We reviewed the literature on sleep in psychiatric disorders and evaluated the data by meta-analysis, a statistical method designed to combine data from different studies. A total of 177 studies with data from 7151 patients and controls were reviewed. Most psychiatric groups showed significantly reduced sleep efficiency and total sleep time, accounted for by decrements in non-rapid eye movement sleep. Rapid eye movement sleep time was relatively preserved in all groups, and percentage of rapid eye movement sleep was increased in affective disorders. Reduction in rapid eye movement sleep latency was seen in affective disorders but occurred in other categories as well. Although no single sleep variable appeared to have absolute specificity for any particular psychiatric disorder, patterns of sleep disturbances associated with categories of psychiatric illnesses were observed. Overall, findings for patients with affective disorders differed most frequently and significantly from those for normal controls.

Sleep and Psychiatric Disorders: A Meta-analysis

Studies examining serotonin (5-hydroxytryptamine; 5HT) in schizophrenia show variable and inconsistent findings, which might reflect the heterogeneity of the disease. When these studies are reviewed in the light of Crow's "two-syndrome" paradigm of schizophrenia, a new trend emerges. It appears that 5HT findings may be related to certain features of Type II schizophrenia such as negative symptoms, degenerative brain changes, and chronicity in the following manner: (1) 5HT2 antagonists, which have recently become available, have been shown to have an antipsychotic effect, particularly on the negative symptom cluster. (2) Decreased levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid have been found to be correlated with cortical atrophy or ventricular enlargement in schizophrenic patients. (3) A subgroup of chronic schizophrenic patients has been shown to have elevated levels of platelet or whole blood 5HT. We propose, then, that 5HT dysfunction might be related to Type II, or negative syndrome, schizophrenia, and that the nature of this dysfunction might involve 5HT postsynaptic receptor hypersensitivity. We further suggest that the pharmacotherapy of schizophrenia should include a 5HT-blocking component, as well as a dopamine-blocking component, and we propose that future research should address the role of selective 5HT receptor hypersensitivity in schizophrenia.

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The Role of Serotonin in Schizophrenia

Difficulties initiating or maintaining sleep are frequently encountered in patients with schizophrenia. Disturbed sleep can be found in 30–80% of schizophrenic patients, depending on the degree of psychotic symptomatology. Measured by polysomnography, reduced sleep efficiency and total sleep time, as well as increased sleep latency, are found in most patients with schizophrenia and appear to be an important part of the pathophysiology of this disorder. Some studies also reported alterations of stage 2 sleep, slow-wave sleep (SWS) and rapid eye movement (REM) sleep variables, i.e. reduced REM latency and REM density. A number of sleep parameters, such as the amount of SWS and the REM latency, are significantly correlated to clinical variables, including severity of illness, positive symptoms, negative symptoms, outcome, neurocognitive impairment and brain structure. Concerning specific sleep disorders, there is some evidence that schizophrenic patients carry a higher risk of experiencing a sleep-related breathing disorder, especially those demonstrating the known risk factors, including being overweight but also long-term use of antipsychotics. However, it is still unclear whether periodic leg movements in sleep or restless legs syndrome (RLS) are found with a higher or lower prevalence in schizophrenic patients than in healthy controls. There are no consistent effects of first-generation antipsychotics on measuresof sleep continuity and sleep structure, including the percentage of sleep stages or sleep and REM latency in healthy controls. In contrast to first-generation antipsychotics, the studied atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone) demonstrate a relatively consistent effect on measures of sleep continuity, with an increase in either total sleep time (TST) or sleep efficiency, and individually varying effects on other sleep parameters, such as an increase in REM latency observed for olanzapine, quetiapine and ziprasidone, and an increase in SWS documented for olanzapine and ziprasidone in healthy subjects. The treatment of schizophrenic patients with first-generation antipsychotics is consistently associated with an increase in TST and sleep efficiency, and mostly an increase in REM latency, whereas the influence on specific sleep stages is more variable. On the other hand, withdrawal of such treatment is followed by a change in sleep structure mainly in the opposite direction, indicating a deterioration of sleep quality. On the background of the rather inconsistent effects of first-generation antipsychotics observed in healthy subjects, it appears possible that the high-potency drugs exert their effects on sleep in schizophrenic patients, for the most part, in an indirect way by suppressing stressful psychotic symptomatology. In contrast, the available data concerning second-generation antipsychotics (clozapine, olanzapine, risperidone and paliperidone) demonstrate a relatively consistent effect on measures of sleep continuity in patients and healthy subjects, with an increase in TST and sleep efficiency or a decrease in wakefulness. Additionally, clozapine and olanzapine demonstrate comparable influences on other sleep variables, such as SWS or REM density, in controls and schizophrenic patients. Possibly, the effects of second-generation antipsychotics observed on sleep in healthy subjects and schizophrenic patients might involve the action of these drugs on symptomatology, such as depression, cognitive impairment, and negative and positive symptoms. Specific sleep disorders, such as RLS, sleep-related breathing disorders, night-eating syndrome, somnambulism and rhythm disorders have been described as possible adverse effects of antipsychotics and should be considered in the differential diagnosis of disturbed or unrestful sleep in this population.

Sleep disturbances in patients with schizophrenia : impact and effect of antipsychotics.

Drug effects on REM sleep and on endogenous depression

The concept of "balanced serotonergic/dopaminergic antagonists" reflects renewed interest in the role of serotonin (5-HT) in schizophrenia. Postmortem brain tissue analysis, cerebrospinal fluid studies, and pharmacological challenges suggest a deficit in 5-HT function in the cortex of patients with schizophrenia. In contrast, however, 5-HT2 antagonism is claimed to have beneficial effects on both positive and negative symptoms of the illness. The authors attempt to resolve this paradox with a model that takes into account the suggestion of a cortical serotonergic hypofunction and a beneficial effect of 5-HT2 antagonism via modulation of subcortical dopamine activity. Although involvement of 5-HT in schizophrenia is supported by compelling evidence, more research is needed to better define its role in pathophysiology and treatment of this illness.

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The role of serotonin in the pathophysiology and treatment of schizophrenia

Oral administration of the serotonin precursor L-5-hydroxytryptophan with a peripheral decarboxylase inhibitor produced Mild to moderate improvement in six of seven chronic undifferentiated schizophrenic patients who were resistant to phenothiazine treatment, as compared to an oral administration of a placebo. Two of four chronic paranoid schizophrenic patients who were resistant to phenothiazine treatment became worse with 5-hydroxytryptophan, one improved. It is presumed that these psychological changes were directly or indirectly produced from increases in brain serotonin. Indirect data from animals and humans indicate that there may be an abnormality in serotonin metabolism in some schizophrenics. While our data are consistent with this hypothesis, other explanations for our data must be entertained.

https://science.sciencemag.org/content/sci/177/4054/1124.full.pdf

Behavioral changes of chronic schizophrenic patients given L-5-hydroxytryptophan.

The sleep of 13 chronic male schizophrenics was studied during a one-month trial of chlorpromazine and compared with one-month placebo periods. Electroencephalographic recordings were made only after the patients had been on chlorpromazine hydrochloride or a placebo for at least three weeks. Sleep latency and awake time were significantly decreased on chlorpromazine while stage II, delta sleep, delta%, nonrapid eye movement (NREM) sleep, REM activity, REM latency, and REM density were significantly increased. There were no significant changes in REM time, REM%, stage II%, and NREM%.

Effect of Prolonged Chlorpromazine Administration on the Sleep of Chronic Schizophrenics

In a therapeutic trial, rapid increases and abrupt discontinuation of the serotonin precursor 5-hydroxytryptophan (5 HTP) produced striking behavioral effects in a group of phenothiazine-resistant chronic schizophrenic patients. These effects were greatly diminished by gradual changes in 5HTP dosages. It is speculated that tolerance and dependence developed to 5HTP administration in these patients and perhaps to serotonin itself. It is further speculated that rapid changes, even from normal serotonin concentration, might be responsible for many of the behavioral effects seen when the metabolism of serotonin is altered.

Jonathan Kaplan

Papers

Behavioral changes of chronic schizophrenic patients given L-5-hydroxytryptophan.

Effect of Prolonged Chlorpromazine Administration on the Sleep of Chronic Schizophrenics

Tolerance and Dependence to Serotonin: A Speculation