The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that perphenazine(Drug information on perphenazine) was nearly as effective as olanzapine(Drug information on olanzapine) in terms of time to discontinuation, and that perphenazine was associated with fewer metabolic adverse effects.22 A recent follow-up study also reported that while perphenazine does not differ from atypical antipsychotics in quality of life, efficacy, and adverse effects, it had lower associated overall health care costs.23
It is generally agreed that atypical antipsychotics may be superior to typical antipsychotics with less risk of extrapyramidal syndrome or tardive dyskinesia. Note, however, that most trials have compared atypical antipsychotics with haloperidol(Drug information on haloperidol) under the assumptions that high and low potency typical antipsychotics have similar efficacy and that atypical antipsychotics are definitely more effective than typical antipsychotics. However, an increasing number of studies suggest that atypical antipsychotics may not differ categorically from typical antipsychotics, and that failure to appreciate this can lead to suboptimal clinical decisions. An accumulating body of evidence suggests that both atypical antipsychotics and typical antipsychotics are heterogeneous with respect to efficacy, adverse effects, and pharmacological profiles.
Treatment of clozapine(Drug information on clozapine)-resistant schizophrenia
Although clozapine is considered the standard pharmacotherapy and the last resort in the management of treatment-resistant schizophrenia, 40% to 70% of patients with treatment-resistant schizophrenia fail to respond to clozapine treatment.8,24 Clozapine-resistant schizophrenia characteristics include persistent active psychotic features despite daily doses of 300 to 900 mg for 8 weeks to 6 months, with plasma drug levels of 350 ng/mL or higher.25 Affected patients have long been problematic in clinical care because no other therapeutic strategies have proved effective.
Since the emergence of clozapine as the prototype of atypical antipsychotics, there have been numerous efforts to delineate clinical and biological predictors of response to this agent. Among conflicting results, several factors have been identified as potential predictors of response. These include severe clinical symptoms, higher levels of functioning before the onset of schizophrenia, low levels of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid, reduced metabolism in the prefrontal cortex, reduced volume of the caudate, and the improvement of P50 gating at the 500-ms prepulse interval.26 However, none of these factors is consistent or specific as a predictor of clozapine response.
Plasma clozapine levels of 350 to 500 ng/mL are correlated with a favorable therapeutic response.26,27 These plasma levels correspond to dosages of 150 to 800 mg/d.27 Although it is not clear whether clozapine has a therapeutic window, higher plasma drug levels may reduce clinical improvement and increase the risk of adverse effects.27
The addition of an atypical antipsychotic to clozapine has been used widely in the treatment of clozapine-resistant schizophrenia. Double-blind and open-label studies have shown that augmenting clozapine with risperidone(Drug information on risperidone) or sulpiride may diminish clinical symptoms of schizophrenia.28-30 Combination trials, case reports, and natural follow-up studies on augmenting clozapine with olanzapine, ziprasidone(Drug information on ziprasidone), or quetiapine(Drug information on quetiapine) are limited and preliminary.
The true effectiveness of augmentation therapy remains inconclusive. Thus the augmentation of clozapine and an antipsychotic drug needs careful assessment for tolerability, adverse effects, potential benefits, and a history of response to the antipsychotic.
The strategy of switching from clozapine to another antipsychotic drug may need to be considered when augmentation fails, when the adverse effects of clozapine are intolerable, or when treatment is an economic burden. Open-label studies and case reports have reported that in some patients, clozapine-resistant schizophrenia responds favorably to olanzapine.1,31,32 Follow-up case studies have shown partial responses to risperidone in patients who had been taking clozapine. Thus, switching from clozapine to an atypical antipsychotic including olanzapine or risperidone could be a beneficial option.
The results of a study by Kho and colleagues33 show that electroconvulsive therapy (ECT) added to clozapine improved positive and negative symptoms of schizophrenia. Although some studies included schizophrenic patients whose condition was not resistant to clozapine therapy, in general the studies suggest that ECT may be a useful augmentation strategy.