Effects of Typical and Atypical Antipsychotics on Sleep in Schizophrenia Patients

Typical and atypical antipsychotic drugs bind to a wide variety of CNS receptors including the 5-HT2A and 5-HT2C receptors. Thus, it seems pertinent to analyze the effects of antipsychotic drugs on sleep variables and the mechanisms involved in their actions on sleep and W. It should be noted that Monti and Monti (2004) and Winokur and Kamath (2008) have provided detailed reviews of work carried out in this area. Our analysis will be limited to the effects on sleep variables of the typical antipsychotics haloperidol, thiothixene, and flupentixol and the atypical antipsy-chotics olanzapine, risperidone, clozapine, quetiapine, and ziprasidone. Various populations were included in the studies to be described: healthy volunteers, outpatients, and hospitalized patients.

Typical antipsychotic drugs including haloperidol, thiothixene, and flupentixol have been shown to reduce stage 2 sleep latency and to increase total sleep time and sleep efficiency. Stage 4 sleep and SWS remained unchanged, whereas REM latency was significantly increased (Taylor et al. 1991; Nofzinger et al. 1993; Wetter et al. 1996; Maixner et al. 1998). Olanzapine given to schizophrenia patients or healthy subjects reduced stage 2 sleep latency and wake time after sleep onset, whereas total sleep time and sleep efficiency were enhanced. Concerning sleep architecture, stage 1 sleep was decreased, whereas stage 2 and SWS were augmented. On the other hand, olanzapine tended to disrupt REM sleep as judged by the reduction of REM sleep duration and the increase of REM latency (Salin-Pascual et al. 1999; Sharpley et al. 2000; Muller et al. 2004).

The limited information on risperidone tends to indicate that the compound improves sleep maintenance and increases SWS in schizophrenia patients (Dursun et al. 1999; Haffmans et al. 2001; Yamashita et al. 2002). In addition, in a study that involved healthy control subjects, risperidone produced a reduction of REM sleep time compared with placebo (Sharpley et al. 2003). The administration of clozapine to schizophrenia patients increased total sleep time, sleep efficiency, and stage 2 sleep. Stage 4 sleep and SWS tended to be reduced, whereas REM sleep was not significantly affected (Wetter et al. 1996; Hinze-Selch et al. 1997; Lee et al. 2001). In the study by Touyz et al. (1978) clozapine was given at a relatively low dose to normal young adults; the effects of the compound were limited to a decrease of stage 1 sleep and REM sleep duration. Cohrs et al. (2004) and Cohrs et al. (2005) examined the effects of quetiapine and ziprasidone on sleep in healthy subjects. The antipsychotic drugs significantly reduced sleep onset latency, wake time after sleep onset, and REM sleep and increased total sleep time, sleep efficiency, stage 2 sleep, and REM latency. To date no studies have been carried on the effect of quetiapine and ziprasidone on sleep of schizophrenia patients.

Typical and atypical antipsychotic drugs produce their effects by blocking, among others, dopamine, serotonin, a-adrenergic, histamine, and acetylcholine (muscarinic) receptors. Irrespective of their chemical structure, antipsychotics show low (olanzapine, quetiapine), intermediate (risperidone, clozapine, ziprasi-done) to high (haloperidol, flupentixol, thiothixene) affinity for the D2 receptor (Table 20.5). In contrast to the classical antipsychotics, the newer antipsychotics show moderate (quetiapine) to high (clozapine, olanzapine, risperidone, ziprasi-done) affinity for the serotonin 5-HT2A receptor and to a lesser extent for the 5-HT2C receptor. The atypical antipsychotics bind with moderate (quetiapine, ziprasidone) and high affinity (olanzapine, risperidone, clozapine) to the a1 adrenoceptor, whereas olanzapine and clozapine display high affinity for both the histamine H1 and the acetylcholine (muscarinic) receptor (Table 20.5). The blockade of D2 receptors could be partly responsible for the improvement of sleep in schizophrenia patients. On the other hand, the increase of SWS and the suppression of REM sleep induced by some of the atypical antipsychotics could be related to the blockade of

Table 20.5 Receptor binding profile of typical and atypical antipsychotics (From Horacek 2000; Reynolds 2004)_

D2

5"HT2A

5-HT2C

«1

Ach (M)

Hi

Haloperidol

+++

+

-

+

+

+

Flupentixol

+++

+

?

+

-

-

Olanzapine

+

+++

++

++

+++

+++

Risperidone

++

+++

+

+++

-

-

Clozapine

++

+

++

+++

+++

+++

Quetiapine

+

+

?

++

-

+

Ziprasidone

++

+++

?

++

-

+

D2 dopamine receptor, 5-HT2A 5-HT2C serotonin receptors, a] adrenergic receptor, ACh (M) cholinergic (muscarinic) receptors, H] histamine receptor. Affinity: (-) absent; (+) low; (++) intermediate; (+++) high; (?) unknown

D2 dopamine receptor, 5-HT2A 5-HT2C serotonin receptors, a] adrenergic receptor, ACh (M) cholinergic (muscarinic) receptors, H] histamine receptor. Affinity: (-) absent; (+) low; (++) intermediate; (+++) high; (?) unknown

5-HT2A receptors. The blockade of aj-adrenergic, histamine Ht, and muscarinic acetylcholine receptors could participate also in the amelioration of sleep provoked by the antipsychotic drugs. This is based on the premise that they produce somnolence, an increased likelihood of falling asleep and reduced concentration (Monti 1987; Heller-Brown and Taylor 1996; Monti and Monti 2000b).

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