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11-11-07, 07:50 PM
Atypical Antipsychotics
The use of atypical antipsychotics in children with AD is based, in part, on their efficacy in the treatment of psychiatric disorders that have behavioral symptoms similar to the core symptoms seen with AD (eg, negative symptoms of schizophrenia), their relatively safe adverse effect profile in comparison with older, conventional antipsychotics, and the possible role of dopamine in the etiology of AD.<sup>[20,22]</sup>
Published reports on the use of atypical antipsychotics (ie, olanzapine, aripiprazole, ziprasidone, quetiapine) include case reports, case series, retrospective reviews, and open-label or double-blind trials ( Table 2 (http://www.medscape.com/viewarticle/555747_Tables#T2) ).<sup>[23-39]</sup>
Olanzapine
Nine reports describing the use of olanzapine in children, adolescents, and adults with AD were found in the literature and included case reports or case series, chart reviews, and open-label or double-blind trials.<sup>[23-30]</sup>
Horrigan et al.<sup>[23]</sup> described the use of olanzapine in a 10-year-old child with severe mental retardation, AD, and bipolar disorder who experienced aggression, explosive rage, hand-flapping, vocalizations, and increased motor activity on a cyclic basis. The child had not responded to treatment with other psychotropic agents (including carbamazepine, valproic acid, fluoxetine, clomipramine, clonidine, molindone, haloperidol, risperidone, naltrexone, buspirone) and had a limited, short-lived (6 mo) response to thioridazine, lithium carbonate, and fenfluramine, despite increasing doses. Olanzapine was initiated at 10 mg daily with concurrent lithium carbonate. Shortly after olanzapine was begun, there was a 75% reduction in target behaviors. Since it was thought that the child might metabolize drugs rapidly, a dose of 10 mg twice daily was used for maintenance therapy. Information on the duration of response to olanzapine beyond 6 weeks was not given.
Olanzapine 10 mg at bedtime resulted in 90% control of target behaviors in a 9-year-old child with mild mental retardation, receptive/expressive language disorder, and bipolar disorder.<sup>[23]</sup> As in the first case, the child had failed therapy with antipsychotics, antidepressants, and mood stabilizers. Improvement in symptoms and behavior was seen within 7 days of beginning treatment with olanzapine. Only mild sedation was reported.
In another case report, an 8-year-old child with AD, aggressive behavior, and hyperactivity remained symptomatic despite several unsuccessful therapeutic trials (including methylphenidate, clomipramine, carbamazepine, haloperidol, thioridazine).<sup>[24]</sup> The addition of buspirone resulted in increased hyperactive behavior. Olanzapine was begun at a dose of 2.5 mg twice daily and increased to 2.5 mg 3 times daily 2 days later. A significant improvement in aggressive and hyperactive behavior was seen. No adverse effects were reported.
Olanzapine was used for treatment of 7 adults and children with developmental disorders.<sup>[25]</sup> For the children, olanzapine was given at a dose of 7.5 or 10 mg daily at bedtime. One child was treated concurrently with dextroamphetamine and the other with risperidone, methylphenidate, and clonidine. Clinically significant improvement in behavior was seen for all patients. The mean duration of treatment was 17.7 months, with sustained effects seen for all patients. Sedation occurred in 4 patients and was managed by administering the drug in the evening.
A chart review was conducted to evaluate olanzapine treatment in 12 children (5-17 y old) with behavioral or developmental disorders.<sup>[26]</sup> Seven children had some degree of mental retardation, most had more than one diagnosis, and 10 had failed therapy with other psychotropic agents. Olanzapine was given for aggression, hyperactivity, self-injurious behavior, hallucinations, and sleep disturbances. Treatment was discontinued in 8 children after a mean of 50 days due to adverse events (6), lack of efficacy (5), exacerbation of symptoms (2), or a combination of these effects. Treatment was considered beneficial in 3 patients. Appetite increase and sedation were the most commonly reported adverse events; slurred speech, drooling, tremulousness, and suicidal ideation also occurred.
Although the efficacy of treatment was not described, London<sup>[40]</sup> reported the onset of mania in a 16-year-old patient treated with olanzapine for severe aggressive behavior, mood instability, atypical ideation, and PDD. The antipsychotic was begun at a dose of 7.5 mg daily to control atypical thinking and behavior. Acute mania developed within 2-3 weeks and gradually resolved with discontinuation of olanzapine.
Three open-label trials of olanzapine in the treatment of AD were found. Potenza et al.<sup>[27]</sup> treated 8 patients (aged 5-42 y, mean ± SD 20.9 ± 11.7 y) with olanzapine for 12 weeks following 4 weeks with no treatment. The dose of olanzapine was initiated at 2.5 mg/day and maintained for at least 2 weeks before dose adjustments were made based on clinical response. Standardized behavioral rating scales were used to determine the response to treatment.
Of 7 patients who completed 12 weeks of treatment, 6 were considered responders. Significant improvement from baseline was also seen for the Ritvo-Freeman Real-Life Rating Scale (RF) overall and subscale (sensory motor behaviors, social relationships, affectual reactions, sensory responses, language use and response) scores, Vineland Adaptive Behavior Scale Maladaptive Behavior total and subscale (including anxiety, impulsivity, temper, and social withdrawal measures; rocking and inappropriate sexual or destructive behaviors) scores, Self-Injurious Behavior Questionnaire scores, and visual analog scale scores of anxious, calm, irritable, restless, aggressive, depressed, and fearful. Significant changes were not seen for other behavioral ratings. Weight gain and sedation were the 2 most frequent adverse events, occurring in 6 and 3 patients, respectively. During the 12 week period, group weight increased from a mean of 62.50 ± 25.37 kg to 70.88 ± 25.06 kg (p = 0.008). Two responders discontinued treatment at 14 and 20 weeks due to continued weight gain.<sup>[27]</sup>
In a second open-label trial, 12 children with AD were randomly assigned to treatment with either olanzapine or haloperidol for 6 weeks following a 1 week period with no treatment.<sup>[28]</sup> The children ranged in age from 4.9 to 11.8 years (mean 7.8 ± 2.1 y). The primary outcome measure used was the Clinical Global Impressions Improvement (CGI-I) scale; secondary measure was the Children's Psychiatric Rating Scale (CPRS) with 4 factors (autism, anger/uncooperativeness, hyperactivity, speech deviance).
No significant difference was seen in CGI-I scores between the 2 treatment groups. For CGI-Severity of Illness (CGI-S) scores, both treatments resulted in nonsignificant improvement from baseline (p = 0.076). Olanzapine and haloperidol were associated with significant improvement from baseline in CPRS autism factor scores (p = 0.0008), for CPRS hyperactivity factor (p = 0.012), and for CRPS anger/uncooperativeness factor (p = 0.049). No significant effect of treatment was seen for CPRS speech deviance factor. Drowsiness and weight gain were the most common adverse events reported, with patients given olanzapine reporting a higher weight gain compared with those who received haloperidol (mean 4.1 vs 1.45 kg; p = 0.04).<sup>[28]</sup>
A third open-label trial enrolled 25 children (aged 6 to 16 y) with AD or PDD-NOS.<sup>[29]</sup> Following a 2 week washout period, olanzapine was started at a dose of 2.5 mg every other day or daily. Of 22 children who completed the trial, 3 were considered responders based on a CGI-I rating of much improved. A CGI-S rating of less ill was achieved by 12 children. Weight gain (mean 4.7 kg), increased appetite, and asthenia were the most frequent adverse events. No clinically significant prolongation of the QT interval was seen on electrocardiogram (ECG). Extrapyramidal symptoms were reported by 3 patients—2 had mild symptoms (gait and extremity rigidity, tremor, increased salivation, and/or leg pendulousness) and 1 had moderate symptoms (gait rigidity).
One double-blind, randomized trial compared olanzapine with placebo in children with PDD, including AD.<sup>[30]</sup> Eleven children (mean age 9 y, range 6-14) were randomly assigned to treatment with either olanzapine or placebo for 8 weeks. The starting dose of olanzapine ranged from 2.5 to 5 mg daily, with a maximum dose of 20 mg/day. The primary outcome variable was the physician-rated CGI-I score at 8 weeks, with secondary outcomes based on Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Overt Aggression Scale-Modified irritability and aggression subscales. Based on CGI-I scores, 3 of 6 children given olanzapine were considered responders, compared with 1 of 5 in the placebo group. No effect of treatment was seen for the secondary outcomes. Mean weight gain with olanzapine—primarily beginning after 3 weeks of treatment—was 3.4 kg ± 2.2 versus 0.68 kg ± 0.68 with placebo (p = 0.028). Sedation and increased appetite were the most common adverse effects associated with olanzapine. No patients experienced extrapyramidal symptoms.
Aripiprazole
One case series was found that described the use of aripiprazole in 5 patients ranging in age from 5 to 18 years (mean 12.2), with PDD.<sup>[31]</sup> Four of the children met criteria for AD; 1 had Asperger's disorder. All 5 children had been treated previously with atypical antipsychotics (2 with risperidone, 3 with olanzapine, 1 with quetiapine), but treatment was discontinued due to lack of efficacy, significant weight gain (7.7-13.6 kg), and/or adverse effects (including movement disorders in 1 child). Treatment with aripiprazole was continued for a minimum of 8 weeks. After 5-6 months, all children experienced improvement in behavior, with 3 considered very much improved and 2 much improved, based on CGI-I scores. Aripiprazole was generally well tolerated, with mild sedation reported; no child experienced extrapyramidal symptoms. Two children lost weight (5.45 and 13.6 kg), while 1 child gained 0.45 kg. The remaining 2 children did not have a change in weight.
In a second case series, Shastri et al.<sup>[32]</sup> reported the results of aripiprazole therapy in 5 adults with intellectual disabilities, including 1 with AD. Treatment was initiated at a dose of 10 mg daily and increased at 6 weeks to 15 mg daily. Use of aripiprazole resulted in improved behavior and a gradual reduction in aggressive behavior. The patient had previously required chlorpromazine or lorazepam for behavioral outbursts that occurred 4-5 times per week. These episodes were reduced to 1 or 2 per month, with little need for additional medications to control behavior. A weight loss of 12.7 kg was seen due to increased physical activity.
Ziprasidone
In a single case report, ziprasidone was used in the treatment of a 7-year-old autistic child with severe agitation (hyperactivity, irritability, impulsivity).<sup>[33]</sup> Ziprasidone 10 mg at bedtime resulted in rapid improvement in agitation, with additional improvements seen in cognition and language after 8 weeks of treatment. Both the parents and physician rated the child as much improved. Benefits were maintained during 8 months of treatment.
McDougle et al.<sup>[34]</sup> published a case series on the use of ziprasidone in AD. Ziprasidone was initiated at a dose of 20 mg at bedtime in patients (aged 9-20 years). Most had been previously treated with atypical antipsychotics, most commonly risperidone or olanzapine, and had failed to respond to treatment. Nine patients had gained weight during previous therapy (9.1-45.5 kg). The dose of ziprasidone was increased, based on patient response and tolerability. No dose increases were done after 6 weeks. Response to therapy was assessed using CGI-I ratings, determined by psychiatrists' evaluations, parents' observations, and progress notes. Patients were treated for a mean of 14.15 weeks.
After at least 6 weeks of treatment, 6 (50%) patients were considered responders; 2 were considered much worse. Sedation was the most common adverse effect, reported by 8 patients. Other reported adverse effects included oral dyskinesia (1), increased appetite (3), agitation (2), insomnia (2), tremor (1), and transient "lisping" (1). Mean change in body weight was -2.65 kg (range -15.9 to +2.7 kg). The mean dose of ziprasidone used was 59.23 mg/day.<sup>[34]</sup>
Cohen et al.<sup>[35]</sup> retrospectively assessed the efficacy and tolerability of ziprasidone in adults with AD and profound mental retardation (9 pts.). Data extracted included weight and Maladaptive Behavioral Scale (MBS) scores 6 months prior to, at initiation, and 6 months after treatment with ziprasidone. In addition, total cholesterol and triglycerides were assessed at baseline and 6 months following treatment. After comparing the average monthly frequency scores for MBS scores 6 months before ziprasidone with those 6 months after treatment, the authors determined that 7 patients had improved or remained clinically stable. Mean dose of ziprasidone used ± SD was 128 ± 4 mg daily. Eight patients lost weight (-5.95 ± 0.45 kg) during ziprasidone treatment; however, 1 patient gained 4.5 kg and another had stable weight posttreatment. Insignificant reductions in both total cholesterol and triglyceride levels were noted in 5 patients.
Quetiapine
A retrospective chart review evaluated the use of quetiapine in 10 children and adolescents with AD or PDD-NOS and related conditions (disruptive behavior, mental retardation, anxiety).<sup>[36]</sup> The mean age was 12 years (range 5-19). Quetiapine was initiated at a dose of 25 mg twice a day, with increases of 25-50 mg twice daily every 4-7 days. Six patients were considered responders to therapy. Adverse effects were described as mild and included sedation (3), tremor (1), and worsening sialorrhea (1). Seven patients experienced some degree of weight gain, ranging from 0.91 to 7.3 kg. Two patients experienced weight loss (-3.6 and -9.5 kg) and 1 patient had no change in weight, for a mean weight change ± SD of ± 1.0 ± 4.7 kg.
Corson et al.<sup>[37]</sup> identified patients (mean age 12.1 y; range 5-28 y) with AD or PDD-NOS treated with quetiapine for a mean of 59.8 weeks. Improvement from baseline was significant, with a mean change in CGI-S scores from markedly ill to moderately ill (p = 0.002). Forty percent of patients were considered responders (much improved or very much improved). However, mean changes in CGI-I scores for the group were considered low, with minimal improvement seen. Response rates were higher among patients with AD (7) compared with those with PDD-NOS (1). Adverse events were experienced by 10 of 20 patients and included persistent sedation (2), insomnia (1), pain (1), and weight gain (5). A mean weight gain of 5.7 ± 5.8 kg was reported (range 0.1-6.8 kg). One patient eventually discontinued treatment due to tardive dyskinesia.
Two open-label trials have evaluated the use of quetiapine in the treatment of AD in children. In one trial, 6 children with AD (mean age 10.9; range 6.2-15.3) were given quetiapine for a total of 16 weeks.<sup>[38,39]</sup> The dose was initiated at 25 mg daily at night and increased by up to 100 mg per week based on response. Behavioral ratings used to evaluate efficacy included ABC (Abberant Behavior Checklist, with subscales of irritability, lethargy, stereotypic behaviors, hyperactivity, inappropriate speech), CGI-Global Improvement scale, RF Scale (with subscales of sensory motor behaviors, social relationships, affectual reactions, sensory responses, language), and CY-BOCS. Only 2 patients completed the trial. Reasons for withdrawal from the study included lack of efficacy, with dose limited due to adverse events of sedation (3), behavioral activation and akathesia (1), and seizure (1). Increased appetite and weight gain were seen in 4 patients during the first 4 weeks of treatment. Mean weight gain was 2.9 ± 3.6 kg (range 0.9-8.2 kg). No difference was seen between baseline and end of treatment scores for any rating scale used. The 2 patients who completed the trial were considered much improved and very much improved.
The second trial included children ranging in age ± SD from 12 to 17.3 years (mean 14.6 ± 2.3).<sup>[39]</sup> Quetiapine was begun at a dose of 25 mg twice daily and titrated to a target dose of 150 mg twice daily. The dose could then be increased by 25 to 75 mg every other week to a maximum of 750 mg daily. Efficacy and safety of treatment were assessed using changes in various behavioral rating scales from baseline to 12 weeks. Six patients completed 12 weeks of treatment. Of the patients who discontinued treatment, 2 stopped due to adverse events—increased aggression/agitation and drowsiness. The most common adverse events reported included sedation (7), weight gain (5), increased agitation (4), and aggression (2). The daily dose of quetiapine ranged from 100 to 450 mg. Only 2 patients were considered responders to treatment based on CGI-I scores. Significant improvements from baseline were only seen for median CPRS and ABC subscales of lethargy, stereotypy, hyperactivity, and inappropriate speech.
http://www.medscape.com/viewarticle/555747_6
The use of atypical antipsychotics in children with AD is based, in part, on their efficacy in the treatment of psychiatric disorders that have behavioral symptoms similar to the core symptoms seen with AD (eg, negative symptoms of schizophrenia), their relatively safe adverse effect profile in comparison with older, conventional antipsychotics, and the possible role of dopamine in the etiology of AD.<sup>[20,22]</sup>
Published reports on the use of atypical antipsychotics (ie, olanzapine, aripiprazole, ziprasidone, quetiapine) include case reports, case series, retrospective reviews, and open-label or double-blind trials ( Table 2 (http://www.medscape.com/viewarticle/555747_Tables#T2) ).<sup>[23-39]</sup>
Olanzapine
Nine reports describing the use of olanzapine in children, adolescents, and adults with AD were found in the literature and included case reports or case series, chart reviews, and open-label or double-blind trials.<sup>[23-30]</sup>
Horrigan et al.<sup>[23]</sup> described the use of olanzapine in a 10-year-old child with severe mental retardation, AD, and bipolar disorder who experienced aggression, explosive rage, hand-flapping, vocalizations, and increased motor activity on a cyclic basis. The child had not responded to treatment with other psychotropic agents (including carbamazepine, valproic acid, fluoxetine, clomipramine, clonidine, molindone, haloperidol, risperidone, naltrexone, buspirone) and had a limited, short-lived (6 mo) response to thioridazine, lithium carbonate, and fenfluramine, despite increasing doses. Olanzapine was initiated at 10 mg daily with concurrent lithium carbonate. Shortly after olanzapine was begun, there was a 75% reduction in target behaviors. Since it was thought that the child might metabolize drugs rapidly, a dose of 10 mg twice daily was used for maintenance therapy. Information on the duration of response to olanzapine beyond 6 weeks was not given.
Olanzapine 10 mg at bedtime resulted in 90% control of target behaviors in a 9-year-old child with mild mental retardation, receptive/expressive language disorder, and bipolar disorder.<sup>[23]</sup> As in the first case, the child had failed therapy with antipsychotics, antidepressants, and mood stabilizers. Improvement in symptoms and behavior was seen within 7 days of beginning treatment with olanzapine. Only mild sedation was reported.
In another case report, an 8-year-old child with AD, aggressive behavior, and hyperactivity remained symptomatic despite several unsuccessful therapeutic trials (including methylphenidate, clomipramine, carbamazepine, haloperidol, thioridazine).<sup>[24]</sup> The addition of buspirone resulted in increased hyperactive behavior. Olanzapine was begun at a dose of 2.5 mg twice daily and increased to 2.5 mg 3 times daily 2 days later. A significant improvement in aggressive and hyperactive behavior was seen. No adverse effects were reported.
Olanzapine was used for treatment of 7 adults and children with developmental disorders.<sup>[25]</sup> For the children, olanzapine was given at a dose of 7.5 or 10 mg daily at bedtime. One child was treated concurrently with dextroamphetamine and the other with risperidone, methylphenidate, and clonidine. Clinically significant improvement in behavior was seen for all patients. The mean duration of treatment was 17.7 months, with sustained effects seen for all patients. Sedation occurred in 4 patients and was managed by administering the drug in the evening.
A chart review was conducted to evaluate olanzapine treatment in 12 children (5-17 y old) with behavioral or developmental disorders.<sup>[26]</sup> Seven children had some degree of mental retardation, most had more than one diagnosis, and 10 had failed therapy with other psychotropic agents. Olanzapine was given for aggression, hyperactivity, self-injurious behavior, hallucinations, and sleep disturbances. Treatment was discontinued in 8 children after a mean of 50 days due to adverse events (6), lack of efficacy (5), exacerbation of symptoms (2), or a combination of these effects. Treatment was considered beneficial in 3 patients. Appetite increase and sedation were the most commonly reported adverse events; slurred speech, drooling, tremulousness, and suicidal ideation also occurred.
Although the efficacy of treatment was not described, London<sup>[40]</sup> reported the onset of mania in a 16-year-old patient treated with olanzapine for severe aggressive behavior, mood instability, atypical ideation, and PDD. The antipsychotic was begun at a dose of 7.5 mg daily to control atypical thinking and behavior. Acute mania developed within 2-3 weeks and gradually resolved with discontinuation of olanzapine.
Three open-label trials of olanzapine in the treatment of AD were found. Potenza et al.<sup>[27]</sup> treated 8 patients (aged 5-42 y, mean ± SD 20.9 ± 11.7 y) with olanzapine for 12 weeks following 4 weeks with no treatment. The dose of olanzapine was initiated at 2.5 mg/day and maintained for at least 2 weeks before dose adjustments were made based on clinical response. Standardized behavioral rating scales were used to determine the response to treatment.
Of 7 patients who completed 12 weeks of treatment, 6 were considered responders. Significant improvement from baseline was also seen for the Ritvo-Freeman Real-Life Rating Scale (RF) overall and subscale (sensory motor behaviors, social relationships, affectual reactions, sensory responses, language use and response) scores, Vineland Adaptive Behavior Scale Maladaptive Behavior total and subscale (including anxiety, impulsivity, temper, and social withdrawal measures; rocking and inappropriate sexual or destructive behaviors) scores, Self-Injurious Behavior Questionnaire scores, and visual analog scale scores of anxious, calm, irritable, restless, aggressive, depressed, and fearful. Significant changes were not seen for other behavioral ratings. Weight gain and sedation were the 2 most frequent adverse events, occurring in 6 and 3 patients, respectively. During the 12 week period, group weight increased from a mean of 62.50 ± 25.37 kg to 70.88 ± 25.06 kg (p = 0.008). Two responders discontinued treatment at 14 and 20 weeks due to continued weight gain.<sup>[27]</sup>
In a second open-label trial, 12 children with AD were randomly assigned to treatment with either olanzapine or haloperidol for 6 weeks following a 1 week period with no treatment.<sup>[28]</sup> The children ranged in age from 4.9 to 11.8 years (mean 7.8 ± 2.1 y). The primary outcome measure used was the Clinical Global Impressions Improvement (CGI-I) scale; secondary measure was the Children's Psychiatric Rating Scale (CPRS) with 4 factors (autism, anger/uncooperativeness, hyperactivity, speech deviance).
No significant difference was seen in CGI-I scores between the 2 treatment groups. For CGI-Severity of Illness (CGI-S) scores, both treatments resulted in nonsignificant improvement from baseline (p = 0.076). Olanzapine and haloperidol were associated with significant improvement from baseline in CPRS autism factor scores (p = 0.0008), for CPRS hyperactivity factor (p = 0.012), and for CRPS anger/uncooperativeness factor (p = 0.049). No significant effect of treatment was seen for CPRS speech deviance factor. Drowsiness and weight gain were the most common adverse events reported, with patients given olanzapine reporting a higher weight gain compared with those who received haloperidol (mean 4.1 vs 1.45 kg; p = 0.04).<sup>[28]</sup>
A third open-label trial enrolled 25 children (aged 6 to 16 y) with AD or PDD-NOS.<sup>[29]</sup> Following a 2 week washout period, olanzapine was started at a dose of 2.5 mg every other day or daily. Of 22 children who completed the trial, 3 were considered responders based on a CGI-I rating of much improved. A CGI-S rating of less ill was achieved by 12 children. Weight gain (mean 4.7 kg), increased appetite, and asthenia were the most frequent adverse events. No clinically significant prolongation of the QT interval was seen on electrocardiogram (ECG). Extrapyramidal symptoms were reported by 3 patients—2 had mild symptoms (gait and extremity rigidity, tremor, increased salivation, and/or leg pendulousness) and 1 had moderate symptoms (gait rigidity).
One double-blind, randomized trial compared olanzapine with placebo in children with PDD, including AD.<sup>[30]</sup> Eleven children (mean age 9 y, range 6-14) were randomly assigned to treatment with either olanzapine or placebo for 8 weeks. The starting dose of olanzapine ranged from 2.5 to 5 mg daily, with a maximum dose of 20 mg/day. The primary outcome variable was the physician-rated CGI-I score at 8 weeks, with secondary outcomes based on Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Overt Aggression Scale-Modified irritability and aggression subscales. Based on CGI-I scores, 3 of 6 children given olanzapine were considered responders, compared with 1 of 5 in the placebo group. No effect of treatment was seen for the secondary outcomes. Mean weight gain with olanzapine—primarily beginning after 3 weeks of treatment—was 3.4 kg ± 2.2 versus 0.68 kg ± 0.68 with placebo (p = 0.028). Sedation and increased appetite were the most common adverse effects associated with olanzapine. No patients experienced extrapyramidal symptoms.
Aripiprazole
One case series was found that described the use of aripiprazole in 5 patients ranging in age from 5 to 18 years (mean 12.2), with PDD.<sup>[31]</sup> Four of the children met criteria for AD; 1 had Asperger's disorder. All 5 children had been treated previously with atypical antipsychotics (2 with risperidone, 3 with olanzapine, 1 with quetiapine), but treatment was discontinued due to lack of efficacy, significant weight gain (7.7-13.6 kg), and/or adverse effects (including movement disorders in 1 child). Treatment with aripiprazole was continued for a minimum of 8 weeks. After 5-6 months, all children experienced improvement in behavior, with 3 considered very much improved and 2 much improved, based on CGI-I scores. Aripiprazole was generally well tolerated, with mild sedation reported; no child experienced extrapyramidal symptoms. Two children lost weight (5.45 and 13.6 kg), while 1 child gained 0.45 kg. The remaining 2 children did not have a change in weight.
In a second case series, Shastri et al.<sup>[32]</sup> reported the results of aripiprazole therapy in 5 adults with intellectual disabilities, including 1 with AD. Treatment was initiated at a dose of 10 mg daily and increased at 6 weeks to 15 mg daily. Use of aripiprazole resulted in improved behavior and a gradual reduction in aggressive behavior. The patient had previously required chlorpromazine or lorazepam for behavioral outbursts that occurred 4-5 times per week. These episodes were reduced to 1 or 2 per month, with little need for additional medications to control behavior. A weight loss of 12.7 kg was seen due to increased physical activity.
Ziprasidone
In a single case report, ziprasidone was used in the treatment of a 7-year-old autistic child with severe agitation (hyperactivity, irritability, impulsivity).<sup>[33]</sup> Ziprasidone 10 mg at bedtime resulted in rapid improvement in agitation, with additional improvements seen in cognition and language after 8 weeks of treatment. Both the parents and physician rated the child as much improved. Benefits were maintained during 8 months of treatment.
McDougle et al.<sup>[34]</sup> published a case series on the use of ziprasidone in AD. Ziprasidone was initiated at a dose of 20 mg at bedtime in patients (aged 9-20 years). Most had been previously treated with atypical antipsychotics, most commonly risperidone or olanzapine, and had failed to respond to treatment. Nine patients had gained weight during previous therapy (9.1-45.5 kg). The dose of ziprasidone was increased, based on patient response and tolerability. No dose increases were done after 6 weeks. Response to therapy was assessed using CGI-I ratings, determined by psychiatrists' evaluations, parents' observations, and progress notes. Patients were treated for a mean of 14.15 weeks.
After at least 6 weeks of treatment, 6 (50%) patients were considered responders; 2 were considered much worse. Sedation was the most common adverse effect, reported by 8 patients. Other reported adverse effects included oral dyskinesia (1), increased appetite (3), agitation (2), insomnia (2), tremor (1), and transient "lisping" (1). Mean change in body weight was -2.65 kg (range -15.9 to +2.7 kg). The mean dose of ziprasidone used was 59.23 mg/day.<sup>[34]</sup>
Cohen et al.<sup>[35]</sup> retrospectively assessed the efficacy and tolerability of ziprasidone in adults with AD and profound mental retardation (9 pts.). Data extracted included weight and Maladaptive Behavioral Scale (MBS) scores 6 months prior to, at initiation, and 6 months after treatment with ziprasidone. In addition, total cholesterol and triglycerides were assessed at baseline and 6 months following treatment. After comparing the average monthly frequency scores for MBS scores 6 months before ziprasidone with those 6 months after treatment, the authors determined that 7 patients had improved or remained clinically stable. Mean dose of ziprasidone used ± SD was 128 ± 4 mg daily. Eight patients lost weight (-5.95 ± 0.45 kg) during ziprasidone treatment; however, 1 patient gained 4.5 kg and another had stable weight posttreatment. Insignificant reductions in both total cholesterol and triglyceride levels were noted in 5 patients.
Quetiapine
A retrospective chart review evaluated the use of quetiapine in 10 children and adolescents with AD or PDD-NOS and related conditions (disruptive behavior, mental retardation, anxiety).<sup>[36]</sup> The mean age was 12 years (range 5-19). Quetiapine was initiated at a dose of 25 mg twice a day, with increases of 25-50 mg twice daily every 4-7 days. Six patients were considered responders to therapy. Adverse effects were described as mild and included sedation (3), tremor (1), and worsening sialorrhea (1). Seven patients experienced some degree of weight gain, ranging from 0.91 to 7.3 kg. Two patients experienced weight loss (-3.6 and -9.5 kg) and 1 patient had no change in weight, for a mean weight change ± SD of ± 1.0 ± 4.7 kg.
Corson et al.<sup>[37]</sup> identified patients (mean age 12.1 y; range 5-28 y) with AD or PDD-NOS treated with quetiapine for a mean of 59.8 weeks. Improvement from baseline was significant, with a mean change in CGI-S scores from markedly ill to moderately ill (p = 0.002). Forty percent of patients were considered responders (much improved or very much improved). However, mean changes in CGI-I scores for the group were considered low, with minimal improvement seen. Response rates were higher among patients with AD (7) compared with those with PDD-NOS (1). Adverse events were experienced by 10 of 20 patients and included persistent sedation (2), insomnia (1), pain (1), and weight gain (5). A mean weight gain of 5.7 ± 5.8 kg was reported (range 0.1-6.8 kg). One patient eventually discontinued treatment due to tardive dyskinesia.
Two open-label trials have evaluated the use of quetiapine in the treatment of AD in children. In one trial, 6 children with AD (mean age 10.9; range 6.2-15.3) were given quetiapine for a total of 16 weeks.<sup>[38,39]</sup> The dose was initiated at 25 mg daily at night and increased by up to 100 mg per week based on response. Behavioral ratings used to evaluate efficacy included ABC (Abberant Behavior Checklist, with subscales of irritability, lethargy, stereotypic behaviors, hyperactivity, inappropriate speech), CGI-Global Improvement scale, RF Scale (with subscales of sensory motor behaviors, social relationships, affectual reactions, sensory responses, language), and CY-BOCS. Only 2 patients completed the trial. Reasons for withdrawal from the study included lack of efficacy, with dose limited due to adverse events of sedation (3), behavioral activation and akathesia (1), and seizure (1). Increased appetite and weight gain were seen in 4 patients during the first 4 weeks of treatment. Mean weight gain was 2.9 ± 3.6 kg (range 0.9-8.2 kg). No difference was seen between baseline and end of treatment scores for any rating scale used. The 2 patients who completed the trial were considered much improved and very much improved.
The second trial included children ranging in age ± SD from 12 to 17.3 years (mean 14.6 ± 2.3).<sup>[39]</sup> Quetiapine was begun at a dose of 25 mg twice daily and titrated to a target dose of 150 mg twice daily. The dose could then be increased by 25 to 75 mg every other week to a maximum of 750 mg daily. Efficacy and safety of treatment were assessed using changes in various behavioral rating scales from baseline to 12 weeks. Six patients completed 12 weeks of treatment. Of the patients who discontinued treatment, 2 stopped due to adverse events—increased aggression/agitation and drowsiness. The most common adverse events reported included sedation (7), weight gain (5), increased agitation (4), and aggression (2). The daily dose of quetiapine ranged from 100 to 450 mg. Only 2 patients were considered responders to treatment based on CGI-I scores. Significant improvements from baseline were only seen for median CPRS and ABC subscales of lethargy, stereotypy, hyperactivity, and inappropriate speech.
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