CURRENT OPINION Drugs 2008; 68 (17): 2411-2417

0012-6667/08/0017-2411/$53.45/0

 2008 Adis Data Information BV. All rights reserved.

Antidepressants for the Treatment of

Insomnia
A Suitable Approach?
Michael H. Wiegand
Department of Psychiatry and Psychotherapy, Sleep Disorders Center, Technical University of Munich,
Munich, Germany

Abstract The popularity of antidepressants in the treatment of insomnia is not supported

by a large amount of convincing data, but rather by opinions and beliefs of the
prescribing physicians on the advantages of these agents compared with drugs
acting on the benzodiazepine receptor or other drugs used for the treatment of
insomnia. The existing data do not allow for clear-cut, evidence-based recommen-
dations concerning the use of antidepressants in insomnia. Our conclusions result
from a few short-term studies on single agents, clinical experience and inferences
from knowledge on the effect of antidepressants in other indications.
At present, prescribing antidepressants for short-term treatment of insomnia
can be useful if there is some amount of concomitant depressive symptomology or
a history of depression, raising the impression that the present insomnia may be a
prodromal sign for a new depressive episode. In all other cases, benzodiazepine
receptor agonists, especially the nonbenzodiazepines among them (the so-called
‘z drugs’) should be the drugs of choice.
For long-term treatment, antidepressants are among the pharmacological
options, in addition to other groups of psychotropics. Off-label use of antidepres-
sants may be considered for chronic insomnia if there is a concomitant depressive
symptomalogy (which is not so pronounced that an antidepressant treatment with
adequate higher doses would be required) and if there is no specific indication for
one of the other groups of psychotropics (e.g. dementia-related nocturnal agita-
tion, in which case an antipsychotic would be preferred, or circadian problems, in
which case melatonin or a melatonin agonist would be favoured).
If antidepressants are used to treat insomnia, sedating ones should be preferred
over activating agents such as serotonin reuptake inhibitors. In general, drugs
lacking strong cholinergic activity should be preferred. Drugs blocking serotonin
5-HT2A or 5-HT2C receptors should be preferred over those whose sedative
property is caused by histamine receptor blockade only. The dose should be as low
as possible (e.g. as an initial dose: doxepin 25 mg, mirtazapine 15 mg, trazodone
50 mg, trimipramine 25 mg).
Regarding the lack of substantial data allowing for evidence-based recommen-
dations, we are facing a clear need for well designed, long-term, comparative
studies to further define the role of antidepressants versus other agents in the
management of insomnia.
2412
For insomnia in general, drugs acting on the
benzodiazepine receptor (encompassing benzodi-
azepines and nonbenzodiazepine benzodiazepine
re-ceptor agonists [‘z drugs’]) are commonly
consid-ered the treatment of choice because their
effective-ness in clinical practice is supported by a
[1]
lot of substantial data (see clinical review and
[2-5]
meta-analyses ). Especially in acute, short-term,
non-complicated insomnia (e.g. insomnia due to an
acute, transient, external stress), drugs acting on the
benzodiazepine receptor clearly have the best bene-
fit-risk profile.
With respect to long-term insomnia treatment, the
use of at least some of these agents is limited by the
risk of tolerance and dependency. However, recent
data demonstrate that 6 months’ treatment with
eszopiclone is efficient over the whole treat-ment
[6,7]
period and there is no evidence of toler-ance.
Similar results were obtained in a 6-month study of
zolpidem extended release, which partly implied
[8]
intermittent (non daily) treatment. In the US, both
agents are approved for long-term use. In contrast, the
European Medicines Agency has ap-proved all
benzodiazepines and z drugs for short-term use only.
Correspondingly, treatment guide-lines restrict the
duration of treatment. However, in practice, off-label
long-term use is widespread. In this unsatisfactory
situation, clinicians have several options and the use
of antidepressants appears to be rather popular. In the
US, the antidepressants trazo-done, amitriptyline and
mirtazapine are among the most commonly used
[9]
drugs for chronic insomnia; elsewhere, other
sedating antidepressants are used (e.g. in Germany,
doxepin, opipramol and trimipra-mine). Walsh and
[10]
Schweitzer point out that a great number of
antidepressant prescriptions in in-somnia are for
insomnia that is not related to depres-sion (e.g.
primary insomnia or co-morbid insomnia related to
conditions other than depression).
This clinical practice contrasts with the paucity
of substantial data on the effects of antidepressants
in insomnia. This is highlighted in several critical
articles and guidelines on the topic. The British
National Health Service’s Clinical Knowledge
Sum-maries on insomnia clearly state “There is no
evi-dence that antidepressants with sedative proper-
ties…help to relieve insomnia in people who do not
have depression, and their use risks potential side
Wiegand
effects”, citing a review in the Drugs and
Therapeu-tics Bulletin.
[11]
[12]
According to Walsh, the popularity of antide-
pressants in insomnia cannot be based on existing
scientific evidence but is due to perceptions and
beliefs of the prescribing physicians, who are con-
vinced of some general advantages of antidepres-sants
as a group in this indication compared with drugs
acting on the benzodiazepine receptor. Anti-
depressants are perceived as safer and as having a
lower tolerance risk, so that even patients with a
specific medical history (e.g. alcohol or benzodiaze-
pine abuse, or dependency in the past) can be treat-ed.
When regarding data from long-term studies in
patients with depression, it can be concluded that
tolerance development is not to be expected, so the
treatment can extend over a far longer period of time.
When there is a pronounced depressive symp-
tomatology, as well as insomnia, these agents may
offer an additional antidepressant action besides sleep
promotion. Some physicians may (erroneous-ly) even
believe that all or most insomnia is a symptom of
depression, so that antidepressant ther-apy appears to
be the treatment of choice.
This article does not aim to discuss the issue of
pharmacological versus nonpharmacological treat-
ment of chronic insomnia; however, it must be kept
in mind that according to the majority of experts,
nonpharmacological treatment should be prioritized
over drug treatment in chronic insomnia (see Reite
[13]
et al. ). A comparative meta-analysis of pharma-
cotherapy and behaviour therapy for persistent in-
[4]
somnia found no differences in several
parameters relevant to sleep quality, apart from
slightly greater reductions on sleep onset latency
with nonpharma-cological therapy.
Most antidepressant drugs affect sleep but, as can
be expected from the heterogeneous nature of the
drugs summarized under this label, these effects can
be extremely different. Recently, Wilson and
[14] [15]
Argyropoulos, and Mayers and Baldwin re-
viewed the data on the effects of antidepressants on
sleep, both in healthy participants and patients with
depression. In the latter group, most antidepressants
improve subjectively-rated sleep, irrespective of ob-
jective (polysomnographic) sleep measurements,
which, in some cases, mirror a worsening of sleep.
 2008 Adis Data Information BV. All rights reserved. 008; 68
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(17)
Antidepressants for Insomnia
Table I. Randomized controlled studies on antidepressants in primary insomnia
Drug Reference
Doxepin Hajak et al.[16]
Trazodone Walsh et al.[17]
Trimipramine Riemann et al.[18]
1. Clinical Studies of Antidepressants
in Insomnia
A more specific overview on studies with chronic
[1]
insomnia is given by Buscemi et al. There are only
three published randomized controlled trials
[16-18]
on
antidepressants in primary insomnia (table I).
In a placebo-controlled study in 47 patients
(with Diagnostic and Statistical Manual of Mental
Disorders [DSM] 4th Edition [DSM-IV] primary
insomnia), doxepin was given over 4 weeks in a dose
between 25 and 50 mg. In the doxepin-treated patients
who completed the study (n = 20), med-ication
significantly increased polysomnographical-ly-
measured sleep efficiency after acute and sub-chronic
(4 weeks) intake, compared with the pa-tients
completing the study who received placebo (n = 20)
without affecting sleep onset latency, which was
normal at baseline. Subjectively rated sleep quality
and working ability were rated significantly improved
by the patients receiving doxepin. No significant
group differences in adverse effects were found, but
two doxepin-treated patients withdrew from the study
because of increased liver enzymes, leukopenia and
thrombopenia.
In a large-scale multicentre study (n = 589 pa-
tients with DSM [3rd Edition, Revised]{DSM-III-R}
primary insomnia), trazodone 50 mg was tested
[17]
against zolpidem 10 mg and placebo over 2 weeks.
Effects were measured by subjective estimations of
self-reported sleep onset latency and self-reported
sleep duration, based on morning ques-tionnaires
(polysomnographic recordings were not performed).
After 1 week, both active treatments significantly
reduced sleep latency (this was more pronounced with
zolpidem than trazodone). After 2 weeks, only the
zolpidem group had a significantly shorter sleep onset
latency than the placebo group, whereas the trazodone
group did not differ from placebo. Both drugs were
also rated efficacious in significantly prolonging
subjective sleep duration
 2008 Adis Data Information BV. All rights reserved.
68 (17)
2413
Year Sample size Dose range (mg) Comparator
(enrolled)
2001 47 25–50 Placebo
1998 589 50 Zolpidem and placebo
2002 65 25–200 Lormetazepam and placebo
compared with placebo during week 1, but not
during treatment week 2. Twelve randomized pa-
tients (two placebo, five zolpidem and five trazo-
done) withdrew from the study because of adverse
events (excessive sleepiness, dizziness, drowsiness,
headache, vomiting, elevated blood pressure).
Treat-ment-emergent adverse events were reported
[16] by 65.4% of placebo patients, 76.5% of zolpidem
pa-tients and 75% of trazodone patients, mainly
head-ache and somnolence.
Trimipramine, given as a mean dose of 100 mg
(range from 25 to 200 mg), was tested against
lormetazepam and placebo in 55 patients with in-
somnia (DSM-III-R primary insomnia or dyssomnia
[18]
not otherwise classified) over 4 weeks. Trimipra-
mine (n = 18) increased polysomnographically-mea-
sured sleep efficiency significantly when compared
with placebo, in contrast with lormetazepam. Trimi-
pamine did not change any of the other polysomno-
graphic sleep variables when compared with place-bo,
whereas lormetazepam reduced the percentage of
wake after sleep onset and the percentage of stage 3
sleep, but increased the percentage of rapid eye
movement sleep. Comparing trimipramine and
lormetazepam, no difference with respect to any of the
polysomnographic sleep variables emerged. Several
subjective sleep parameters were improved by both of
the drugs compared with placebo (Pitts-burgh Sleep
[19]
Quality Index [PSQI ] sum score, sleep quality and
evening well-being subscales of the SF-A
[20]
[Schlaffragebogen by Gortelmeyer¨ ]). In addition,
trimipramine improved the ‘feeling rested in the
morning’ subscale of the SF-A compared with
placebo. In direct comparison, trimipramine was
superior to lormetazepam in the ‘evening well-be-ing’
and the ‘feeling rested in the morning’ sub-scales of
the SF-A, whereas the other subjective variables
(including the PSQI total score) showed no
differences between drugs.
Table II summarizes the four existing open-label
studies on antidepressants in primary insomnia.
Drugs 2008;
2414
Table II. Open-label studies on antidepressants in primary insomnia
Drug Reference
Doxepin Hajak et al.[21]
Nefazodone Wiegand et al.[22]
Paroxetine Nowell et al.[23]
Trimipramine Hohagen et al.[24]
[22]
The open-label study on nefazodone demon-
strated primarily a favourable effect for some sub-
jective sleep variables (PSQI total score and some
PSQI subscales). Polysomnographic variables dem-
onstrated a significant decrease in the number of
intermittent awakenings, but also some other less
favourable effects: sleep onset latency was signifi-
cantly prolonged and slow-wave sleep decreased. A
high number of patients (11 of 32) withdrew be-
cause of adverse effects, mainly absence of
expected effect, worsening of insomnia and/or
increased ner-vousness.
[23]
The open-label study on paroxetine included
15 patients with DSM-IV primary insomnia who
were treated with a flexible dose of paroxetine
(median dose 20 mg) at bedtime over 6 weeks. Of
the 14 patients who completed the study (1 with-
drew because of adverse effects), 11 improved with
treatment and 7 of these no longer met diagnostic
criteria for insomnia. Improvement was clear in
subjective sleep variables (PSQI scores), but was
not reflected in polysomnographic sleep
parameters. This demonstrates the gap between
subjective and objective estimations of sleep
because polysomno-graphic studies on paroxetine,
like other serotonin reuptake inhibitors (SRIs),
notoriously show a wors-ening of ‘objective’ sleep.
The results for doxepin
[21]
and trimipramine
[24]
in the respective open-label studies resemble those
ob-served in the controlled trials on these agents
subse-quently performed and described previously.
Thus, it can be concluded that there is evidence for
the efficacy of doxepin, trimipramine and trazo-done
in the short-term treatment of insomnia; the ev-idence
for nefazodone and paroxetine is less con-vincing.
However, there are only two studies direct-ly
comparing the effects of an antidepressant with an
agent acting on the benzodiazepine recep-tor
(trazodone vs zolpidem and trimipramine vs
[17,18]
lormetazepam). There is no single study com-
paring an antidepressant with another drug class in
Wiegand
Year Sample size (enrolled) Dose range (mg)
1996 10 25
2004 32 100–400
1999 15 10–30
1994 19 25–200
the long-term treatment of insomnia (e.g. a sedating
antipsychotic, antihistamine, melatonin or a me-
latonin agonist). This is not a major criticism be-
cause the same is true for the benzodiazepine
recep-tor agonists.
The duration of the studies was in all cases re-
stricted to a few weeks. Therefore, there is no infor-
mation on long-term efficacy or long-term adverse
effects. Thus, a critical evaluation of the usefulness of
antidepressants in long-term treatment of insom-nia
cannot be based on direct evidence from ade-quate
studies. Instead, we have to rely on indirect evidence
and unsystematic clinical experience.
2. Potential Advantages and
Disadvantages of Antidepressants
versus Other Agents
Considering antidepressants as a group, the anti-
depressant component is a possible advantage in many
cases where a certain degree of depressed mood
accompanies insomnia, without fulfilling cri-teria of a
mood disorder but potentially being posi-tively
influenced by an antidepressant (a hypothesis that has
not yet been tested). Second, a tolerance development
is not expected, permitting long-term use, and there is
no abuse or addiction potential. However, the latter
advantage is shared with other drug groups used in the
treatment of chronic insom-nia (e.g. antihistamines,
melatonin and melatonin agonists, and
antipsychotics). As we now know, the same is true for
the nonbenzodiazepine benzodiaze-pine receptor
agonists eszopiclone and zolpidem, which, contrary to
former opinion, do not lead to dependency
development when administered over several months;
these data have led to new perspec-tives in the
[25-27]
treatment of chronic insomnia. With
antipsychotics and antihistamines, antidepressants
share the disadvantage of a broader spectrum of
adverse effects, interaction effects and contraindica-
tions, compared with drugs acting on the benzo-
 2008 Adis Data Information BV. All rights reserved. Drugs 2008;
68 (17)
Antidepressants for Insomnia
diazepine receptor. In addition, it must be empha-
sized that tricyclic antidepressants are potentially
lethal in overdose.
Sedating antipsychotics have been used for the
treatment of insomnia, especially in the elderly. The
rationale for their use in this setting is their clinically
proven efficacy in complex, acute, often dementia-
related states including insomnia, agitation and diso-
rientation (not related to parasomnias). There is a
growing tendency to study these drugs with respect to
their effect in the treatment of insomnia. In an open-
[28]
label pilot study, Wiegand et al. found an
impressive sleep-promoting property of quetiapine in
very low doses (25–75 mg).
3. Choice of Antidepressant
Within the group of antidepressants, the sedating
tricyclics trimipramine and doxepin have the advan-
tage of a positive effect in insomnia, proven by
controlled clinical trials.
[16,18]
With respect to dox-
epin, it could be demonstrated that it preserves noc-
[21]
turnal melatonin secretion patterns, in contrast with
[29]
flunitrazepam; however, it is not clear in how far
these results are generalizable to both sedat-ing
tricyclics and benzodiazepinones. However, the strong
anticholinergic properties of the tricyclics reduce
tolerability, and result in several contraindi-cations
and potential interactions, especially in eld-erly
people. The sleep promoting action of tricyclics is
mainly based on histamine antagonism, which,
regarding the half-lives of the drugs, can lead to
hangover effects in the morning, even long-lasting
excessive daytime sleepines.
The efficacy of trazodone is based on a controlled
study.
[17]
Trazodone lacks anticholinergic effects,
which is an advantage; however, there is a higher risk
of orthostatic hypotony and ventricular arrhyth-mias.
Evidence-based data on mirtazapine in prima-ry
insomnia have not yet been published. Like trazo-
done, mirtazapine lacks anticholinergic activity;
however, there is a spectrum of adverse effects, which
include paradoxical agitation and the induc-tion of
restless legs symptomatology. It is remark-able that
mirtazapine, in addition to its antihis-taminergic
action, influences sleep positively by inhibiting
serotonin 5-HT2A and 5-HT2C receptors; this is a
novel sleep-promoting mechanism, which does not
cause drowsiness or enhance slow-wave
 2008 Adis Data Information BV. All rights reserved.
2415
sleep. Quetiapine and agomelatine also have a 5-
HT2C inhibiting action.
SRIs and antidepressants combining serotonergic
and noradrenergic modes of action, as well as bupro-
pion, are not first-choice drugs for insomnia; how-
ever, an indirect positive action on subjective sleep is
possible when inactivity due to some depressive
symptomatology during daytime is part of the prob-
lem (this may be the mechanism underlying the
[23]
paroxetine data ). Among the antidepressants that
will appear on the market in the future, agomelatine
appears promising for insomnia because its mecha-
nism of action does not encompass the antihistamin-ic
pathway (it combines melatonin MT1 and MT2
receptor agonism with 5-HT2C receptor ant-agonism).
Thus far, data on agomelatine indicate a favourable
effect on sleep and very good tolerabili-
ty.[30,31]
In the discussion on antidepressants in insomnia,
the question of pharmacokinetics, which is so im-
portant in benzodiazepines and benzodiazepine re-
ceptor agonists, has been neglected. Theoretically,
compounds with a shorter half-life should be pre-
ferred. The three compounds for which placebo-
controlled studies have been performed have rather
long half-lives (trimipramine 24 hours; doxepin
15–20 hours [active metabolite 80 hours];
trazodone 9 hours). Mirtazapine and amitriptyline
also have long half-lives (20–40 hours and 10–28
hours, re-spectively). Opipramol and trazodone
have shorter half-lives (<9 hours). Agomelatine has
an ultra-short half-life of 1–2 hours. The clinical
consequences of the large differences have still to
[32]
be investigated and discussed.
When an antidepressant for chronic insomnia
appears indicated but is not sufficient for treating
severe insomnia symptoms, there is the option of
adjunctive eszopiclone and zolpidem, which has
proven safe and effective in the treatment of depres-
[33] [34]
sion (e.g. see Asnis et al. and Becker ) as well as
[35]
in other psychiatric conditions.
4. Conclusion
For short-term medication in insomnia, there is
no evidence at all of superiority or a better benefit-
risk ratio of antidepressants over benzodiazepines
and z drugs; thus, the latter should be the treatment
Drugs 2008; 68 (17)
2416
of choice, especially the z drugs, as these can be
maintained in patients in whom short-term
treatment turns into longer term treatment. At
present, pre-scribing antidepressants (in particular
doxepin, mirtazapine, trazodone and trimipramine)
for short-term treatment of insomnia appears useful
if there is some amount of concomitant depressive
symptoma-tology or a history of depression, raising
the impres-sion that the present insomnia may be a
prodromal sign for a new depressive episode; in
these cases, a z drug can be added to improve the
sleep-promoting effect.
For long-term treatment of insomnia, antidepres-
sants are among the pharmacological options, in
addition to several other groups of psychotropic
drugs, including the z drugs eszopiclone and zolpi-
dem, some antipsychotics, antihistamines, mela-
tonin and melatonin agonists. The existing data do
not allow for clear-cut, evidence-based recommen-
dations regarding the use of antidepressants in in-
somnia; these conclusions result from short-term
studies with single agents, from clinical experience
and from what is known on the efficacy and tolera-
bility of antidepressants in other indications.
Off-label use of antidepressants may be consid-
ered for chronic insomnia if there is a concomitant
depressive symptomatology (which is not so pro-
nounced that an antidepressant treatment with ade-
quate, higher doses would be required), and if there
is no specific indication for one of the other groups
of psychotropics (e.g. dementia-related nocturnal
agitation, in which case an antipsychotic would be
preferred, or circadian problems, in which case me-
latonin would be favoured).
If an antidepressant is used to treat insomnia, a
sedating one should be used in preference to activat-
ing agents such as SRIs. In general, preference should
be given to drugs lacking strong cholinergic activity.
Drugs blocking 5-HT2A or 5-HT2C recep-tors should
be used in preference to those with sedative properties
caused by histamine receptor inhibition only. Also, in
long-term insomnia treat-ment, antidepressant can be
combined with es-zopiclone or zolpidem. The dose
should be as low as possible (e.g. as an initial dose:
doxepin 25 mg, mirtazapine 15 mg, trazodone 50 mg,
trimipramine 25 mg). With respect to the prevalence
of adverse effects and interaction risks, a continuous
monitor-
Wiegand
ing for adverse events is necessary when
administer-ing antidepressants; with tricyclic
antidepressants, the dangers of (potentially lethal)
overdose should be taken into account.
Regarding the lack of substantial data allowing
for evidence-based recommendations, we are
facing a clear need for well designed, long-term
compara-tive studies to further define the role of
antidepres-sants versus other agents in the
management of insomnia.
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this article. The author has received speaker
honoraria from AstraZeneca, Cephalon and Servier.
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Correspondence: Professor Michael H. Wiegand, Depart-ment of
Psychiatry and Psychotherapy, Sleep Disorders Center,
Technical University of Munich, Ismaninger Str. 22, Munich, D-
81675, Germany.
E-mail: michael.wiegand@lrz.tum.de
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