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.

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.

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.

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.

Sleep stability with home sleep recording and automatic sleep stage analysis.

Three home sleep recordings were conducted in 12 normal subjects using the Oxford Medilog 9000 system with automatic sleep stage analysis (SS90III). Each night was separated by 1 week. No significant differences were noted for any sleep parameter, with the mean intraindividual variation less than 20% for most parameters. This indicates that sleep patterns are stable over time.

Evaluation of first night effect using ambulatory monitoring and automatic sleep stage analysis.

Home sleep recordings were conducted over three consecutive nights in 12 normal subjects using the Oxford Medilog 9000 system and automatic sleep stage analysis. The equipment was well tolerated and adequate sleep recordings were obtained on each test evening. The results showed that there was no significant differences over the three nights for any of the sleep parameters measured.

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.

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.

Slow wave sleep and 5-HT2 receptor sensitivity in generalised anxiety disorder: a pilot study with ritanserin.

Eight patients with generalised anxiety disorder (GAD) and eight matched healthy controls had their polysomnogram measured on two occasions separated by 1 week. On one occasion they received the 5-HT2 receptor antagonist, ritanserin (5 mg orally) and on the other matching placebo. The increase in slow wave sleep produced by ritanserin was the same in GAD patients as in healthy controls. These findings do not support the hypothesis that GAD is associated with a generalised hypersensitivity of brain 5-HT2 receptors; however, the present data cannot exclude the presence of a regionally specific change in this receptor subtype in anxiety disorders.

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.

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.

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.

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 consistent with a reduction in brain 5-HT2 receptor function.

Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans.

The effects of the selective 5-HT2 receptor antagonists, ritanserin (1, 5 and 10 mg) and ICI 169.369 (50 and 100 mg), were studied on the sleep EEG of healthy volunteers using home-based Medilog 9000 cassette monitoring. Ritanserin (5 and 10 mg) produced a significant increase in slow wave sleep (SWS) while ICI 169,369 also increased SWS but only at a dose of 100 mg. These findings are consistent with the proposal that selective 5-HT2 receptor blockade increases SWS in humans; however, the data cannot exclude involvement of the closely related 5-HT1c receptor in this effect.

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 and 5-HT2 receptor sensitivity during maintenance tricyclic antidepressant treatment.

The 5-HT2 receptor antagonist cyproheptadine significantly increased slow wave sleep in 12 healthy control subjects but not in 12 patients with a history of major depression, maintained on tricyclic antidepressant treatment. Cyproheptadine produced a similar reduction in REM sleep in both groups of subjects. The results are consistent with the hypothesis that tricyclic antidepressant treatment alters brain 5-HT2 receptor sensitivity, but a primary abnormality in slow wave sleep regulation in depressed patients cannot be excluded.

Sleep and 5-HT2 receptor sensitivity in recovered depressed patients.

The increase in slow wave sleep which followed administration of the 5-HT2 receptor antagonist, ritanserin, was not significantly different between a group of 12 recovered, drug free depressed patients and a group of 12 health matched controls. The results suggests that there is no underlying abnormality in the 5-HT2 receptor regulation of slow wave sleep in recovered depressives, and that abnormalities in this measure reported previously in such patients may have been caused by use of concomitant tricyclic antidepressant medication. The baseline sleep parameters did not differ between recovered depressives and controls with the exception of stage 1 sleep, which was increased in the patient 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.

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.

Increased slow wave sleep with 5-HT2 receptor antagonists: detection by ambulatory EEG recording and automatic sleep stage analysis.

The effect on slow wave sleep (SWS) of 5-HT antagonists with different affinities for 5-HT(1) and 5-HT(2) receptors was investigated using ambulatory EEG monitoring in normal volunteers. The selective 5-HT( 2) antagonists, ritanserin and cypropheptadine, increased SWS while the non-selective 5-HT antagonist metergoline did not. The histamine H( 1)-receptor antagonist, mepyramine, was similarly without effect on SWS. These findings suggest that home ambulatory monitoring with automatic sleep stage analysis may be useful in detecting the effect of selective 5-HT( 2) receptor antagonists on SWS.