Safety and Tolerability of Antipsychotic Treatment in Young Patients With Schizophrenia
Christoph U. Correll, MD
Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY
Atypical antipsychotics have proven efficacy over placebo for treating early-onset schizophrenia ().1–4 In addition, no significant differences in efficacy were found among active treatment groups in the TEOSS trial,5 which compared olanzapine and risperidone with the midpotency typical antipsychotic molindone. The atypical antipsychotics aripiprazole, olanzapine, quetiapine, and risperidone are approved by the FDA for treating schizophrenia in adolescents aged 13 to 17 years. Studies6,7 have suggested superior efficacy of the atypical antipsychotic clozapine over olanzapine for treatment-refractory early-onset schizophrenia, but, due to the potentially severe, even fatal, side effect of granulocytopenia, clozapine is recommended for use only in adults who have undergone 2 unsuccessful trials of standard antipsychotic treatment.
Safety and Tolerability
The recent dramatic increase in the use of antipsychotics for children and adolescents is partly due to the perceived greater safety profile of atypical agents over the first-generation antipsychotics.8 However, children and adolescents appear to have a greater susceptibility to certain acute and intermediate side effects than adults when receiving atypical antipsychotics and should be monitored closely to avoid long-term consequences.9
EPS. In the TEOSS study,5 patients receiving molindone also had blinded prophylactic treatment with an anticholinergic agent (ie, benztropine 0.5 mg/bid) to counteract EPS, while the olanzapine and risperidone groups received a placebo add-on. Nevertheless, 45% of patients in the molindone group required additional anticholinergic treatment, compared with 34% of the risperidone group and 14% of the olanzapine group. A randomized, placebo-controlled trial2 of adolescents with schizophrenia found that 15% of patients receiving 10 mg/d of aripiprazole and 30% of those taking 30 mg/d had a parkinsonian event, compared with 7% of those taking placebo.
Akathisia, however, seems to be less common than other EPS (such as parkinsonism) in youths. In the TEOSS study,5 treatment for akathisia was needed in 13%, 11%, and 7% of patients in the molindone, olanzapine, and risperidone groups, respectively. The trial2 of aripiprazole in adolescents with schizophrenia found that patients receiving 10 mg/d of aripiprazole had a rate of akathisia equal to that of placebo (5% for both groups), while patients receiving 30 mg/d had a rate of 12%. A study3 of adolescents receiving either risperidone or placebo found a 9% rate of akathisia for the group receiving 1 to 3 mg/d of risperidone, a 10% rate for the group receiving 4 to 6 mg/d of risperidone, and a 4% rate for those receiving placebo.
Tardive dyskinesia is a disfiguring and potentially disabling adverse effect of involuntary movements that can be irreversible. A review10 of 10 trials of children and adolescents (N = 783) treated with atypical antipsychotics (primarily risperidone) found an annual rate of tardive dyskinesia of 0.4%. This figure compares favorably with a rate of 0.8% for adults treated with atypical antipsychotics and a rate of 5.4% for adults treated with haloperidol.11 Thus, the risk of tardive dyskinesia appears to be low in children and adolescents, but a concern exists that, with longer treatment exposure and/or use of higher doses, the rate of tardive dyskinesia may increase.
Prolactin levels. Most antipsychotics affect prolactin levels in both youths and adults, but the effect may be more pronounced in children and adolescents. A review12 of studies of children and adolescents with schizophrenia showed risperidone to produce the greatest prolactin elevation, followed by haloperidol. Olanzapine and ziprasidone, generally considered prolactin-neutral in adults, had intermediate effects on prolactin elevation. Quetiapine and clozapine appeared to be prolactin-neutral in both children and adults, while aripiprazole, a partial dopamine D2 agonist, may lower prolactin levels below baseline levels.2,13 Elevated prolactin levels do not necessarily lead to symptoms (such as galactorrhea, amenorrhea, or delayed puberty), and prolactin levels may normalize over time despite continued treatment.12
Weight gain. Data have shown that, in general, pediatric patients seem to be at greater risk for antipsychotic-induced weight gain than adults.9 In placebo-controlled trials, aripiprazole2,13 was associated with the least weight gain, risperidone3,14 and quetiapine4,15 had intermediate effects, and olanzapine1,16 produced the greatest weight gain. In the TEOSS study,5 patients receiving olanzapine gained 6.1 kg over 8 weeks compared with 3.6 kg for patients receiving risperidone. Molindone appeared to be weight-neutral; however, more than half of the patients receiving molindone lost weight, possibly rebounding from prior weight gain due to other agents.
A cohort study17 (N = 272) suggested that weight gain is severe and rapid in antipsychotic-naïve patients treated not only with olanzapine but also with quetiapine, risperidone, and aripiprazole. After about 11 weeks of treatment, patients gained 8.5 kg with olanzapine, 6.1 kg with quetiapine, 5.3 kg with risperidone, and 4.4 kg with aripiprazole. Further, a high rate of patients in each group gained a clinically relevant amount of weight, ie, ≥ 7% of their body weight ().17 Patients in a comparator group who either refused participation or who were nonadherent to medication gained only 0.2 kg during the trial, suggesting that at least the short-term weight gain was attributable to the medications and not to other causes, such as the new onset of a psychiatric disorder or hospitalization.
Metabolic changes. A cross-sectional study18 of 95 hospitalized children and adolescents with exposure to an atypical antipsychotic found that 2 of 3 patients were overweight and about half had elevated triglycerides or low HDL cholesterol. These conditions, which are associated with metabolic syndrome and later cardiac conditions, can be adverse effects from antipsychotics; however, antipsychotics have differing metabolic risk profiles.
For example, in the cohort study17 of antipsychotic-naïve youth, olanzapine treatment significantly elevated glucose levels and significantly worsened all lipid parameters except for HDL cholesterol (P ≤ .02 for all). Quetiapine significantly elevated all lipid parameters except for HDL cholesterol (P ≤ .05 for all) but not glucose levels, while risperidone significantly worsened triglycerides only (P ≤ .05). Patients receiving aripiprazole did not experience significant elevations in glucose or any lipid parameters and experienced a small decrease in total triglyceride levels, even though they gained an average of 4.4 kg during the study. Taken together, these disparate findings suggest that some agents may have weight-independent effects on metabolic parameters ().17 A subanalysis found no difference in risk for metabolic changes between prepubertal and postpubertal patients. However, dosing may play a role in metabolic changes. High doses of olanzapine (more than 10 mg/d) led to greater metabolic changes but not greater weight gain, and doses of risperidone higher than 1.5 mg/d led to both more weight gain and more metabolic changes.17
Children and adolescents appear to be at greater risk than adults for antipsychotic side effects, such as EPS, prolactin elevation, weight gain, and metabolic effects. Antipsychotics have varying degrees of risk for these effects, and clinicians should conduct a careful risk-benefit assessment when choosing medications for young patients. Careful monitoring for early or severe weight gain or metabolic disturbances is essential, and switching medications may be necessary if intolerable adverse effects occur.
For Clinical Use
- Aripiprazole, olanzapine, quetiapine, and risperidone are approved by the FDA for treating adolescents with schizophrenia aged 13 to 17 years
- Carefully monitor young patients taking atypical antipsychotics for early or severe weight gain and other adverse effects
- Consider the differing adverse effect profiles when choosing medications for young patients
aripiprazole (Abilify), benztropine (Cogentin and others), clozapine (FazaClo, Clozaril, and others), haloperidol (Haldol and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon)
EPS = extrapyramidal symptoms, FDA = US Food and Drug Administration, HDL = high-density lipoprotein, PANSS = Positive and Negative Syndrome Scale, TEOSS = Treatment of Early-Onset Schizophrenia Spectrum Disorders
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- Kryzhanovskaya L, Schulz SC, McDougle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009;48(1):60–70.
- Findling RL, Robb A, Nyilas M, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry. 2008;165(11):1432–1441.
- Haas M, Unis AS, Armenteros J, et al. A 6-week, randomized, double-blind, placebo-controlled study of the efficacy and safety of risperidone in adolescents with schizophrenia. J Child Adolesc Psychopharmacol. 2009;19(6):611–621.
- Findling RL, Kline K, McKenna K, et al. Efficacy and safety of quetiapine in adolescents with schizophrenia: a 6-week, double-blind, randomized, placebo-controlled trial. Poster presented at 55th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 29, 2008; Chicago, IL.
- Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study. Am J Psychiatry. 2008;165(11):1420–1431.
- Kumra S, Kranzler H, Gerbino-Rosen G, et al. Clozapine and "high dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry. 2008;63(5):524–529.
- Shaw P, Sporn A, Gogtay N, et al. Childhood-onset schizophrenia a double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry. 2006;63(7):721–730.
- Olfson M, Blanco C, Liu L, et al. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry. 2006;63(6):679–685.
- Correll CU, Penzner JB, Parikh UH, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin North Am. 2006;15(1):177–206.
- Correll CU, Kane JM. One-year incidence rates of tardive dyskinesia in children and adolescents treated with second-generation antipsychotics: a systematic review. J Child Adolesc Psychopharmacol. 2007;17(5):647–656.
- Correll CU, Leucht S, Kane JM. Lower risk of tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161(3):414–425.
- Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45(7):771–791.
- Findling RL, Nyilas M, Forbes RA, et al. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(10):1441–51.
- Haas M, Delbello MP, Pandina G, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2009;11(7):687–700.
- DelBello MP, Findling RL, Earley WR, et al. Efficacy of quetiapine in children and adolescents with bipolar mania: a 3-week, double blind, randomized, placebo-controlled trial. Poster presented at: 46th annual meeting of the American College of Neuropsychopharmacology; December 9–13, 2007; Boca Raton, FL.
- Tohen M, Kryzhanovskaya L, Carlson G,et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry. 2007;164(10):1547–56.
- Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents [published correction appears in JAMA. 2009;302(21):2322]. JAMA. 2009;302(16):1765–1773.
- Patel NC, Hariparsad M, Matias-Akthar M, et al. Body mass indexes and lipid profiles in hospitalized children and adolescents exposed to atypical antipsychotics. J Child Adolesc Psychopharmacol. 2007;17(3):303–311.