A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients

Abstract

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2 = 0.50-0.51, p < 0.001). Only depressive symptoms did not contribute significantly to these results (p > 0.10). Path analysis showed that the greater mean change (p < 0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine

“…We used path analysis (16,17) to determine whether a differential efficacy for negative symptoms favoring either olanzapine, haloperidol, or placebo was due to direct and/or indirect therapeutic effects. Figure 1 shows a generic path model illustrating the relationships between direct effects and indirect effects (from positive, depressive, and extrapyramidal symptoms) on negative symptoms.…”

“…To explore further the existence of a direct therapeutic effect on primary negative symptoms, we again analyzed data with a path analysis technique (16,17). Application of this technique permitted determination of a direct treatment effect on negative symptoms after accounting for secondary differences in positive, depressive, and/or extrapyramidal symptoms.…”

The Role of Serotonin in Antipsychotic Drug Action

“…In contrast to the possibly unique effectiveness of clozapine in diminishing positive symptoms in treatment resistant schizophrenic patients, the atypical antipsychotic drugs (with the possible exception of quetiapine) and some 5-HT 2a or 5-HT 2a/2c antagonists, appear to be more effective in decreasing negative symptoms than haloperidol, (Kane et al 1988;Meltzer 1992Meltzer , 1997Moller et al 1995;Tollefson and Sanger 1996). Sertindole, risperidone, ziprasidone, M100907, and ritanserin have all been found effective in treating negative symptoms (Arvanitis and Miller 1997;Arato et al submitted).…”

“…Sertindole, risperidone, ziprasidone, M100907, and ritanserin have all been found effective in treating negative symptoms (Arvanitis and Miller 1997;Arato et al submitted). Various types of analyses to partial out the effect on negative symptoms from the effect on positive and depressive symptoms and EPS suggest that the effect on negative symptoms is direct (Moller et al 1995;Tollefson and Sanger 1996). These diverse compounds share relatively high 5-HT 2a receptor blockade without D 2 antagonism, whereas chlorpromazine and high dose loxapine, which produce high levels of D 2 and 5-HT 2a receptor blockade in vivo, do not improve negative symptoms.…”

On Schizophrenia and New Generation Drugs

“…Meltzer suggests a direct effect on primary negative symptoms with risperidone and olanzapine, but this is based on path analysis where some, but not all, sources of variance are in the model (Moller et al 1995;Tollefson and Sanger 1997). The hypothesized direct effect in these studies is based upon the statistical term "unexplained variance."…”