 mg/day (one). Five patients developed EPS over a period of several months: Four (11%) developed akathisia and one developed a course tremor. Overall, positive symptoms improved significantly more than negative symptoms. For example, delusions, hallucinations, and excitation improved in approximately 65% of patients. Some negative symptoms (e.g., flat affect and autistic behavior) showed little improvement, but other negative symptoms (e.g., anergy, muteness, bizarre behavior, and thought blocking) showed improvement in 11% to 22% of the patients. Nine (90%) of 10 patients who had predominantly negative symptoms did not improve clinically.

Levkovitch et al. (1994) treated 13 adolescents (7 males and 6 females; mean age, 16.6 years; range, 14 to 17 years) who were diagnosed with adolescent-onset schizophrenia with clozapine. All had experienced treatment failures, with an average of three traditional antipsychotics. Patients received an average daily dose of 240 mg of clozapine for a mean of 245 days. After 2 months, 10 patients (76.9%) showed significant improvement of at least a 50% decrease in scores on the Brief Psychiatric Rating Scale (BPRS); 2 patients showed more modest improvements. Clozapine was discontinued after 2 days in one patient because of significant orthostatic hypotension. Other untoward effects were tiredness in four (30.8%) patients, hypersalivation in one (7.7%), and temperature elevation in one (7.7%). No leukopenia occurred during weekly monitoring.

Frazier et al. (1994) treated 11 hospitalized adolescents (age range, 12 to 17 years; mean, 14.0 ± 1.5 years) diagnosed with childhood-onset schizophrenia with a 6-week open trial of clozapine. Subjects were chronically and severely ill and had received at least two previous neuroleptic medications without significant clinical benefit or experienced intolerable untoward effects. Following a 4-week washout/observation period, clozapine was begun at 12.5 or 25 mg/day. Dose was titrated individually based on symptom response versus untoward effects and increased by one to two times the initial dose every 4 days to a potential maximum of 900 mg/day. The main untoward effects responsible for limiting dose increases were tachycardia (three patients) and sedation (seven patients). Other untoward effects reported included hypersalivation (eight patients), weight gain (seven), enuresis (four), constipation (four), orthostatic hypotension (two), nausea (one), and dizziness (one).

Extrapyramidal untoward effects also occurred: Four adolescents developed akathisia after several months and one developed a coarse tremor. The mean dose of clozapine at the end of the 6-week period was 370.5 mg/day (range, 125 to 825 mg/day). Six (55%) of the patients improved over 30% on the BPRS on optimal dose of clozapine, compared with admission ratings when nine of the patients were receiving other drugs; nine (82%) of the patients improved on clozapine over 30% on the BPRS compared with ratings during the washout period. Nine of the 11 patients also received 6-week courses of haloperidol following 4-week washout/observation periods during their hospitalizations; of these, 5 (56%) showed more than a 30% improvement on the BPRS while on clozapine, compared with earlier ratings while on haloperidol. Both positive and negative symptoms of schizophrenia improved (Frazier et al., 1994).

Mozes et al. (1994) treated four children with clozapine; the three males and one female, 10 to 12 years of age, were diagnosed with schizophrenia and had not responded satisfactorily to other neuroleptics. Clozapine was begun in doses of 25 to 100 mg/day and titrated upward. Three patients had significantly reduced symptomatology in <2 weeks. Further decreases in both positive and negative symptoms occurred during the next 10 to 15 weeks of treatment. All four children improved significantly on the BPRS, with a mean reduction of 41 within 15 weeks. At the time of the report, patients had been in treatment between 23 and 70 weeks, and maintenance dosage ranged from 150 to 300 mg/day. The most frequent untoward effect was drooling, which spontaneously decreased over time; drowsiness, experienced by three patients, peaked during the first week and then gradually faded away. Excitatory EEG changes occurred in three patients, and dosage was not increased to decrease the likelihood of seizures. Of note, two cases of TD caused by previous neuroleptic drugs disappeared on clozapine.

Kumra et al. (1996) reported a double-blind study comparing clozapine and haloperidol in 21 hospitalized patients (11 males, 10 females; mean age, 14.0 ± 2.3 years) who had been diagnosed with schizophrenia by DSM-III-R (American Psychiatric Association [APA], 1987) criteria by age 12 and who were treatment refractory. All patients had failed to respond to at least two standard neuroleptics, often at high doses, and augmented with mood stabilizers or antidepressants; most patients also had failed to respond to risperidone. Medications were discontinued over a 2-week period, which was followed by a 4-week washout before active medication whenever this could be tolerated. Patients were randomly assigned to a 6-week parallel treatment with clozapine (N = 10) or haloperidol (N = 11); the two groups did not differ significantly on any demographic variables. To maintain the blind and to minimize any extrapyramidal effects secondary to haloperidol, all patients receiving that drug were prescribed up to 6 mg/day of benztropine, whereas subjects on clozapine received identical placebo tablets. Initial doses were based on patients’ weights and ranged from 6.25 to 25 mg/day for clozapine and from 0.25 to 1.0 mg/day for haloperidol. Increases in the dose by one or two times the initial dose were permitted every 3 to 4 days if clinically indicated. Three patients receiving clozapine and one patient on haloperidol were unable to complete the 6-week trial because of severe untoward effects and were dropped during the fourth and fifth weeks, and the ratings of the final week were carried forward in data analysis. The mean dose of haloperidol during the last treatment week was 16.0 ± 8 mg/day (range, 7 to 27 mg/day) or 0.29 ± 0.19 mg/kg/day (range, 0.08 to 0.69 mg/kg/day). The mean dose of clozapine during the last treatment week was 176 ± 149 mg/day (range, 25 to 525 mg/day) or 3.07 ± 2.59 mg/kg/day (range, 0.34 to 7.53 mg/kg/day); the mean dose of clozapine for the seven subjects who completed the entire 6-week trial was higher: 239 ± 134 mg/day. Clozapine was statistically superior to haloperidol on ratings at the 6-week endpoint on the BPRS (P = .04), the Bunney-Hamburg Psychosis Rating Scale (P = .02), the Scale for the Assessment of Positive Symptoms (P = .01), and the Scale for the Assessment of Negative Symptoms (P = .002). Clozapine was also superior to haloperidol on the depression (P = .02), thinking disturbance (P = .05), withdrawal (P = .03), and total (P = .03) rating scores on the BPRS. After the double-blind study was completed, the 11 patients who received haloperidol were administered clozapine openly for 6 weeks. The combined sample of 21 subjects was rated on the Clinical Global Impressions (CGI) Scale as follows: very much improved, 2 (9.5%); much improved, 11 (52.4%); minimally improved, 7 (33%); and worsened, 1 (4.8%). The authors also noted that for some patients, clinical improvement continued and peaked only after 6 to 9 months of treatment, as has been reported for adults.

Despite the superiority of clozapine over haloperidol, Kumra et al. (1996) noted serious untoward effects secondary to clozapine. Five of the 10 patients in the double-blind portion developed toxic hematopoietic effects with an ANC
of <1,500. In three patients, the WBC normalized spontaneously and they were successfully restarted on clozapine; the other two patients, however, had recurrences of neutropenia when rechallenged with clozapine and were dropped from the study. One patient developed myoclonus and had a tonic-clonic seizure the next day; epileptiform spikes continued on the EEG despite lowering the dose of clozapine and antiepileptic medication, and clozapine was discontinued. Another patient who had bifrontal and posterior delta wave slowing during the study had tonic-clonic seizures as an outpatient on 275 mg/day of clozapine and continued to have petit mal seizures despite a reduction in dosage and treatment with valproate sodium, necessitating discontinuation of clozapine. Three of the 11 patients treated openly with clozapine also developed significant EEG changes associated with worsening behavior, such as increased aggression, psychosis, or irritability. Two of these individuals improved with a reduction of the dose of clozapine and addition of valproate sodium; however, the third experienced further clinical deterioration and facial myoclonus with associated EEG spikes, which required the discontinuation of clozapine. Children and adolescents appear to be at greater risk than adults to develop clinically significant EEG changes. One patient on clozapine had clinically significant increases in liver enzymes and two had tachycardias of more than 100 beats per minute. The authors also felt that excessive weight gain occurred secondary to clozapine; the two best responders during the doubleblind protocol gained the most weight. Only one patient was dropped from the haloperidol group, and that was for signs of incipient neuromalignant syndrome; the discontinuing of haloperidol and initiation of supportive measures resulted in normalization of laboratory abnormalities and vital signs within a few days. The extrapyramidal tract untoward effects expected from haloperidol were minimized by the prophylactic benztropine. This study provides significant support for the importance of clozapine in treatment-resistant schizophrenia in children and adolescents but underscores the importance of monitoring the WBC for untoward effects, such as neutropenia/agranulocytosis, and to monitor EEGs for epileptiform changes, to observe for myoclonic movements that may progress to tonic-clonic seizures, and for seizures as the pediatric age group may be at greater risk for all of these than are adults.

In a naturalistic treatment study, Kranzler et al. (2005) administered open-label clozapine, using a flexible titration schedule, to 20 treatment-refractory adolescents (14 males, 6 females; median age 14.19 years; age range 8.5 to 18 years) diagnosed with schizophrenia and hospitalized in a long-term treatment facility (Bronx Children’s Psychiatric Center) to evaluate its effectiveness in the treatment of aggression. Subjects were judged to be acutely ill and required a change of medication because of the severity of their psychosis and aggression when clozapine was introduced. The current medication regime was continued and there was a slow cross taper with clozapine. Using a mirror-image study design, effectiveness was measured by comparing the number of emergency oral and injected medications and frequency of seclusion or restraint events in the 12 weeks immediately preceding the trial of clozapine and during a similar period (from week 12 through 24 of clozapine treatment) when optimal clozapine levels had been reached. The mean dose at week 24 was 476 ± 119 mg/day, and 11 of the 20 subjects were on clozapine monotherapy. Comparison of preclozapine and optimal clozapine measures implemented for aggressive behavior showed significant decreases in emergency oral medication (P = .000), injectable medication (P = .007), and seclusion events (P = .003). Another significant finding was that patients who had been hospitalized for a shorter length of time when started on clozapine showed a significantly greater reduction in seclusion events than subjects who had been hospitalized for longer periods when the switch to clozapine was made (P = .033). These data suggested that, in such a patient population, clozapine reduces the incidence and severity of violence and aggression and may hasten discharge to a
less restrictive setting. The authors think that clozapine treatment may be underutilized because of concerns about its untoward effects and the necessary frequent monitoring with blood tests.

There is a “Black Box Warning” that there is increased mortality in elderly patients with dementia-related psychosis who are treated with atypical antipsychotic drugs including risperidone.

Kumra et al. (1997) reviewed the medical records of the 13 children and adolescents (3 males and 10 females) diagnosed with schizophrenia who were admitted to the NIMH over a period of 28 months and treated with risperidone. Two of the three males, but none of the females, showed evidence of steatohepatitis with obesity, elevated liver enzyme values, and evidence of fatty liver on ultrasound, which was confirmed by biopsy in one case. Following discontinuation of risperidone, liver function tests returned to normal within 2 weeks to 3 months. The authors noted that two additional males who were subsequently admitted developed hepatotoxicity during long-term treatment with risperidone. The authors strongly recommended determining baseline liver function tests, obtaining liver aminotransferases, cholesterol, and triglycerides every 3 months, and monitoring weight frequently in pediatric patients who are being maintained on risperidol. Males in this age range may be particularly at risk for hepatotoxicity.

Szigethy et al. (1999) retrospectively reviewed the charts of 38 children and adolescents (32 males, 6 females; mean age, 10.6 ± 3.7; age range, 4 to 17 years) who had been treated with a mean dose of 2.5 mg/day (range, 0.5 to 10.0 mg/day) or 0.05 mg/kg/day (range, 0.01 to 0.11 mg/kg/day) of risperidone for a mean of 15.2 ± 10.0 months (range, 1 to 35 months) to assess hepatic function during risperidone treatment and to identify any clinical factors associated with hepatic dysfunction. Diagnoses of the subjects were autistic disorder (N = 12), other PDDs (N = 8), mood disorders (N = 6), disruptive behavior disorders (DBDs) (N = 7), and psychotic disorders (N = 5). Thirty-seven (97.4%) of the subjects had normal values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin after treatment with risperidone for a mean duration of 12.2 ± 9.8 months
(range, 1 to 30 months). The thirty-eighth subject, who had received 24 months of risperidone and a peak dose of 4 mg/day, had an ALT of 46 U/L, 7 U/L above the upper limit of normal, which was not considered clinically significant. Baseline liver function tests were available for 14 subjects; comparison of these values with those obtained after an average of 5.47 ± 4.9 months (range, 1 to 19 months) showed no clinically meaningful increases. All subjects for whom baseline weights were available gained weight during treatment (see following text). The authors noted that obesity itself is associated with both steatohepatitis and elevated transaminases and that weight gain alone may have caused the elevated ATL in their patients. Overall, the authors concluded from their review that the risk for risperidone-induced hepatotoxicity is probably low in relatively short-term therapy in this age group.

Weight gain is often a problem in patients treated with risperidone, usually secondary to a marked increase in appetite. Horrigan and Barnhill (1997) noted a positive correlation between the degree of clinical improvement, increased appetite, and weight gain. They noted that serotonin plays a role in signaling satiety and that, by blocking 5-HT₂ receptors, risperidone may cause dysregulation of the “satiety switch.”

In their chart review of 38 patients who received risperidone, Szigethy et al. (1999) reported that weight gain occurred in all 23 subjects for whom baseline weights were available; mean baseline weight was 37.92 ± 16.0 kg (range, 15.0 to 73.6 kg), and mean end-of-study weight was 48.28 ± 18.97 kg (range, 19.10 to 82.95 kg). The mean weight gain was 1.01 ± 0.73 kg/month (range, 0.18 to 3.1 kg/month). The mean duration of risperidone therapy for all 38 subjects was 15.2 ± 10.0 months (range, 1 to 35 months), demonstrating that risk of weight gain with risperidone therapy is an important therapeutic issue.

Martin et al. (2000) conducted a retrospective chart review comparing 37 child and adolescent inpatients treated for a minimum of 6 continuous months with risperidone, with 33 inpatients having no exposure to atypical antipsychotics with regard to baseline weight, standardized z scores of weight for age and gender, and percentage of subjects whose weight increased ≥7% (chosen a priori as the standard cutoff for extreme weight gain in clinical trials). After 6 months of risperidone, significantly more subjects on risperidone (78%) versus 24% of controls gained ≥7% of their baseline weight (P = .001). A significant difference was evident within 2 months of treatment (P = .001). Risperidone-treated subjects gained an average of 1.2 kg/month over the 6-month study, and their weight gain showed no tendency to plateau during that period. There was no correlation between dose of risperidone and demographic or clinical characteristics such as discharge diagnosis or concomitant medication. Weight gain is an important consideration in the treatment of children and adolescents with risperidone and must be considered in the risks and benefits discussed as part of the informed consent process.

Risperidone may cause elevations of prolactin that are significantly above normal values and may persist during chronic administration. This is discussed in detail and relevant literature reviewed under the section “Prolactin Levels” in Chapter 2.

Epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events (AEs) in patients treated with atypical antipsychotic drugs, including risperidone (PDR, 2006).

Orthostatic hypotension, dizziness, tachycardia, increase of QTc interval on ECG to >450 msec, insomnia or somnolence, constipation, rhinitis, and many other untoward effects have been reported.

The efficacy and safety of risperidone in the short-term treatment of schizophrenia in adolescents aged 13 to 17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment.

In the first trial (study 1), patients were randomized into one of three treatment groups: Risperdal 1 to 3 mg/day (N = 55, mean modal dose = 2.6 mg), Risperdal 4 to 6 mg/day (N = 51, mean modal dose = 5.3 mg), or placebo (N = 54). In the second trial (study 2), patients were randomized to either Risperdal 0.15 to 0.6 mg/day (N = 132, mean modal dose = 0.5 mg) or Risperdal 1.5 to 6 mg/day (N = 125, mean modal dose = 4 mg).

In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15 to 0.6 mg/day group in study 2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS) score. Results of the studies demonstrated efficacy of Risperdal in all dose groups from 1 to 6 mg/day compared with placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1-to-3-mg/day group was comparable to the 4-to-6-mg/day group in study 1, and similar to the efficacy demonstrated in the 1.5-to-6-mg/day group in study 2. In study 2, the efficacy in the 1.5-to-6-mg/day group was statistically significantly greater than that in the 0.15-to-0.6-mg/day group.

Doses higher than 3 mg/day did not reveal any trend toward greater efficacy (Risperdal [package insert], 2010).

The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. The Research Units on Pediatric Psychopharmacology (RUPP) Autism Network Study Part 1 was a randomized 8-week, multisite, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study. This study was to compare the safety and efficacy of risperidone and placebo in the treatment of severe tantrums, aggression, and/or self-injurious behavior (SIB) in 101 children (82 males, 19 females; age range 5 to 17 years, mean age 8.8 + 2.7 years) who were diagnosed with autistic disorder by DSM-IV (APA, 1994) criteria (McCracken et al., 2002). The primary outcome measures were the Irritability subscale of the Aberrant Behavior Checklist (ABC) and the Clinical Global Impressions-Improvement (CGI-I) Scale; a positive response required a minimum 25% reduction on the Irritability score and a rating of 1 or 2 (much improved or very much improved) on the CGI-I Scale at time 8 weeks. Forty-nine subjects were assigned to risperidone and 52 to placebo.

The initial dose of risperidone was determined by subjects’ weights. More than 90% of these subjects were below 12 years of age and most weighed more than 20 kg (16 to 104.3 kg). Children weighing ≤20 kg received 0.25 mg daily; those weighing 20 to 45 kg received 0.5 mg daily at bedtime for the first 3 days and then increased to 0.5 mg twice daily on Day 4 followed by titration in 0.5-mg increments to a maximum of 1 mg in the morning and 1.5 mg at bedtime by Day 29. Children weighing ≥45 kg were prescribed medication at a somewhat accelerated rate to achieve a maximum permitted dose of 1.5 mg in the morning and 2.0 mg
at bedtime. The final mean dose of risperidone was 1.8 + 0.7 mg/day, with a range of 0.5 to 3.5 mg.

At time 8 weeks, subjects on risperidone had a 56.9% decrease on the Irritability subscale of the ABC versus 14.1% decrease for subjects receiving placebo (P < .001). On the CBI-I Scale, 75.5% of subjects on risperidone were rated 1 or 2 (very much improved or much improved) versus only 11.5% of subjects on placebo. Positive responders included 69% of the risperidone group versus only 12% of the group on placebo (P < .001). The authors also noted that, compared with the group receiving placebo, the risperidone group improved significantly on the Stereotypy and Hyperactivity Scales, but there were no significant differences on the Social Withdrawal and Inappropriate Speech Scales of the ABC. The authors also noted that 23 of the 34 subjects who were “responders” continued to show benefit after 6 months on medication.

No child dropped out of the study because of AEs; no serious AEs occurred in the risperidone group and most were mild and self-limited (e.g., fatigue/drowsiness subsided in most subjects within 4 to 6 weeks). Increased appetite (“mild” 49% vs. 25%, P = .03; “moderate” 24% vs. 4%, P = .01), fatigue 59% versus 27%, drowsiness 49% versus 12% (P < .001), dizziness 16% versus 4% (P = .05), and drooling 27% versus 6% (P = .02) were each significantly more frequent in the risperidone group than in the placebo group. Over the 8-week study, subjects on risperidone gained significantly more weight—an average of 2.7 + 2.9 kg versus 0.8 + 2.2 kg for subjects in the placebo group (P < .001). Three (6%) of the subjects in the risperidone group withdrew from the study because of lack of clinical efficacy versus 18 (35%) of the subjects in the placebo group, of whom 12 withdrew because of lack of clinical efficacy (P = .001).

The authors concluded that risperidone was safe and effective with a favorable risk-benefit ratio in the short-term treatment of children diagnosed with autistic disorder. Significant improvements were noted in tantrums, aggression, SIB, stereotypic behavior, and hyperactivity.

Aman et al. (2005) reported further on the long-term safety and efficacy of risperidone for up to 6 months in the subjects in an 8-week double-blind, placebocontrolled trial reported by McCracken et al. (2002). Upon completion of this 8-week study, 37 placebo nonresponders were treated with risperidone on an open basis for an additional 8 weeks; of these subjects, 30 who responded to risperidone then entered a 16-week open extension phase of treatment with risperidone (Scahill et al., 2001). Of the 34 risperidone responders in the initial 8-week double-blind, placebo-controlled trial, 30 entered the 16-week open extension phase of treatment with risperidone. An additional 3 subjects who were in the risperidone group during the initial 8-week placebo-controlled double-blind study but did not meet all criteria to be “responders” were also enrolled in the 16-week extension phase for a total of 63 subjects; the authors noted that including these 3 subjects in the analyses did not alter clinical results for any outcome. Finally, upon completing the 16-week open extension, 32 of the 63 subjects were rerandomized in an additional 8-week, double-blind phase to either continue therapy with risperidone (N = 16) or to enter a placebo substitution phase (N = 16) during the first 4 weeks of which risperidone was reduced by 25% of the dose each week with only placebo being given for the last 4 weeks. The authors noted that only 32 subjects participated in this final phase as interim analysis showed that significantly more subjects relapsed on placebo compared with those maintained on risperidone (62.5% vs. 12.5%, P = .01), and they then stopped this portion of the study.

Regarding AEs, subjects on risperidone experienced the following significantly more frequently than those on placebo: daytime tiredness (94% vs. 54% “at all” and 37% vs. 12% moderate/severe; P < .0001), difficulty waking (P = .05), excessive saliva/drooling (29% vs. 16%; P = .04), and dizziness/loss of balance (22% vs. 8%; P = .04). On the other hand, difficulty falling asleep (65% vs. 47%; P = .02)
and anxiety (48% vs. 32%; P = .05) were significantly more frequent in the placebo group than in the risperidone group. Excessive appetite was reported in 82% of the risperidone group versus 38% in the placebo group. There was significantly greater weight gain in the risperidone group; however, the authors noted that weight gain decelerated over time with ongoing risperidone treatment. There were no significant changes in height. As noted in the preceding text, only three (6.1%) of the subjects who were treated with risperidone dropped out of the study during the initial 8-week period (McCracken et al., 2002).

During the 16-week extension, six (9.5%) of the subjects treated with risperidone dropped out because of AEs and two of these were because of seizures, which did not appear to be related to risperidone (Aman et al., 2005). The authors concluded that safety and tolerability remained favorable in treating these subjects. They cautioned that the number of patients in the study was too small to identify infrequent/rare AEs and likewise too short in duration to determine rates of TD, obesity, and diabetes.