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Clozapine Enhances Neurocognition and Clinical Symptomatology More Than Standard Neuroleptics

Potkin, Steven G. MD; Fleming, Kirsten PhD; Jin, Yi MD; Gulasekaram, Bala MD

Journal of Clinical Psychopharmacology: October 2001 - Volume 21 - Issue 5 - p 479-483

Neurocognition and clinical symptomatology were evaluated in 27 patients with schizophrenia during a double-blind, placebo-controlled, crossover study involving clozapine, an atypical antipsychotic agent, and haloperidol, a conventional neuroleptic. Patients were assessed 5 to 6 weeks after initiation of each phase. Clinical symptomatology, based on Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms ratings, markedly improved after treatment with both haloperidol and clozapine. The beneficial effects of clozapine were statistically significantly greater than the effects from the haloperidol treatment. Regarding neurocognition, both agents proved efficacious in improving performance on nearly all measures compared with placebo. In addition, as compared with haloperidol, clozapine significantly improved performance on Trails B, Verbal Fluency, and measures of delayed verbal memory, and it tended to increase performance on most measures. Additional analyses indicated that the improvement on neurocognitive measures was not because of symptom amelioration; rather, neurocognitive deficits seem to be an intrinsic enduring feature of schizophrenia. The superiority of clozapine over haloperidol may be related to clozapine’s unique psychopharmacologic profile.

Department of Psychiatry and Human Behavior, University of California, Irvine, UCI Medical Center, Orange, California

Received March 11, 1999; accepted after revision September 11, 2000.

Address requests for reprints to: Dr. Kirsten Fleming, Department of Psychiatry and Human Behavior, 101 City Drive South, Orange, CA 92686. Address e-mail to:

COGNITIVE DYSFUNCTION IS characteristic of schizophrenia. In fact, after the emergence of psychosis, investigators have noted that there is often a drop in IQ, from 10 to 15 points, as assessed by standardized intelligence measures. 1,2 Even more specific and significant are the decreases in memory and executive functions. Executive function refers to the ability to make plans and remain flexible in the face of life’s many ambiguities, such as cognitive skills that discriminate humans from other animals (because of humans’ highly involved prefrontal cortex) and that predict one’s ability to function independently in the world. A goal of increasing attention in the psychopharmacologic treatment of schizophrenia is the amelioration of these cognitive deficits.

Currently there are two major categories of drugs used to treat schizophrenia, conventional antipsychotic agents such as haloperidol, and the newer, atypical antipsychotics. Conventional antipsychotics are primarily D2-dopamine-receptor antagonists and cause extrapyramidal side effects (EPS). Atypical antipsychotics, unlike most conventional drugs, also antagonize serotonergic receptors and produce far fewer EPS. The standard atypical antipsychotic is clozapine, which has superior efficacy compared with typical agents, especially in individuals who were previously considered treatment-refractory. 3,4 Moreover, clozapine has been found to improve negative symptoms and enhance the quality of life and social and occupational functioning in patients. 5

The literature on the cognitive effects of both class of drugs is inconsistent and complex. 6 The equivocality is in part because of methodologic differences in drug dosages, length of studies, use of concomitant medications, cohort compositions, and neurocognitive assessment measures. Nevertheless, some patterns have appeared. First, regarding typical neuroleptic effects, it seems that initial short-term treatment may result in worsened motor function and attention. 7–9 These abnormalities, however, may partially reverse, because studies have shown an improvement in psychomotor speed, attention, and memory and executive functions over time with continued treatment. 7,8,10 Importantly however, a patient’s performance still remains somewhat impaired and considerably worse than at premorbid levels. 11 The first cognitive study with clozapine reported that it failed to improve any domain of cognition. 12 This early study had methodologic limitations, however, because only 15 patients were assessed, 11 of whom were also receiving concomitant medications.

In contrast, the subsequent studies to date have found some enhancement in cognition with clozapine therapy. Hoff and associates 12 assessed 17 patients, first while receiving typical neuroleptics and again after 12 weeks of clozapine treatment. Similar to Goldberg and associates, 2 Hoff and associates found a decrement on visual memory, but improvements on spatial, attentional and motor speed measures. Another set of studies was conducted by Meltzer’s group, 13,14 who assessed larger cohorts of treatment-and non–treatment-refractory patients. The first study involved treatment-refractory patients who were first tested drug-free, 6 weeks after beginning clozapine treatment, and again after 6 months. Improvements were found in several areas, including Verbal Fluency and memory. In the study by Lee and associates, 14 another large cohort of patients was assigned to receive either typical neuroleptic treatment or clozapine. As in the earlier investigation, clozapine therapy resulted in improvements in several areas, most notably on attention and Verbal Fluency, whereas typical agents produced minimal improvement. The most comprehensive study was conducted by Buchanan and colleagues, 15 who used a double-blind, parallel-group design involving 19 patients who received clozapine and 19 who received haloperidol. Patients were first evaluated at baseline condition, in which they were being tapered from the standard, typical neuroleptic, fluphenazine, and at the end of a 10-week trial. The patients who received haloperidol demonstrated a decrement of performance on measures of Verbal Fluency and block design, whereas, there were no changes in cognitive functioning in the clozapine-treated group. Of these patients, 33 continued in a year-long trial of clozapine and demonstrated significant improvements in Verbal Fluency, block design, and figure closure. Because a control group was not included, the contribution of any practice effects was not studied. The final study 16 compared the effects of placebo, fluphenazine, and clozapine in fixed order on reaction-time measures. None of the treatments significantly differed from one another on reaction time; however, clozapine did improve performance on a task, requiring patients to respond to tones in a trial necessitating responses to two stimuli. This study sought to determine the effects of clozapine as compared with placebo and haloperidol by using a double-blind, within-patient, crossover design. To date, this is the largest crossover investigation of its kind.

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The patients for this study consisted of 27 inpatients, (23 men and 4 women) with schizophrenia according to DSM-III-R criteria based on structured interviews. Patients were recruited from Metropolitan State Hospital and the outpatient clinics of the University of California, Irvine. Written informed consent was obtained from all participants. Two thirds of the patients were treatment-refractory to standard neuroleptic agents. Exclusionary criteria included an identifiable neurologic disorder, mental retardation, a current history of alcohol or drug dependence, or positive urine drug screens. The mean age of the patients was 34.9 years (range, 25–47). The mean duration of illness was 15.9 years (range, 2–35). Clozapine was initiated at 25 mg/day and titrated to a range from 300 to 500 mg/day. Haloperidol was adjusted to a plasma concentration of 10 to 20 μg/mL by a nonblinded pharmacist. Benztropine (2 mg, twice a day) was also administered during the haloperidol arm. Identical-appearing capsules protected the study blind. All patients were tested three times in a counterbalanced, crossover, double-blind design. All inpatients received 5-to 6-week drug regimens of haloperidol, clozapine, and a placebo phase, although, the placebo arm always occurred in the middle phase.

Clinical ratings were obtained with the Brief Psychiatric Rating Scale 17 (BPRS) and the Scale for the Assessment of Negative Symptoms 18 (SANS). The ratings were made within 2 days of the neurocognitive testing. Neurocognitive raters and psychiatric raters were blind to drug condition. Patients were administered a comprehensive neurocognitive battery consisting of the following measures: Wechsler Adult Intelligence Scale–Revised (WAIS-R 19), Wechsler Memory Scale Revised, Trails A and Trails B, 20 Verbal Fluency Test, 21 Wisconsin Card Sorting Test, Rey Auditory Verbal Learning Test, 22 and Boston Naming Test, 23 by an experienced psychologist.

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Clinical symptomatology markedly improved when patients were medicated (Table 1). Repeated measures, within-patient analyses of variance (ANOVAs) were conducted, and when significant, follow-up analyses were conducted with dependent post hoc analyses. There was improvement for both agents in BPRS scores (F [2,52] = 11.27, p = 0.0001). Post hoc analyses revealed that there were significant improvements in symptoms from both haloperidol and clozapine (p = 0.009, p = 0.001, respectively) to placebo. There was significantly more overall symptom amelioration from clozapine, as compared with haloperidol (p = 0.04). The BPRS index of positive symptoms demonstrated improvement after treatment (F [2,52] = 3.7, p = 0.02). Post hoc analyses indicated that there were significant improvements from placebo to clozapine and a trend for improvement between haloperidol and clozapine (p = 0.01 and p = 0.06, respectively). On the SANS, which is considered a specific test for negative symptomatology we found an overall improvement in scores (2,52) F = 7.8, p = 0.001. There were significant improvements in negative symptomatology from placebo for both haloperidol and clozapine (p = 0.004 and p = 0.0004, respectively).

Table 1

Table 1

Table 2 presents the neurocognitive performance for the three phases. The overall ANOVAs were significant for the WAIS-R measures (p < 0.001), the Wechsler Memory Scale indices (WMS-R) (p < 0.05), Trails A and B (p < 0.05), Verbal Fluency (p = 0.001), Verbal List Learning–Trial 5 (p = 0.009), and Delayed Recall and Recognition from the List Learning Test (p < 0.01). On those measures, (with the exception of Trails B) both haloperidol and clozapine significantly improved performance over baseline placebo levels. The improvements on Trails B were because of improvement from clozapine treatment and not haloperidol. Of the previously mentioned 14 tests, clozapine improved performance more than haloperidol on 11 of them. Clozapine results were significantly better than haloperidol on Trails B (p = 0.01), Verbal Fluency (p = 0.02), and both Delayed Recall and Recognition on Verbal List Learning (p = 0.01 and p = 0.05, respectively). There were no improvements in the Wisconsin Card Sorting Test or the Boston Naming Test. The latter measure, a test of object naming, was not expected a priori to be modified by pharmacotherapy.

Table 2

Table 2

Although the crossover design presumably precluded the effect of order of drug treatment, we further ensured that this was the case by conducting multivariate analyses of variance, with order as the independent factor. The results revealed that order of drug administration was not significant for any variable. Next, we examined whether improvement in cognition occurred as a function of clinical improvement by conducting analyses of covariance with change in clinical symptomatology on the BPRS as the covariate and found that the significance on all measures remained, confirming earlier reports that cognitive improvement was not a function of clinical symptom improvement. 2,15

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The results of this study confirm earlier investigations demonstrating the beneficial effects on psychiatric symptomatology and cognition created by psychopharmacologic therapy in patients with schizophrenia. Standard neuroleptic haloperidol and the atypical antipsychotic clozapine created significant improvements. Although these agents were successful in terms of ameliorating psychiatric symptomatology and improving neurocognition, our analyses indicated that clinical symptoms and cognition are separate dissociable domains. 2,13,24

Although both treatments improved cognitive and psychiatric outcomes, clozapine was superior in both realms. Regarding symptomatology, clozapine was superior in overall psychiatric improvement; closer investigation revealed that clozapine’s efficacy involved both positive and negative symptoms, which is consistent with previous investigations. 3,4 Although this study assessed the relatively short-term effects of clozapine, prior studies 14,15 indicate that long-term improvement is maintained, and in particular, negative-symptom-amelioration may continue up to 1 year. 4

Clozapine’s effects on neurocognition were equally impressive and largely consistent with earlier work. Specifically, although clozapine was more effective than haloperidol at increasing performance in nearly all cognitive domains, statistical significance was achieved on the following tests: Trails B, Verbal Fluency, and Delayed Verbal Recall and Recognition. The first two measures are speed tests of executive function. Clozapine, in contrast to haloperidol, enhances dopaminergic release and alters metabolism in the frontal cortex while having relatively less effect in the basal ganglia. 25,26 The effect of reduced basal ganglia involvement might result in an improvement in speed and attention and use of frontal cortical networks—necessary skills to perform Trails B and Verbal Fluency successfully. The improvement in verbal memory after clozapine treatment is consistent with earlier work 14; however, the biological mechanism has not yet been elucidated. Improvement in verbal memory is particularly significant because it has been found to be highly predicative of subsequent social and vocational functioning, as well as quality of life. 15,27,28 A caveat regarding our memory results is that benztropine, which was coadministered with haloperidol, is known to have a deleterious effect on measures of secondary memory (e.g., WMS-R memory and List Learning). 10,29–31 It is possible that without the influence of coadministered benztropine, haloperidol might have improved memory to a greater degree; however, any possible beneficial effects on memory would not likely outweigh the resultant EPS. Consistent with prior investigations, 2,12 clozapine did not improve performance more than haloperidol on two measures—visual memory and the Wisconsin Card Sorting Test. A number of studies have also found that clozapine may cause some decrement on the Wisconsin Card Sorting Test. 2,12,13 This could be related to clozapine’s relatively strong affinity for D1-receptors which have been shown to be involved in executive processes. 32 There is a possibility that withdrawing the patients from both of the active drug treatments may have produced a state of drug withdrawal that may have accounted for some of the improvements during the treatment arms.

In summary, haloperidol and clozapine were effective at treating both psychiatric symptomatology and cognitive dysfunction. Clozapine was superior to haloperidol in ameliorating both clinical symptoms and neurocognitive deficits, although its effects in these two realms seem to be dissociable. Although these findings, combined with previous investigations, are cause for renewed optimism, it is noteworthy that cognitive functioning was not normalized and remained quite impaired, although significantly improved. It is plausible that these remaining cognitive deficits are responsible for limiting the vocational and social outcomes in these patients, even once symptoms have been brought under control. Clearly, future work needs to delineate the specific pharmacologic-receptor effects that would result in the greatest improvement in cognition.

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