Atypical Antipsychotics for Treatment of Schizophrenia Spectrum Disorders
By Kathryn R. Cullen, MD, Sanjiv Kumra, MD, James Regan, Marcus Westerman, MD, and S. Charles Schulz, MD |
March 1, 2008
Dr Cullen is an instructor in the division of child and adolescent psychiatry and a postdoctoral research fellow at the Center for Neurobehavioral Development; Dr Kumra is chair of the division of child and adolescent psychiatry; Mr Regan is a junior scientist in the department of psychiatry; Dr Westerman is a resident in psychiatry; and Dr Schulz is chair of the department of psychiatry at the University of Minnesota, Minneapolis. Drs Cullen, Kumra, and Westerman and Mr Regan report no conflicts of interest concerning the subject matter of this article. Dr Schulz reports that he is a consultant for Lilly, AstraZeneca, and Vanda; he is on the speakers' bureau of Lilly, AstraZeneca, and Bristol-Myers Squibb; and he has received grants from Abbott, AstraZeneca, Lilly, and the MIND Institute.
The most recent atypical antipsychotic to become available in the United States is aripiprazole(Drug information on aripiprazole), a high-affinity partial dopamine(Drug information on dopamine) D2 agonist, serotonin 5-HT1A agonist, and 5-HT2A antagonist.39 Large-scale, pivotal trials with aripiprazole for adults with chronic schizophrenia have consistently shown efficacy, with relatively minor adverse effects on body weight, metabolic parameters, prolactin levels, and sedation.40-42
Since aripiprazole is newer in the United States, there are fewer data that assess this drug in young patients. However, one randomized controlled trial has recently been completed, which led to the approval of aripiprazole in the treatment of adolescents with schizophrenia. Robb and colleagues10 studied 300 adolescents with schizophrenia (aged 13 to 17 years) who were randomized to either 6 weeks of active treatment with fixed dosages of aripiprazole (10 or 30 mg/d) or placebo. More than 85% of patients completed the 6-week study. At the end of the study, both the 10 mg and 30 mg doses showed significant differences from placebo on the PANSS total score and several secondary end points. Across treatment outcome measures, however, efficacy tended to be greater at 30 mg than at 10 mg, with earlier evidence of statistical separation from placebo and numerically greater improvements from baseline.
The majority of spontaneously reported adverse effects were EPS, including akathisia and somnolence, which were rated as either mild or moderate in severity.13 Mean change in weight from baseline was minimal (10 mg, no change; 30 mg, 0.2 kg; placebo, 20.8 kg). Also, a mean decrease in prolactin levels from baseline to end of study was observed in all treatment groups (10 mg, 212 ng/ mL; 30 mg, 217 ng/mL; placebo, 29 ng/mL). These data suggest that the incidence of weight gain and hyperprolactinemia is likely to be minimal in youths receiving aripiprazole.
Clinicians can now begin to draw from emerging data to guide them in the choice of atypical antipsychotics for teenagers with early-onset schizophrenia spectrum disorders. A recent open-label, randomized comparison between olanzapine(Drug information on olanzapine) (mean dosage, 8.2 mg/d) and risperidone(Drug information on risperidone) (mean dosage, 1.6 mg/d) in 25 children with early-onset schizophrenia spectrum disorders found that both medications were comparably efficacious in decreasing symptoms, and both were associated with a similar number of adverse effects, the most important being weight gain.43 Olanzapine had a nonsignificantly lower dropout rate. A recent chart review noted increased EPS in risperidone versus olanzapine and quetiapine(Drug information on quetiapine).44
Efficacy and tolerability of risperidone, olanzapine, and haloperidol(Drug information on haloperidol) were compared in youths with psychosis in a randomized controlled comparative trial.45 In this study, all treatments led to a significant reduction of psychotic symptoms. Olanzapine showed the greatest efficacy followed by risperidone and then haloperidol. As expected, the primary adverse effects were sedation, EPS, and weight gain.
The sparsity of controlled trial data on the comparative effectiveness and safety of the atypical antipsychotics in adolescents represents a significant gap in our current knowledge. Only the TEOSS study funded by NIMH has directly compared first-line treatment with risperidone and olanzapine versus a first-generation antipsychotic (molindone) in a large group of adolescents with schizophrenia spectrum disorders.27,46 However, data from this study are still unavailable. In the face of limited comparative efficacy data, the choice of antipsychotics for teenage patients with early-onset schizophrenia spectrum disorders depends largely on consideration of what is known about the adverse effect profile for each medication.
Since a substantial number of patients do not respond to first-line medication, considerable research has been devoted to assessing options for managing patients with treatment-resistant schizophrenia, defined as failure of 2 or more first-line antipsychotics. These studies have focused on clozapine(Drug information on clozapine) and olanzapine. An early retrospective study found olanzapine to be an effective substitute for clozapine in adolescents with treatment-resistant schizophrenia47; however, in an open-label comparison in a similar population, Kumra and colleagues48 observed that olanzapine was effective but inferior in efficacy to clozapine.
More recently, an open-label study found olanzapine to cause sustained improvement over 1 year in 8 of 9 children with treatment-resistant schizophrenia.49 Two double-blind, randomized trials that compared clozapine with olanzapine for youths with treatment-resistant schizophrenia have now been published. In the first, Shaw and colleagues50 reported that clozapine (mean final dosage, 327 mg/d) was significantly superior in efficacy to olanzapine (mean final dosage, 19.1 mg/d) after 8 weeks, although olanzapine was associated with fewer adverse effects. A recent 12-week, randomized, double-blind comparison between clozapine and high-dose olanzapine in refractory early-onset schizophrenia showed that clozapine (mean final dosage, 403.1 mg/d) was superior to olanzapine (mean final dosage, 26.2 mg/d) in reducing psychosis and negative symptoms, but both medications were associated with significant weight gain and related metabolic abnormalities.51 These findings suggest that clozapine remains the agent of choice in treatment-resistant schizophrenia, despite its significant risks.
In the treatment of adolescents, it is important to consider potential developmental differences of this group that may impact course and treatment response. Compared with adult-onset schizophrenia, naturalistic data suggest that the course of illness is more severe in early-onset illness.52,53 Study findings have suggested that youth treated with antipsychotic medications may be more sensitive to EPS.54 In addition, olanzapine may be more sedating in children and adolescents compared with adults.55 In light of recent data that suggest that risperidone may have adverse effects on spatial working memory in adults with first-episode schizophrenia, the long-term safety of atypical antipsychotics on the developing brain needs to be clarified.56
A growing body of research assessing the use of atypical antipsychotics in adolescents with early-onset schizophrenia spectrum disorders suggests that medications are effective in reducing symptoms and improving function. Although these medications are associated with a lower incidence of adverse motor effects compared with typical antipsychotics, the atypical antipsychotics are associated with a number of important adverse effects including sedation and metabolic abnormalities. Furthermore, increasing evidence suggests that because of developmental differences, adolescents may be especially vulnerable to a whole range of adverse effects. While a limited data set is available that suggests some differences between atypical antipsychotics in terms of their adverse-effect profiles, additional comparative studies of the efficacy and tolerability of atypical antipsychotics are needed to inform the clinician's choice of initial antipsychotic.
Of the adverse effects associated with atypical antipsychotics, metabolic effects may be the most significant problem. Weight gain is of primary importance for teenagers: it contributes to subjective distress and nonadherence and has long-term medical consequences.57 The atypical antipsychotics share a class warning for hyperglycemia and, thus, symptoms of diabetes and fasting blood sugars need to be monitored.58,59
Given that patients with schizophrenia are approximately twice as likely as the general population to die of cardiovascular disease,60 and that most of them will require long-term therapy, their physical health must be safeguarded. At the same time, because longer duration of untreated psychosis may predict poorer long-term outcomes in first-episode psychosis, physicians are compelled to treat early and aggressively to improve outcomes for their young patients with early-onset schizophrenia spectrum disorders.5
Fortunately, considerable research has been devoted in recent years to begin to characterize the mechanism of these problems, which will hopefully guide interventions to decrease adverse effects. A recent study by Klein and colleagues61 demonstrated reduced weight gain in adolescents treated with olanzapine while taking metformin(Drug information on metformin), but further research is needed to guide clinicians in managing these difficulties.
In conjunction with medication management of youths with early- onset schizophrenia spectrum disorders, it is important to keep in mind the social contextual issues that commonly occur in this population. There is often confusion and fear in the family regarding the nature of the illness and presenting symptoms that may delay treatment seeking. Shock and denial regarding the diagnosis commonly emerge during the early treatment phase. Since treatment noncompliance or discontinuation is a significant concern, early psychoeducation and support is crucial.
In addition, since response to currently available treatments remains suboptimal for many teenagers with schizophrenia, it is important to examine whether the use of adjunctive psychosocial treatments improves outcome.
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