Effect of Clozapine on the Sleep Pattern in the Rat

Spierings, Egilius L.H.; Dzoljic, M.R.; Godschalk, M.

doi:10.1159/000136734

Cited by 9 publications

(11 citation statements)

References 10 publications

(13 reference statements)

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“…In agreement with previous findings (Spierings et al, 1977;Ongini et al, 1993), clozapine promoted non-REM sleep. The present study Clozapine alters sleep-wake behavior S Sorge et al…”

Section: Discussionsupporting

confidence: 93%

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Clozapine Alters Sleep-Wake Behavior in Rats

Sorge

Pollmächer

Lancel

2004

Neuropsychopharmacol

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Clozapine is an atypical antipsychotic agent showing therapeutic efficacy superior to that of classical neuroleptics. Clozapine has strong sedative effects, but detailed studies on the drug influencing sleep in rodents are lacking. We studied the effects of clozapine on sleep and body temperature in rats. Clozapine (0, 2.5, and 7.5 mg/kg) was given i.p. to male Wistar rats at the beginning of the rest period. After administration of 7.5 mg/kg clozapine, animals were significantly more awake during the first 2 h postinjection. In parallel, the slow-wave activity (SWA) was suppressed. In the following 2 h non-REM sleep was markedly increased, whereas the SWA returned to baseline. At both doses clozapine decreased overall wakefulness and increased non-REM sleep on the first treatment day, which was associated with prolonged non-REM sleep episodes. These effects were transiently present even after subchronic treatment (7 days). After acute treatment, 7.5 mg/kg clozapine significantly reduced REM sleep and pre-REM sleep due to an increase in REM sleep latency and a reduction in the number of REM sleep episodes. Furthermore, clozapine produced a transient decrease in brain temperature that was followed by a moderate, but long-lasting elevation. To conclude, clozapine affected sleep-wake behavior in a way comparable to its effects in humans, suggesting that the rat is a suitable model for further studies on the underlying mechanisms.

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“…In agreement with previous findings (Spierings et al, 1977;Ongini et al, 1993), clozapine promoted non-REM sleep. The present study Clozapine alters sleep-wake behavior S Sorge et al…”

Section: Discussionsupporting

confidence: 93%

“…In rats, clozapine reportedly promotes non-REM sleep and suppresses REM sleep (Spierings et al, 1977;Ongini et al, 1993). However, there is no study that analyzed shortand long-time effects of clozapine on sleep-wake behavior after acute and subchronic treatment.…”

Section: Introductionmentioning

confidence: 99%

Clozapine Alters Sleep-Wake Behavior in Rats

Sorge

Pollmächer

Lancel

2004

Neuropsychopharmacol

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“…High-dose risperidone has been shown to inhibit REM sleep as in the study [23]. Clozapine, inconsistent with our findings, has been found to reduce REM sleep but promote non-REM sleep [22]. This discrepancy might be a result of its more complex pharmacological action [48].…”

Section: Discussioncontrasting

confidence: 63%

“…Since the acetylcholine and monoamines are all known to be involved in the regulation of sleep, these drugs are expected to modify the sleep-wake cycle [22,23,24]. Along the sleep-wake cycle, sympathetic and parasympathetic activity fluctuates cyclically, with higher vagal activity during quiet sleep (QS) and higher sympathetic activity during wakefulness and paradoxical sleep (PS) [25,26].…”

Section: Introductionmentioning

confidence: 99%

Influence of Antipsychotic Agents on Heart Rate Variability in Male WKY Rats: Implications for Cardiovascular Safety

et al. 2012

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Background: Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. Methods: In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. Results: Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. Conclusion: Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use.

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“…Polysomnographic studies of sleep-wake patterns in rats have consistently reported that low doses of risperidone increased the amounts of deep slow-wave sleep (dSWS) and decreased both wakefulness and light sleep (ISWS) in rats [11]. Fol-lowing chronic administration in rats, clozapine produced a slight increase of SWS, reduced rapid eye movement (REM) sleep [12,13], and exerted its most prominent effect on SWS [13]. In schizophrenic patients, likewise, it has been reported that risperidone improves sleep quality, sleep continuity, and increases NREM [14], while clozapine may have sleep-inducing properties [15] and olanzapine produces a significant dose-related increase in SWS and sleep continuity in terms of decreased waking [16].…”

Section: Introductionmentioning

confidence: 99%

The Atypical Antipsychotics Risperidone, Clozapine and Olanzapine Differ Regarding Their Sedative Potency in Rats

Ahnaou

Megens²,

Drinkenburg³

2003

Neuropsychobiology

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The atypical antipsychotics risperidone, clozapine and olanzapine were studied for their ability to antagonise apomorphine-induced stereotypy and to affect electroencephalographic (EEG) activity in rats. The compounds antagonised apomorphine-induced stereotypy with ED₅₀s of 0.15 mg/kg s.c. for risperidone, 0.42 mg/kg s.c. for olanzapine and 1.3 mg/kg s.c. for clozapine. At a dose close to that required for apomorphine antagonism (0.16 mg/kg s.c.), risperidone induced only minor changes in EEG power spectral activity. At a higher dosage (0.63 mg/kg s.c.) it increased the power density in the high frequency range (9.8–18.6 Hz), characteristic of a sedative-like effect. Olanzapine and clozapine caused a dose-dependent increase in power density in all frequency bands. These effects were already present at doses (0.04 and 0.16 mg/kg s.c., respectively) 10 times below those required for apomorphine antagonism. The effects increased dose-dependently and were pronounced at the doses required for apomorphine antagonism. These results in rats are in agreement with the clinical observation that risperidone has less propensity for inducing sedation at therapeutic dose levels than olanzapine and clozapine.

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Effect of Clozapine on the Sleep Pattern in the Rat

Cited by 9 publications

References 10 publications

Clozapine Alters Sleep-Wake Behavior in Rats

Clozapine Alters Sleep-Wake Behavior in Rats

Influence of Antipsychotic Agents on Heart Rate Variability in Male WKY Rats: Implications for Cardiovascular Safety

The Atypical Antipsychotics Risperidone, Clozapine and Olanzapine Differ Regarding Their Sedative Potency in Rats

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