Ann L. Sharpley

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Effect of pharmacologic treatments on the sleep of depressed patients

Antidepressant drugs produce striking effects on sleep architecture that are best understood in terms of their interactions with the monoamine pathways controlling sleep and wakefulness. Many different antidepressant drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs), decrease rapid eye movement (REM) sleep. The reduction in REM sleep produced by antidepressants may be an important part of their mechanism of action; however, the ability of new antidepressant compounds, such as nefazodone and moclobemide, to increase REM sleep throws doubt on this suggestion. The effects of antidepressants on slow-wave sleep (SWS) are quite diverse; in general, antidepressants having significant 5-HT2A/2C receptor antagonist properties increase SWS, whereas other drugs, such as SSRIs or MAOIs, either lower SWS or produce no change. Sleep continuity is improved acutely following administration of antidepressants with sedating properties such as certain TCAs, trazodone, and mianserin. Some nonsedating drugs (ritanserin and nefazodone) also improve sleep continuity measures, possibly through 5-HT2A/2C receptor blockade.

5-HT2C receptor activation decreases appetite and body weight in obese subjects

Abstract We studied the effect of 2 weeks administration of the 5-HT2C receptor agonist, m-chlorophenylpiperazine (mCPP), on appetite and body weight in 18 moderately obese subjects in a double-blind, placebo-controlled trial. mCPP caused a small but significant (0.75 kg) reduction in body weight and in subjective ratings of hunger. Plasma prolactin was significantly elevated by the final dose of mCPP. Our data suggest that during 2 weeks treatment in humans, mCPP may continue to activate brain 5-HT2C receptors, and that this effect is associated with decreases in appetite and body weight.

Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT2C receptors in vivo

BACKGROUND The study aimed to determine the effects of the atypical antipsychotic agent, olanzapine, on the polysomnogram in healthy subjects. We predicted that olanzapine, via serotonin(2C) (5-HT(2C)) receptor blockade, would increase slow-wave sleep (SWS). METHODS We studied the effects of single evening doses of olanzapine (5 mg and 10 mg orally) on the polysomnogram of 9 healthy male volunteers, using a placebo-controlled, double-blind, cross-over design. RESULTS Compared to placebo, the 5-mg and 10-mg doses of olanzapine significantly increased SWS, sleep continuity measures, and subjective sleep quality. In addition, 10 mg of olanzapine suppressed rapid eye movement (REM) sleep and increased REM sleep latency. CONCLUSIONS Olanzapine (5 mg and 10 mg) produced substantial (59.1% and 83.3%) and highly significant dose-related increases in SWS in humans probably via blockade of brain 5-HT(2C) receptors. 5-HT(2C) receptor antagonism may account for some of the therapeutic and adverse effects of olanzapine therapy.

The effects of paroxetine and nefazodone on sleep : a placebo controlled trial

We studied the effect of acute (1 day) and subacute (16 days) administration of the new antidepressant, nefazodone (400 mg daily), and the selective serotonin re-uptake inhibitor (SSRI), paroxetine (30 mg daily), on the sleep polysomnogram of 37 healthy volunteers using a random allocation, double-blind, placebo-controlled design. Compared to placebo, paroxetine lowered rapid eye movement (REM) sleep and increased REM latency. In addition, paroxetine increased awakenings and reduced Actual Sleep Time and Sleep Efficiency. In contrast, nefazodone did not alter REM sleep and had little effect on measures of sleep continuity. We conclude that in contrast to typical SSRIs, nefazodone administration has little effect on sleep architecture in healthy volunteers.

Low dose melatonin improves sleep in healthy middle-aged subjects

We studied the effects of single evening doses of melatonin (0.3 mg and 1.0 mg orally) on polysomnographically measured sleep in 15 healthy middle-aged volunteers, using a placebo-controlled, double-blind, cross-over design. Compared to placebo, the 1.0 mg dose of melatonin significantly increased Actual Sleep Time, Sleep Efficiency, non-REM Sleep and REM Sleep Latency. These data are consistent with the hypothesis that low dose melatonin has hypnotic effects in humans. It is possible that administered melatonin may have a role to play in the treatment of sleep disorders.

Effects of carbamazepine on sleep in healthy volunteers

Gold PW, Kaye W, Robertson GL, Ebert M (1983): Abnormal regulation of arginine vasopressin in plasma and cerebrospinal fluid of patients with anorexia nervosa. N Engl J Med 308: 1117-l 123. Heinz ER, Martinez J, Haenggeli A (1977): Reversibility of cerebral atrophy in anorexia nervosa. J Comput Assist Tomgr 1:415-418. Hoffman GW, Ellinwood EH, Rockwell WJK, Herfkens RJ, Nishita JK, Guthrie LF (1989): Cerebral atrophy and Tl measured by magnetic resonance imaging in bulimia (submitted for publication). Kohlmeyer K, Lehmkuhl G, Poutska F (1983): Computed tomography of anorexia nervosa. AJNR 4:437-438. Lankenau H, Swigar ME, Bhimani S, Luchins D Quinlan DM (1985): Cranial CT scans in eating disorder patients and controls. Compr Psychiatry 26:136-147. Nussbaum M, Shenker IR, Marc I, Klein M (1980): Cerebral atrophy in anorexia nervosa. J Pediatr 96:867-869. Raichle ME, Grubb RL, Eichling JO (1980): Central neuroendocrine regulation of brain water permeability. Brain Res Rev 1:219-235. Rowe JW, Shelton RL, Helderman JH, Vestal RE, Robertson GL (1979): Influence of the emetic response on vasopressin release in man. Kidney int 16:729-735.

Depression and sleep disorders: clinical relevance, economic burden and pharmacological treatment.

A wide range of studies have been published over the past two decades that involve the intersection of sleep EEG, insomnia, psychiatric illness (especially depressive disorders) and psychopharmacology. Much of value has been discovered, but there have also been false starts and contradictory results. There is in fact strong evidence that insomnia is associated with medical and psychiatric illness and that the sleepiness associated with insomnia is the cause of many accidents. Thus, the direct (visits to doctors, cost of sleeping medication, complications from use of these medications) and indirect (accidents, quality of life) costs of insomnia are enormous and constitute a major public health problem in the industrialized countries. Believing that it is now timely to assess the state of this important research area, a consensus conference was convened on June 26–28, 1998, in Porto Cervo (Italy) to attempt to clarify the important issues and findings on the clinical effect of the different classes of antidepressant drugs on sleep quality in depression. The participants’ consensus on some of the main topics is presented with the hope that this discussion and analysis will contribute to productive research in this important field.

Nefazodone-a novel antidepressant- may increase REM sleep

Nefazodone, an analogue of the antidepressant drug trazodone, has a pharmacological profile distinct from that of tricyclic antidepressants (TCAs) and selective 5-hydroxytryptamine (5HT) uptake inhibitors. Biochemical and behavioral studies indicate that nefazodone possesses 5-HT2 receptor antagonist properties with little affinity for histamine H~ receptors and ott-adrenoceptors (Taylor et al 1982). In addition, nefazodone is moderately active as an inhibitor of the synaptic uptake of noradrenaline (NA) and 5-HT (Yocca et al 1985). Nefazodone has two active metabolites, hydroxy-nefazodone (which pharmacologically resembles nefazodone) and m-chlorophenylpiperazine (mCPP). The pharmacological properties of mCPP appear to include agonist properties at 5-HTIA and 5-HT~c receptors with antagonist effects at 5-HT2 and 5-HTa receptors (Hamik and Peroutka 1989). Controlled trials indicate that the clinical efficacy of nefazodone is superior to placebo and equivalent to that of TCAs in the treatment of rr,ajor depression (Feighner et ai 1989; Fontaine et al 1991; Weise et al 1991). It is well established that antidepressant drugs produce characteristic changes in sleep architecture that almost invariably include a reduction in the amount

Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors?

The effect of lithium on slow wave sleep (SWS) was studied in ten normal male volunteers using home based cassette sleep recording and automatic sleep stage analysis. Lithium increased SWS, an effect consisten with a reduction in brain 5-HT2 receptor function.