Which antipsychotic is best?
Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.11-13
Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics11-13 and perhaps comparable efficacy to clozapine in some studies.2,14-17 Risperidone appeared to be comparable to clozapine in some studies,18,19 whereas clozapine’s superiority was evident in others.14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,22 patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine16 and risperidone with clozapine.18
Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.23 Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).
Table 1
Antipsychotic combinations: Few studies support efficacy
| Study | Design | Patients | Results |
|---|---|---|---|
| Shiloh et al, 1997a | 10-week, double-blind, placebo-controlled | 28 patients nonresponsive to typical antipsychotics and partially responsive to clozapine received add-on sulpiride,* 600 mg/d, or placebo | The sulpiride group showed improvements in positive and negative symptoms |
| Josiassen et al, 2005b | 12-week, randomized, double-blind, placebo-controlled | 40 schizophrenia patients unresponsive or partially responsive to clozapine randomized to clozapine + placebo or clozapine + risperidone, 6 mg/d | Mean BPRS total and positive symptom subscale scores reduced in both groups but reductions were greater in the clozapine/risperidone group; reduction in SANS also was observed in the clozapine/risperidone group |
| Genç et al, 2007c | 8-week, randomized, single-blind | 56 treatment-resistant schizophrenia patients randomly assigned to clozapine + amisulpride* or clozapine + quetiapine | Both groups improved at week 8 as measured by BPRS, SANS, SAPS, and CGI; however, patients receiving amisulpride showed greater improvement |
| Muscatello et al, 2011d | 24-week, randomized, double-blind, placebo-controlled | 31 treatment-resistant schizophrenia patients receiving clozapine randomized to receive adjunctive aripiprazole or placebo | Aripiprazole showed beneficial effect on positive and general psychopathologic symptomatology, but no significant effects on executive cognitive function |
| Takahashi et al, 1999e | 8-week, randomized, single-blind, crossover | 10 neuroleptic-treated patients received add-on risperidone and mosapramine* | Both additions resulted in significant, yet modest, improvement; no significant difference in PANSS between risperidone and mosapramine |
| *Not available in the United States BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; PANSS: Positive and Negative Syndrome Scale; SANS: Scale for the Assessment of Negative Symptoms; SAPS: Scale for the Assessment of Positive Symptoms | |||
| Source: References a. Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry. 1997;171:569-573. b. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005;162(1):130-136. c. Genç Y, Taner E, Candansayar S. Comparison of clozapine-amisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a single-blind randomized study. Adv Ther. 2007;24(1):1-13. d. Muscatello MR, Bruno A, Pandolfo G, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophr Res. 2011;127(1-3):93-99. e. Takahashi N, Terao T, Oga T, et al. Comparison of risperidone and mosapramine addition to neuroleptic treatment in chronic schizophrenia. Neuropsychobiology. 1999;39(2):81-85. | |||
What about augmentation?
Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.26 Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.