Clozapine placebo-controlled studies

Therapeutic Efficacy. Early evidence supporting clozapine s efficacy came from one double-blind, placebo-controlled study and six other neuroleptic-controlled, random-assignment studies (43, 57, 58, 59 and 60 Novartis, unpublished data). When compared with neuroleptics such as CPZ and haloperidol, clozapine was found to be more effective (i.e., three studies found clozapine significantly superior and two others found a trend favoring clozapine ( p = 0.10)). When the results of these studies were combined, the probability that clozapine is superior to neuroleptic antipsychotics was highly statistically significant ( p = 1 x 1CT °) (Table 5-11 and Table 5-12). 

Phenylpropanolamine 75 mg/day did not promote weight loss in a randomized, placebo-controlled study in 16 patients with schizophrenia who had gained at least 10% of their body weight while taking clozapine (307). 

Their use in children and adolescents has been extensively reviewed (583-585). Typical neuroleptic drugs have been assessed in three randomized, double-blind, placebo-controlled studies in 122 patients and atypical drugs in five (one clozapine, n = 21 two amisulpride, n = 36 and two tiapride, n = 59). The studies were of short durations, 4—10 weeks. Extrapyramidal signs occurred in 25-73% of those treated with the typical neuroleptic drugs. 

Poliak P, Tison F, Rascol O, Destee A, Pere JJ, Senard JM, Durif F, Bourdeix I. Clozapine in drug induced psychosis in Parkinson s disease a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry 2004 75 689-95. 

In a 12-week, double-blind, randomized, placebo-controlled study in 40 patients with treatment-resistant schizophrenia (funded by Johnson Johnson Pharmaceutical Research Development), the addition of risperidone to clozapine improved overall symptoms and positive and negative symptoms (49). The adverse events profile of clozapine + risperidone was similar to that of clozapine + placebo. Clozapine + risperidone did not cause additional weight gain, agranulocytosis, or seizures compared with clozapine + placebo. All the patients completed 12 weeks of treatment however, the small sample size precluded definitive conclusions. 

Nielsen J, Emborg C, Gydesen S, Dybbro J, Aagaard J, Haderup K, et al. Augmenting clozapine with sertindole a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2012 32(2) 173-8. 

Goff DC, Leahy L, Berman I, Posever T, Herz L, et al. 2001. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 21 484-487. 

In summary, existing drug treatments for schizophrenia are of limited efficacy and have substantial side effects. New treatment can arise only on the basis of a new hypothesis. The phospholipid hypothesis of schizophrenia provides the theoretical basis for treatment with PUPA supplementation. Pre vlous studies using n-6 supplementation have had mixed results. We now have evidence from a double-blind, placebo-controlled trial that EPA, but not DHA, is effective in reducing the symptoms of schizophrenia. It is possible that the response to EPA is impaired by concomitant treatment with antipsychotic drugs that damage membrane phospholipids. The best treatment effects of EPA have been seen in patients who are otherwise unmedicated or who are currently taking clozapine. This remains to be explored further. 

Other atypical antipsychotics commonly prescribed for treatment of autism include olanzapine, quetiapine, ziprasidone, and clozapine (Oswald and Sonenklar, 2007). Placebo-controlled trials of these agents in ASD populations have not been reported, with the exception of a small pilot study of olanzapine in which three of six children treated with olanzepine were rated as responders, compared to one of five in the placebo group (Hollander et al., 2006b). Open-label studies (reviewed by... 

The combination of clozapine and lithium has been studied in a randomized controlled trial in 10 patients with schizophrenia and 10 with a schizoaffective disorder taking clozapine with either lithium or placebo for 4 weeks (299). The combination was well tolerated, except for reversible neurotoxic reactions in two patients with schizophrenia, and safety measures showed no significant variations. The authors concluded that the lithium added to clozapine appears to afford potential benefit in schizoaffective disorders without harmful effects for schizophrenia, however, it did not afford improvement but posed a risk of lithium toxicity. 

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