The questionnaire studies and clinical experience summarized above lead to a ques-tion that has to be answered by objective measures: are the sleep-wake difficulties observed in persons with schizophrenia part of the disease or a side-effect of treat-ments? In addition to testing clinical hypothesis with neurobiological tools, the re-sults of sleep recordings can point toward neurobiological mechanisms underlying the disease. Indeed, sleep is thought to be governed by a multi-leveled set of ex-ecutive and permissive mechanisms, encompassing chronobiology and the control of the REM-non-REM cycles and involving all the central neurotransmitter systems mentioned above (for a review see [12]).
Laboratory polysomnographic studies in acutely ill, drug-na¨ıve patients and in neuroleptic-withdrawn patients
Sleep in schizophrenia has been studied in the laboratory from the first days of modern polysomnography, in the middle of the last century, because of the seductive intu-itively derived equation between thought disorders and the dreaming state. Recording conditions, inclusion/exclusion criteria and comparison groups were, however, far from optimal according to today’s standards. Two more recent reports have used sta-tistical meta-analysis techniques and stringent selection criteria to analyze published studies according to rules warranting for a minimum of control over confounding variables. The first meta-analysis [13] reported on only three studies and found in-creased sleep latency, dein-creased total sleep time and dein-creased slow-wave sleep (SWS; stage 3 + stage 4) in groups with schizophrenia compared to controls. Our own, more recent meta-analysis [14] included 20 polysomnographic studies (321 per-sons with schizophrenia and 331 controls). The group with schizophrenia showed increased sleep latency, decreased total sleep time and decreased sleep efficiency but no differences in SWS. We also found that sleep disorders were more pronounced in patients withdrawn from neuroleptics compared to neuroleptic na¨ıve patients. These results suggest that sleep disorders in schizophrenia are not a direct consequence of neuroleptic use but are an intrinsic feature of the disease.
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Literature reviews and introductory paragraphs of research reports often cite as a fact that SWS duration and REM sleep latency are both shortened in schizophrenia.
Still, a detailed analysis of the literature shows that the evidence is far from consistent.
In the 20 studies reviewed by Chouinard et al. [14], 13 specifically compared SWS in patients with schizophrenia to controls, and only 2 of those (15 %) found a significant difference. When only stage 4 was considered, this proportion doubled (33 %, or 4 of the 12 available studies). It is, thus, possible that more refined measures of sleep such as quantified analysis of EEG slow-wave activity may be more sensitive to group effects regarding SWS. A comparable situation prevails with regards to REM sleep latency: out of the 20 studies reviewed by Chouinard et al. [14] that compared REM sleep latency, 10 (50 %) found a significantly shorter value in the schizophrenia group, while the result was not significant in the 10 others. Again, uncontrolled variables may be responsible for this variability between studies. For example Tandon et al. [15]
showed that the duration of the neuroleptic-free period has an impact on REM sleep in schizophrenia. They found that previously treated patients withdrawn for 2–4 weeks had a shorter REM sleep latency (and greater REM sleep duration) in comparison to patients withdrawn for more than 4 weeks. Gender differences could also explain why the present meta-analysis did not reveal any significant results for REM sleep latency.
Goldman et al. [16] have found a significant relation between reduced REM sleep latency and poor outcome in females, but not in males. This suggests that male and female patients with schizophrenia have different pathophysiological mechanisms underlying REM sleep latency.
Finally, it has to be noted that statistical meta-analysis methodology has its limits.
Meaningful dependent variables often cannot be included as moderator variables due to the fact that not enough studies report on them, including duration of the illness, chronicity, diagnosis subtype, scale symptoms (e.g. , positive and negative symptoms), and subtypes of neuroleptic treatment. Moreover, such variables are often found to be heterogeneous within most of the studies themselves, so that they cannot not be used with meta-analytic methods. Other variables more closely related to sleep itself are often not controlled for, such as the possibility of napping on the day of recording or the inclusion of participants with a co-morbid sleep disorders (such as sleep apnea and sleep-related periodic limb movements). Figure 1 represents a schematized hypnogram demonstrating most of the sleep disorders described in the literature using laboratory recordings of untreated persons with schizophrenia.
In any case, it is a fact that sleep disorders are an intrinsic feature of schizophre-nia. Studies in drug-na¨ıve and neuroleptic-withdrawn conditions prove that pa-tients with schizophrenia have sleep disorders that are not necessarily a conse-quence of neuroleptic treatments, even though it must be remembered that sleep in neuroleptic-withdrawn schizophrenia patients is not comparable to that of drug-na¨ıve patients [14].
Effects of neuroleptics on laboratory sleep measures
Most studies concerning the effects of neuroleptics on sleep using clinically rele-vant doses have shown statistically significant improvement on measures of sleep
Sleep disturbance in schizophrenia 129
Fig. 1. Schematized hypnogram demonstrating most of the sleep disorders described in the literature using laboratory recordings of untreated persons with schizophrenia. One category of sleep disorders in schizophrenia is the “insomnia type”, with long sleep latency, numerous and/or long awakenings, and short sleep duration. Another type of sleep disorders is more concerned with sleep organization, e.g. ., short duration of SWS and/or short latency to the onset of REM sleep. Not all disorders are found in every study since variables such as symptoms or diagnosis subtype, severity and chronicity may influence the results (see text). REMS, REM sleep. A REM sleep period is defined as a succession of REM sleep epochs not interrupted for more than 15 min.
continuity, although not necessarily up to normal values. The effects of neuroleptics on subjective measures of sleep have been described in the previous section and are generally positive besides their sedative side-effects (see above). The reports on sleep architecture using polysomnography are contradictory and depend on the previous treatment-withdrawal regimen and the characteristics of the replacement molecule, not mentioning the fact that double-blind placebo-controlled protocols are disappointingly uncommon in the field. Although neuroleptics undoubtedly have an impact on sleep, studies show that different neuroleptics have different effects on the sleep pattern in patients with schizophrenia. The most recent complete, detailed review on the effects of neuroleptics on sleep in schizophrenia by Monti and Monti [17] shows that typical neuroleptics such as haloperidol, thiothixene, and flupenthixol improve preferentially sleep continuity measures (sleep latency and nocturnal awak-enings), while atypical neuroleptics such as olanzapine, risperidone, and clozapine facilitate SWS as well. As mentioned above, neuroleptics interact with most of the central neurotransmitter systems involved in the regulation of vigilance: classical and atypical neuroleptics block dopaminergic, noradrenergic, serotoninergic, cholinergic and histaminergic receptors [18], therefore interacting with variable potency on the control of sleep organization. There is a consensus according to which consolida-tion of sleep continuity is achieved through dysfacilitaconsolida-tion of wake mechanisms via α-adrenergic, histaminergic, and cholinergic receptors antagonists. Irrespective of the issue as to whether or not SWS and REM sleep are normal in schizophrenia,
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neuroleptics are thought to facilitate SWS through 5-HT2receptor blockade, and the inhibition of REM sleep is probably mediated via D2receptor blockade. Noteworthy is the fact that acute melatonin in schizophrenia has been shown to modify sleep in the direction opposite to what should have been expected, with increased signs of insomnia compared to placebo [19].