Interferon-α induces negative biases in emotional processing in patients with hepatitis C virus infection: a preliminary study.

BACKGROUND: Treatment of medical patients with the inflammatory cytokine, interferon-α (IFN-α), is frequently associated with the development of clinical depressive symptomatology. Several important biological correlates of the effect of IFN-α on mood have been described, but the neuropsychological changes associated with IFN-α treatment are largely unexplored. The aim of the present preliminary study was to assess the effect of IFN-α on measures of emotional processing. METHOD: We measured changes in emotional processing over 6-8 weeks in 17 patients receiving IFN-α as part of their treatment for hepatitis C virus infection. Emotional processing tasks included those which have previously been shown to be sensitive to the effects of depression and antidepressant treatment, namely facial expression recognition, emotional categorisation and the dot probe attentional task. RESULTS: Following IFN-α, patients were more accurate at detecting facial expressions of disgust; they also showed diminished attentional vigilance to happy faces. IFN-α produced the expected increases in scores on depression rating scales, but there was no correlation between these scores and the changes in emotional processing. CONCLUSIONS: Our preliminary findings suggest that IFN-α treatment produces negative biases in emotional processing, and this effect is not simply a consequence of depression. It is possible that increased recognition of disgust may represent a neuropsychological marker of depressive disorders related to inflammation.

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.

The effect of Li 1370, extract of Ginkgo biloba, on REM sleep in humans.

Ginkgo biloba extracts (GBE) have been shown to be as effective as anti-cholinesterase inhibitors in improving the cognitive test scores of patients with dementia. Although it has been assumed that GBE works via its antioxidant and vascular effects, some evidence has emerged that GBE may have some pro-cholinergic activity. We wished to test the hypothesis that a standardised preparation of GBE, Li 1370, increases cholinergic activity by measuring its effect on the sleep polysomnogram. In particular, latency to Rapid Eye Movement (REM) sleep is sensitive to cholinergic activity. For this purpose we recruited 10 healthy volunteers of both sexes and recorded sleep polysomnograms in a randomised cross-over study, comparing sleep polysomnograms taken the night after a single evening dose of Li 1370 (240 mg) with sleep polysomnograms taken after an evening dose of placebo. No significant differences in sleep parameters (including REM sleep measures) were detected; however sleep efficiency measures and subjective sleep quality reports showed that Li 1370 was well tolerated.

Decreased tryptophan availability but normal post-synaptic 5-HT2c receptor sensitivity in chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) has been associated with increased prolactin (PRL) responses to the serotonin (5-HT) releasing agent fenfluramine. It is not known whether this abnormality is due to increased 5-HT release or heightened sensitivity of post-synaptic 5-HT receptors. METHODS: We measured the increase in plasma PRL produced by the directly acting 5-HT receptor agonist, m-chlorophenylpiperazine (mCPP), in patients with CFS and healthy controls. We also compared the ability of mCPP to lower slow wave sleep (SWS) in the sleep polysomnogram of both subject groups. Finally, we measured plasma amino-acid levels to determine whether tryptophan availability differed between CFS subjects and controls. RESULTS: mCPP elevated plasma PRL equivalently in patients with CFS and controls. Similarly, the decrease in SWS produced by mCPP did not differ between the two subject groups. Plasma-free tryptophan was significantly decreased in CFS. CONCLUSIONS: The sensitivity of post-synaptic 5-HT2c receptors is not increased in patients with CFS. This suggests that the increased PRL response to fenfluramine in CFS is due to elevated activity of pre-synaptic 5-HT neurones. This change is unlikely to be due to increased peripheral availability of tryptophan.

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.

Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) 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.

Antidepressant-like effect of Hypericum perforatum (St John's wort) on the sleep polysomnogram.

We studied the effect of two doses (0.9 mg and 1.8 mg) of Hypericum perforatum (St John's wort) on the sleep polysomnogram of healthy subjects using a placebo-controlled, cross-over design. Both doses of hypericum significantly increased the latency to rapid eye movement (REM) sleep without producing any other effect on sleep architecture. Our data are consistent with the proposed clinical antidepressant efficacy of hypericum, and raise the possibility that its pharmacological mechanism of action may be similar to that of conventional antidepressant medication.

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

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.

Assessment and treatment of insomnia (including a case control study of patients with Primary Insomnia).

Insomnia is a subjective term describing the perception of disturbed or inadequate sleep. Causes include medical diseases, psychiatric disorders, drugs, behavioural factors, circadian dysrhythmias and primary sleep disorders. Insomnia is common, affecting approximately one-third of the total population, and of these about 10% consider it a chronic problem. Insomnia is more common in females and increases with age. Many people with insomnia resort to ineffective or dangerous self-treatment regimens and the combination of alcohol with non-prescription drugs is common. We have carried out a study on 20 patients with Primary Insomnia and were able to demonstrate significant differences in both descriptive and objective EEG data between those with Primary Insomnia and controls. Careful evaluation of the sleep problem and accurate diagnosis are essential in order to choose the right treatment for an individual patient. When a specific problem is identified (psychiatric, physical, behavioural), then the underlying cause needs to be treated. Insomnia can be treated by either non-pharmacological or pharmacological intervention, and often both are used simultaneously. It is recommended that hypnotic treatments should be used for no more than one month.

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.

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.

Melatonin phase advances circadian rhythm.

We studied the effect of acute (1 day) and subacute (7 days) treatment with melatonin (0.5 mg) on the endogenous rhythms of melatonin secretion in 12 healthy male volunteers, using a placebo-controlled, double-blind, cross-over design. Melatonin given at 1700 h for 7 days significantly advanced the onset of endogenous melatonin secretion, while a single dose was without effect. These data are consistent with the hypothesis that melatonin plays a role in the organisation of circadian rhythms in humans and suggest that appropriately timed melatonin administration may provide a means of altering the timing of circadian cycles.

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.

Effects of hydrocortisone on brain 5-HT function and sleep.

The effects of hydrocortisone administration (20 mg, orally, twice daily) on the sensitivity of brain 5-HT1A receptors in healthy volunteers were studied using a buspirone challenge paradigm. The effects of hydrocortisone administration on sleep architecture were also studied. Hydrocortisone treatment significantly attenuated the hypothermic and cortisol responses to buspirone; however, the prolactin and growth hormone responses were unchanged. Hydrocortisone also decreased the amount of rapid eye movement sleep (REM). The ability of hydrocortisone to attenuate 5-HT1A receptor mediated hypothermia and decrease REM sleep is shared by certain antidepressant treatments and may be related to the effects of corticosteroids on mood.

Slow wave sleep in humans: role of 5-HT2A and 5-HT2C receptors.

We studied the effects of the 5-HT2 receptor antagonists, ritanserin and ketanserin, on the sleep of healthy volunteers in order to clarify the role of 5-HT2A and 5-HT2C receptors in the regulation of slow wave sleep (SWS) in humans. Ritanserin, 5 mg, produced a substantially larger increase in SWS (51.4%) than either ketanserin, 20 mg (17.2%) or ketanserin, 40 mg (24.4%). Ritanserin has a significantly higher affinity than ketanserin for 5-HT2C receptor binding sites in the human brain and, based on estimates of per cent occupancy by the two compounds at brain 5-HT2A and 5-HT2C receptors, we conclude that SWS in humans is primarily regulated by 5-HT2C receptors.

5-HT 2C receptor sensitivity during treatment with selective serotonin re-uptake inhibitors.

We studied the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRIs) on the sensitivity of brain 5-HT(2C) receptors, by measuring the decrease in slow wave sleep (SWS) that follows administration of meta-chlorophenylpiperazine (mCPP) (7.5 mg orally). mCPP significantly lowered SWS both in patients taking SSRIs and in a group of healthy controls. There was, however, no difference in the response between the two groups. The results do not support the suggestion that repeated SSRI treatment alters the sensitivity of 5-HT(2C) receptors in the human brain. The present study, however, cannot exclude the possibility that a decrease in 5-HT(2C) receptor sensitivity was offset by higher plasma levels of mCPP in the SSRI-treated group.

Effect of lofepramine on 5-HT function and sleep.

We studied the effect of the tricyclic antidepressant lofepramine (140-210 mg daily for 16 days) on 5-hydroxytryptamine 1A (5-HT1A) receptor sensitivity in healthy volunteers, using a buspirone neuroendocrine challenge paradigm (30 mg orally). We also studied the effect of lofepramine on platelet 5-HT content and sleep architecture. Lofepramine treatment did not alter the hypothermic, endocrine or amnesic effects of buspirone but significantly lowered platelet 5-HT content and decreased rapid eye movement sleep. Our findings suggest that at clinically used doses, lofepramine inhibits the uptake of 5-HT and produces changes in sleep architecture characteristic of tricyclic antidepressants. However, lofepramine does not appear to alter the sensitivity of 5-HT1A receptors.