Psychopharmacology Unit, University of Bristol
Psychopharmacology Unit, University of Bristol
Psychopharmacology Unit, University of Bristol
Psychopharmacology Unit, University of Bristol
Psychopharmacology Unit, University of Bristol
Bristol-Myers Squibb, 141 Staines Road, Hounslow, Middlesex TW3 3JA
Psychopharmacology Unit, University of Bristol
Psychopharmacology Unit, University of Bristol
Correspondence: David Nutt, Psychopharmacology Unit, University Walk, Bristol BS8 1TD, UK
Declaration of interest Funding and medication were provided by Bristol-Myers Squibb Pharmaceuticals, UK.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To compare the objective and subjective effects on sleep of paroxetine and nefazodone in patients with moderate to severe depression.
Method Forty patients with depression were randomised to take paroxetine 20-40 mg/day or nefazodone 400-600 mg/day for 8 weeks. Objective and subjective quality of sleep and depression measures were assessed throughout.
Results Nefazodone significantly increased objective sleep efficiency and total sleep time, and improved subjective sleep on days 3 and 10. Paroxetine decreased sleep efficiency early in treatment and some sleep disruption remained at week 8. Paroxetine but not nefazodone produced marked suppression of rapid eye movement (REM) sleep.
Conclusions Nefazodone improves sleep in early treatment compared with paroxetine in patients with moderate to severe depression. These effects are seen within the first 2 weeks of treatment and diminish thereafter.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Antidepressants and sleep
One of the new compounds, nefazodone, is said to confer an advantage over
the SSRIs in improving sleep, even before the onset of antidepressant action.
This clinically useful characteristic is shared with the TCAs but the latter
group, unlike nefazodone, is handicapped by danger in overdose and troublesome
anticholinergic side-effects. By contrast, the SSRIs are not considered
sleep-promoting. Disturbed sleep is one of the most frequent and distressing
symptoms in moderate and severe depression. Objective sleep changes in
depression include shortened rapid eye movement (REM) latency, disruption of
sleep continuity, early morning waking and reduction of slow wave sleep,
particularly in the first sleep cycle
(Benca et al, 1992).
Antidepressants such as the TCAs and SSRIs produce marked suppression of REM
sleep. The TCAs tend to improve sleep fragmentation acutely whereas SSRIs
decrease sleep continuity until there is resolution because of improvement of
the depressive illness (Wilson et
al, 2000).
Nefazodone weakly antagonises the reuptake of serotonin (5-HT) and
noradrenaline (Tatsumi et al,
1997); it also blocks the post-synaptic 5-HT2 receptor
and the 1-adrenoceptor, but does not block histamine or
cholinergic receptors, the supposed mechanism producing the sedative effects
of TCAs (Cusack et al,
1994). In a multi-centre sleep laboratory study in major
depression (Rush et al,
1998) nefazodone improved sleep over an 8-week period compared
with fluoxetine. No study, however, has looked at the first 2 weeks of
treatment or at patients sleeping in their home environment.
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patient population
Consecutive referrals to a hospital psychiatric out-patient clinic and
direct referrals from two general practices were assessed for eligibility in
the study. They were screened with full medical and psychiatric history,
mental state examination and physical examination. To be randomised into the
study, patients had to fulfil diagnostic criteria for DSMIV
(American Psychiatric Association,
1994) moderate to severe depression, scoring 18 or over on the
Hamilton Rating Scale for Depression (HRSD;
Hamilton, 1960). Exclusion
criteria included schizophrenia, history of mania, active suicidal ideation,
alcohol misuse and illicit drug use. Patients unable to maintain a consistent
sleep pattern, such as shift workers or those with a current sleep/wake
disorder, were also excluded. Pre-menopausal women were required to have a
negative pregnancy test at screening and to take precautions against pregnancy
during the trial. Subjects who had previously taken psychoactive medication
including benzodiazepines were required to undergo a 2-week (or 5-week in the
case of fluoxetine) washout period before entering the trial. In the event,
six of the patients had received benzodiazepines, none in the previous year,
and four patients had received fluoxetine in the previous year, one stopping
for the study.
Patients who had received any other investigational drug up to 30 days before the initiation of therapy, or who were participating in another clinical study at the time of the assessment, were not considered for inclusion in this protocol. Pregnant or nursing females, or women of child-bearing potential who were not using adequate methods of birth control were also excluded.
Determination of sample size
This was calculated to detect the smallest clinically relevant differences
in two sleep parameters measured by electroencephalogram (EEG) (total sleep
time and number of awakenings) with an 80% power (P=0.05) based on
variance data from a previous sleep study conducted in our laboratory
(Wilson et al, 2000),
and the two-sample method (Gore &
Altman, 1982) was applied. The estimated sample size was 18
patients in each group providing valid data for at least three sleep
assessment days (see later). The target sample size was then extended to 22,
to allow for dropouts. In the event of the study, fewer dropouts occurred than
had been anticipated.
Study design and medication
Forty patients were randomly assigned on day 1 of the study, after the
baseline period, to receive either nefazodone or paroxetine. Randomisation was
carried out by Bristol-Myers Squibb, in blocks of four, so that in any one
block there were two patients taking nefazodone and two taking paroxetine. All
study medication was re-encapsulated. Capsules and container bottles were
identical in shape, but of two different colours. Medication was provided for
an extra 3 days a week, to allow for late follow-up visits. Treatment was
taken in a twice daily regimen by mouth, with patients taking one or two
capsules from the nefazodone/placebo bottle twice a day and a capsule from the
paroxetine/placebo bottle in the morning. Patients commenced on day 1 with
either morning nefazodone (100 mg twice daily), evening nefazodone (100
mg+placebo) or morning paroxetine (20 mg+placebo), evening placebo. After 1
week, the dose of nefazodone was increased to 200 mg twice daily and that of
paroxetine remained at 20 mg once a day. Further titration was according to
clinical response and side-effects, and occurred during scheduled visits or
urgent visits if there were any problems. Adverse events were monitored
specifically from a checklist of 95 symptoms and recorded during each visit.
Patients also had 24-h telephone access to an investigator if anything
untoward occurred. The patients were instructed to return all unused
medication in the original package at each visit. No additional psychoactive
medication was allowed during the washout and treatment phase of the study.
Wherever possible, all other non-psychotropic concomitant medications and
non-pharmacological therapies were recorded and kept constant for the duration
of the study.
Assessments
At baseline, a physical examination was performed; vital signs (pulse,
blood pressure) were recorded, and demographic data were collected.
Information about previous episodes of depression was obtained from case notes
and patients' and relatives' recollection. A pregnancy test was performed as
indicated above. A baseline EEG was performed using the home ambulatory
monitoring system (Medilog, Oxford Instruments Medical, Old Woking). Subjects
were visited in their homes during the evening and the recording equipment for
electro-encephalography, electro-oculography and electromyography was
attached, according to the standard sleep montage
(Rechtschaffen & Kales,
1968). The subjects were then left to sleep normally at home. They
were asked not to bathe or shower with the equipment on but told that
otherwise they could carry out their normal domestic routine; they were asked
not to drink alcohol for the 48 h before the recording but were allowed their
normal caffeine intake. They were instructed to keep to their normal bedtime
routine and to press the event marker on the recorder when they turned out the
lights and tried to sleep, and on waking finally the following morning.
Subjective measures of sleep using the St Mary's Hospital Sleep Questionnaire
(SMHSQ; Leigh et al,
1988) were obtained on the morning after the recording. Thereafter
sleep recordings and subjective sleep questionnaires (SMHSQ and Leeds Sleep
Evaluation Questionnaire (LSEQ; Parrott
& Hindmarch, 1978)) were performed at days 3 and 10 and week 8
of treatment. Patients kept a diary of sleep quality and number of awakenings
for the first 21 days of treatment.
Sleep analysis
Sleep was scored automatically by the Medilog 9002 with visual correction
by an experienced sleep scorer (J.A.H.) according to the Rechtshaffen &
Kales (1968) criteria. The following parameters were derived from the sleep
recordings. (a) Staging time the interval between the patient pressing
the event markers (when these were omitted, the sleep scorer judged these
times from the EEG recording when the patient closed their eyes at night and
when they opened them and started to move around in the morning). (b) Total
sleep time (TST) time in all stages of sleep. (c) Sleep efficiency
%TST/staging time. (d) Number of awakenings these had to be
greater than 16 s in duration. (e) Sleep onset latency time from the
patient pushing the button to start their night's sleep to the first 2 min of
stage 2 sleep. (f) Duration of stage 1-4, and REM sleep and REM onset latency
the time to the first continuous 2 min of REM from the onset of stage
2 sleep. (g) Wakefulness after sleep onset total time spent awake
after sleep onset.
Efficacy of the antidepressant treatment was measured with the HRSD (Hamilton, 1960), MontgomeryÅsberg Depression Rating Scale (MADRS; Montgomery & Åsberg, 1979) and CGI Severity and Improvement scales (Guy, 1976). These were completed by the clinician at baseline, days 3 and 10, and at the end of weeks 3, 4, 6, 8, 16 and 24 (end of study) or at any point that a patient was prematurely withdrawn from the study.
Statistical analysis
Statistical analysis of objective sleep measures was carried out using
STATA version 5.0 for Windows (STATA Corporation). Descriptive statistics were
derived for each of the variables. Tests for normality showed that the
variables stage 1, stage 3, sleep onset latency, REM onset latency and
wakefulness after sleep onset were not normally distributed. The values for
stage 1 sleep and sleep onset latency and wakefulness after sleep onset were
normalised by logarithmic transformation, and those for stage 3 sleep, REM
onset latency and wakefulness after sleep onset, by square root
transformation. Complete data-sets (four sleep assessments) were available for
29 individuals and this resulted in an unbalanced design. Consequently, a
sequential fitting of the different sum of squares was used. Split plot
analysis of variance (split plot ANOVA) was used to investigate the effects of
the two drugs on all the sleep variables. This analysis separates the variance
ascribable to pre-treatment differences between the two treatment groups,
resulting from the effect of time, the interaction between time and treatment
and the effect of the treatments themselves.
Data from HRSD, MADRS and CGI severity and improvement scales were
tabulated using both the observed values and with last observation carried
forward (LOCF) in the whole (intent to treat; ITT) group. Number of responders
(50% or more reduction on baseline HRSD) and remitters (HRSD 8) were
tabulated for each treatment group. Total scores for the rating scales were
analysed using ANOVA, first at baseline and on the change from baseline at the
end of the specific weeks and end-point (subject's last available
observation).
Descriptive statistics, comparison tests at days 3, 10 and week 8 and ANOVA were performed on the scores of LSEQ, the items 5, 6, 9-11 and 13 of SMHSQ and the sleep items of HRSD. Values from the daily diary of sleep quality were analysed with descriptive statistics and scrutinised for possible trends in the data. An average score for each week of the study was compared for the two groups.
Adverse events were cross-tabulated by treatment, severity and clinical estimate of relation to study medication, to detect any evidence of drug-related trends or increased incidence.
All statistical tests and analysis of subjective and mood measures were performed using the standard SPSS package (version 10.0 for Windows).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Patients excluded from the sleep analysis were: one patient who completed baseline only; one patient who completed baseline and day 3, but day 10 recording was technically unsatisfactory; and one patient whose baseline recording was technically unsatisfactory. One other patient's day 3 recording was technically unsatisfactory but baseline, day 10 and week 8 were included, and six other patients had no week 8 recording as they left the study.
The mean nefazodone dose (and standard deviation (s.d.)) used in the study was 495 mg/day (82.6) and for paroxetine it was 29.5 mg/day (8.9), well within the therapeutic range advised for these drugs in the treatment of depression.
Analysis of sleep
In the paroxetine group, four patients at day 3 and one patient at day 10
had no REM sleep at all. In these patients the REM latency was taken to be the
staging time minus sleep onset latency.
Table 3 shows polysomnographic data of sleep parameters with results of ANOVA statistical analysis.
|
There were significant pre-treatment differences between the two treatment groups on nearly all the sleep measures, with sleep in the paroxetine group being generally worse. This occurred entirely by chance, as allocation was random. As described in the Method section, we separated this baseline difference from the treatment effects.
There were significant drug effects on total sleep time, sleep efficiency (see Fig. 1) and wakefulness after sleep onset, with nefazodone improving these and paroxetine worsening them early in treatment but both drug groups returning towards baseline by 8 weeks. Stage 1 sleep and number of awakenings also showed significant treatment effects and these were more obvious at 8 weeks, with both measures being increased in the paroxetine group (see Fig. 2). Number of awakenings showed a significant time x treatment effect, with the nefazodone group showing an early decrease and returning towards baseline at 8 weeks and the paroxetine group continuing to increase during treatment.
|
|
There were highly significant treatment differences on REM sleep, with paroxetine increasing REM latency (see Fig. 3) and decreasing the amount of REM throughout the 8 weeks' treatment. The nefazodone group showed a slight increase in REM and decrease in REM latency. Neither slow wave sleep nor stage 2 sleep showed significant time or group differences.
|
Subjective data from the SMHSQ were not distributed normally and there was a significant difference between the two treatment groups at baseline.
Changes from baseline scores were derived for all patients and these were found to be distributed normally and therefore used in subsequent testing. A significant difference was found at night 3 for sleep quality (item 5: how well did you sleep?) (T=2.12, d.f.=36, P=0.04) with the nefazodone group showing greater improvement from baseline. On the ANOVA there was a treatment effect for sleep quality (P=0.042) and for sleep depth (P=0.042) with the nefazodone group showing more improved scores on both (Table 4 and Fig. 4).
|
|
There was no significant treatment effect on the variables of LSEQ but the factor behaviour following wakening showed a trend for less clumsiness and tiredness in the morning with paroxetine and more with nefazodone. The differences from baseline, however, were small. The week-by-week analysis of the sleep diary averages for sleep quality (how well I slept) and continuity (how many times did you wake up?) and the HRSD sleep items were not significantly different in the two groups.
Analysis of antidepressant efficacy and safety
Response was defined as a 50% or greater reduction from the initial HRSD
score, whereas remission was defined as a final HRSD score of 8 or less. There
was no significant difference between the two medications in these variables.
At week 8 (end of the sleep study), 11 patients on nefazodone and 16 patients
on paroxetine were responding to treatment. At the end of the 24-week study, a
total of 12 in the nefazodone group and 14 in the paroxetine group had
responded to treatment, while 9 patients on nefazodone and 12 patients on
paroxetine wer classified as remitters. Between 8 and 24 weeks, 2 patients in
the paroxetine group had experienced a worsening.
There were no significant differences between the two drugs in HRSD, MADRS, CGI Severity and Improvement scales, either on observed data or on LOCF data. The data from HRSD scores (LOCF) are presented in Fig. 5. Data from the MADRS questionnaire, which has only one question about sleep, were as follows (observed cases): nefazodone group baseline 27.5 (s.d.=4.1), 8 weeks 13.0 (s.d.=7.7); paroxetine group baseline 27.1 (s.d.=3.5), 8 weeks 8.4 (s.d.=6.2).
|
There were no serious adverse events related to either of the medications. One patient on paroxetine was hospitalised for worsening of her primary diagnosis of depression and emerging suicidal ideation, following the day 3 visit. The randomisation code was broken and the patient was continued on open-label paroxetine and made a good recovery. Table 5 shows the non-serious side-effects attributable to the medications. These were similar to those described in previous reports.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
REM sleep suppression remains marked throughout treatment with paroxetine but nefazodone has, if anything, a small non-significant promoting effect on REM, as in other studies (Sharpley et al, 1992). This is different from the TCAs, which produce a similar and sometimes more marked sleep promotion early in treatment but also produce a marked suppression of REM sleep.
Subjective effects
In our study, both drugs were well tolerated and equally effective in
treating depression. Patients taking nefazodone reported increased subjective
sleep quality and increased subjective depth of sleep as early as day 3 of
treatment. The difference between the two drugs was decreased as the treatment
progressed and by the end of the study was not statistically significant. This
could be explained by some early sleep-promoting effect of nefazodone, or a
decrease of sleep disruption caused by the SSRIs as neuroadaptive changes take
place in the brain with prolonged administration and depression improves.
Another possible explanation is a change in the perception and/or reporting of
sleep difficulties by depressed patients as their clinical status evolves. In
a previous study with fluvoxamine (Wilson
et al, 2000), subjective complaints about poor sleep were
decreased when patients improved, in spite of lack of significant changes in
objective measures of sleep (polysomnography).
Comparison with other studies
The SSRIs have become a first line treatment of depression over the past
decade. They offer significant advantages compared with the old compounds
(TCAs and monoamine oxidase inhibitors), such as fewer side-effects and
non-lethality in overdose. However, some useful properties of the TCAs, such
as the promotion of sleep, do not apply to SSRIs. Indeed the SSRIs can
increase wakefulness, reduce total sleep time and sleep efficiency. Generally,
they have an alerting effect in acute treatment, although sleep disruption can
ease with long-term treatment (Wilson
et al, 2000). This alerting effect sometimes results in
the use of additional short-term treatment with a benzodiazepine or other
hypnotic, with all the well-known problems associated with such a regime.
Sleep problems are very prominent in depressive illness, with up to 95% of
patients with moderate to severe depression suffering one or more problems
with their sleep (Thase,
1999). Therefore, new antidepressants that do not cause further
sleep disruption (unlike the SSRIs) and are safe in overdose (unlike the TCAs)
could offer an important advantage, especially in patients with pronounced
sleep difficulties.
Pharmacological mechanisms
The main action of nefazodone is to block post-synaptic 5-HT2
receptors (Taylor et al,
1995). Evidence for the involvement of 5-HT2 receptors
in depression comes from various areas of research. Although this relationship
is complex and not yet very well understood, it appears that down-regulation
of these receptors could be crucial for the ability of antidepressant drugs to
exert their action (Attar-Lévy
et al, 1999; Yatham
et al, 2000), although this finding has not been
replicated in all studies (Massou et
al, 1997). The effectiveness of nefazodone has been
established both in the acute and the long-term treatment of depression in a
number of randomised controlled trials
(Feiger et al, 1999;
Keller et al, 2000).
The relationship of 5-HT neurotransmission and sleep is a complex one
(Sharpley & Idzikowski,
1991). SSRIs are sleep-disturbing early in treatment, presumably
as a consequence of increased 5-HT function. Post-synaptic 5-HT2
blockade, by drugs such as ritanserin, has a promoting effect on deep non-REM
sleep. Trazodone, an antidepressant which shares the 5-HT2-blocking
property of nefazodone, is also sleep-promoting
(Mouret et al,
1988).
Clinical relevance
We compared the effect of nefazodone and an SSRI on sleep of out-patients
with depression, with particular emphasis on the early stages of treatment. We
considered that the onset of treatment is a crucial period. The patient's
morale is at its lowest and the antidepressant has not yet exerted its effect,
therefore the symptoms are at their peak. Further sleep disruption, such as
that caused by the SSRIs, can lead either to disaffection with the treatment
and early drop-out or poor compliance, negatively affecting the overall
outcome, or it could require additional treatment with a hypnotic.
Another difference with the previous study was that patients were studied in their home environment. Patients studied overnight in a sleep laboratory need a period of adjustment to the unfamiliar surroundings and this only adds to the inconveniences already produced by the illness itself. As in our previous study, we found patients more likely to volunteer for the study once they knew that home recordings were involved.
Paroxetine was chosen as a comparator because it is the only SSRI for which sedative properties have been reported (Kerr et al, 1997), as opposed to the previously studied fluoxetine. As well as home-based objective sleep assessment, we also used more extensive subjective sleep measures in an attempt to clarify the effect of the two drugs in a variety of sleep parameters. The (unusual for SSRIs) sedative properties of paroxetine in some patients, which could relate to its weak anti-cholinergic effects, could also account for the small differences seen in this study, compared with the clear superiority of nefazodone over fluoxetine in promoting sleep, as reported by Rush et al (1998).
We conclude that nefazodone is an effective and safe antidepressant that could be a preferable choice over the SSRIs in patients with depression who have prominent sleep problems.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
ACKNOWLEDGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Anderson, I. M., Nutt, D. J. & Deakin, J. F. W. (2000) Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology, 14, 3-20.[CrossRef][Medline]
Attar-Lévy, D., Martinot, J.-L., Blin, J., et al (1999) The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biological Psychiatry, 45, 180-186.[CrossRef][Medline]
Benca, R. M., Obermeyer, W. H., Thisted, R. A., et al (1992) Sleep and psychiatric disorders. A meta-analysis. Archives of General Psychiatry, 49, 651-668; discussion 669-670.[Abstract]
Cusack, B., Nelson, A. & Richelson, E. (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology, 114, 559-565.[Medline]
Feiger, A. D., Bielski, R. J., Bremner, J., et al (1999) Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression. International Clinical Psychopharmacology, 14, 19-28.[Medline]
Gore, S. M. & Altman, D. G. (1982) Statistics in Practice. London: BMA.
Guy, W. (1976) ECDEU Assessment manual for psychopharmacology, revised. US Department of Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health, 179-222.
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56-62.
Keller, M. B., McCullough, J. P., Klein, D. N., et al
(2000) A comparison of nefazodone, the cognitive
behavioural-analysis system of psychotherapy, and their combination for the
treatment of chronic depression. New England Journal of
Medicine, 342,
1462-1470.
Kerr, J. S., Fairweather, D. B. & Hindmarch, I. (1997) The effect of paroxetine and dothiepin on subjective sleep in depressed patients. Human Psychopharmacology, 12, 71-73.[CrossRef]
Leigh, T. J., Bird, H. A., Hindmarch, I., et al (1988) Factor analysis of the St. Mary's Hospital Sleep Questionnaire. Sleep, 11, 448-453.[Medline]
Massou, J. M., Trichard, C., Attar-Lévy, D., et al (1997) Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors. Psychopharmacology, 133, 99-101.[CrossRef][Medline]
Montgomery, S. A. & Åsberg, M. (1979) A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382-389.[Abstract]
Mouret, J., Lemoine, P., Minuit, M. P., et al (1988) Effects of trazodone on the sleep of depressed patients. Psychopharmacology, 95, S37-S43.[Medline]
Parrott, A. C. & Hindmarch, I. (1978) Factor analysis of a sleep evaluation questionnaire. Psychological Medicine, 8, 325-329.[Medline]
Rechtschaffen, A. & Kales, A. (1968) A Manual of Standardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute.
Rush, A. J., Armitage, R., Gillin, J. C., et al (1998) Comparative effects of nefazodone and fluoxetine in outpatients with major depressive disorder. Biological Psychiatry, 44, 3-14.[CrossRef][Medline]
Sharpley, A. L. & Idzikowski, C. (1991) Neurotransmitters and sleep. In Serotonin, Sleep and Mental Disorder (eds C. Idzikowski & P. J. Cowen), pp. 195-213. Petersfield: Wrightson Biomedical Publishing.
Sharpley, A. L., Walsh, A. E. S. & Cowen, P. J. (1992) Nefazodone a novel antidepressant may increase REM sleep. Biological Psychiatry, 31, 1070-1073.[Medline]
Tatsumi, M., Groshan, K., Blakely, R. D., et al (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. European Journal of Pharmacology, 340, 249-258.[CrossRef][Medline]
Taylor, D. P., Carter, R. B., Eison, A. S., et al (1995) Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug. Journal of Clinical Psychiatry, 56 (suppl. 6), 3-11.
Thase, M. E. (1999) Antidepressant treatment of the depressed patient with insomnia. Journal of Clinical Psychiatry, 60 (suppl. 17), 28-31.[Medline]
Wilson, S. J., Bell, C., Coupland, N. J., et al (2000) Sleep changes during long-term treatment of depression with fluvoxamine a home-based study. Psychopharmacology, 149, 360-365.[CrossRef][Medline]
Yatham, L. N., Liddle, P. F., Shia, I.-S., et al
(2000) Brain serotonin2 receptors in major
depression. Archives of General Psychiatry,
57,
850-858.
Received for publication June 20, 2001. Revision received February 22, 2002. Accepted for publication February 25, 2002.
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Psychiatric Bulletin | Advances in Psychiatric Treatment | All RCPsych Journals |