Allelic variation in the 5-HT 2C receptor (HT2RC) and the increase in slow wave sleep produced by olanzapine

Abstract

The 5-HT 2C receptor gene has been localised to the X chromosome and contains a C-G polymorphism at codon 23 (nucleotide 68) such that serine replaces cysteine in the receptor in about 15% of the population (Lappalainen et al. 1995;Sodhi et al. 1995). Sodhi et al (1995) found that patients with schizophrenia who possessed serine alleles of the 5-HT 2C receptor experienced a better therapeutic response to clozapine, an atypical antipsychotic agent which includes 5-HT 2C receptor antagonism among its pharmacological properties. This raises the possibility that the functional consequences of 5-HT 2C blockade may differ between subjects according to their 5-HT 2C receptor genotype. Drugs that antagonise 5-HT 2C receptors produce dose-related increases in slow wave sleep (SWS) in the sleep polysomnogram (EEG) (Sharpley et al. 1990). The aim of the present study was to assess whether the increase in SWS that follows administration of the atypical antipsychotic and 5-HT 2C receptor antagonist, olanzapine (Sharpley et al. 2000), differed in subjects with serine substituted 5-HT 2C receptors.DNA was extracted from buccal swabs or blood samples using standard methods. Genotype was identified using a previously described method using restriction analysis of a 104 bp fragment using the Hsp92II isoschizomer of NlaIII (Burnett et al. 1997). From this procedure we identified two groups of 12 healthy male volunteers, who possessed the cysteine (CYS) (mean age 36.9 years, range 23-57 years) and serine (SER) (mean age 38.5 years, range 21-53 years) substituted 5-HT 2C receptors, respectively. Prior to entry into the study, which was approved by the local ethics committee, subjects underwent medical and psychiatric screening to ensure they had no past or present history of sleep disturbance, psychiatric disorder or significant physical illness, and were free of psychotropic medication for at least 3 months. Subjects were studied on 2 nights, each separated by 7-14 days, and were randomly allocated to receive single oral doses of olanzapine 5 mg and matching placebo, given 4 h before their pre-arranged bedtime in a double-blind, parallel group design.Home based sleep recordings were made using the Oxford Medilog cassette monitoring system. Standard sleep montage electrodes were applied in the Research Unit and the subjects then returned home to sleep as usual. Subjects' sleep routines were kept constant for all study nights and preceding nights. The records were analysed using the Oxford Medilog sleep stager (9200), which provides measures for all aspects of sleep architecture according to standard criteria (Rechtschaffen and Kales 1968). In addition, the tapes were visually inspected and edited by a scorer blind to treatment status. The sleep data were analysed with a two-way repeated measures analysis of variance (ANOVA) with "olanzapine" (olanazapine versus placebo) as a main within-subject factor and "genotype" (CYS versus SER) as the between-subjects factor.The ANOVA showed a significant effect of olanzapine treatment on SWS (m...

Sleep quality in schizophrenia and the effects of atypical antipsychotic medication

“…Both doses were associated with significant increases in SWS, sleep continuity, and subjective sleep quality. A second study by the same group comparing 5 mg of olanzapine with placebo confirmed the sleep changes observed before (22).…”

“…On the other hand, the difference could be unrelated to an antipsychotic effect and could be a direct impact of the atypical agents mediated through a distinct pharmacological property that is lacking in conventional neuroleptics. One argument against the extension of the antipsychotic effect hypothesis is that the antipsychotic impact of both conventional and atypical drugs takes several days if not weeks to become apparent, whereas improvements in sleep have been reported after single doses of olanzapine (21)(22)(23)(24). The impact on sleep is therefore more likely to be due to different pharmacological profiles between the conventional and atypical antipsychotics than simply associated with their antipsychotic effects.…”

Clinical Pharmacology of Other Drugs Used as Hypnotics

“…Uncontrolled and placebo-controlled treatment studies using these medications as primary or adjunctive treatments demonstrate improved subjective sleep quality and reduced sleepiness in patients with schizophrenia, 178,179 unipolar depression, 180,181 and bipolar depression. [183][184][185][186][187] Similar self-reported and PSG effects have been demonstrated in small clinical studies of patients with depression, 188 mania, 189 and schizophrenia. [183][184][185][186][187] Similar self-reported and PSG effects have been demonstrated in small clinical studies of patients with depression, 188 mania, 189 and schizophrenia.…”

Sleep architecture and cognitive changes in olanzapine-treated patients with depression: A double blind randomized placebo controlled trial

“…A large majority of these studies, regardless of treatment type, found that improving sleep continuity measures resulted in improvements in mood. Olanzapine has been shown to increase sleep continuity, subjective sleep measures and SWS in healthy volunteers [40-42] while an association between changes in sleep architecture and mood improvement in patients with MDD remains unclear [13]. Finally, Olanzapine has also been shown to improve cognition in schizophrenic patients [43]; however, its impact on cognition in depressive patients has not yet been fully described.…”