Abstract
Atypical antipsychotics are often prescribed to target symptoms of irritability in children and adolescents with autism and related disorders (Stigler and McDougle 2008). To date, risperidone has been the most studied atypical antipsychotic in children and adolescents with PDDs. The drug has been shown to treat irritability effectively in this population in several open-label as well as double-blind, placebo-controlled trials (Findling et al. 1997; McDougle et al. 1997; Nicolson et al. 1998; Masi et al. 2001; Research Units on Pediatric Psychopharmacology (RUPP) Autism Network 2002; Shea et al. 2004; McDougle et al. 2005). These favorable results supported the recent Food and Drug Administration (FDA) approval of risperidone for irritability in youths with autism, 5–16 years of age. Although risperidone has been shown to be beneficial, its use is often limited by concerns regarding weight gain and metabolic dysregulation, as well as extrapyramidal symptoms (EPS). In addition, the drug can be associated with pharmacokinetic interactions and fluctuations in blood levels (Karlsson et al. 2005).
Paliperidone is a drug recently approved by the FDA for the treatment of schizophrenia in adults. Paliperidone is the major active metabolite of risperidone and the only atypical antipsychotic to use osmotic controlled release system (OROS) technology, which provides controlled drug delivery for up to 24 hours (Karlsson et al. 2005). In contrast to risperidone, CYP2D6 has a limited role in the overall elimination of paliperidone. Most of the drug (59%) is excreted largely unchanged in the urine (Vermeir et al. 2005).
To compare dosages of paliperidone to risperidone, a virtual comparison of the two drugs was conducted (Schooler et al. 2006). The authors combined data from all available randomized placebo-controlled studies of risperidone and paliperidone in adults with schizophrenia. Paliperidone 6–12 mg/day was found to be similarly efficacious to risperidone 4–6 mg/day, with some tolerability benefits. In addition, paliperidone 6–12 mg/day was found to be more efficacious than risperidone 2–4 mg/day, but was associated with increased tachycardia.
Three 6-week, randomized, double-blind, placebo-controlled, parallel-group, dose–response studies have been conducted that established the efficacy and tolerability of paliperidone for acute symptoms of schizophrenia in adults (Davidson et al. 2007; Kane et al. 2007; Marder et al. 2007). Meltzer and colleagues (2008) conducted a pooled analysis of these three multicenter studies that involved 1,326 subjects. Subjects were randomly assigned to 3, 6, 9, 12, or 15 mg/day of paliperidone or placebo. The primary end point was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to end point. Overall the authors found that the PANSS total score, PANSS subscale factor, and Personal and Social Performance scale score significantly improved at study end point for all dosages of the drug (p ≤ 0.001). Headache, insomnia, nausea, and tachycardia were among the most common adverse effects in all treatment groups. In terms of EPS, regardless of treatment group, median Simpson–Angus Rating Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale scores were 0 at baseline and end point. There were no clinically significant differences between paliperidone and placebo in weight gain, glucose measures, lipid measures, or proportion of subjects with abnormal QTc intervals on electrocardiograms (ECGs). In terms of prolactin levels, median increases in prolactin concentration were greater in female (81 ng/mL) than in male subjects (24 ng/mL). Although maximum median increases in prolactin generally occurred on day 15 and then decreased slightly, prolactin levels remained elevated above the upper limit of the reference range (1.4–24.2 ng/mL, females; 1.6–18.8, males) over 6 weeks of treatment. Adverse events potentially related to prolactin, such as gynecomastia, galactorrhea, or amenorrhea, were reported in 1–2% of subjects who received placebo or paliperidone at doses of 3–12 mg/day, and in 4% of patients who received paliperidone at 15 mg/day. Overall, paliperidone was found to be effective and well tolerated in this group of subjects with acute symptoms of schizophrenia.
In summary, autism is a complex neurobiological disorder that lasts throughout a person's life. Severe disruptive behaviors often observed in autism not only are significantly impairing for individuals with autism, but also are extremely difficult for their caregivers to manage. Given the clear benefits of risperidone in youths and adults with autism, it appears that paliperidone, an active metabolite of risperidone, could hold great promise in this population. Research to date suggests a low incidence of EPS as well as weight gain. Furthermore, paliperidone only requires once-daily dosing and does not have significant pharmacokinetic interactions. In this report, we describe our favorable clinical experience with paliperidone in the first 2 patients whom we treated.
Materials and Methods
The sample included 2 individuals, ages 16 and 20 years old, with autism and co-morbid mental retardation. Diagnoses were made by board-certified child and adolescent psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000). Written informed consent for treatment was obtained from the patients' legal guardians. Both patients received concomitant psychotropic medications for all or part of the trial. These medications were continued at the same dosages throughout the paliperidone trial in 1 patient and discontinued during the trial in the other patient. In 1 of 2 patients, treatment with an atypical antipsychotic (ziprasidone) had recently been discontinued because of lack of effectiveness.
In one case, risperidone 8 mg/day was directly switched to paliperidone 12 mg/day. In the other case, paliperidone was initiated at 3 mg/day and the dosage was increased, as tolerated, to treat remaining target symptoms. Vital signs, including heart rate, blood pressure, height, and weight were obtained at baseline and at every follow-up visit. An ECG was obtained in each patient during treatment with paliperidone. In addition, labwork (complete blood count [CBC], liver function tests, fasting glucose, fasting lipid panel, including total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides) was obtained periodically. Global improvement, as measured by the Clinical Global Impressions–Improvement (CGI-I) scale (Guy 1976), was assigned at the time of last assessment. In this report, the CGI-I scale was focused on the target symptom domain of irritability (aggression, SIB, tantrums). The CGI-I scale is rated from 1 to 7 (1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse). In this report, patients were judged treatment responders if assigned a posttrial CGI-I rating of 1 = “very much improved” or 2 = “much improved.”
Results
Case 1
A. is a 20-year-old Caucasian male with a developmental history of decreased eye contact, a preference for solitary activities, and little interest in sharing items of interest or interacting with others. A. was reported to have significant delay in language development and to date uses little purposeful communication. He engages in echolalia and demonstrates repetitive interests and activities, including hand flapping and body rocking. A. functions best with a structured daily routine. Due to A.'s history, he was diagnosed with autism based on DSM-IV-TR criteria. He also met criteria for a diagnosis of moderate mental retardation.
In addition to exhibiting core symptoms of autism, A. also had a history of severe irritability that included multiple daily episodes of aggression, SIB, and tantrums. The SIB primarily involved significant head banging. Prior adequate medication trials included fluvoxamine, mirtazapine, olanzapine, chlorpromazine, haloperidol, quetiapine, and lithium. These medications were ineffective and A. was gradually placed on a regimen of risperidone 4 mg twice daily, guanfacine 1 mg twice daily, and valproic acid extended-release 1500 mg nightly. Despite maintaining this medication regimen for approximately 7 months, A. continued to exhibit severe SIB. Due to the intensity of his behavior, risperidone was directly replaced with paliperidone 12 mg/day without a titration period. Prior to this medication change, baseline labwork was obtained that revealed a normal CBC, liver function tests, and fasting glucose level. Fasting lipid panel revealed an elevated total cholesterol of 232 (reference range, ≤200) and triglycerides of 317 (reference range, ≤150); low HDL of 35 (reference range, ≥40); and normal LDL of 134 (reference range, 118–142).
Paliperidone treatment resulted in a significant improvement in aggression, SIB, and tantrums in multiple settings. Due to this notable reduction in irritability, he was judged to be “much improved,” with a CGI-I score of 2. A. tolerated this medication switch without difficulty. No adverse effects, EPS, or clinically significant changes in vital signs occurred. Labwork obtained at 36 weeks continued to demonstrate a normal CBC, liver function tests, and fasting glucose level. Fasting lipid panel measures improved, with a total cholesterol of 212, HDL of 42, LDL of 132, and triglycerides of 192. An ECG was normal. He has remained on this dosage of paliperidone for 42 weeks. Over this treatment duration, A.'s weight has decreased by 2 pounds (from 204 pounds to 202 pounds).
Case 2
B. is a 16-year-old Caucasian female with a history of severe impairment in social interaction, including lack of eye contact, failure to develop peer relationships, and lack of imaginative play. B. does not share items of interest with others and prefers to be alone. She also has a history of language delay and engages in echolalia. Over time, B.'s use of language has improved; however, she continues to have great difficulty maintaining conversations. She engages in repetitive behaviors and activities, including lining up objects and body rocking. Changes in routine tend to result in an escalation of disruptive behaviors. B. met DSM-IV-TR criteria for autism, as well as mild mental retardation. A diagnosis of intermittent explosive disorder was added to describe her severe irritability, which included impulsive aggression toward others, as well as SIB. B. also has a seizure disorder that was diagnosed in early childhood.
Due to B.'s irritability, she has received several prior adequate medication trials that were reported as ineffective. These trials included quetiapine, risperidone, aripiprazole, and valproic acid. On initial assessment, B. presented with a medication regimen of ziprasidone 80 mg twice daily, naltrexone 75 mg daily, and diazepam 10 mg three times daily. In addition, B. remained on a stable dosage of oxcarbazepine 300 mg daily for her seizure disorder, which was well controlled. Baseline labwork revealed a normal CBC and fasting glucose level. Liver function tests were elevated (aspartate aminotransferase [AST], 74 [reference range, 15–41]; alanine aminotransferase [ALT], 108; [reference range, 0–45]). Fasting lipid panel revealed an elevated total cholesterol of 268 and LDL of 191, a normal HDL of 53, and normal triglycerides of 119.
B.'s behavior continued to increase in severity and included physical aggression, SIB, and tantrums. The behaviors occurred multiple times a day on a daily basis. Ziprasidone was tapered and discontinued over a period of 1 month. Paliperidone was subsequently initiated at a dosage of 3 mg daily. B. remained at this dosage for 4 weeks and experienced modest improvement in her symptoms overall. It was then decided to increase her dosage to 6 mg daily to target her symptoms more adequately. B. responded very well to this dose, with a significant improvement in her symptoms of irritability (aggression, SIB, tantrums). She was judged to be “very much improved,” with a CGI-I score of 1. Due to its effectiveness, both the naltrexone and diazepam were successfully tapered and discontinued over a period of 2 months and 4 months, respectively. Repeat labwork obtained at 44 weeks continued to demonstrate a normal CBC and fasting glucose level. Her liver function tests had normalized. Fasting lipid panel measures improved, with a total cholesterol of 230, HDL of 50, LDL of 160, and triglycerides of 118. An ECG was normal. She has been maintained at this dosage of paliperidone for 50 weeks. No adverse effects have been observed or recorded. No EPS or changes in vital signs occurred. Over the 50 weeks of treatment, B has lost 10 pounds (from 162 pounds to 152 pounds).
Discussion
This report illustrates our initial clinical experience with paliperidone in the first 2 individuals with autism whom we treated. Both patients were responders to treatment, as judged by CGI-I ratings of “much improved” or “very much improved.” Paliperidone, at final dosages of 12 and 6 mg daily, respectively, resulted in clear improvement in symptoms of irritability, including aggression, SIB, and tantrums. Notably, the drug's effectiveness was maintained in these patients over a relatively long duration of 42 and 50 weeks, respectively.
The effectiveness of paliperidone in these 2 patients may be due to the fact that it is the major active metabolite of risperidone, a drug that has had established efficacy in individuals with autism. However, in patient A., a positive paliperidone response occurred despite the lack of response to a prior adequate trial of risperidone.
Overall, paliperidone was very well tolerated. Paliperidone's mechanism of action and decreased propensity for drug–drug interactions may have contributed to the compound's tolerability (Karlsson et al. 2005; Marder et al. 2007). Furthermore, the use of the OROS system to deliver drug without the rapid fluctuations in plasma concentrations that are characteristic of immediate release formulations may have been associated with a low occurrence of adverse effects (Ereshefsky et al. 2003; Karlsson et al. 2005; Kane et al. 2007). The absence of EPS in this sample may be due to a relationship between plasma concentrations and D2 receptor occupancy, with an estimated six-fold decrease in D2 receptor occupancy noted with extended-release versus immediate release compounds (Karlsson et al. 2005; Marder et al. 2007).
Of particular interest, paliperidone treatment in these 2 subjects was associated with weight loss over an extended treatment duration. In 1 subject, weight loss was minor (2 pounds) and may have been due to discontinuation of risperidone. However, in the other subject who lost 10 pounds, the weight loss was not likely associated with discontinuation of ziprasidone, naltrexone, or diazepam, because these drugs had not caused significant weight gain. In addition to the weight loss observed, laboratory testing revealed an improvement in fasting lipid measures in both subjects. This finding coincides with the overall relatively small amount of weight gain and dyslipidemia found in the aforementioned studies of this drug to date in adults with schizophrenia. Although the lack of weight gain and improvement in fasting lipid measures may be an insignificant finding due to the small sample size, it will be important to delineate whether this was due to the 2 patients' older age or if a decreased propensity for weight gain and dyslipidemia extends into younger adolescents and children.
Limitations
Despite these encouraging preliminary results, many factors clearly limit the reliability and validity of these findings. This report involves only 2 patients. The treatment occurred in a naturalistic, unblinded, and uncontrolled manner. Furthermore, both patients received concomitant psychotropic medications during at least a portion of their paliperidone trial. On the other hand, dosages were held constant in the patient who remained on concomitant medications throughout the trial. Diagnoses were made by board-certified child and adolescent psychiatrists; however, a “gold standard” diagnostic instrument such as the Autism Diagnostic Inventory–Revised (ADI-R) (Lord et al. 1994) was not used. Prospective measures assessing improvement in target symptoms and adverse effects, as well as laboratory measures such as prolactin levels, were not included in this report. It will be important to assess all of these areas in future research studies.
Clinical implications
This report provides initial clinical information on the treatment of irritability with paliperidone in 2 individuals with autism. Our preliminary experience suggests that paliperidone may be an effective and well-tolerated treatment for severe irritability in adolescent and adult patients with autism. Future controlled research is needed across age groups to better understand the efficacy and tolerability of paliperidone in this population.
Footnotes
Disclosures
Dr. Stigler has affiliations with Bristol-Myers Squibb Co., Eli Lilly and Co., and Janssen Pharmaceutica. Dr. Erickson has affiliations with Bristol-Myers Squibb Co., F. Hoffman-La Roche, Ltd., and Seaside Therapeutics. Ms. Mullett has no financial relationships to disclose. Dr. Posey has affiliations with Bristol-Myers Squibb Co., Eli Lilly and Co., Forest Research Institute, Janssen Pharmaceutica, and Shire. Dr. McDougle has affiliations with Bristol-Myers Squibb Co., F. Hoffman-La Roche, Ltd., and Forest Research Institute. The authors are solely responsible for writing this manuscript.
This study was supported, in part, by a Daniel X. and Mary Freedman Psychiatric Research Fellowship Award (Dr. Stigler), an investigator-initiated research grant from Janssen Pharmaceutica (Dr. Stigler), the National Institutes of Health (K12 UL1 RR025761, Dr. Erickson), and the National Institute of Mental Health (K23 MH082119, Dr. Stigler; K23 MH68627, Dr. Posey; R01 MH072964, Dr. McDougle).