Inadequate treatment response to des‐enkephalin‐gamma‐endorphin compared with thioridazine and placebo in schizophrenia

Abstract

The possibility of an involvement of peptidergic systems in schizophrenia has been under investigation for a number of years. Studies of the efficacy of des-tyr-gamma-endorphin were equivocal; more recent studies with des-enkephalin-gamma-endorphin have reported some activity but the peptide has only been investigated as an adjunct to neuroleptic medication, apart from one very small active reference comparator study. In the multicentre study reported here, 96 patients suffering from schizophrenia (DSM-III with a current exacerbation if chronic) were allocated randomly to double-blind treatment with either des-enkephalin-gamma-endorphin (DE-gamma-E) (Org 5878) 10 mg given as a once daily intramuscular injection for 4 weeks, thioridazine 400 mg orally in 2 divided doses or placebo using a double-dummy technique to preserve blindness. There was a significant advantage for thioridazine compared with placebo registered on all measures at weeks 3 and 4. There was no difference between DE-gamma-E and placebo. There was a significant difference between thioridazine and DE-gamma-E at weeks 3 and 4 registered on the MSS and at week 3 registered on the BPRS. The lack of efficacy of DE-gamma-E suggests that the theories that the endorphins have an important role in schizophrenia have to be revised. The need for well designed placebo controlled studies for assessing efficacy in schizophrenia is emphasized.

Placebo controlled studies in acute schizophrenia – an issue of concern

“…When other general methodological standards (Collins et al, 1992) are also respected, such design, no doubt, fulfills all scientific and registration requirements for pivotal study. Critical appraisal of the methodological rigor of the studies referred to (NIMH study, 1964;Reardon et al, 1966;Hekimian and Friedhoff, 1967;Clark et al, 1971;Hamill and Fontana, 1975;Shopsin et al, 1979;Price, 1987;Borison et al, 1989;Herrera et al, 1990;Chouinard, 1990;Montgomery et al, 1992;Chouinard et al, 1993) was, however, not the objective of our analysis.…”

“…It is worth noting that the patients in this study were defined as "acutely ill, newly hospitalized patients" and 50% of them were experiencing their fust psychotic episode. The largest recent studies in acute schizophrenics are probably the 3-arms comparative study of Montgomery et al (1992) with 33 patients on placebo and 61 patients on active drugs (thioridazine and des-enkephalin-gammaendorphin); and the 6-arms study of Chouinard et al (1993) comparing various doses of risperidone (/) = 92) with placebo (/; = 22) and haloperidol (/; = 21).…”

“…Obviously, this reflects the lack of generally accepted standard for such studies, including definition and operational criteria for treatment outcome and efficacy measures. In addition, particularly striking was the proportion of patients treated concomitantly with benzodiazepines (75%-80% in placebo and 50-70% in drug groups (Chouinard, 1990;Montgomery et al, 1992;Chouinard et al, 1993) which is not irrelevant in view of the fact that some antipsychotic potential and potentiation of neuroleptic action for this substance class has been repeatedly discussed (Lingjaerde, 1991;Wolkowitz and Pickar, 1991).…”