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Cognitive Effects of a Single Dose of Atypical Antipsychotics in Healthy Volunteers Compared With Placebo or Haloperidol

Chung, Young-Chul MD, PhD*†; Park, Tae-Won MD, PhD*†; Yang, Jong-Chul MD, PhD*†; Huang, Guang-Biao MD*; Zhao, Tong MD*; Oh, Keun-Young MD; Kim, Min-Gul MD

Journal of Clinical Psychopharmacology: December 2012 - Volume 32 - Issue 6 - p 778–786
doi: 10.1097/JCP.0b013e318272d10c
Original Contributions
Free

Cognitive dysfunction in patients with schizophrenia is a strong correlate of poor outcome than any other symptom domain. To have greater knowledge about the effects of antipsychotics on cognitive function, subjects of this study were healthy volunteers who had no confounding variables typically found in patients with schizophrenia. The cognitive function of healthy volunteers in response to single doses of haloperidol, risperidone, aripiprazole, and amisulpride in a double-blind placebo-controlled trial was investigated. Assessments for the computerized neurocognitive test, mental and physical sedation, and extrapyramidal symptoms were performed within 1 week before (baseline) and approximately 4 hours after drug administration. Compared to the placebo, single administration of amisulpride at 400 mg in healthy volunteers enhanced word fluency test performance and remained intact after controlling for sedation and extrapyramidal symptoms. Significant improvement in some measurements of the computerized neurocognitive test was also observed in each antipsychotic-treated group but may have been related to practice effect. These findings suggest that amisulpride may have cognitive-enhancing effects in healthy volunteers.

From the *Department of Psychiatry, Chonbuk National University Medical School; †Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital; and ‡Clinical Pharmacology Unit, Chonbuk National University Hospital & Research Institute of Clinical Medicine, Jeonju, Korea.

Received May 23, 2011; accepted after revision April 6, 2012.

Reprints: Young-Chul Chung, MD, PhD, Department of Psychiatry, Chonbuk National University Medical School, Keumam Dong 634-18, Jeonju 561-712, Korea (e-mail: chungyc@jbnu.ac.kr).

This paper was supported in part by funding from the Research Institute of Clinical Medicine at Chonbuk National University Hospital.

Cognitive dysfunction is associated with key features of schizophrenia, such as outcome and adaptive dysfunction. With 20% to 60% of variance in functional outcome linked to differences in cognitive functioning,1 such deficits are a strong correlate of poor outcome than any other symptom domain.2 Thus, cognitive performance is viewed as a crucial target of pharmacologic treatments for schizophrenia. Earlier reviews suggested that first-generation antipsychotic drugs did not improve cognitive performance in schizophrenia, although studies concluded that low doses of typical antipsychotics seem to have favorable cognitive effects.3,4 Many recent clinical trials, however, although with methodological shortcomings and several meta-analyses,5,6 have suggested relative superiority of second-generation antipsychotic drugs over first-generation drugs with regard to their effects on cognitive dysfunction in patients with schizophrenia. This optimistic view about second-generation antipsychotic drugs has been severely challenged by 2 recent large-scale and nonindustry-sponsored studies, that is, the Clinical Antipsychotic Trials of Intervention Effectiveness7 and the European First Episode Schizophrenia Trial.8 These 2 studies reported no significant differences in the magnitude of cognitive improvement between typical and atypical antipsychotic drugs. Moreover, Reilly et al9,10 reported adverse effects of second-generation antipsychotics (ie, olanzapine or risperidone) on spatial working memory in first-episode schizophrenia. One reason for these controversial findings may be that studies on how antipsychotic drugs affect cognitive function are hampered by numerous confounding factors that can affect test results (eg, a patient’s clinical state, various levels of motivation, concomitant medication, or practice effects).

Investigating antipsychotic drug effects in healthy subjects provides a method for controlling these variables. Studies with risperidone and healthy volunteers have reported mixed results: one study11 demonstrated significant impairment of the Digit-Symbol Substitution Test (DSST), whereas others12,13 reported no effects on executive functioning, attention, and memory. Additionally, 2 studies on olanzapine both reported impairment of memory performance in healthy volunteers.14,15 Amisulpride at 400 mg produced cognitive impairment on the fifth day of administration,16 whereas low doses of amisulpride (50–200 mg) led to mixed findings.17,18 Aripiprazole is a recently introduced second-generation antipsychotic that has a receptor-binding profile distinct from that of other second-generation antipsychotics. This drug is a partial agonist at D2 and 5-hydroxytryptamine (5-HT)1A receptors and is also an antagonist at 5-HT2A receptors. Based on the hypothesis that aripiprazole would act as a dopamine agonist in circumstances of low dopamine receptor stimulation,19 this drug may have beneficial effects on cognitive dysfunction in schizophrenia. Several studies have reported improvement of cognitive function after switching to aripiprazole from typical20 or atypical antipsychotics.21 However, no studies had investigated the effects of aripiprazole on cognitive performance in healthy volunteers.

We hypothesized that amisulpride and aripiprazole would cause no or minimal impairment in cognitive performance in healthy volunteers. The main objective of this study was to assess cognitive function in healthy volunteers in response to single doses of haloperidol, risperidone, aripiprazole, and amisulpride in a double-blind placebo-controlled trial. Adverse events caused by these drugs were also evaluated.

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MATERIALS AND METHODS

Subjects

Eighty healthy volunteers were recruited via advertisements. Before acceptance as a participant, volunteers agreed to a psychiatric interview using the screening module of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, non-patient edition,22,23 a routine physical examination, a screen of hematological and biochemical parameters, and an electrocardiogram. Participants were excluded if they had any of the following: a current or past diagnosis of a psychiatric or neurological disorder, alcohol or drug abuse or dependence (except for nicotine), and other significant medical conditions. Participants entered an agreement to avoid drinking alcohol, coffee, and other caffeine-containing beverages for at least 24 hours before the experiment and to avoid any medications for the duration of the study. All participants provided written informed consent in accordance with a protocol approved by the hospital’s ethics committee.

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Study Design

This was a placebo-controlled, double-blind, randomized, 5-armed parallel study. The volunteers were housed in an inpatient psychiatric unit from the early morning of the day of the experiment until 4 hours after the administration of study medication, and they returned 24 hours later for further evaluation of adverse events. They received a single dose of one of the 5 study medications between 8:00 and 9:00 A.M.: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, 2 mg risperidone, or matching placebo capsules (Fig. 1).

FIGURE 1

FIGURE 1

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Assessments

The Computerized Neurocognitive Test (CNT) 40 (MaxMedica, Inc, Seoul, Korea) was used to assess cognitive functioning. The tests included the auditory continuous performance test (CPT), auditory verbal learning test, digit span test, Stroop test, Trail-Making Test (TMT) A and B, Wisconsin Card Sorting Test (WCST), and word fluency test. Subjects were also asked to complete a visual analog scale24 that involved measuring 4 subdomains: mental sedation (alert-drowsy, muzzy-clear headed, mentally slow–quick witted, and attentive-dreamy), physical sedation (strong-feeble, well coordinated–clumsy, lethargic-energetic, and incompetent-proficient), tranquilization (calm-excited, contented-discontented, troubled-tranquil, and tense-relaxed), and other types of feelings (happy-sad, antagonistic-amicable, interested-bored, withdrawn-gregarious). We only used the first 2 dimensions, which were presented as 10-cm lines, and the 2 extremes of each item were given at opposite ends. Parkinsonism and akathisia were evaluated with the Simpson-Angus Scale (SAS)25 and the Barnes Akathisia Rating Scale (BARS),26 respectively. A SAS score (total score divided by 10) of 0.3 or more indicated parkinsonism. A BARS global score of 2 or more was considered significant. As baseline, the CNT was performed within 1 week before drug administration and was repeated approximately 4 hours after administration; other assessments were conducted immediately before drug administration and approximately 4 hours after administration. Adverse events of the study drugs were assessed at 2, 4, and 24 hours after drug administration using both self-reporting and a sheet of 10 items that was prepared based on the most commonly reported adverse events from previous studies related to the study medications. The evaluation time points after administration were chosen based on the time-to-peak plasma concentration (Tmax) parameters for the study medications.27–30 Objective ratings and the CNT were performed by a trained psychiatrist (C.H.) and a research nurse (H.K.), respectively, who were blind to the study objective and medication types of subjects.

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Data Analysis

Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 11 for Windows. A paired t test was performed to compare continuous variables between baseline and the 4-hour post-administration point within each group. Between-group analysis was conducted on the CNT change scores from baseline using an analysis of variance with Bonferroni-corrected t tests to detail differences between the individual groups. To rule out confounding effects by sedation and extrapyramidal symptoms (EPS), change values of mental sedation and SAS scores were included as covariates. A significance level of 0.05 was established.

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RESULTS

Participants’ Characteristics

Eighty subjects volunteered for the study, but two were excluded: one had a gynecological problem, and the other had acute abdominal discomfort during the screening phase. Demographic data are shown in Table 1. Of the total participants, 43 were men and 35 were women, and the mean age was 28.6 years. Mean education in years was 18.55, and mean body mass index was 21.55. No significant differences between the groups were detected for any of the variables.

TABLE 1

TABLE 1

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Effects on Cognitive Function

The results of the effects of antipsychotics on cognitive function are summarized in Table 2. The within-group analyses revealed that correct response and commission error of the auditory CPT changed significantly in the amisulpride, aripiprazole, haloperidol, and risperidone groups; whereas no changes in the auditory CPT were observed in the placebo group. Scores of the auditory verbal learning test increased significantly in all 5 groups including the placebo. Reaction time for the TMT B decreased significantly in the amisulpride, aripiprazole, and placebo groups, whereas the reaction time for the TMT A decreased significantly only in the amisulpride and placebo groups. No significant differences in the WCST were observed between baseline and at 4 hours after administration in all groups. Word fluency test scores increased significantly in the amisulpride and placebo groups. However, between-group analysis for CNT change values from baseline to end point revealed a significant difference only in the animal category of the word fluency test (Table 3). Post hoc results showed significant differences between the amisulpride group and the aripiprazole, haloperidol, risperidone, or placebo group. Further analyses with mental and physical sedation scores and SAS scores as covariates showed that a significant difference in the word fluency test persisted after controlling for such variables (data not shown). Subsequent post hoc results remained the same as the analysis of variance results.

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Effects on Sedation and Extrapyramidal Symptoms

Table 4 shows that all antipsychotics and placebo significantly increased mental sedation, physical sedation, and SAS and BARS scores from baseline to end point. Analysis of covariance with baseline values as a covariate left only mental sedation as a significant variable, and post hoc analyses indicated significant differences between the aripiprazole or risperidone group versus placebo group. When a SAS score greater than 0.3 was applied as a cutoff score for EPS, only the risperidone and aripiprazole groups were identified with mild EPS.

TABLE 4

TABLE 4

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Adverse Events

The most common adverse events were sedation, cognitive slowing, decreased salivation, and headache, which were observed frequently at 4 hours after administration (Table 5). They were mostly mild in severity, but moderate symptoms occurred in 6 subjects of the risperidone group (sedation, 6; cognitive slowing, 6; dizziness, one; anxiety, one; and abdominal discomfort, one) and one in the placebo group (sedation).

TABLE 5

TABLE 5

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DISCUSSION

In this study, effects of amisulpride, aripiprazole, haloperidol, and risperidone on cognitive function were investigated using a double-blind placebo-controlled design in healthy volunteers. Overall, impairment of the auditory CPT was observed in all antipsychotic-treated groups, but no overall difference was detected between the groups. Improvement in the auditory verbal learning test, TMT A and B, or word fluency test was observed in different antipsychotic drug groups and the placebo group. As for the between-group analysis for CNT change values, a significant difference was only found in the word fluency test, which was not affected by confounding factors such as mental and physical sedation and the SAS score.

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Effects of Antipsychotics on the Auditory CPT

Within-group analysis revealed that single administration of amisulpride, aripiprazole, haloperidol, and risperidone produced significant impairment in the auditory CPT, which was absent after administration of the placebo. However, between-group comparison of change scores from baseline to end point in the auditory CPT demonstrated no significant differences among the 5 treatment groups. In a previous study, 400 mg of amisulpride exerted no effect on sustained attention,16 a neurocognitive component measured by the CPT, after the initial doses (on day 1) but produced greater impairment after the final dose (on day 5) than the placebo. Mixed findings were found for haloperidol: one study reported no effect on the continuous attention task by haloperidol at 2, 4, or 6 mg31; but another study reported greater impairment in sustained attention by single and repeated administration of haloperidol at 4 mg compared to the placebo.16 Our results suggest that antipsychotics tend to produce some detrimental effects on sustained attention, but the effects are not large enough to produce a significant difference compared to the placebo. No effects of antipsychotics on sustained attention in the present study are in agreement with previous studies: amisulpride at 300 mg and risperidone at 3 mg had no effect on executive functioning,13 amisulpride at 50 mg and 200 mg was devoid of any clinically relevant impairment on psychomotor and memory tests,32 and haloperidol at 3 and 2.5 mg had no effect on the choice reaction test33 and was not associated with impairing effects on psychomotor function or verbal memory, respectively.14 In contrast, many existing studies reported detrimental effects on cognitive function by antipsychotics: aripiprazole at 20 mg modestly impaired performance in the DSST34; haloperidol at 3 mg produced significant impairment in the rapid information-processing task,33 and at 4 and 6 mg caused significant impairment of performance in the DSST31; risperidone at 2 mg caused deleterious effects on the DSST11; and olanzapine at 10 mg significantly impeded memory performance and psychomotor function.14,15 Possible reasons for these discrepant findings may be attributable to different study designs, such as dose of study medications, timing of tests, and age of the subject. For example, administration of haloperidol impaired attention tasks (digit vigilance task) at 6 hours35 or 9 hours17 after dosing although Tmax for haloperidol is 2 to 4 hours after oral administration. Hence, the results may have been different if more evaluations were conducted beyond 4 hours. In several studies11,33 that reported the detrimental effects of antipsychotics on cognitive function, the mean subject age was older than 30, whereas the mean subject age in the present study was 28.6 years (range, 24–36 years). Perhaps young subjects (younger than 30 years) are more resistant to harmful effects of antipsychotics on cognitive function.

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Effects of Antipsychotics on the Auditory Verbal Learning Test, TMT A and B, and Word Fluency Test

For the auditory verbal learning test, TMT A and B, and word fluency test, significant improvement was observed after administration of the study medications including the placebo, although the types of tests that improved differed depending on the type of antipsychotics. These improvements cannot be interpreted as direct enhancing effects by antipsychotics because no significant differences were detected when compared to the placebo group; they instead may have been related to the practice effect. The effect sizes for improvement by antipsychotics were not different from those of the placebo (data not shown). The possibility of the practice effect by antipsychotics may be understandable since the interval between test and retest was very short (<10 days), and participants were young and highly educated. This is supported by Peretti et al18 who reported that even neuroleptic-treated subjects, like placebo-treated subjects, were able to improve their solution strategies with practice. Thus, the importance of taking the practice effect into account should be kept in mind when interpreting the results of several pharmacotherapeutic clinical trials that support the beneficial effects of antipsychotics on cognitive function. In general, measures with greater problem-solving components, such as performance IQ, category tests, and WCST, are subject to larger practice effects than those with fewer similar demands.36 Although our finding of no improvement in the WCST in all 5 treatment groups was unexpected, it may have been related to a ceiling effect because subjects were young and highly educated. Nevertheless, between-group analysis of change scores from baseline to end point in the aforementioned tests as well as other tests (ie, the digit span test, Stroop test, and WCST) demonstrated no significant differences between the 5 treatment groups, except for the word fluency test.

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Effect of Amisulpride on the Word Fluency Test

Post hoc results of between-group analysis demonstrated that only amisulpride at 400 mg significantly improved performance in the word fluency test compared to the placebo. This finding was unexpected given the hypothesis that a low dose of amisulpride (<400 mg) blocks presynaptic D2/D3 receptors in the cortical area, leading to enhanced dopamine release, which may be beneficial to cognitive dysfunction in schizophrenia.37,38 The preferential antagonism by amisulpride of presynaptic dopamine autoreceptors is reflected behaviorally by its potent blockade of apomorphine-induced yawning and hypomotility in the rat.39 In studies with healthy volunteers, a single administration of amisulpride at 400 mg14 and at low doses (50, 200, or 300 mg)13,17,18,32 did not affect cognitive performance or produce cognitive slowing in the Tower of Toronto puzzle task. However, a recent clinical trial40 on amisulpride supports our proposition that a high dose (400 mg) of amisulpride may also have a cognitive-enhancing effect. In that study, the effects of amisulpride on neurocognitive functions were examined in patients with schizophrenia who either began or switched to amisulpride compared to healthy controls. At mean ± SD doses of 489.47 ± 256.13 mg and 529.82 ± 301.02 mg prescribed at 8 weeks and 1 year, respectively, the patient group showed a relatively greater effect size than the control group in a test similar to the word fluency test, the Controlled Oral Word Association Test and the TMT, signifying that improvement in performance may not be accounted for by the practice effect. The possible mechanism for the beneficial effects of amisulpride on cognitive function may be related to its selective D3 antagonist activity given that dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats.41 Even when sedation and the SAS score were treated as covariates, the amisulpride-placebo difference remained intact, perhaps because a significant increase in mental sedation and EPS were observed only in aripiprazole and risperidone groups, and not in the amisulpride group. Taken together, this is the first report demonstrating improvement in the word fluency test by single administration of amisulpride at 400 mg in healthy volunteers. Further research is needed to replicate our observation on the effect of amisulpride on cognitive function.

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Effects of Aripiprazole on Cognitive Performance

It was of interest to see no significant effects of aripiprazole on cognitive performance compared to placebo. Aripiprazole is an antipsychotic with a unique pharmacology as a dopamine D2 receptor partial agonist. In molecular studies using C-6 glioma cells42 or Chinese hamster ovary cells43 expressing D2L receptor, aripiprazole has been reported to show partial agonism at the postsynaptic dopaminergic transmission. Substantial evidence points to cognitive-enhancing effect of dopamine agonists.44–47 This dopamine D2 receptor partial agonist action of aripiprazole may be related to the underlying mechanisms for beneficial effects of aripiprazole on cognitive function in several clinical trials with schizophrenia.48,49 However, it should be noted that aripiprazole’s partial agonism may be appear at low endogenous dopamine tone or high receptor reserve within the system.42,43 Therefore, it is reasonable not to see dopamine D2 receptor agonism and subsequent cognitive improvement by aripiprazole in healthy volunteers with the assumption that endogenous dopamine tone or receptor reserve of the participants in our study is within reference range. Our finding about aripiprazole may be supported by the recent brain imaging study in rats that aripiprazole induced no significant change in blood perfusion in the medial prefrontal cortex.50 However, as steady state of plasma concentrations is reached by day 14 after administration of aripiprazole,51 our results should be interpreted cautiously warranting further investigation on the effects of long-term administration of aripiprazole.

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Effects of Antipsychotics on Sedation

For the effects of antipsychotics on the visual analog scale, only mental sedation, not physical sedation, was affected by aripiprazole and risperidone, which may signify the need to differentiate the 2 types of sedation in clinical practice. In addition, aripiprazole increased mental sedation significantly compared to the placebo although the usual recommendation for taking aripiprazole is in the morning. This finding suggests that one should be cautious of sedation when prescribing aripiprazole, especially to young drug-naive patients.

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Limitations

This study had several limitations. First, a single administration does not match the usual clinical situation. Approximately 5 days for haloperidol and risperidone or 14 days for aripiprazole are needed to reach the steady state of a drug’s plasma concentration.52 In addition, most studies that test the procognitive potential of antipsychotics in patients are generally 4 to 12 weeks in duration. Our results should be interpreted with these caveats in mind. However, because of ethical problem, it is impractical to conduct repeated dosing study in healthy volunteers. A biomarker assessment to examine the physiological effects of a single-dose antipsychotic such as auditory-evoked response, event-related potential, or functional magnetic resonance imaging would provide much more information that could help translate the current findings to schizophrenia. Second, smoking was not controlled, which is an important variable affecting cognitive function. Although we advised participants to smoke in the usual way, it may have affected the results. Third, extrapolation of our results to patients with schizophrenia should be done with caution because fundamental differences exist in the physiological or neuroanatomical characteristics of these 2 populations. Fourth, the time of assessments after administering study medications was 12:00 noon to 2:00 P.M., which may have contributed to the increased report of sedation. Thus, a more appropriate time point for assessment should be considered in future studies.

In conclusion, the present study demonstrated that compared to the placebo, single administration of amisulpride at 400 mg in healthy volunteers enhanced word fluency test performance and remained intact after controlling for sedation and EPS. Our positive findings on amisulpride in enhancing cognitive function may have clinical implications in choosing antipsychotics for patients with schizophrenia. In addition, improvement of performance in some CNT measurements by antipsychotics may be attributable to the practice effect and underscores the need to include healthy control groups to validate the medication effect of cognitive improvement in patients with schizophrenia.

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ACKNOWLEDGMENTS

The authors thank Hye-Sun Shin, Hye-Kyung Kwon, and Heavenly Father for their help in preparing the manuscript.

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AUTHOR DISCLOSURE INFORMATION

The authors declare no conflicts of interest.

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Keywords:

amisulpride; cognitive function; word fluency; volunteers

© 2012 Lippincott Williams & Wilkins, Inc.