Elsevier

Biological Psychiatry

Volume 51, Issue 12, 15 June 2002, Pages 972-978
Biological Psychiatry

Original article
The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone

https://doi.org/10.1016/S0006-3223(02)01370-7Get rights and content

Abstract

Background: Neurocognitive deficits are core features of schizophrenia that are linked to functional outcome for the disorder. Recent studies and reviews have concluded that newer antipsychotic medications are better for neurocognitive deficits than conventional antipsychotic medications; however, one difficulty in interpreting this literature is that the comparisons have mainly been with high doses of conventional medications. This study examined the neurocognitive effects of low-dose haloperidol compared with risperidone over a 2-year period.

Methods: Sixty-two patients were randomly assigned to medication (starting at 6 mg of each medication) and administered neurocognitive batteries six times over the course of follow-up. At 6 months, the mean dose of haloperidol was 5.0 mg, and the mean dose of risperidone was 6.0 mg. Neurocognitive data were reduced into cluster scores and a global summary score.

Results: We found no significant overall differences in treatment effects on the cluster scores or the global score. The global score revealed a significant group by time interaction, reflecting the fact that the haloperidol group tended to improve initially and then stay stable, whereas the risperidone group improved more gradually over the follow-up period.

Conclusions: This study did not provide support for neurocognitive advantages of a newer antipsychotic medication over a low-dose conventional medication. We speculate that conventional medications may have neurocognitive benefits at low doses that are neutralized or reversed at higher doses.

Introduction

The neurocognitive deficits of schizophrenia comprise a separate domain of the illness that is relatively independent of psychotic symptoms and closely related to functional outcome Goldberg and Gold 1995, Green 1996, Green et al 2000. The range of deficits is broad and includes problems in perception, attention, memory, and problem solving (Green 2001). Partly because neurocognitive deficits are linked to functional outcome, there is strong interest in finding ways to improve neurocognition in schizophrenia. The effects of conventional medications on neurocognitive deficits are generally minimal Blyler and Gold 2000, Cassens et al 1990. There have been some instances of improvement on attentional measures and some short-term detrimental effects of psychomotor skills, but the effects of conventional medications are generally negligible despite their clear benefits for psychotic symptoms.

The situation with newer antipsychotic medications seems to be more promising. Recently, there have been several reviews of this literature and a meta-analysis Harvey and Keefe 2001, Keefe et al 1999, Meltzer and McGurk 1999. Two conclusions can be safely drawn from these reviews. First, the methods of these studies are generally not optimal. Many of the studies are within-group switch studies in which patients are initially assessed while taking a conventional medication (baseline) and then reassessed when taking a newer antipsychotic medication. In these studies, changes in performance are confounded with other time-related factors (e.g., practice effects). Second, despite these limitations, all of the reviews conclude that the newer medications seem to be better for neurocognition than the older medications. There are sufficient controlled studies to justify this conclusion, including several with double-blind, randomized designs. The drugs that have been studied most in these reviews are clozapine, risperidone, and olanzapine; however, it is likely that the same conclusions apply to all of the newer medications. It is currently unclear whether the differences between newer and older antipsychotic medications stem from a true benefit of the newer medications (i.e., better than no medications) or from fewer adverse effects.

In one review, Harvey and Keefe (2001) make the important observation that the conclusions from the literature thus far are based on comparisons of newer medications with conventional antipsychotic medications that were administered at relatively high doses. Specifically, for the within-subject switch studies, the mean dose of baseline conventional medications was 924 (CPZ equivalents). When a conventional study arm was included in a parallel group design, the mean dose was 736. The possibility that dosage may influence results was recently demonstrated by a meta-analysis that found the newer medications had comparable effects on clinical psychopathology when compared with lower doses (defined as 12 mg/day or less) of haloperidol (Geddes et al 2000). Hence, the question remains open as to whether the neurocognitive advantages of newer antipsychotic medications are present when compared with low doses of conventional medications. To explore this question, we examined the neurocognitive effects of low-dose haloperidol in a randomized controlled comparison with risperidone over a 2-year period.

Section snippets

Study setting and sample

Sixty-two individuals with a diagnosis of DSM-IV schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV (First et al 1997) participated in this study, which was conducted in the Schizophrenia Outpatient Clinic at the VA Greater Los Angeles Healthcare System. Each subject had had at least two documented episodes of acute schizophrenic illness or at least 2 years of continuing psychotic symptoms. Selection criteria included 1) a stable outpatient status

Results

None of the clusters showed a significant main effect for medication (all p values > .40). Clusters 1 (Perceptual Discrimination) and 3 (Executive Functioning) showed a trend for a week by medication interaction [F(4,59) = 2.41, p = .06 and F(4,54) = 2.34, p = .07 for clusters 1 and 3, respectively]. These trends reflected a tendency for the risperidone group to start more slowly and then catch up to the haloperidol group over time. On cluster 1, medication effects were significant at week 4 [F

Discussion

This study failed to find simple group differences between low-dose haloperidol and risperidone over a 2-year period. The haloperidol group showed an initial improvement between baseline and week 4 that was maintained, with little change, for the remainder of the follow-up period. In contrast, the risperidone group showed a gradual increase in performance over the course of the follow-up until it (nonsignificantly) surpassed the haloperidol group. Although there were significant differences in

Acknowledgements

This work was supported by Grant MH41573 to Dr. Marder and by the Research Service of the Department of Veterans Affairs. The Janssen Research Foundation provided medication for this study. The authors thank Sun Hwang, M.S., M.P.H. for help with the statistical analyses and Mark McGee for help in preparing the graphics.

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