Original articleThe neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone
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.
References (27)
- et al.
Recent and remote memory dissociationMedication effects and hippocampal function in schizophrenia
Biol Psychiatry
(1997) - et al.
Neuropsychological performance in chronic schizophrenia in response to neuroleptic dose reduction
Biol Psychiatry
(1993) - et al.
Manual and Computer Program for Forced-Choice, Partial Report Span of Apprehension TestVersion 1
(1987) - et al.
Multilingual Aphasia Examination Manual (revised)
(1978) - et al.
Cognitive effects of typical antipsychotic treatmentAnother look
- et al.
NeurolepticsEffects on neuropsychological function in chronic schizophrenic patients
Schizophr Bull
(1990) - et al.
The California Verbal Learning Test (Manual)
(1987) - et al.
Structured Clinical Interview for DSM-IV Axis I Disorders - Patient Edition, Biometrics Research Department
(1997) - et al.
Atypical antipsychotics in the treatment of schizophreniaSystematic overview and meta-regression analysis
BMJ
(2000) - Glynn SM, Marder SR, Liberman RP, et al (in press): Supplementing clinic based skills training for schizophrenia with...
Neurocognitive functioning in patients with schizophrenia
What are the functional consequences of neurocognitive deficits in schizophrenia?
Am J Psychiatry
Schizophrenia RevealedFrom Neurons to Social Interactions
Cited by (197)
The effect of antipsychotics on the cognitive performance of individuals with psychotic disorders: Network meta-analyses of randomized controlled trials
2021, Neuroscience and Biobehavioral ReviewsThe past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review
2019, Journal of Psychiatric ResearchSchizophrenia dimension-specific antipsychotic drug action and failure in amphetamine-sensitized psychotic-like rats
2018, European NeuropsychopharmacologyIn utero exposure to atypical antipsychotic drug, risperidone: Effects on fetal neurotoxicity in hippocampal region and cognitive impairment in rat offspring
2017, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :It is hypothesized from our study that hippocampus and striatum (possibly the basal ganglia, composed of corpus striatum, globus pallidus, subthalamic nucleus, and substantia nigra) played an important role to work in a coordinated manner for modulating the learning and memory functions in MWM and in other mazes used in these paradigms. This disruptive effects of RIS on cognitive functions corroborate with the limited reports of some investigators (Green et al., 2002; Rosengarten and Quartermain, 2002; Karl et al., 2006; Zuo et al., 2008). Clinical and non-clinical reports on in utero exposure to RIS and cognitive impairment in young ones are very limited for a valid comparison.