Antidepressants and their effect on sleep
Andrew G. Mayers1,2 & David S. Baldwin1
1. University of Southampton; 2. Southampton Solent University
Perinatal Mental Health
The Lodge, Tatchbury Mount
Calmore, Southampton, SO40 2RZ
Tel: +44 (0)23 8087 4330
Fax: +44 (0)23 8087 4360
Given the relationship between sleep and depression, there is inevitably going to be an effect of antidepressants on
sleep. Current evidence suggests that this effect depends on the class of antidepressant used and the dosage. The extent
of variation between the effects of antidepressants and sleep may relate to their mechanism of action. This systematic
review examines randomised-controlled trials (RCTs) that have reported the effect that antidepressants appear to have
on sleep. RCTs are not restricted to depressed populations, since several studies provide useful information about the
effects on sleep in other groups. Nevertheless, the distinction is made between those studies, because the participant’s
health may influence the baseline sleep profiles and the effect of the antidepressant. Insomnia is often seen with
monoamine oxidase inhibitors (MAOIs), with all tricyclic antidepressants (TCAs) except amitriptyline, and all selective
serotonin reuptake inhibitors (SSRIs), as well with venlafaxine and moclobemide. Sedation has been reported with all
TCAs except desipramine, with mirtazapine and nefazodone, the TCA-related maprotiline, trazodone and mianserin,
and with all MAOIs. REM sleep suppression has been observed with all TCAs except trimipramine, but especially
clomipramine, with all MAOIs and SSRIs and with venlafaxine, trazodone and bupropion. However, the effect on sleep
varies between compounds within antidepressant classes, differences relating to the amount of sedative or alerting
(insomnia) effects, changes to baseline sleep parameters, differences relating to REM sleep, and the degree of sleep-
related side effects.
Key words: Antidepressants, sleep, review, randomised-controlled trials
The review exercise was undertaken by exploring the Ovid® database, searching the CINAHL
(1982 - May 2005), EMBASE (1980 – May 2005), Ovid MEDLINE® (1966 – May 2005) and
PsychINFO (1985 – May 2005). A search strategy was undertaken to improve the likelihood of
including high quality randomised controlled-trials (RCTs) that used a double-blind randomisation
of participants into groups of at least 5 (per group), included in a baseline and follow-up
examination of the effect of antidepressants on sleep, where those antidepressants were compared to
placebo (placebo-controlled trials) and/or to other antidepressants (comparator trials). Papers were
selected regardless of the nature of the participants. Antidepressant effects on sleep may vary with
the current health of the participant and it is important to make that distinction. Careful
consideration is also paid to the dose of antidepressant as that may explain some of the variation
between studies in similar participant groups. A more general overview is also presented on the
mechanisms of action of differing classes of antidepressants that might explain the effect they
appear to have on sleep.
Following exclusions, 120 papers were examined, 53 of which included placebo. Those papers are
presented in Table 1. The following section presents general findings for each antidepressant class,
and indicates the mechanisms that might be responsible for those effects. Within each class some of
the more specific findings for each antidepressant are examined. Rather than duplicate the data from
Table 1, only the most important aspects are described.
Several mechanisms are important in the effects of antidepressant treatment on sleep. Increases in
the availability of serotonin and noradrenaline appear to be associated with the suppression of REM
sleep, but also with increases in sleep fragmentation (Wilson and Argyropoulos, 2005). The
pathways responsible for these actions vary across antidepressant class and with individual
medications, but generally refer to action on pre-synaptic autoreceptors, post-synaptic 5HT receptor
sites (such as the 5-HT1A and 5-HT2 receptors), α1- and α2-adrenoceptors and histamine H1
receptors. 5-HT1A stimulation may be associated with REM sleep suppression; 5-HT2 agonism may
be related to sleep disturbance. Inhibition of α2-adrenoceptors autoreceptors increases availability of
noradrenaline, and therefore may be associated with fragmentation of sleep. Blockade of the other
receptor sites (α1-adrenoceptors and histamine H1) may facilitate sleep promotion (Wilson and
Tricyclic Antidepressants (TCAs)
There is much variation between TCAs in the effect on sleep architecture, and with regard to
sedating and alerting properties. The British Association for Psychopharmacology (BAP) guidelines
(Anderson et al., 2000) suggest that sedation is ‘relatively common or strong’ with amitriptyline,
dothiepin and clomipramine, while this ‘may occur or is moderately strong’ with imipramine,
desipramine and nortriptyline. Sedation may be useful in depressed patients with insomnia, but
might not be welcome in those patients wishing to avoid daytime sleepiness.
The mechanisms thought to be responsible for sleep effects in TCAs vary with specific compounds.
Most TCAs inhibit the reuptake of both serotonin and noradrenaline, but the relative extent that they
do this varies, and may explain some of the differences in sedation and REM sleep suppression. All
TCAs except lofepramine block histamine H1 receptors, and all but desipramine block α1-
adrenoceptors. The blockade of histamine H1 receptors may be related to sleep promotion (Haas and
Panula, 2003), but the evidence for an effect on REM sleep or SWS is weak (Wilson and
Argyropoulos, 2005). Antagonism of α1-adrenoceptors is more likely to explain the sedative
properties of TCAs, as might the 5-HT2 blockade action, as seen with amitriptyline and
trimipramine (which are particularly associated with sedation).
(Staner et al., 1995) found that amitriptyline (150mg) produced more alerting effects than
paroxetine (30mg). (Kerkhofs et al., 1990) demonstrated that amitriptyline (150mg) and fluoxetine
(60mg) both produced significant REM sleep suppression. (Casper et al., 1994) showed that
patients presented better improvement in early morning awakening, and nocturnal wakings with
amitriptyline (100-150mg) than imipramine (100-150mg); although this was only for those who had
responded to treatment. (Kerr et al., 1993) observed that amitriptyline (75mg) was associated with
significantly shorter sleep latency, but more drowsiness, than fluoxetine (20mg) on the Line
Analogue Rating Scale for Sedation (LARS) scale. However (De Ronchi et al., 1998) found no
between-group differences for patients in respect of Leeds Sleep Evaluation (LSEQ) scores between
amitriptyline (50-100mg) and fluoxetine (20mg).
Other patient groups
(Mertz et al., 1998) found that amitriptyline (50mg) reduced REM sleep in gastroenterology
patients, compared to placebo, while (Carette et al., 1995) demonstrated fewer changes in REM
sleep parameters in fibromyalgia patients (dosage, 25mg). This is just one example where the dose
may be a significant factor in contrasting findings. For fibromyalgia patients (Hannonen et al.,
1998), subjective sleep ratings were significantly improved from baseline with amitriptyline (25-
37.5mg), compared to placebo. In a study of cancer patients with neuropathic pain (Mercadante et
al., 2002), it was found that drowsiness was significantly higher with amitriptyline (25-30mg) than
placebo. In another study (Mertz et al., 1998), amitriptyline (50mg) was associated with poorer
sleep efficiency for patients with functional dyspepsia, compared to placebo. In a study of patients
with chronic pain (Versiani et al., 1999), amitriptyline (50-250mg) was associated with better
improvements in Hamilton Rating Scale for Depression (HAMD; (Hamilton, 1960)) sleep scores
than fluoxetine (20mg), although daytime drowsiness was a significantly greater problem with
(Rosenzweig et al., 1998) found that subject-rated alertness and behaviour upon waking was
significantly poorer with amitriptyline (50mg) than placebo. This hangover effect was confirmed by
(Hindmarch et al., 2000) who demonstrated that sedation and trouble waking were significantly
worse for amitriptyline (50mg), compared to placebo.
Clomipramine may be associated with sedation, but has also been linked with insomnia (Anderson
et al., 2000). While most TCAs suppress REM sleep to some extent, clomipramine appears to be
the most marked in this respect (Winokur et al., 2001). Clomipramine is associated with the most
potent serotonin reuptake inhibition of all the TCAs (Wilson and Argyropoulos, 2005).
(Lepine et al., 2000) demonstrated no differences between clomipramine (50-150mg) and sertraline
(50-200mg) on LSEQ and HAMD sleep scores, but both showed significant improvements on all
four LSEQ factors (Ease of getting to sleep (EGS); perceived quality of sleep (QOS); ease of
awakening (EOA); and behaviour following wakefulness (BFW)).
(Lacey et al., 1977) found that clomipramine (25-75mg) was associated with slightly longer
nocturnal awakenings than placebo, and almost completely suppressed REM sleep.
(Sonntag et al., 1996) demonstrated that imipramine (50-200mg) significantly increased sleep
latency, while trimipramine (50-250mg) was associated with a non-significant decrease; imipramine
was associated with significantly less total sleep time, and significantly more nocturnal awakenings
than trimipramine. (Volkers et al., 2002) found that imipramine (mean dose 220mg) was associated
with significantly more nocturnal restlessness than fluvoxamine (mean 201mg).
Other patient groups
In a study of patients reporting panic disorder or agoraphobia, (Cassano et al., 1994) imipramine
(25-250mg) was associated with more sedation than placebo (although less than alprazolam; 1-
10mg), but significantly more insomnia than placebo and alprazolam. (Sonntag et al., 1996) found
that imipramine (50-200mg) was associated with decreased total sleep time, while this was
increased with trimipramine (50-250mg); sleep efficiency was significantly more improved with
trimipramine but wakings were significantly more frequent with imipramine.
(Wolf et al., 2001) showed that trimipramine (150mg) was associated with improved sleep
efficiency, longer sleep, and fewer nocturnal arousals, compared to fluoxetine (20mg).
Other patient groups
(Riemann et al., 2002) found that trimipramine (mean 100mg) was not associated with REM sleep
suppression, when compared to placebo with insomnia patients. Unlike other TCAs, which are
associated with REM suppression, trimipramine is not associated with the reuptake inhibition of
serotonin (Wilson and Argyropoulos, 2005).
(Kupfer et al., 1991) demonstrated that desipramine (100-200mg) significantly reduced sleep
latency after just one day of treatment, but this significantly increased again within a week and
throughout the remainder of the 4-week study. Desipramine was associated with shorter sleep
latency than fluvoxamine (200mg), and presented better sleep efficiency. In another study (Shipley
et al., 1985), desipramine (50-250mg) was associated with more nocturnal waking, shorter sleep,
and less efficient sleep than amitriptyline (50-150mg). Unlike other TCAs, desipramine is not
associated with α1-adrenoceptor blockade (Wilson and Argyropoulos, 2005), which may explain
why it does not promote sleep as well. It is also associated with less serotonin reuptake inhibition
than most other TCAs.
(Reynolds, III et al., 1997) demonstrated that nortriptyline (80-120mg) was associated with longer
sleep latency than placebo. Nortriptyline also showed initial suppression of REM sleep, with
prolonged REM latency and reduced REM proportion, but this rebounded in later REM periods to
show greater REM production and density than placebo.
Other patient groups
In a study of patients with skin complaints (Hammack et al., 2002), total sleep time improved for
those treated with nortriptyline (100mg), compared to placebo. However, daytime sleepiness was
reported as a problem in the treatment group.
(Stephenson et al., 2000) demonstrated that drowsiness side effects were more common with
dothiepin (150mg) than fluoxetine (20mg). (Ferguson et al., 1994) found that HAMD sleep scores
were significantly reduced with dothiepin (150mg), compared to placebo (but were similar to
doxepin). (Blacker et al., 1988) showed that dothiepin (75-150mg) was associated with more
immediate improvement of EGS and QOS perceptions on LSEQ than amitriptyline (75-100mg) or
mianserin (30-75mg), although was similar to trazodone (150mg). LSEQ perceptions of BFW were
poor during the first week for all the comparator compounds, but improved thereafter.
(Ramaekers et al., 1995) found that dothiepin (75-150mg) was associated with increased trouble in
waking, but longer total sleep time than placebo. (Wilson et al., 2002) demonstrated that dothiepin
(75-150mg) was associated with poorer sleep efficiency than placebo (and fluoxetine 20mg), but
shorter nocturnal awakenings than fluoxetine; REM sleep latency was significantly shorter for
dothiepin than for fluoxetine. (Wilson et al., 2000) showed that dothiepin (100mg) was associated
with longer TST, shorter nocturnal disturbances, better sleep efficiency, and better sleep quality
than fluvoxamine (100mg).
(Ferguson et al., 1994) found that clinician-rated HAMD sleep scores were significantly reduced
with doxepin (150mg), compared to placebo, while (Feighner et al., 1986) showed that doxepin
(100-225mg) was related to significantly better improvements on these scores than bupropion (300-
Other patient groups
Sleep efficiency and sleep quality were significantly improved for insomnia patients taking doxepin
(25-50mg), compared to placebo (Hajak et al., 2001), while doxepin (25mg) was associated with
significantly increased total sleep time, and significantly reduced sleep latency and length of
nocturnal awakenings, compared to placebo with insomnia patients and healthy volunteers (Hajak et
Monoamine oxidase inhibitors (MAOIs)
MAOIs have been associated with increased sleep latency, poorer sleep efficiency, and increased
nocturnal disturbances (Winokur et al., 2001). Insomnia has been reported for phenelzine,
tranylcypromine and isocarboxazid (Anderson et al., 2000), while significant REM sleep
suppression has been noted with phenelzine and tranylcypromine (Winokur et al., 2001). However,
REM rebound is noted subsequent to the withdrawal of medication (Kupfer and Bowers Jr, 1972).
There is a paucity of RCTs with MAOIs. Moclobemide, a reversible MAOI, has been associated
with less REM sleep suppression than traditional MAOIs (Winokur et al., 2001). Sedation is not
reported with moclobemide, although minor insomnia has been noted (Anderson et al., 2000).
MAOIs increase the availability of monoamines, but REM suppression often appears later than with
TCAs and SSRIs (Wyatt et al., 1971).
(Nolen et al., 1993) found that tranylcypromine (20-100mg) significantly increased REM sleep
latency and almost completely suppressed REM sleep overall. Sleep latency was also increased, but
patients reported deeper and more refreshed sleep than with brofaromine (50-250mg).
(Giller et al., 1982) demonstrated that isocarboxazid (20mg) did not differ from placebo on HAMD
sleep scores, but treatment responders tended to sleep better overall with isocarboxazid than with
(Sogaard et al., 1999) found that moclobemide (300-450mg) was associated with poorer BFW
scores on LSEQ than sertraline, while sleep was observed to better with moclobemide (450mg) than
with toloxatone (100mg; (Lemoine and Mirabaud, 1992)).
Other patient groups
(Hannonen et al., 1998) demonstrated that moclobemide (450-600mg) was associated with poorer
subjective sleep satisfaction and fatigue (not assessed with a specific scale) than amitriptyline (25-
37.5mg) in patients with fibromyalgia.
Two trials involving moclobemide with healthy participants ((Dingemanse et al., 1992), 450mg;
(Ramaekers et al., 1992), 200mg) suggest that moclobemide has no effect on sleep, when compared
to placebo or other antidepressants.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs are frequently associated with insomnia (Anderson et al., 2000); around one-quarter of
depressed patients in clinical trials report insomnia (Winokur et al., 2001). Less well documented is
that SSRIs may cause daytime somnolence, particularly at higher doses (Beasley Jr et al., 1992).
EEG studies of sleep confirm that SSRIs immediately suppress REM sleep, and continue to do so
throughout treatment; REM parameters return to normal once the SSRI is discontinued (Winokur et
The observed effects on sleep of SSRIs are thought to be due to the effects of increased levels of on
5-HT1A and 5-HT2 receptors. Activation of 5-HT1A receptors is probably responsible for REM
suppression (Gillin et al., 1994), but is unlikely to mediate sleep fragmentation. This is more likely
to be due to stimulation of 5-HT2 receptors (Lawlor et al., 1991). By definition, SSRIs block
serotonin reuptake, but some also block noradrenaline reuptake. Both actions have been associated
with REM suppression and sleep disruption (Wilson and Argyropoulos, 2005).
(Mendels et al., 1999) found that citalopram (20-80mg) was associated with significant
improvements in HAMD sleep scores, relative to placebo; although daytime sleepiness was a
significantly greater problem for those taking citalopram than for placebo. (Rosenberg et al., 1994)
demonstrated that citalopram (10-60mg) was associated with significantly better HAMD sleep
scores (from baseline), but did not differ from imipramine (50-100mg). (Leinonen et al., 1999)
showed that subjective ratings for all LSEQ factors significantly improved with citalopram (20-
60mg), although not as quickly as with mirtazapine (15-60mg).
Escitalopram is a relatively new antidepressant in the SSRI class. It has been developed from one of
the isomers of citalopram, so whilst chemically identical, it may be more beneficial than citalopram
if the efficacy elements reside in that single isomer; it may also possess less side effects than the
original combination. There are currently no RCTs that specifically examine escitalopram in
placebo or comparator trials. In a recent pooled analysis (Lader et al., 2005), which compares data
from RCTs involving citalopram and escitalopram, it was shown that escitalopram (10-20mg)
showed significantly better improvements on the Montgomery-Asberg Depression Rating Scale
(MADRS; Montgomery and Åsberg, 1979) item 4 (sleep) at all time points (weeks 1, 4, 6 & 8);
citalopram (20-40mg) was only significantly better at week 6. The proportion of patients with sleep
problems (at baseline MADRS item 4 ≥ 4) improving by endpoint (MADRS item 4 ≤ 1) was
significantly higher with escitalopram than citalopram. However, prospective RCTs specifically
examining sleep are required.
(Jindal et al., 2003) found that sertraline (mean 142mg) suppressed REM sleep and increased sleep
latency (although not significantly), compared to placebo. (Lepine et al., 2000) showed that
sertraline (50-200mg) and clomipramine (50-150mg) significantly improved LSEQ (all factors) and
HAMD sleep scores, but there were no between-group differences. (Bennie et al., 1995)
demonstrated that sertraline (50-100mg) was associated with fewer reports of trouble in sleep
initiation than fluoxetine (20-40mg), but with poorer perceptions on waking. Although overall
LSEQ scores were significantly improved for both groups, they differed on individual items:
sertraline showed better EGS scores than fluoxetine, but poorer EOA and BFW.
(Paul et al., 2002) found that sertraline (50-150mg) was associated with significantly more
insomnia than with placebo.
(Rush et al., 1998) found that sleep was significantly less efficient, and nocturnal awakenings were
significantly greater, with fluoxetine (20-40mg) when compared to nefazodone (100-500mg).
Fluoxetine significantly suppressed REM sleep, while nefazodone significantly increased the time
spent in REM sleep. (Wolf et al., 2001) demonstrated that fluoxetine (20mg) was associated with
less efficient, shorter and more disrupted sleep than trimipramine (150mg); fluoxetine suppressed
REM sleep, whereas trimipramine did not. (Satterlee and Faries, 1995) showed that HAMD sleep
scores tended to show better improvement for fluoxetine (20mg) than placebo, but this was not
significant. (Winokur et al., 2003) found no differences between fluoxetine (20-40mg) and
mirtazapine (15-45mg) in respect of HAMD sleep scores; both showing significant improvements.
However, improvements in sleep latency and total sleep time were not as marked for fluoxetine as
they were for mirtazapine, which resulted in more efficient sleep and less nocturnal disturbances
Other patient groups
(Wolfe et al., 1994) found that self-reported sleep quality perceptions were significantly better with
fluoxetine (20mg) than placebo for patients with fibromyalgia.
(Vasar et al., 1994) demonstrated that fluoxetine (20mg) increased REM sleep latency and reduced
overall REM proportion, increased sleep stages 2 and 3, increased sleep latency and worsened sleep
efficiency, compared to placebo.
(Volkers et al., 2002) found that fluvoxamine (mean 201mg) was associated with more fragmented
sleep than imipramine (mean 220mg), while (Kupfer et al., 1991) demonstrated greater sleep
disruption for fluvoxamine (200mg) than desipramine (100-200mg). (Perez and Ashford, 1990)
showed that fluvoxamine (100-300mg) was associated with poorer EGS ratings on the LSEQ than
mianserin (60-180mg) but fluvoxamine was related to better BFW ratings. While fluvoxamine
(100mg) and fluoxetine (20mg) did not differ in their effect on sleep in the first month of treatment,
after that HAMD sleep scores were significantly better for fluvoxamine (Dalery and Honig, 2003).
(Silvestri et al., 2001) found that fluvoxamine (100mg) was less disruptive to sleep than paroxetine
(20mg), but tended to be associated with greater REM sleep suppression. (Wilson et al., 2000)
demonstrated that fluvoxamine (100mg) was associated with shorter and more disrupted sleep than
with dothiepin (100mg) or placebo. Although poorer subjective sleep quality was reported for
fluvoxamine than dothiepin, perceptions upon waking were better.
(Dunbar et al., 1993) found that HAMD sleep scores were significantly more improved with
paroxetine (10-50mg) than placebo. (Staner et al., 1995) showed that paroxetine (30mg) was more
alerting than amitriptyline (150mg). Sleep quality was rated significantly more poorly with higher
doses of paroxetine (40mg vs. 20mg) than with amitriptyline (75mg) or placebo (Robbe and
O'Hanlon, 1995). (Schatzberg et al., 2002) demonstrated that HAMD sleep scores were poorer with
paroxetine (20-40mg) than mirtazapine (15-45mg). (Hicks et al., 2002) found that sleep time was
less, and disruption greater, for paroxetine (20-40mg) compared to nefazodone (400-600mg). REM
sleep was shown to be significantly more suppressed with paroxetine than nefazodone, and
subjective sleep ratings showed greater improvements with nefazodone.
(Dorman, 1992) demonstrated that LSEQ scores were significantly more likely to be improved with
paroxetine (15mg) than mianserin (30mg); paroxetine was significantly improved from baseline on
all four factors; mianserin only for BFW. In an RCT where the time of dose was randomised (Wade
and Aitken, 1993), HAMD scores were significantly better for morning doses of paroxetine (15-
30mg) than evening doses.
Other patient groups
(Capaci and Hepguler, 2002) found that sleep disruption did not improve as well with paroxetine
(20-40mg) as it did for amitriptyline (10-20mg) in fibromyalgia patients.
(Ridout et al., 2003) demonstrated that paroxetine (20mg) was associated with longer sleep latency
and poorer reports of sleep quality than mirtazapine (15-30mg). (Sharpley et al., 1996) observed
greater suppression of REM sleep for paroxetine (30mg) than for nefazodone (400mg).
Venlafaxine blocks the reuptake of serotonin and noradrenaline, mostly the former in lower doses
(less than 150 mg), with little effect on post-synaptic receptor sites. Increases in these monoamines
are related to REM suppression and sleep fragmentation (Wilson and Argyropoulos, 2005).
(Luthringer et al., 1996) found that venlafaxine (225mg) was associated with significant REM sleep
reduction, and significantly increased nocturnal disturbance, compared to placebo. (Cunningham et
al., 1994) demonstrated that HAMD sleep scores were improved following venlafaxine (25-
200mg), but significantly less so than with trazodone, and no different to placebo. (Guelfi et al.,
2001) showed that HAMD sleep scores were also significantly poorer for venlafaxine (75-375mg)
than mirtazapine (15-60mg).
Reboxetine inhibits the reuptake of noradrenaline, and is not associated with direct activity at post-
synaptic receptor sites. No RCTs were found in the systematic review, but one uncontrolled study
showed evidence of transient sleep disruption, but persistent REM suppression, with 2mg (b.d.) of
reboxetine in 12 dysthymic patients (Ferini-Strambi et al., 2004), and (Kuenzel et al., 2004) found
nocturnal disturbance and reduced sleep efficiency with reboxetine (8-10mg) in 8 depressed
Trazodone is associated with weak serotonin reuptake blockade, and with antagonist actions at α1-
adrenoceptors, 5-HT1A and 5-HT2 receptors. The effects on α1-adrenoceptor and 5-HT2 receptor sites
may explain why there is more evidence of sleep promotion with this compound. However,
trazodone has also shown to suppress REM sleep in some studies (Mouret et al., 1988), which
seems at odds with the relative lack of serotonin reuptake antagonism and the inhibition of 5-HT1A
(Wilson and Argyropoulos, 2005). The reasons for this are unclear.
(Mashiko et al., 1999) found that sleep scores on HAMD were significantly better improved for
trazodone (50-100mg) than placebo, although the effect was better in lower doses. (Nierenberg et
al., 1994) demonstrated that trazodone (50-100mg) was associated with significantly better patient-
rated sleep quality (Pittsburgh Sleep Quality Index) and clinician-rated sleep scores (Yale-New
Haven Hospital Depression Symptom Inventory) than was placebo. (Blacker et al., 1988) observed
better improvements in subjective sleep ratings with trazodone (150mg) than with amitriptyline (75-
100mg) or mianserin (30-75mg). (Moon and Davey, 1988) demonstrated similar improvements for
all LSEQ scores with trazodone (150mg) and mianserin (30-60mg), although trazodone tended to
show more rapid improvements.
Other patient groups
(Le Bon et al., 2003) showed that trazodone (100mg) was associated with significantly better sleep
efficiency and significantly less nocturnal disturbance than placebo in alcohol dependent patients.
(Walsh et al., 1998) found that subjective ratings of sleep initiation, nocturnal awakenings, and
sleep quality were significantly better for trazodone (50mg) than placebo for insomnia patients, but
did not differ from the effects of the hypnotic drug zolpidem (10mg). (Saletu-Zyhlarz et al., 2001)
observed significantly suppressed REM sleep for trazodone (100mg), compared to placebo, in
dysthymic insomnia patients.
(Ware et al., 1994) observed significantly more REM sleep suppression with trazodone (100mg)
than with nefazodone (200mg).
Nefazodone has mild serotonin reuptake blocking properties, and stronger 5–HT2 antagonist effects.
It is not associated with REM suppression, as might be expected (Wilson and Argyropoulos, 2005),
The blockade of α1-adrenoceptor sites, and the 5-HT2 receptor probably underlie the beneficial
effects on sleep continuity that have been observed.
(Feighner et al., 1998) found that nefazodone (100-600mg) was associated with significantly better
improvements in HAMD sleep scores than placebo. Previous analyses indicated that nefazodone
was associated with less nocturnal disturbance than fluoxetine (Rush et al., 1998) or paroxetine
(Hicks et al., 2002). While nefazodone shows clear benefits for sleep, it is no longer available in
In contrast to some findings in depressed groups, (Vogel et al., 1998) showed that nefazodone (200-
400mg) reduced total sleep time, and increased nocturnal awakenings, when compared to placebo,
in 120 healthy volunteers.
Mianserin is an antagonist at α1-adrenoceptor sites and 5-HT2 receptors, which may promote sleep
but also with inhibition of the α2-adrenoceptor, and with moderate inhibition of noradrenaline
reuptake (Wilson and Argyropoulos, 2005), which may fragment sleep and suppress REM sleep.
This compound has been associated with sleep promotion properties, particularly in comparison to
SSRIs, as this review has shown, possibly through inhibition of histamine H1 receptors. There are
no RCTs that explore the effects of mianserin on REM sleep, but uncontrolled studies have
suggested slight suppression (Maeda et al., 1991).
(Smith and Naylor, 1978) found that mianserin (30mg) was associated with significantly better
nurse-rated, and patient-rated, improvements in total sleep time than placebo. (Granier et al., 1985)
demonstrated that mianserin (30mg) was associated with significantly better improvements in
HAMD sleep scores than nomifensine (50mg). Mianserin (10-20mg) was associated with
significantly reduced HAMD sleep scores compared to placebo for depressed women with cancer
(Costa et al., 1985) However, this may have been compounded by the addition of the hypnotic drug
nitrazepam (2.5-10mg) for those patients with persistent insomnia.
Mirtazapine blocks α2-autorecptors, 5-HT2 receptors and H1 receptors. α2-adrenoceptor inhibition
increases noradrenaline, thus suppressing REM sleep and disrupting sleep continuity; while the
other actions tend to promote sleep. The improvements in sleep with mirtazapine are more likely to
be the result of 5-HT2 receptor inhibition (Haddjeri et al., 1995).
(Leinonen et al., 1999) found that mirtazapine (15-60mg) was associated with more rapid
improvements in QOS and BFW on the LSEQ than was citalopram (20-60mg). Earlier analyses
comparing mirtazapine to other antidepressants, indicated less nocturnal disturbance and better
sleep efficiency than with fluoxetine (Winokur et al., 2003) or paroxetine (Ridout et al., 2003), and
better HAMD sleep scores than with paroxetine (Schatzberg et al., 2002) or venlafaxine (Guelfi et
(Aslan et al., 2002) demonstrated that mirtazapine (30mg) was associated with significantly greater
improvements in sleep efficiency, including fewer nocturnal disturbances than with placebo, but did
not affect REM sleep measures.
Bupropion is used as an agent to facilitate smoking cessation, and as an antidepressant in the US
and some other countries. Its mechanism of action is not fully understood, but may involve
noradrenaline reuptake, which is associated with REM suppression, and enhanced dopamine
availability (Wilson and Argyropoulos, 2005), which is not. However, RCT evidence suggests that
bupoprion is associated with REM suppression.
(Ott et al., 2002) found no differences with regard to sleep measures between bupoprion (150-
400mg) and placebo, although treatment response was associated with significant REM
Other patient groups
(Haney et al., 2001) observed that bupropion (300mg) was associated with poorer sleep than
placebo in patients withdrawing from marijuana; total sleep time and getting to sleep were
particularly poor for those taking bupropion in the first 3 days of withdrawal. However, when
nicotine smokers were examined during withdrawal, no differences were detected between
bupropion (150-300mg) and placebo (Shiffman et al., 2000).
Milnacipran inhibits the reuptake of serotonin and noradrenaline (Bourin et al., 2005), but does not
blockade histamine H1 or the α1-adrenoceptor site. It might be expected that this compound would
be associated with REM suppression and less sedation, but RCTs are scarce. Uncontrolled studies
suggest no long term effect on REM sleep, and improved sleep efficiency (Lemoine and Faivre,
(Poirier et al., 2004) demonstrated that milnacipran was associated with improvements in subjective
sleep ratings (sleep latency, sleep quality and waking), but did not differ from placebo in this
Other psychotropic medications
Since sleep disturbance is often found with antidepressants, particularly in the form of insomnia
with SSRIs, hypnotic medications have been added to an antidepressant to offset the sleep problem.
The addition of the novel antipsychotic risperidone has been found to reduce sleep disturbance in
resistant depression (Ostroff and Nelson, 1999), but there is much more evidence for hypnotics. In
one study of SSRI-treated depressed patients (Asnis et al., 1999), those receiving fluoxetine (≤
40mg), sertraline (≤ 100mg) or paroxetine (≤ 40mg), who reported significant insomnia, were
entered into a double-blind phase where they were randomised to zolpidem (10mg) or placebo for 4
weeks, followed by single-blind placebo for 1 week.
Those receiving zolpidem demonstrated improved sleep (longer TST, better sleep quality, and
reduced WASO) and significant improvements in subsequent daytime perceptions. In the single-
blind phase of placebo, the zolpidem group presented significant worsening of sleep, but no
evidence of withdrawal effects. In another study (Londborg et al., 2000), depressed outpatients
were randomised to fluoxetine (20mg) plus clonazepam (0.5-1mg), or fluoxetine plus placebo.
Significantly more patients showed improvements in sleep disturbance in the cotherapy group than
with placebo, although sedation was reported more often with cotherapy than with placebo.
Antidepressants are associated with differing effects on sleep profiles, with variations between and
within classes: sometimes there is conflicting evidence for individual compounds. The effect on
sleep is related to pharmacological properties such as the degree of inhibition of serotonin or
noradrenaline reuptake, the effects on 5-HT1A and 5-HT2 receptor sites, and actions at α1- and α2-
adrenoceptors, and histamine H1 sites. The effect that an antidepressant has on sleep is important
because it may influence the clinician’s decision regarding which antidepressant to prescribe to
There is much variation in the reported effects on sleep from TCAs. Amitriptyline (Hindmarch et
al., 2000), trimipramine (Sonntag et al., 1996), nortriptyline (Hammack et al., 2002), dothiepin
(Blacker et al., 1988) and doxepin (Hajak et al., 2001) have all been associated with sedation, while
imipramine (Volkers et al., 2002) and desipramine (Shipley et al., 1985) are less likely to be linked
with sedation, but have been associated with insomnia; the evidence is less clear with
clomipramine. At the same time, amitriptyline (Rosenzweig et al., 1998), nortriptyline (Hammack
et al., 2002) and (particularly) dothiepin (Wilson et al., 2002) have frequently been linked with
poorer reports of daytime drowsiness. Improved subjective ratings of sleep have been reported with
amitriptyline (De Ronchi et al., 1998), clomipramine (Lepine et al., 2000), imipramine (Ware et al.,
1989) and doxepin (Hajak et al., 2001).
Clinician ratings of sleep (via HAMDS) have improved with amitriptyline (Versiani et al., 1999),
clomipramine (Lepine et al., 2000), imipramine (Rosenberg et al., 1994), dothiepin (Corne and
Hall, 1989) and doxepin (Feighner et al., 1986). EEG studies suggest that sleep length and
efficiency are increased, and nocturnal disturbances reduced, for amitriptyline (Casper et al., 1994),
clomipramine (Eberhard et al., 1988), trimipramine (Wolf et al., 2001), nortriptyline (Reynolds, III
et al., 1997) and doxepin (Hajak et al., 1996); although one study of nortriptyline suggested longer
sleep latency (Hammack et al., 2002) and another found no improvement in total sleep time for
amitriptyline (Raigrodski et al., 2001). Greater disturbance, and less sleep, is reported with
imipramine (Volkers et al., 2002) and desipramine (Shipley et al., 1985). REM sleep suppression is
reported with all TCAs except trimipramine (Riemann et al., 2002). Patients who report difficulty
getting to sleep are more likely to benefit from amitriptyline, trimipramine, nortriptyline, dothiepin
and doxepin. These patients are less likely to benefit from imipramine and desipramine.
Not much data is available on sleep effects with MAOIs. In general, they are associated with greater
nocturnal disturbance and shorter sleep times, with insomnia common (Winokur et al., 2001).
MAOIs have been reported to significantly suppress REM sleep (Nolen et al., 1993). The few RCTs
that were found during this review appear to support these findings. Nevertheless, subjective reports
of sleep were favourable with tranylcypromine (Nolen et al., 1993) and isocarboxazid (Giller et al.,
1982). All the same, MAOIs appear to present few benefits for the troubled sleeper. The reversible
MAOI moclobemide is less associated with REM sleep suppression, and appears not to effect sleep
notably (Ramaekers et al., 1992).
SSRIs are commonly associated with insomnia (Anderson et al., 2000), although occasionally
daytime sleepiness has been reported with higher doses (Beasley Jr et al., 1992). Despite this,
patients’ subjective sleep reports whilst taking SSRIs are frequently positive, as are clinicians’
ratings. However, EEG studies frequently show greater fragmentation of sleep with SSRIs. REM
sleep suppression is frequently found with these compounds. In RCTs, prolonged sleep latency and
reduced sleep time have been noted with sertraline (Jindal et al., 2003), fluoxetine (Gillin et al.,
1997), fluvoxamine (Wilson et al., 2000) and paroxetine (Hicks et al., 2002), particularly when
compared to placebo and against the sedative TCAs. However, patient-rated LSEQ scores have
been shown to improve with citalopram (Leinonen et al., 1999), sertraline and fluoxetine (Aguglia
et al., 1993), comparing well with TCAs in this respect, although not so well as some of the newer
Clinician-rated HAMDS scores were improved in the trials that investigated citalopram (Mendels et
al., 1999), sertraline (Lepine et al., 2000), fluoxetine (Winokur et al., 2003), fluvoxamine (Dalery
and Honig, 2003) and paroxetine (Dunbar et al., 1993). It is unlikely that a patient with a history of
sleep disturbance will benefit from SSRI treatment. There are few differences between SSRIs,
unlike TCAs. Some studies suggest that sertraline and fluoxetine present similar improvements in
LSEQ scores (Aguglia et al., 1993), while others show better improvement with sertraline (Bennie
et al., 1995); sertraline was also shown to produce fewer reports of insomnia than fluoxetine.
Fluvoxamine appears to be associated with less sleep disruption than paroxetine (Silvestri et al.,
No general comments can be made about ‘other’ antidepressants, since their mode of action varies
widely. Venlafaxine and reboxetine appear to be similar to SSRIs in REM sleep suppression and
nocturnal disturbance (Luthringer et al., 1996), and to present similar improvements in clinician-
rated HAMD sleep scores (Cunningham et al., 1994). Trazodone has been found to have favourable
sleep outcomes in a number of trials, showing better improvements in subjective sleep ratings than
TCAs (Moon and Davey, 1988), and performing equally well against placebo with the hypnotic
zolpidem in respect of insomnia and sleep time (Walsh et al., 1998).
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on sleep time and nocturnal disturbance, with a quicker, but less sustained improvement profile
(Bruijn et al., 1999). HAMD sleep scores have been shown to be better with mirtazapine than
venlafaxine (Guelfi et al., 2001), and similar to fluoxetine (Winokur et al., 2003).
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Table 1: Effect of antidepressants on sleep: summary of randomised controlled trials
See table footnotes for key to abbreviations
Lead Author, Year
Outcome, following treatment
AMI sig improvement disturbed sleep wks 4 & 8 (p=.008; p<.001), PAR sig
improved wk 8 (p=.002), AMI sig better than PAR at wks 4 & 8 (p=0.002; p<.001);
AMI sig improvement non-refreshed sleep wks 4 & 8 (p=.008; p<.001), PAR sig
improved wk 8 (p=.031), AMI sig better than PAR wk 8 (p=.011)
Drowsiness sig more intense with AMI vs. PLC (p=.036)
AMI did not increase TST or reduce EMG activity, compared to PLC
AMI group showed sig increases in subjective ratings of sedation and difficulty
waking (p<.05), compared to PLC; MIL not different to PLC
HAMDS reduced with both drugs, but sig more for AMI (-3.3) than FLX (-1.9;
p<.001); daytime somnolence reported sig more often AMI (40.0%) than FLX
AMI sig improvement subjective sleep (p<0.001) & fatigue (p<0.01); MOC group
no improvement, but PLC group also showed improvement in these ratings (p<.05)
AMI sig better improvements in HAMDS than SER (AMI -2.4; SER -1.8; p=.008)
AMI worsened subjective alertness (poorer ease of waking, p=0.002; poorer
behaviour following waking, p=.009 – suggesting ‘hangover’ effect); BEF
maintained alertness; no other subjective sleep variables affected
No difference between drugs on LSEQ ratings, except ease of waking (AMI 132.8,
LOR 167.6; p=.047), suggesting poorer subjective waking for AMI
AMI poorer SE, increased arousal, and reduced REM sleep, compared to PLC (no
LSEQ sig increased for AMI (94.7) & FLX (108.6), no between-group differences
AMI group showed sig improvements in restful sleep, compared to PLC (p<.001)
No difference on HAMDS between drugs, but both showed decrease (AMI: 4.90 vs.
1.74; MIR: 4.80 vs. 1.66; within-group significance not reported)
Self-reported sleep perceptions improved at days 15, 30 & 45 for PAR (p<.01) and
days 30 & 45 for AMI (p<.01); no between-group differences
Both drugs reduced REM sleep, but only PAR demonstrated an alerting effect
Groups only investigated in respect of NonREM parameters; neither group
presented changes in NonREM after treatment
Sig greater improvement in EMA & WASO for AMI, compared to IMI, wks 2
(p=.008), 3 (p=.009) & 4 (p=.04); improvements earlier for AMI than IMI, but only
in treatment responders; both groups reported less SL, EMA and WASO wk 1,
regardless of treatment response (p<.001), only responders continued improvement
by wk 4 (p=.003)
AMI or PLC used as adjunct to opiods in 3 day postop following arthroplasty; SL
ratings sig better in AMI group, compared to PLC (p<.025)
Versiani, 1999 50-250mg Depressed patients 157 8 weeks
Hannonen, 1998 25-37.5mg 1: Moclobemide 450-
600mg; 2: Placebo
1: Befloxatone 10mg
130 12 weeks
Srisurapanont, 1998 Mean 57.7mg Lorazepam (mean) 2.1mg Opiate withdrawal
27 5 days
Mertz, 1998 50mg/night Placebo 14 4 weeks
De Ronchi, 1998
Mirtazapine (mean) 94.2-
Ataoglu, 1997 Fibromyalgia
68 6 weeks
See paroxetine; AMI = active control in this pct
100-250mg Imipramine 100-250mg
Kerrick, 1993 50mg Placebo Hip or knee
28 3 days
Kerr, 1993 75mg Fluoxetine 20mg Elderly depressed
66 7 weeks LSEQ scores improved both groups; AMI sig shorter SL wk 1 than FLX (p<.05), no
other between-group differences (including no sig rating of ‘hangover’ for AMI,
despite quick sedation at wk 1); however, LARS scores indicated that FLX patients
less drowsy than AMI at wks 1 & 2 (p<.05)
Both groups sig decrease REM% (p<.001) and increase in REML (p<.001), but no
AMI group ‘slept better’ from second week, compared to PLC; AMI pts slept for
longer than PLC pts, sig so at wk 2 (p<.01)
Both groups showed lengthened REML, and less REM time
Both groups showed increase in TST (approx 2 hrs per day; ns), but actual time in
bed was sig more reduced in TRZ (4 hrs) than AMI (1.5; p=.005)
AMI group showed sig reduction in HAMDS; no such change with femoxetine
LSEQ items sig increased from baseline in both groups (p<.001), but no sig
between-group differences; HAMDS sig reduced for both groups (p value not
specified), but no sig between groups differences
Sig improvement both groups sleep disturbance (p<.01); no between-group
Randomly assigned to PLC then CLO 6 weeks later, or CLO then PLC; CLO
nights slightly more WMINS than PLC (ns); CLO nights sig less REM% (p<.001)
than PLC (REM almost totally suppressed with CLO)
IMI more fragmentation of motor activity during sleep (p<.05) than FLUV
Kerkhofs, 1990 150mg Fluoxetine 60mg Depressed patients 34 6 weeks
Zitman, 1990 75mg Placebo Chronic pain
39 12 weeks
See trazodone, the main focus of this paper
See Desipramine, the main focus of this paper
50-150mg Sertraline 50-200mg
Eberhard, 1988 25-150mg Maprotiline 50-150mg Depressed patients 52 6 weeks
Lacey, 1977 25-75mg Placebo Healthy volunteers 12 4 nights
Mean 220 mg
Mirtazapine (mean) 77mg
Bruijn, 1999 Mean 235mg Depressed
107 4 weeks
MIR rapid improvements in sleep wk 2, normalising by wk 4; IMI more gradual
improvement, exceeding MIR by wk 4
Both groups similar reductions HAMDS (IMI: 2.44/-1.16; BRO: 2.16/-1.46; ns)
TRIM sig increased TST, after 4 wks, sig reduced WMINS immediately and
through to 4 wks, sig increased REM time immediately and through to 4 wks, sig
reduced REML immediately, but increased again to 4 wks (ns); IMI sig increased
SL by end of 4 wks, sig increased stage 1 sleep immediately and through to 4 wks,
sig reduced REM time immediately, but sig increased again to 4 wks, sig increased
REML immediately, but sig reduced this again to 4 wks; no p values stated
All groups showed reduction in HAMDS, but not sig between groups
Van Laar, 1995
1. Citalopram 10-30mg
2. Citalopram 20-60mg
1: Alprazolam 1-10mg
in primary care
1994(Cassano et al.,
25-250mg 1168 8 weeks Sig more sedation for ALP (58%) than IMI (31%) or PLC (21%); sig more
insomnia for IMI (22%) than ALP (3%) and PLC (12%)
Ware, 1989 75-200mg Trimipramine 75-200mg Depressed patients
30 4 weeks Both groups reported shorter SL initially, but IMI increasing SL after 7 days, TRIM
continued improving; TST increased TRIM, but decreased IMI (p=.02), TST and
SE sig improved for TRIM (P<.01), WASO greater for IMI than TRIM (P<.01),
REML sig increased for IMI, TRIM no change, REM% sig decreased for IMI
(P<.01), TRIM no change
TRIM did not suppress REM sleep; LOR decreased WMINS and SWS, increased
REM sleep, compared to PLC; sleep returned to normal when switched to PLC
TRIM sig higher SE (p<.05), longer TST (p<.05), shorter WASO (p<.01); FLX
decreased REM% (p<.01) increased REML (p<.05)
Wolf, 2001 150mg Depressed geriatric
19 6 weeks
1996(Sonntag et al.,
DES sig reduced SL day 1, sig increased by day 7 to end (p=.01), sig increased
stage 2 sleep day 1 to end (p<.001), sig reduced REM% at day 1, increased day 2 to
end (p<.001), sig increased REML at day 1, decreased day 2 to end (p<.001); FLX
sig increased SL at day 1 (p<.001), decreased day 7 to end (ns), sig increased
WMINS at day 1 to end (p<.001), sig reduced SE at day 1, returning to baseline by
day 7 (p<001), sig reduced REM% by day 1, increasing at end (p<.001), sig
increased REML by day 1, still further day 2, reduced from day 7 to end (p<.001);
groups sig differed on SL (FLX>DES), SE (DES>FLX) and REML (FLX>DES)
Compared to baseline, DES 50mg sig more WASO (P<.01), more stage 2 sleep
(p<.01), less REM% (p<.001), greater REML (p<.001); DES 150mg sig less
REM%, greater REML (all p<.001); DES 150-250mg sig more stage 1 sleep
(p<.05), stage 2 sleep (p<.01), less REM% (p<.001), greater REML (p<.001);
compared to AMI, DES sig more WASO (p<.01), more WMINS (p<.01), less TST
(p<.05), poorer SE (p<.01) less REM time (p<.01)
TST increased by 0.5 hours with NOR, decreased by 0.3 hours with PLC (p=.02);
NOR more likely to report sleepiness as a side effect than PLC (ns; p=.09)
NOR decreased REM time and increased REM density; no change PLC; REM sleep
NOR group reverted to baseline after withdrawal; subjective SQ returned to normal
NOR sig longer SL (p=.02), longer REML (p=.01), less REM proportion (p=.001)
greater REMD (p<.001) more REM production throughout (p<.001)
Both active drugs less REM sleep time than PLC day 10 (p=.001) & day 36 (p=.04);
FLX group longer REML than PLC and DOT day 10 (p=.003); both active groups
longer REML than PLC day 36 (p=.03); DOT group poorer SE than FLX & PLC
day 36 (p=.04); FLX group more WMINS than DOT day 10 (p=.03)
Shipley, 1985 1: 50mg
Amitriptyline 50-150mg Depressed
33 4 weeks
Patients with severe
Taylor, 1999 Mean 70.8mg Placebo 27 6 months
Reynolds, 1997 80-120 ng/mL Placebo 40 1 year
1: Fluoxetine 20mg
Stephenson, 2000 150mg Fluoxetine 20mg Depressed patients 125 6 weeks No between-group differences on LSEQ scores, but disturbed sleep/drowsiness side
effects reported more often in DOT group
DOT reported increased difficulty waking days 1-3 (p=.043), FLX on days 17-21
(p=.02); DOT days 1-3 estimated 43 minutes longer TST than PLC (p=.02)
HAMDS sig reduced for DOT and DOX, compared to PLC (p<.05)
1: Fluoxetine 20mg
Ferguson, 1994 150mg/night Depressed patients 579 10 weeks
Corne, 1989 75-100mg Depressed patients
in primary care
100 6 weeks No between-group differences on HAMDS, but tiredness/drowsiness side effects
reported more often in DOT group and response quicker for DOT
DOX sig increased SE compared to PLC (p<.05); DOX sig improved SQ (P<.001);
but, pts with severe insomnia rebound (after treatment withdrawal) were sig more
likely to have taken DOX than PLC
DOX sig improved SL, TST, and WMINS in both study groups, compared to PLC
Hajak, 1996 25mg Placebo Insomnia patients
No RCTs found
No RCTs found
HAMDS sig improved in DOX, compared to BUP (p<.05)
Sig improvements in sleep for DOX, relative to PLC
Same dataset as Hameroff, 1984
Both treatments sig increase REML (P=.02), more so BRO, slightly reduced stage 1
sleep (ns), sig increased stage 2 (p<.001), increased stage 3 (ns), and sig reduced
stage 4 (p=.001); SWS reduced overall and approached sig (p=.07); both groups sig
reduced REM (p<.001), particularly TRAN; shorter TST reports, more WASO and
waking more tired with BRO, SL longer, but sleep deeper and more refreshed with
No HAMDS score changed overall, although those who responded best to active
drug tended to report less sleep disturbance
No differences detected on sleep variables between groups
No differences in reports of SQ, but MIA group showed increased sleep, and
reported daytime drowsiness/fatigue; MOC appeared to have little effect on sleep
Sig more MOC group showed improved sleep patterns than TOL
1: Mianserin 10mg
CIT group sig improvement in HAMDS relative to PLC (p<.05), but somnolence
reported as side effect in twice as many CIT group as PLC
Compared to PLC, SER increased SWS 1st sleep cycle (ns), decreased SWS 2nd
cycle (p=.05), longer REML (p<.001); SER group showed increase SL (ns), but no
worsening SE; subjective (PQSI) ratings showed sig improvements for both groups
(p<.001), but no between-groups differences
SER group showed more insomnia than PLC (p=.002), more nocturnal awakenings
(p=.007) and more problems returning to sleep (p>.001)
No between-group differences in respect of worsening or improvement of insomnia
No RCTs found
Paul, 2002 50-150mg Placebo Healthy volunteers 19 5 weeks
Fava, 2002 50-200mg 1: Fluoxetine 20-60mg
2: Paroxetine 20-60mg
1: Paroxetine mean
2: Fluoxetine mean
Depressed patients 284 16 weeks
Kroenke, 2001 Mean 72.8mg Depressed patients
573 9 months All groups increase (improvement) MOS sleep scores, but no between-group
SER group showed sig improvement on LSEQ Item 4 (integrity of behaviour on
waking); no other sleep differences between groups
SER near-sig improvement LSEQ scores relative to FLX at 18 wks (p=.08; p=.13 at
24 wks); sleep & rest item of SIP sig improvement in favour of SER (p=.04)
Both groups showed sig improvement in LSEQ scores (p<.05), across all items;
tendency for SER to present less difficulty in getting to sleep than FLX, while FLX
tended to feel better on waking than SER, but no between-group differences overall
Both groups showed sig improvement in LSEQ scores, but there was no difference
between the groups; although FLX group reported more insomnia than SER
No between-group differences HAMDS; both sig reduction wk 2 to wk 8 (p<.05);
MIR better improvement SL & TST, compared to FLX; trend better improvement
SE for MIR; FLX non-sig reduction SWS, increased WASO, increased REML,
reduced REM time (p=.033), non-sig reduction SWS; MIR showed sig reduction SL
(p=.0015), longer TST (p=.04), better SE (p=.0004), less WASO (p=.0008)
Subjective sleep did not differ between groups until wk 4, then SQ favoured FLUV
(ns); HAMDS improvement was sig greater with FLUV than FLX at wks 4 and 6
Sechter, 1999 50-150mg Fluoxetine 20-6mg 238 24 weeks
Aguglia, 1993 Mean 72mg Fluoxetine mean 28mg Depressed
108 8 weeks
Dalery, 2003 20mg Fluvoxamine 100mg Depressed
184 6 weeks
De Ronchi, 1998
No significant between-group differences
SE sig increased with NEF (p=.05), sig reduced with FLX (p=.05), FLX sig poorer
than NEF (p=.01); WASO sig reduced with NEF (p=.01), sig increased with FLX
(p=.01), FLX sig poorer than NEF (p=.01); SWS sig reduced both groups (p=.01);
REM time sig reduced with FLX (p=.01), sig increased NEF (p=.01), NEF sig
longer than FLX (p=.01); improvements sig greater for NEF than FLX on HAMDS
(both improved) and sleep items on IDS-C and IDS-SR
FLX sig decreased SE and REM time, increased WASO and REML; NEF sig
decreased %AMT, but did not alter SE or WASO, REM time or REML; both
groups showed sig improvement in some clinician- and patient-rated sleep
disturbance scores, but NEF group generally improved more than FLX group
NEF increased SE, reduced WASO & %AMT; FLX increased WASO & REML,
reduced REM time; NEF increased REM sleep, decreased REML; NEF greater SE,
less WASO, less %AMT more REM sleep, shorter REML than FLX; sig greater
improvement subjective sleep disturbance NEF than FLX; NEF reported better SQ
HAMDS scores were improved for FLX relative to PLC (but ns); HAMDS scores
worsened more often with PLC than FLX (ns); HAMDS scores improved more
often with FLX than PLC (ns)
FLX sig increased SL (p=.03), reduced SE (p=.03), increased REML (p=.04),
reduced REM% (p=.01), increased stage 2% (p=.03), increased stage 3% (p=.02),
PLC ns; no within/between-group differences subjective sleep measures
SQ improved for FLX group (p=.03)
PAR disrupted sleep more than FLUV; REM sleep suppressed (especially for
FLUV) rebounded during withdrawal (especially for PAR)
FLUV shorter TST than DOT & PLC, more WMINS than PLC, poorer SE than
DOT or PLC, more WASO than DOT or PLC, shorter SL than PLC, less time in
REM sleep than PLC; DOT more SWS than PLC and FLUV, longer REML than
OT or PLC; FLUV reported poorer SQ than DOT and PLC; DOT group reported
more difficulty waking than FLUV and PLC, FLUV superior to PLC
Armitage, 1997 20-40mg Nefazodone 200-500mg Depressed
43 8 weeks
Satterlee, 1995 20mg Placebo Depressed
89 8 weeks
Wilson, 2000 100mg Dothiepin 100mg Healthy volunteers 12 3 days
LSEQ rating of SL sig better for MIA than FLUV at days 3 & 5 (p<.05), better
rating of feelings on waking for FLUV than MIA at day 3 (p<.05); MIA better
subjective SL, feeling more drowsy & fewer wakings than FLUV, FLUV easier
waking up than MIA (all ns)
PAR and MIR reported sig increased sedation (LARS); sig lengthening LSEQ SL
PAR vs MIRC day 2, not PLC; sig reduction SL MIRPC vs PLC; SL sig higher
PAR vs other treatments day 3; SL sig lower MIRPC vs other treatments wk 4;
LSEQ SQ sig poorer PAR vs PLC, sig better both MIR groups vs PLC; MESS
indicated increased sleepiness with MIRPC days 1 and 2, with no other sig effects
HAMDS score sig lower MIR than PAR wks 1 (p<.001), 2 (p=.006), and 6
(p=.005); ns wk 8 (p=.062)
TST, SE and WMINS worsened PAR, improved NEF, early in treatment, tended
towards baseline by wk 8; WASO sig worse by wk 8 PAR; REML sig increased,
REM time sig reduced PAR; NEF slightly decreased REML but increased REM
time; subjective data (SMHSQ) indicated greater improvements in SQ and depth of
sleep for NEF; no LSEQ factor showed sig between-group differences
LSEQ: CT got to sleep more easily and quickly, felt more drowsy at sleep onset
than PAR alone; CT group felt less drowsy at sleep onset than MIR alone; no
between-group differences SQ; CT tended to have greater difficulty waking than
PAR alone; no different to MIR alone; CT felt more tired on waking, PAR alone; no
different to MIR alone
PAR reduced REM sleep, increased REML and WASO, reduced TST and SE; NEF
did not alter REM sleep and had little effect on sleep continuity
AMI group showed severe drowsiness, but this disappeared after 1 week; PAR 20
mg had no effect on sleep; PAR 40 mg group showed poorer SQ
HAMDS sig better for am dosing; trend towards better LSEQ scores for am dosing
HAMDS scores sig more reduced for PAR than PLC at each week of trial (p<.05)
6 out of 10 LSEQ scores sig improved PAR, 1 factor sig increased MIA (p<.05); 4
of factors worsened MIA, mostly re poorer waking (ns)
Same dataset as Dunbar, 1993
Same dataset as Dunbar, 1993
Sig greater decrease in HAMDS for PAR (-2.41) than PLC (-0.81; p=.001)
1: Mirtazapine 15-30 mg
2: Mirtazapine 15mg bid
(positive control; MIRPC)
Schatzberg, 2002 20-40mg Mirtazapine 15-45mg Elderly depressed
246 8 weeks
Hicks, 2002 20-40mg Nefazodone 400-600mg 40 8 weeks
1: Mirtazapine 30mg
2: Combination MIR/PAR
1: Amitriptyline 75mg
am vs. pm dosing
Up to 225mg
MIR sig better HAMDS than VEN at all time points (p=.03)
VEN sig less REM time than PLC wk 1 & month 1,VEN sig reduced REM wk 1
(p<.05); REML sig longer VEN than PLC at both time points, VEN sig increase
REML wk 1 (p<.01); VEN more WASO than PLC, sig so month 1 (p<.05)
HAMDS scores reduced for all groups by wk 6; TRZ sig more than VEN and PLC;
VEN HAMDS remained higher PLC
TRZ increased SE immediately through to 4 weeks; no improvement for PLC; TRZ
also improved WASO, %AMT, and non-REM sleep
TRZ associated with sig increase in SWS, increase in REML and decrease in
TRZ 50mg & 75mg sig better improvement HAMDS and HAMAS; 50mg sig better
than 100mg; self-rated TST sig longer for 50mg vs. 100mg, and 75mg vs. 100mg
Both groups sig better ratings ease falling asleep (p=.005), WASO (p=.04), WMINS
(p=.002) & SQ (p=.003) than PLC, no differences TRZ vs ZOL; SL decreased &
TST increased ZOL and TRZ (p<.05), SL sig shorter ZOL than TRZ (p=.037)
TRZ sig fewer WASO than PLC; NEF sig less % stage 2 sleep than all other
groups, sig less stage 3% than TRZ and BUS; NEF sig more REM% than PLC, but
TRZ & BUS sig less REM% than PLC; TRZ & BUS sig longer REML than NEF
and than PLC (all sig post-hoc comparisons to p=.05)
HAMDS scores sig improved for TRZ at days 7 (p<.001) and 14 (p<.05)
TRZ sig lower (better) PSQI TST score (p=.003), sig lower overall score (p=.01)
than PLC, TRZ near sig lower scores than PLC on SQ & SL (p=.06); Y-NH HDSI
sleep scores sig better for TRZ than PLC middle insomnia (p=.03), late insomnia
(p=.005) & overall sleep scores (p=.008); more pts improved with TRZ than PLC
on PQSI (p=.004) and Y-NH HDSI sleep scores (p=.008)
Both groups showed sig improvements on LSEQ factors for ease of getting to sleep,
sleep quality, ease of waking, and feelings upon waking (p<.0001), but no sig
differences between them; TRZ improved at faster rate than MIA
All groups showed improved ease of getting to sleep and quality of sleep; this was
immediate, although greatest for TRZ and DOT (p values not specified); feelings
upon awakening were impaired in all groups until day 7, when these measures
improved (in all groups except MIA, where improvement started at day 14)
HAMDS scores sig better improved with NEF (-2.3) than PLC (-1.1; p<.01)
Cunningham, 1994 25-200mg 1: Trazodone 50-500mg
Depressed patients 225 6 weeks
Le Bon, 2003
No RCTs found
Saletu-Zyhlarz, 2001 100mg Placebo 11 3 nights
Mashiko, 1999 50, 75, 100mg Dose ranging 75 4 weeks
Walsh, 1998 50mg 1: Zolpidem 10mg
306 2 weeks
Ware, 1994 100mg 1: Nefazodone 200mg
2: Buspirone 10mg
Healthy volunteers 12 3 nights
Blacker, 1988 150mg Amitriptyline 75-100mg
Dothiepin 75-150 mg
Depressed patients 227 6 weeks
Vogel, 1998 200-400mg Placebo Healthy volunteers 22 16 days REM time, REML, REMD & REM% all remained unchanged, relative to baseline
and PLC; TST sig less NEF than PLC day 1 (P<.05), normalised by day 2; WMINS
sig more with NEF than PLC day 1 (p<.05)
SL sig greater for NEF 100mg and NEF 200mg, but not IMI, than PLC (p<.05) on
day 1; no sig differences by day 7
Subjective estimates TST increased MIR and MIA throughout (p<.001), no
between-group differences; SQ rated better MIR than MIA (p=.021); drowsiness
was reported sig more often with MIR and MIA, compared to PLC (p=.015)
MIA reduced HAMDS, by end of trial; not PLC
MIA group showed sig greater reduction in HAMDS (p<.05) than co-therapy
Van Laar, 1995
1:Nefazodone 100mg; 2:
200mg; 3: Placebo
and clobazam 22.5-45mg
Melitracen 30mg and
1: Maprotiline 75-225mg
Van Moffaert, 1983
MIA greater improvement in HAMDS scores than nomifensine (p<.05)
MIA greater improvement in insomnia factor of HAMD than co-therapy, at wks 1
(p=.02) and 4 (p<.01)
MIA sig better than PLC at reducing early insomnia day 14 (p<0.05), no other sig
between-group differences HAMDS; no sig between-group differences LSEQ, but
all sig reduced throughout (including PLC)
MIA group sig improvements nurse-observed TST, compared to PLC, wks 1
(P<.005) and 2 (p<.05); patient-rated estimates of TST sig improved MIA vs PLC
wks 1 (p=.02) and 2 (p<.01); self-rated SL shorter MIA than PLC wk 1 (p<.01); pts
woke sig later with MIA than PLC wks 1 (p<.01) and 2 (p<.05)
MIR improved sleep continuity, compared with PLC, increased SE, decreased
WASO and WMINS; SWS time increased; no sig effect on REM sleep
LSEQ ‘getting to sleep; GTS’ improved both groups, similar between groups until
wk 2, when GTS for FD sig better than ED (p=.021); TST estimates increased both
groups, but FD exceeded ED wks 1 (p=.01) and 2 (p=.04); sig fewer FD pts than
ED reported middle insomnia (p=.042) and early insomnia (p=.008) by wk 2
Edwards, 1983 30-90mg 58 6 weeks
Smith, 1978 30mg Placebo Manic-depressive
39 2 weeks
2: 15mg wk1,
Dose ranging (fixed dose,
FD vs. escalating dose
MIR group showed faster ‘improvement of sleep’, SQ and improved alertness
following awakening on LSEQ, relative to CIT
No between-group differences, at 1 week relative to baseline; but BUP responders
showed increase REML, non-responders showed decrease – a sig relationship
In withdrawal phase, problems with sleep were worse for BUP than PLC,
particularly during first 6 fays of withdrawal; SMHSQ ‘difficulty sleeping’ and TST
were sig poorer with BUP between days 1-3 (p<.005) and days 4-6 (p<.01)
No differences found between BUP and PLC regarding HAMDS scores on nicotine
Haney, 2001 300mg Placebo Marijuana
10 4 weeks
Shiffman, 2000 1: 150mg
91 2 weeks
Nofzinger, 1995 Mean 25mg 1: Fluoxetine mean 428
18 Up to 17
SE increased for all groups, but particularly for BUP (p<.05); REML increased
with CBT, dramatically increased for FLX, but decreased for BUP (p<.0001),
REM% was unchanged with CBT and FLX, but increased with BUP (p<.01)
Effects on sleep between the groups were limited
Subjective sleep ratings (adapted from LSEQ) improved but no between-group
Medication abbreviations: ALP Alprazolam ; AMI Amitriptyline; BRO Brofaromine; BUP Bupropion; BUS buspirone; CIT Citalopram; CLO Clomipramine; DES Desipramine; DOT Dothiepin; DOX
Doxepin; FLUV Fluvoxamine; FLX Fluoxetine; IMI Imipramine; MIA Mianserin; MIL Milnacipran; MIR Mirtazapine; NEF Nefazodone; NOR Nortriptyline; PAR Paroxetine; PLC Placebo; SER Sertraline;
TOL Toloxatone; TRAN Tranylcypromine; TRIM Trimipramine; TRZ Trazodone; VEN Venlafaxine; ZOL Zolpidem
Other abbreviations: %AMT percentage of awake and movement time; CBT Cognitive behaviour therapy; EMA Early morning awakening; EMG Electromyogram (muscle activity); HAMAS Hamilton Rating
Scale for Anxiety, Sleep Scores; HAMDS Hamilton Rating Scale for Depression, Sleep Scores; IDS-C Inventory for Depressive Symptomatology (Clinician-rated); IDS-SR (self rated); LARS Line Analogue
Rating Scale for Sedation; LSEQ Leeds sleep evaluation questionnaire; MESS Milford Epworth sleepiness scale; MOS Medical Outcome Study scale; PQSI Pittsburgh Sleep Quality Index; PSG
Polysomnography; REM Rapid Eye Movement Sleep; REMD REM density; REML REM Latency; REM% proportion time in REM sleep; SE Sleep efficiency; SIP Sickness Impact Profile; SL Sleep Latency;
SMHSQ St Mary’s Hospital Sleep Questionnaire; SQ Sleep Quality; SWS Slow Wave Sleep; TST Total Sleep Time; WASO Wakings After Sleep Onset; WMINS Length of those wakings; Y-NH HDSI Yale-
New Haven Hospital Depression Symptom Inventory
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