http://ajp.psychiatryonline.org. Treatment of Cognitive Impairment in Early Psychosis: A Comparison of Risperidone and Haloperidol in a Large Long-Term Trial.
Article
Treatment of Cognitive Impairment in Early Psychosis: A Comparison of Risperidone and Haloperidol in a Large Long-Term Trial Philip D. Harvey, Ph.D. Jonathan Rabinowitz, Ph.D. Marielle Eerdekens, M.D. Michael Davidson, M.D.
Objective: Cognitive impairment is a major determinant of functional outcome in schizophrenia. Treatment of cognitive impairment at the time of the first episode may have the potential to change functional outcomes of the illness. This study examined changes associated with treatment with risperidone compared with haloperidol in aspects of cognitive functioning known to be associated with functional outcomes. The study was conducted in a large group of patients experiencing their first episode of schizophrenia. Method: Cognitive assessments were conducted in 533 patients experiencing their first episode of schizophrenia or a related psychosis who had been randomly assigned to receive low doses of risperidone or haloperidol. The cognitive assessments were repeated at several different followup intervals; 359 patients were reexamined at the 3-month follow-up. The assessments included examinations of verbal and visuospatial episodic memory, vigilance, executive functioning, processing speed, and verbal fluency. Patients’ clinical symptoms were also rated with the Positive and Negative Syndrome Scale.
Results: Improvements from baseline were found in the risperidone-treated patients for episodic memory, verbal fluency, vigilance, executive functioning, and visuomotor speed. Haloperidol-treated patients also showed improvements from baseline in episodic memory, vigilance, and visuomotor speed but not in executive functioning or verbal fluency. Comparison of differential treatment effects on a composite measure of cognitive functioning found that risperidone was significantly more beneficial than haloperidol after 3 months of treatment. Changes in Positive and Negative Syndrome Scale scores were correlated overall with improvement in the haloperidol-treated patients but not in the risperidone-treated patients. Conclusions: Treatment with risperidone at the time of the first episode of schizophrenia is associated with wide-ranging improvements in cognitive functioning. Overall improvement is significantly greater with risperidone than with haloperidol. Further, cognitive improvement associated with treatment with risperidone was not influenced by changes in symptoms, but that relationship was significant in haloperidol-treated patients. (Am J Psychiatry 2005; 162:1888–1895)
C
ognitive impairment is now seen as an inherent feature of schizophrenia (1) and has been documented in many different domains, including attention (2), executive functioning (3), episodic memory (4), verbal skills (5), and processing speed (6). Cognitive deficits may represent a core pathophysiological feature of the illness because at the time of the first psychotic episode these impairments are very similar in profile and severity to those seen in patients with more chronic illness (7). These deficits are apparently present even before the onset of the first psychotic features of the illness (8) and appear to worsen slightly as illness onset approaches (9). A cross-sectional association between cognitive deficits and poor social and occupational outcomes has been demonstrated (10). In patients with an established illness, the correlation between cognitive and functional impairments is consistent across wide variations in the severity
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of lifetime functional impairment (11). It has been argued recently (12) that treatment of cognitive deficits, through a variety of means, has the potential to change the functional outcome of the illness, although this remains to be demonstrated directly. This possibility is important because conventional antipsychotic treatments appear not to have a particularly beneficial impact on aspects of functional outcome such as independent living (13). Early treatment of cognitive impairments may have important implications because disability may develop early in the course of illness, often within 6 months of initial diagnosis (14). Treatment with novel antipsychotic medications has been suggested to be superior to first-generation treatments for enhancement of cognition in a variety of populations (15, 16), such as first-episode patients (17), patients with chronic illness (18, 19), treatment-refractory patients (20), and elderly patients (21). These data suggest Am J Psychiatry 162:10, October 2005
HARVEY, RABINOWITZ, EERDEKENS, ET AL.
that risperidone, olanzapine, quetiapine, ziprasidone, and clozapine are associated with improvements in cognitive performance. Several questions have been raised about some of these findings, however. Many studies used research methods that are susceptible to biases, such as open-label designs. Other studies have used comparison doses of conventional medications that were high relative to the doses of the novel antipsychotics (16). Green et al. (22) found that there was little difference in cognitive change between lower doses of haloperidol and relatively high doses of risperidone in chronically ill patients. Finally, some of the studies did not consider the previous medications patients had been taking before they were randomly assigned to study medications. In many studies, patients who were poor responders to one medication and selected for the trial could be assigned to receive the same medications, which may be a source of bias. This article presents the results of a study that is not subject to most of those concerns. Patients who were in the early stages of psychosis, who met criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder, and who had received less than 12 weeks of lifetime treatment with antipsychotic medications were included. These patients were randomly assigned to receive treatment with low doses of risperidone or haloperidol. The patients were enrolled in a long-term treatment protocol and were examined with a battery of cognitive assessments previously shown to be relevant to functional outcome. Thus, participants did not have extensive previous treatment, they were treated with low doses of medication in a randomized double-blind protocol, and the data were examined with intent-to-treat analyses. The study continued for up to 5 years (until the last enrolled participant completed 2 years of treatment), but this first report presents the cognitive functioning changes from baseline to 3 months of treatment with the two target medications.
Method Subjects The current randomized controlled trial enrolled patients experiencing an early episode of schizophrenia in 12 countries. The characteristics of the patients randomly assigned to the two treatment groups were similar; there were no significant differences in sex, race or ethnicity, age, diagnosis, or previous neuroleptic treatment (Table 1). Diagnostic information was collected by using the Structured Clinical Interview for DSM-IV. About half of the subjects had a diagnosis of schizophrenia, 68% were men, and their mean age was in the 20s. Patients provided written informed consent to receive doubleblind treatment with risperidone or haloperidol for a period of 2 or more years. They were informed that they could terminate their participation at any time for any reason. Patients were excluded from participation if they were unable to read their native language; had a history of head trauma, seizure disorder, or other neurological condition; had a diagnosis of mental retardation; had experienced previous psychotic episodes; or if there was any Am J Psychiatry 162:10, October 2005
TABLE 1. Baseline Characteristics of 338 Patients With FirstEpisode Schizophrenia Spectrum Disorders Randomly Assigned to Risperidone or Haloperidol Treatment for Whom Baseline and 3-Month Cognitive Data Were Available Characteristic
Age (years) Age at onset of first psychotic symptoms (years) Men Women
Risperidone (N=169) Mean SD
Haloperidol (N=169) Mean SD
24.95
6.88
25.99
6.94
23.00 25.16
6.70 7.63
24.21 25.67
6.33 7.63
N Male sex Race or ethnic group White Black Hispanic Other DSM-IV diagnosis Schizophrenia Schizoaffective disorder Schizophreniform disorder No previous neuroleptic exposure
%
N
%
111
65.7
117
69.2
129 19 5 16
76.3 11.2 3.0 9.5
132 16 3 18
78.1 9.5 1.8 10.7
124 8 37
73.4 4.7 21.9
110 13 46
65.1 7.7 27.2
60
35.5
46
27.2
suggestion that the presence of any other diagnosis (e.g., substance abuse) would exclude a diagnosis of schizophrenia. The study was conducted in accordance with good clinical practice after it was approved by the local institutional review boards. Subjects were recruited in the United States, Canada, United Kingdom, South Africa, Australia, New Zealand, Finland, Germany, Austria, France, the Netherlands, and Israel. To participate in the cognitive assessments, patients were required to be native speakers of the language in which they were tested, although nonnative speakers were involved in the other assessments.
Treatment Patients were randomly assigned to receive double-blind treatment with either risperidone or haloperidol on a one-to-one randomization basis with equivalent dosing strategies. Subjects were started on 1 mg/day of the study drug and titrated up to 4 mg/day or, in exceptional cases, to a maximum of 8 mg/day. Patients were treated with trial medication for a median of 192 days (range=2 to 1,502) in the risperidone group and for a median of 218 days (range=1 to 1,514) in the haloperidol group (z=0.116, p=0.90, Mann-Whitney test). The mean modal total doses were 3.3 mg/ day of risperidone and 2.9 mg/day of haloperidol. We have reported the efficacy and safety results elsewhere (23). Briefly, we found that scores on the Positive and Negative Syndrome Scale subscales (24) and Clinical Global Impression (CGI) severity and change scales (25) improved significantly over baseline and that there were no significant differences between the treatment groups. Three-quarters of the patients achieved initial clinical improvement, defined as a reduction greater than 20% in total score on the Positive and Negative Syndrome Scale. However, among those who achieved clinical improvement, KaplanMeier survival analysis revealed that 42% of the risperidone group relapsed, compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone and 205 days for haloperidol (log rank=7.10, p=0.008). There were significantly more extrapyramidal side effects and use of adjunctive medications in the haloperidol group and greater prolactin elevation in the risperidone group. Relatively fewer patients in the risperidone group received concomitant medications as treatments for extrahttp://ajp.psychiatryonline.org
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COGNITIVE IMPAIRMENT IN EARLY PSYCHOSIS TABLE 2. Cognitive Performance at Baseline and Change From Baseline to 3-Month Follow-Up for Patients With FirstEpisode Schizophrenia Spectrum Disorders Randomly Assigned to Risperidone or Haloperidol Treatment Baseline Risperidone (N=256) Measure Verbal fluency Category Letter Sum of category and letter Visuospatial episodic memory: Wechsler Memory Scale— Revised Visual Reproduction Immediate recall total score Delayed recall total Rey Verbal Learning Test Learning trials 1–5 Long-delay free recall Recognition discriminability Vigilance: Continuous Performance Test d′ total Processing speed: WAIS-R Digit Symbol age-corrected score Executive functioning: Wisconsin Card Sorting Test Categories Perseverative errors
Analysisa
Haloperidol (N=250)
Mean
SD
Mean
SD
F
df
p
36.06 29.28 65.27
11.77 11.07 20.96
36.25 28.76 64.85
10.70 11.32 19.78
0.55 0.00 0.11
1, 506 1, 504 1, 503
0.46 0.99 0.74
31.08 25.92
7.39 9.94
31.38 27.13
7.63 9.57
0.05 0.74
1, 499 1, 494
0.82 0.39
42.30 8.58 86.21 0.69 6.94
11.73 3.91 17.43 0.65 2.47
41.85 8.67 86.54 0.79 7.09
11.83 3.70 17.59 0.79 2.70
0.01 0.64 0.06 1.09 0.36
1, 488 1,503 1, 502 1, 463 1, 501
0.93 0.42 0.81 0.30 0.55
3.8 21.79d
2.15 15.32
4.20 20.81e
2.17 16.48
3.31 0.28
1, 479 1, 480
0.07 0.60
a
Comparisons of baseline scores between haloperidol and risperidone based on analysis of covariance (ANCOVA) controlling for age and education. b Comparisons of change from baseline within treatment groups based on one-sample t tests. c Comparisons of change from baseline between haloperidol and risperidone based on ANCOVA controlling for baseline, age, and education. pyramidal side effects. These differences were statistically significant for β-blocking agents (p
