The Effects of Risperidone on the Cognitive Performance of Individuals With Schizotypal Personality Disorder

To the Editors

Cognitive dysfunction is a core feature of schizophrenia and is present in most patients with the illness, frequently preceding the onset of other symptoms and persisting even after other symptoms have been effectively treated.¹ These abnormalities, which are the best predictor of impairments in various aspects of functional outcome in schizophrenia,^2,3 predict poorer treatment adherence^4,5 and increased tendency for relapse in first episode patients.⁶

Several of the cognitive deficits found in patients with schizophrenia are also present in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD).^7–10 We have previously demonstrated that the cognitive impairments of individuals with SPD are amenable to treatment with pharmacological agents, in particular those that modulate catecholamine functioning. In particular, 4 weeks of treatment with guanfacine, significantly improved the context processing abilities of SPD participants compared with those treated with placebo.¹¹ In addition, treatment of SPD patients with a low dose of risperidone resulted in a significant reduction in negative and general symptoms over 3 weeks.¹²

There is some evidence that second generation, or atypical antipsychotics, improve the cognitive performance of individuals with schizophrenia.^13,14 Based on these results, we sought to evaluate the impact of risperidone on the cognitive functioning of individuals with SPD. We hypothesized that risperidone would result in improvements in the cognitive performance of SPD participants, in that guanfacine was more effective at reducing cognitive impairments in people with SPD than in schizophrenia.^11,15

We recruited male or female participants between the ages of 18 and 60 years from the outpatient clinics at the Mount Sinai Medical Center (New York, NY) and the Bronx Veterans Affairs Medical Center (Bronx, NY). Participants were required to meet Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for SPD. When there was comorbidity with other personality disorders, SPD was judged by to be the primary diagnosis. All patients received a urine toxicology screen. See our previous publications for the full diagnostic assessment. The study was approved by the institutional review boards at the 2 institutions, and all participants signed a written informed consent statement. Data were collected from 1995 to 2001.

Patients were randomly assigned in a 1:1 ratio to receive risperidone or placebo in identical tablets. All patients received a single-blind 2-week placebo lead-in followed by a double-blind 10-week medication trial. The dosage of risperidone was titrated upward in a stepwise design, beginning with 0.25 mg/d for the first week, 0.5 mg/d for weeks 2 and 3, 1.0 mg/d for weeks 4 and 5, 1.5 mg/d for weeks 6 and 7, and 2.0 mg/d for the remaining weeks. Cognitive performance was assessed at baseline, as well as at weeks 6 and 12. The cognitive assessment battery consisted of measures of a range of neuropsychological functions, including spatial and verbal working memory, vigilance, spatial memory, and word list learning (for a more complete description of these assessments, please see our previous work⁷). For all the dependent variables, we computed change scores from baseline to 6 and 12 weeks. We then conducted a series of univariate analyses of variance comparing the change scores of individuals in our risperidone group to those in our placebo group.

Thirty-one participants entered into the study, 19 of whom were randomized to risperidone and 12 to placebo. Several participants in both groups dropped out of the study for various reasons, such as boredom or fatigue, ostensibly not related to group assignment. Two participants in the risperidone group were withdrawn, 1 because of an increase in suicidal ideation and 1 because of galactorrhea. In total, 9 participants in the placebo group and 11 participants in the risperidone group completed all 12 weeks of the trial and were included in the analysis. The groups did not differ significantly in the number of participants who terminated prematurely (Fisher exact test, P = 0.452, NS). The groups were also comparable in terms of age, education, sex, vocabulary scores, or block design performance (all Ps = NS). Clinical response to risperidone was previously reported¹² in a sample that included 23 of the 31 participants in the current study; raw scores on the symptom assessment of the current sample are presented in Table 1.

TABLE 1.

Results of Cognitive Assessments at Baseline, Week 6 and Week 12

	Risperidone Group			Placebo Group
	Baseline	Week 6	Week 12	Baseline	Week 6	Week 12
	mean (SD)	mean (SD)	mean (SD)	mean (SD)	mean (SD)	mean (SD)
PANSS positive	11.9 (4.7)	10.4 (2.8)	9.4 (2.5)	13.1 (5.6)	12.2 (3.5)	12.3 (4.3)
PANSS negative	13.9 (4.7)	12.2 (5.8)	12.1 (5.2)	16.8 (7.8)	16.9 (7.5)	16.0 (6.2)
PANSS general	26.9 (7.7)	23.9 (6.2)	22.1 (5.2)	31.9 (10.6)	32.1 (9.6)	28.9 (9.9)
WMS-VR	33.1 (5.1)	34.00 (5.9)	34.9 (7.1)	32.3 (5.0)	37.5 (0.6)	34.2 (4.1)
WMS-VR LD	29.1 (8.4)	31.6 (7.0)	36.8 (13.5)	29.9 (6.8)	36.5 (1.0)	34.4 (3.9)
WLL trail 5	12.8 (5.3)	14.2 (5.1)	15.7 (5.3)	14.8 (4.9)	16.0 (4.9)	19.5 (3.5)
WLL LD	10.9 (4.2)	12.7 (4.9)	15.7 (6.6)	13.0 (5.4)	14.0 (6.4)	16.8 (5.0)
CPT d′	0.9 (0.5)	1.5 (0.8)	1.3 (0.83)	2.0 (1.3)	2.3 (1.1)	2.3 (1.0)
PASAT	31.0 (5.9)	34.6 (14.3)	36.7 (13.5)	34.6 (11.5)	41.4 (7.3)	44.8 (5.2)
DOT 30 s delay	1.2 (1.4)	1.6 (1.6)	0.91 (0.61)	1.4 (1.3)	1.9 (1.0)	1.4 (1.6)

PANSS indicates Positive and Negative Syndrome Scale; WMS-VR, Wechsler Memory Scale Visual Reproduction Test raw score; WMS-VR LD, Wechsler Memory Scale Visual Reproduction Test 30-minute delay interval raw score; WLL Trial 5, Word List Learning total words recalled at trial 5; WLL LD, Word List Learning total words recalled after 20-minute delay interval; CPT d′, signal detection continuous performance test number of errors of omission; PASAT, Paced Auditory Serial Addition Test total number of correct responses; DOT 30s delay, Dot test distance error at the 30 sec delay minus the distance error in the copy condition.

Raw scores for the cognitive assessments at baseline, week 6 and week 12, are presented in Table 1. There were no significant differences between the risperidone group and the placebo group in change from baseline on any of the cognitive variables following either 6 weeks, all Fs < 2.5, all Ps > 0.15, or 12 weeks, all Fs < 1.2, all Ps > 0.28, of treatment.

DISCUSSION

We hypothesized that individuals with SPD, who frequently demonstrate a similar profile of cognitive impairment to individuals with schizophrenia, would benefit from treatment with risperidone, as they had previously been shown to benefit from other cognitive enhancement therapies. The results of the current study did not support this hypothesis and are not as large as those seen in the generally negative Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial looking at schizophrenia patients and atypical antipsychotics.¹⁶ These data suggest that although antipsychotic medications may reduce clinical symptoms in SPD, they may not have a substantial benefit for cognitive functioning.

There are several possible explanations for our failure to find statistically significant results. The small sample size and high number of drop-outs led to modest power. Furthermore, examination of baseline performance in both groups suggests that the SPD patients were less impaired on cognitive measures than cohorts in our previous studies. Although we failed to find statistically significant differences between individuals with SPD treated with risperidone and those treated with placebo on our cognitive assessments, more severe cognitive impairment in SPD might have responded to risperidone. Future research on other treatments targeting these deficits in SPD is warranted, especially in those individuals who demonstrate cognitive abnormalities that are closer to the severity of what is seen in schizophrenia.