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Primary Psychiatry. 2008;15(5):61-69
Antidepressants and Insomnia
Gary K. Zammit, PhD
ABSTRACT
Needs Assessment: The use of trazodone as an adjunctive therapy for insomnia is
increasing while clinical evidence of the safety and efficacy of this approach is lacking. Recent studies of a combination of a hypnotic and an antidepressant offer the
potential for a safer, more efficacious course of action.
Mood disorders and insomnia are often comorbid conditions,
sharing a complex and bi-directional relationship. Complicating
Learning Objectives:
the situation, mood stabilizers can disrupt sleep in a variety of
• List three treatment strategies for depression with comorbid insomnia.
• Name the most commonly used adjunctive insomnia therapy for depressed patients
treated with an antidepressant.
• Discuss recent research on the efficacy of combining an antidepressant with a
hypnotic to treat depression with comorbid insomnia.
different ways depending on a drug’s mechanism of action, dosage level, and timing of administration. The treatment of comorbid
depression and insomnia can be achieved through the use of a
Target Audience: Primary care physicians and psychiatrists.
CME Accreditation Statement: This activity has been planned and implemented in
sedating antidepressant, a combination of two antidepressants,
accordance with the Essentials and Standards of the Accreditation Council for Continuing
Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of
Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited
by the ACCME to provide continuing medical education for physicians.
or a combination of an antidepressant in conjunction with a hypnotic. Common practices typically include the concomitant use of
Credit Designation: The Mount Sinai School of Medicine designates this educational
an alerting and a sedating antidepressant. However, the empirical
activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim
credit commensurate with the extent of their participation in the activity.
evidence supporting this approach is limited, and there are few
Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School
indicators that sedating antidepressants are efficacious in the
ment of comorbid and primary insomnia.
of Medicine to ensure objectivity, balance, independence, transparency, and scientific
rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience
any relevant financial relationships and to assist in resolving any conflict of interest
that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.
This information will be available as part of the course material.
INTRODUCTION
This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and
professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman,
MD, editor of Primary Psychiatry and professor of psychiatry at New York University
School of Medicine. Review Date: March 27, 2008.
treatment of primary insomnia. This article examines the evidence
supporting the efficacy and safety of mood stabilizers in the treat-
Drs. Hollander and Sussman report no affiliation with or financial interest in any
organization that may pose a conflict of interest.
Psychiatric disorders and chronic insomnia are often comorbid with each other. The presence of insomnia symptoms in
individuals with a current episode of major depressve disprder
(MDD) has been shown to approach 80% to 90%.1-4 The
incidence of comorbid insomnia is higher when anxiety
complicates the clinical presentation, affecting approximately
To receive credit for this activity: Read this article and the two CME-des-
ignated accompanying articles, reflect on the information presented, and then
complete the CME posttest and evaluation found on page 85. To obtain credits,
you should score 70% or better. Early submission of this posttest is encouraged:
please submit this posttest by May 1, 2010 to be eligible for credit. Release date:
May 1, 2008. Termination date: May 31, 2010. The estimated time to complete all three
articles and the posttest is 3 hours.
Dr. Zammit is president and CEO of Clinilabs, director of the Sleep Disorders Institute, and clinical associate professor at the Columbia University College of Physicians and Surgeons in New York City.
Disclosure: Dr. Zammit is a consultant to Boehringer-Ingelheim, sanofi-aventis, Sepracor, and Takeda; receives research support from Forest, GlaxoSmithKline, Pfizer, sanofi-aventis, Sepracor, Takeda Pharmaceuticals North
America, Transcept, and Wyeth; and receives honoraria from Takeda.
Acknowledgments: The author would like to thank Ms. Bridget Banas for her assistance in the preparation of this manuscript.
Please direct all correspondence to: Gary Zammit, PhD, Clinilabs, Inc, 423 W. 55th St, 4th Floor, New York, NY 10019; Tel: 212-994-4560; Fax: 212-523-1704; E-mail: [email protected]; Website:
www.clinilabs.com.
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90% with a concurrent anxiety disorder.1 Furthermore, mood
disorder symptoms are typically more pronounced in people
with insomnia symptoms.5-10
Insomnia is often a precursor to depression. Several longitudinal studies have examined the incidence of psychiatric
disorders over periods ranging from 1–40 years following the
initial diagnosis of insomnia.11-17 In every study completed to
date, insomnia has been found to be a significant risk factor for
the subsequent onset of depression, with a greater incidence of
affective disorder found in people with insomnia. These findings
do not suggest that insomnia is merely part of a prodrome that
occurs in close temporal association with affective disorders, as
depression may first appear several years after the initial diagnosis
of insomnia. In addition to these findings, it has been shown
that insomnia is a precursor to the recurrence of depression in
patients in remission,18,19 and that persistent sleep disturbance is
associated with non-response to antidepressant therapy.20
While insomnia often precedes the onset of affective illness,
symptoms of depression and insomnia may be concurrent.
Complicating this picture is the fact that many antidepressants used to treat depression disturb sleep, potentially
exacerbating the relationship between the two disorders. The
type of sleep disturbance produced by depression pharmacotherapy varies based on the compound’s mechanism of action
and the dosage employed. Effects may include decrements in
rapid eye movement (REM) sleep, a lengthening of the time
to sleep onset, and an increase in nocturnal arousals (Table
1). This article reviews the effectiveness and safety of several
treatment options for comorbid depression and insomnia.
from only 6.5% to almost 42% over the same period.
The conclusion that the use of sedating antidepressants
for the treatment of insomnia rose between 1987 and 1996
was based on reported medication doses. The therapeutic
daily dosage of trazodone for depression therapy is 150–600
mg/day. Doses below this level may provide sedative effects
but are not expected to combat the symptoms of depression. By 1996, two-thirds of all trazodone mentions were
associated with a daily dose of ≤100 mg—strongly suggesting that antidepressant effects were not the intended results.
Furthermore, almost 40% of treatment mentions in 1996
were concomitant with the mention of another antidepressant. This analysis is consistent with a more recent survey of
psychiatrists’ prescribing practices.22 The survey was conducted at a psychopharmacology review course to investigate the
management of antidepressant-induced side effects. Almost
80% of the survey respondents indicated that they would
prescribe trazodone to address selective serotonin reuptake
inhibitor (SSRI)-induced insomnia.
TREATMENT OPTIONS
In light of the common use of trazodone as adjunctive insomnia therapy in depressed patients, it is important to remember
that several treatment approaches are available. Insomnia comorbid with depression may be treated using a single hypnotic, a
single antidepressant, a combination of two antidepressants, and
a combination of one antidepressant and one hypnotic.23
Option 1: A Single Hypnotic
PRESCRIBING PATTERNS
There is no evidence to support the treatment of patients
with MDD and comorbid insomnia with a hypnotic medication alone. Even though these medications are highly efficacious in ameliorating sleep disturbances in a wide range of
patient populations, neither the older benzodiazepine nor the
newer non-benzodiazepine hypnotics have been shown to be
effective therapy for MDD.
Between 1987 and 1996, the pharmacologic treatment
of insomnia decreased markedly. A recent review21 covering
this period found that drug mentions (ie, patient contact
that resulted in drug therapy or a mention of drug therapy)
fell by >50% for hypnotics, and were down approximately
25% for all forms of insomnia pharmacotherapy combined.
Antidepressants used for the treatment of insomnia were the
only drug category showing signs of growth—tripling in drug
mentions over this period.
In 1996, the two drugs mentioned most frequently for the
treatment of insomnia were trazodone, a sedating tricyclic antidepressant (TCA), and zolpidem, a non-benzodiazepine hypnotic.
Trazodone is indicated for the treatment of depression, but not
specifically labeled for use as a hypnotic. Over the 10-year period
examined, the total number of trazodone mentions was steady.21
However, mentions associated with antidepressant action fell
from >70% of all occurrences in 1987 to only 31% in 1996. In
contrast, the number of mentions associated with insomnia rose
Primary Psychiatry
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Option 2: A Single Antidepressant
A single, sedating antidepressant can be employed as a treatment for both insomnia and depression. Candidates for this
therapeutic approach include the TCAs and several atypical
antidepressants.23 Most of these TCAs inhibit the reuptake of
noradrenaline and serotonin and block histamine (H)1 receptors and α1-adrenoceptors.24 Amitriptyline and trimipramine,
both particularly associated with sedation, also block serotonin
(5-HT)2 action.24 Trazodone is an antagonist at the α1adrenoceptors, 5-HT1A, and 5-HT2 receptors.24 Nefazodone
has strong 5-HT2 antagonist properties and mild serotonin
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Antidepressants and Insomnia
reuptake-blocking effects.24 Finally, mirtazapine blocks 5-HT2
receptors, H1 receptors, and α2-adrenoceptors.24
Some practitioners use a single, sedating antidepressant to
treat comorbid depression and insomnia. When administered at
therapeutic doses for depression, these medications are known to
produce sedative side-effects that may be exploited in an effort
to treat insomnia and to provide relief from depression. This
approach has intuitive appeal, as the use of one medication to
TABLE 1
SLEEP EFFECTS OF ANTIDEPRESSANTS*24,86-88
NAW
Effects in
Non-Depressed Patients
Daily Dosage (mg)
Lat
TST
SWS
REM
T: 100–300
↓
↑
↓
↓
Daytime sedation ↑
↓
REM ↓ , NAW ↑
TCAs
Amitriptyline
S: 25–150
Clomipramine
T: 100–250
Desipramine
T: 75–200
↓
↑
↓
Doxepin
T: 100–300
↓
↓
↓
Lat ↓ , TST ↑
↓
↓
↓
TST ↓ , NAW ↑
↓
↓
TST ↑ , daytime sedation ↑
↑
TST ↑
S: 25–150
Imipramine
T: 100–300
Nortriptyline
T: 50–150
Trimipramine
T: 100–300
↓
↑
S: 25–150
SSRIs
Citalopram
T: 20–60
Fluoxetine
T: 20–60
Fluvoxamine
T: 100–300
Paroxetine
T: 20–60
Sertraline
T: 50–200
↓
↑
↓
↓
↓
REM ↓
↓
↓
TST ↓ , REM ↓
↓
Lat ↑ , REM ↓
↓
Insomnia symptoms ↑
↓
No effect
↑
MAOIs
Moclobemide
T: 150–600
Phenelzine
T: 45–90
Tranylcypromine
T: 30–60
↑
↑
↓
↓
Atypical Antidepressants
Bupropion
T: 100–450
Mianserin
T: 30–90
Mirtazapine
T: 15–45
TST ↓
↑
↑
↓
↑
↓
↑
↓
↑
NAW ↓
↓
S: 15–30
Nefazodone
T: 150–450
↑
↓
TST ↓ , NAW ↑
S: 50–150
Trazodone
T: 150–600
↓
↑
REM ↓ , NAW ↓
↓
S: 25–150
Venlafaxine
T: 75–375
↓
↓
↑
* Blank spaces indicate no established effect.
Lat=sleep latency; TST=total sleep time; SWS=slow wave sleep; REM=rapid eye movement sleep; NAW=number of awakenings; TCAs=tricyclic antidepressants; T=therapeutic;
S=sedating; ↓ decrease; ↑ increase; SSRIs=selective serotonin reuptake inhibitors; MAOIs=monoamine oxidase inhibitors.
Zammit GK. Primary Psychiatry. Vol 15, No 5. 2008.
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treat multiple disorders has the advantage of minimizing the risks
associated with drug-drug interactions and may make patient
compliance easier. However, the utility of this approach may be
limited by current treatment guidelines and safety concerns.
with amitriptyline in measures of early morning awakenings,20
nocturnal waking,20 and sleep latency30 as compared to the
results produced by imipramine or fluoxetine. Doxepin has
been shown to significantly improve Hamilton Rating Scale for
Depression (HAM-D) sleep scores as compared to placebo31 and
bupropion.32 Trimipramine has been reported to improve sleep
efficiency, increase sleep time, and reduce nocturnal awakenings
as compared to both fluoxetine33 and imipramine.34
The atypical antidepressants most often used to treat
depression and comorbid insomnia are mirtazapine, nefazodone, and trazodone.24 Mirtazapine has been shown to produce a range of effects on sleep in depressed patients. Rapid
improvements on quality of sleep and other subjective sleep
assessments have been seen with mirtazapine as compared
to citalopram,35 while improvements in sleep efficiency and
nocturnal distress have been seen relative to both fluoxetine36
or paroxetine treatment.37 It is of interest that HAM-D sleep
item scores have been shown to improve more when patients
are treated with mirtazapine than with either venlafaxine38
or paroxetine.39 Nefazodone has also been shown to improve
HAM-D sleep item scores relative to treatment with placebo.40 It also produces less nocturnal disturbance than either
fluoxetine41 or paroxetine.42
Trazodone’s effects on sleep in depressed patients are perhaps
better characterized than that of any other sedating antidepressant. Two studies have found that, relative to placebo, trazodone
objectively increases total sleep time, sleep efficiency, and slow
wave sleep (SWS) with limited next-day sedative effects.43,44 It has
also been shown that trazodone 75 mg results in increases in SWS
and improvements in HAM-D scores and subjective assessments
of daytime alertness.45 Higher doses of trazodone also appear to
have effects on depression and sleep. Trazodone (150–400 mg)
produces significant improvement in symptoms of depression and
changes in objective measures of sleep architecture.46 Specifically,
sleep latency declined, and total sleep time, SWS, and sleep efficiency increased following active treatment. Doses of 400–600
mg produce significant improvements in Montgomery-Asberg
Depression Rating Scale (MADRS) scores (>60% reduction),
reduce sleep latency, and increase total sleep time and SWS.47
Option 3: A Combination of Two
Antidepressants
This approach typically involves employing a therapeutic
dose of a non-sedating antidepressant (eg, SSRIs, monoamine
oxidase inhibitors [MAOIs]) to treat depression, and a lower,
non-therapeutic dose of a sedating antidepressant to treat
insomnia. While this strategy has been used with some popularity, there are relatively few data demonstrating the safety
and efficacy of this approach.23,25,26
Option 4: A Combination of One
Antidepressant and One Hypnotic
This treatment approach enables clinicians to decouple the
treatment for depression from the treatment of insomnia. This
approach represents an important treatment option because
it is often necessary to experiment with different antidepressants, titrate dosage levels, and modify dose timing to find
the most appropriate therapy for an individual with MDD.
Employing a hypnotic as an adjunctive treatment enables the
clinician to directly and immediately address a patient’s insomnia symptoms while still making necessary adjustments to the
pharmacotherapeutic used to treat depression. When present,
antidepressant-induced insomnia typically occurs during the
first 3–4 weeks of treatment.27 Therefore, addressing sleep
complaints early may provide rapid relief to the patient and
may also contribute to compliance with depression therapy.
EVIDENCE SUPPORTING THE USE OF
A SINGLE ANTIDEPRESSANT
Efficacy
The SSRIs and MAOIs are generally alerting; these drugs
tend to exacerbate existing insomnia symptoms or produce
treatment-related insomnia (Table 1). As such, they are not
considered appropriate for addressing insomnia symptoms in
depressed patients as monotherapy.
In contrast, the TCAs commonly produce sedation as a side
effect, even though they also tend to suppress REM sleep like
the SSRIs and MAOIs. Three TCAs appear to offer the greatest potential for combining both antidepressant and hypnotic
effects,24 namely, amitriptyline,28,29 doxepin,28 and trimipramine. Improvements were seen in depressed patients treated
Primary Psychiatry
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Safety
Employing a sedating antidepressant to treat both depression and comorbid insomnia is appealing because of the
reduced opportunity for drug-drug interactions and the
potential increase in patient compliance due to a less complex
treatment regimen. However, the available literature suggests
caution should be exercised when considering this approach.
A recent conference that reviewed the evidence supporting
the use of both TCAs and SSRIs resulted in a published statement suggesting that TCAs are no longer justified as first-line
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Antidepressants and Insomnia
antidepressant therapy in most situations.48 This position
reflects concerns about the differential efficacy and safety
profiles of the TCAs relative to newer therapies.
Two of the three sedating atypical antidepressants reviewed
here are also of questionable value as first-line treatment.
First, mirtazapine is indicated for the treatment of depression
but often is used as an alternative or augmentation therapy
for depression rather than a first-line monotherapy.49 Second,
sales of nefazodone have been discontinued in several countries including the United States (branded version) due to
concerns of liver toxicity.
The process of elimination leaves trazodone as the most
likely candidate for monotherapy in depression with comorbid insomnia. However, while trazodone is considered to be
safer than the TCAs, it remains associated with a series of
significant side effects. The most common adverse events seen
with trazodone at doses of ≥75 mg/day are drowsiness, dizziness, dry mouth, nausea, vomiting, constipation, headache,
hypotension, and blurred vision.50 A review of published data
from controlled trials in depressed patients found that 25%
to 30% of patients experienced some treatment-emergent
adverse event attributed to trazodone.51 Reported discontinuation rates from clinical trials were relatively high (25% to
60%), with 25% to 50% specifically attributable to adverse
events.50 Most importantly, a recent literature review identified a sizable number of reports of treatment-emergent
cardiac events.52 Adverse events noted in clinical studies and
case reports include hypotension, ventricular arrhythmias,
cardiac conduction disturbances, and exacerbation of ischemic attacks. Torsades de pointes, a prolongation of the QTc
interval, and other cardiac arrhythmias, have been observed
in patients treated with trazodone.53-57 Finally, a review of
psychotropics and priapism found that almost 80% of cases
reviewed were associated with trazodone, while the balance
was associated with antipsychotics.58
small samples and, therefore, may be of limited applicability
to the general population of patients with depression.
In one study,59 trazodone 100 mg or placebo was given to
patients (N=12) stable on different SSRIs for a period of 7
days. At the end of this period, trazodone co-therapy significantly increased total sleep time and SWS, and reduced the
number of awakenings seen on polysomnography. Another
study60 examined the impact of prescribing trazodone for
patients (N=17) with an incomplete response to fluoxetine
or bupropion. In this evaluation, trazodone produced significantly more improvement than placebo in several subjective
measures of sleep.
Trazodone has been added to fluoxetine in one study of a
group of depressed patients (N=8) for the purposes of either
improving sleep or as a possible antidepressant potentiator.61 Three of the eight patients experienced improvements
in both sleep and depression symptoms. A second group of
patients on fluoxetine (N=16) was given adjunctive trazodone for complaints of insomnia.62 All patients had a positive
hypnotic response, but five discontinued trazodone due to
excessive sedation.
Trazodone was compared to placebo in depressed patients
(N=7) who developed insomnia while treated with the MAOI
brofaromine.63 Trazodone increased SWS and was associated
with subjective reports of better and deeper sleep. A review
of MAOI-induced insomnia treated with trazodone found 13
case-studies.64 Twelve reported an initial positive response to
co-therapy while only nine were able to continue treatment
without intolerable side effects.
Depressed patients (N=50) participated in a 4-week study
of the atypical antidepressant venlafaxine with adjunctive
trazodone, as needed, for the development of comorbid
insomnia.65 The timing and dosage of trazodone was left to
the discretion of the clinicians to simulate a naturalistic setting. Patients who received adjunctive trazodone had a lower
response to venlafaxine monotherapy on MADRS measures
of insomnia and inner tension. Once trazodone was introduced, these patients showed improvements in insomnia
symptoms but not in other measures of depression.
EVIDENCE SUPPORTING THE USE OF
A COMBINATION OF TWO ANTIDEPRESSANTS
Other Antidepressants
Aside from trazodone, very little information is available
about the impact on sleep parameters of sedating antidepressants used as adjunctive therapy to any of the alerting SSRIs
or MAOIs.
Efficacy
Trazodone
Trazodone is the most widely used sedating antidepressant
used as adjunctive therapy to other antidepressants. Given
the frequency with which this treatment course is pursued,
it is remarkable that the combination of trazodone and other
antidepressants has not been ardently investigated. Of the
studies that have been conducted, almost all have employed
Primary Psychiatry
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Safety
Trazodone
In one study of trazodone as adjunctive therapy for fluoxetine, five of eight patients were unaffected by the addition
of trazodone to fluoxetine or had intolerable adverse drug
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G.K. Zammit
reactions.61 In a second study62 of trazodone-fluoxetine cotherapy, all patients reported marked daytime sedation with
five of 16 discontinuing trazodone as a consequence. The
implications of these case reports suggest that the utility of
the combination of fluoxetine and trazodone may be limited
by adverse effects.
Co-administration of trazodone and brofaromine produced
few adverse events and was well tolerated by study participants.63 A review of several case studies of trazodone-MAOI
co-therapy found that one of 13 patients was unable to tolerate the combination initially and another three discontinued
this course of treatment due to side effects over a longer
period of time.64
Serotonin syndrome has been described when trazodone
was prescribed in combination with nefazodone.66 Serotonin
syndrome has also been reported following the use of venlafaxine and fluoxetine.67
with persistent comorbid insomnia.71 Patients who participated in this study were diagnosed with depression, treated
stably with the SSRIs fluoxetine, sertaline, or paroxetine, and
complained of sleep onset difficulty or too-short sleep time
at least 3 nights a week and associated with daytime impairment. Over a 4-week period, treatment with zolpidem 10 mg
lengthened sleep time, improved sleep quality, reduced the
number of awakenings, and improved multiple measures of
daytime functioning as compared to placebo.
A recent study evaluated the co-administration of eszopiclone 3 mg with the SSRI fluoxetine in patients with MDD
over an 8-week period.72 Compared to fluoxetine alone, the
fluoxetine-eszopiclone group demonstrated statistically significant improvements in all sleep parameters evaluated at
all time points. Measures included sleep latency, wake time
after sleep onset, total sleep time, sleep quality, and depth of
sleep. Importantly, eszopiclone also resulted in a greater treatment response to fluoxetine as measured by improvements
on the 17-item HAM-D, Clinical Global Impression (CGI)
Improvement scale, and CGI Severity scale. Furthermore, a
significantly greater percentage of individuals in the co-therapy group were classified as responders (59% versus 48%) and
remitters (42% versus 33%) at the end of the study.
Other Sedating Antidepressants
Co-administration of the atypical antidepressant venlafaxine and the TCAs clomipramine or imipramine has been well
tolerated.68 Venlafaxine has been used as adjunctive therapy
when patients have realized only partial response to the TCA.
However, no effects on sleep parameters were reviewed.
Adjunctive paroxetine has been employed to increase the
effectiveness of TCAs (amitriptyline and imipramine) in
patients who had not sufficiently responded after 3 weeks of
monotherapy.69 This combination increased TCA serum levels as intended and was well tolerated. Effects on sleep were
not reviewed.
When used in combination, the SSRI fluoxetine was
shown to increase TCA plasma levels for several members of
this class of antidepressants.70 This increase was highest with
clomipramine and imipramine and less notable with amitriptyline. These pharmacokinetic changes did not induce side
effects in the patients evaluated. The effects on sleep were
not reviewed.
Safety
In the zolpidem-SSRI-induced insomnia study, adverse
events were similar between the placebo and zolpidem
groups.71 There was no evidence of dependence or withdrawal
from zolpidem during the placebo substitution period at the
conclusion of the study.
Zolpidem drug-drug interaction studies have been conducted with two TCAs and two SSRIs.73 Co-administration
of zolpidem and imipramine produced a 20% decrease in
peak levels of imipramine and an additive effect of decreased
alertness. Chlorpromazine in combination with zolpidem
produced no pharmacokinetic interactions; however, decreases in alertness and psychomotor performance were potentiated. Both of these studies evaluated single-dose interactions
in healthy volunteers. Thus, the results may not be predictive
for chronic administration in depressed patients.
Zolpidem-fluoxetine interactions were examined in both
single-dose and multiple-dose studies. A single-dose study
in male volunteers with zolpidem 10 mg and fluoxetine 20
mg at steady-state levels did not find any clinically significant pharmacokinetic or pharmacodynamic interactions.73,74
Healthy females participated in a multiple-dose study of
zolpidem and fluoxetine at steady-state concentrations.73 The
only significant change in this evaluation was a 17% increase
in the half-life of zolpidem. No changes in psychomotor performance were seen.
EVIDENCE SUPPORTING THE USE OF
A COMBINATION OF ONE ANTIDEPRESSANT AND ONE HYPNOTIC
Efficacy
Although numerous drug-drug interaction studies have
been conducted to evaluate the interaction between hypnotics and antidepressants, efforts to evaluate the effectiveness of
co-administration of these treatments on comorbid depression and insomnia are still in the early stages.
The use of zolpidem was examined in SSRI-treated patients
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Antidepressants and Insomnia
Healthy female volunteers were dosed with sertraline
50 mg for 17 days. Once steady-state levels were reached,
subjects were dosed for 5 consecutive nights with zolpidem
10 mg. The pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem, but zolpidem Cmax
was significantly higher (43%) and Tmax was significantly
decreased (53%).
Adverse events and dropout rates were similar between the
placebo and eszopiclone groups in the 8-week eszopiclonefluoxetine MDD study.72 The frequency of adverse events
continued to be similar between both groups during the placebo washout period at the conclusion of study.75 No evidence
of withdrawal effects, rebound insomnia, or rebound depression was observed. A single-dose study of co-administration
of eszopiclone 3 mg with paroxetine 20 mg (7 days) found no
pharmacokinetic or pharmacodynamic interactions.73
Zaleplon was evaluated in three single-dose antidepressant
drug interaction studies.73 Zaleplon 20 mg co-administered
with the TCA imipramine 75 mg potentiated decrements in
next-day alertness and psychomotor performance as compared
to either compound administered alone. There was no alteration
of the pharmacokinetics of either drug. In two separate studies,
neither co-administration of zaleplon with the SSRI paroxetine
20 mg (7 days) or with the atypical antidepressant venlafaxine
150 mg resulted in any pharmacokinetic or pharmacodynamic
changes to either zaleplon or the antidepressant.
Ramelteon is the newest hypnotic approved for the treatment
of insomnia in the US. It has been evaluated for use in conjunction with two SSRIs. A single-dose of ramelteon 16 mg was
co-administered with fluvoxamine 100 mg (3 days).73 This combination increased the area under the curve (AUC)0-inf of ramelteon by approximately 190-fold, and the Cmax by approximately
70-fold. This effect appeared to be specific to fluvoxamine and
cytochrome P450 1A2 inhibitors rather than being a class effect
which could be expected to occur with other SSRIs.
A multiple dose study of co-administration of ramelteon
and sertraline was conducted.76 Ramelteon had no effect on
the systemic availability of sertraline. Decreases in ramelteon
AUC and Cmax (23% and 43%, respectively) were deemed
clinically irrelevant due to ramelteon’s highly variable intersubject pharmacokinetic profile.
ANTIDEPRESSANTS AND NONDEPRESSED PATIENTS
A small number of studies have evaluated the efficacy of
antidepressants in non-depressed, primary insomnia patients.
The extremely limited nature of this evidence and the small
scale of most of these studies strongly argues against the use of
antidepressants as hypnotics in non-depressed patients.
The largest study (N=306) reported to date has been the
only placebo-controlled study of trazodone in insomnia
patients.77 Over a 2-week period, trazodone improved sleep
latency and total sleep time relative to placebo during the
first week of treatment only. The loss of efficacy during the
second week suggests that trazodone is not an appropriate
insomnia treatment choice for non-depressed patients. No
other trazodone studies have been reported in primary insomnia patients.
A low-dose formulation of doxepin is currently in development as a hypnotic. Three published studies have examined
doxepin’s effects in primary insomnia patients. A placebocontrolled, 4-week study of doxepin 25–50 mg (N=47) found
that active treatment improved sleep efficiency and sleep
quality over the entire treatment period.78 Notably, more
rebound insomnia was observed in the doxepin treatment
group during the placebo run-out period. Adverse effects
were comparable between the two groups, but two doxepin
patients discontinued due to adverse effects. In the second
study, patients (N=10) were treated with placebo for 1 night
and doxepin 25 mg for 3 weeks.79 Relative to placebo, sleep
was improved after one dose of doxepin during the doubleblind phase of the trial. At the end of 3 weeks of open-label
treatment, doxepin also improved sleep relative to baseline
values. Adverse events and rebound insomnia remained a
concern in some patients. Finally, a 2-night cross-over study80
(N=67) was employed to evaluate doxepin 1–6 mg. All three
doses improved wake time during sleep, total sleep time,
and sleep efficiency relative to placebo. The safety profile of
doxepin was similar to that of placebo with no evidence of
anticholinergic effects, memory impairment, or significant
hangover/next-day residual effects.
Two studies evaluated paroxetine in primary insomnia
patients. Fifteen insomnia patients were treated for 6 weeks
with a flexible dose of paroxetine (median dose=20 mg).81 At
the end of the treatment period, 11 patients had improved
TABLE 2
HYPNOTICS
Dosage
Sleep
Initiation
Sleep Maintenance
Eszopiclone
1–3 mg
+
+
Ramelteon
8 mg
+
-
Zaleplon
5–20 mg
+
-
Zolpidem
5–10 mg
(CR formulation:
6.26–12.5 mg )
+
+ (CR formulation)
+=improvement; -=no consistent effect; CR=controlled release.
Zammit GK. Primary Psychiatry. Vol 15, No 5. 2008.
Primary Psychiatry
© MBL Communications
67
May 2008
G.K. Zammit
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and seven no longer met the diagnostic criteria for insomnia.
Subjective measures of sleep quality and daytime function
were significantly improved, but neither objective nor subjective measures of sleep quantity were consistently changed
with treatment. One participant dropped out due to adverse
side effects. A double-blind comparison82 of paroxetine and
placebo in older adults (N=27) found improvements in subjective sleep quality and several measures of daytime function.
Sleep efficiency, sleep latency, and wake time appeared to be
unaffected by active treatment. Both evaluations suggest that
paroxetine is ineffective for treating primary insomnia.
Trimipramine was studied in two groups of primary
insomnia patients.83 It was shown to produce significant
improvements in sleep efficiency, total sleep time, wake time
after sleep onset, sleep quality, and next-day well-being in 19
primary insomnia patients (mean dose=166 mg ). Side effects
included dry mouth and the anticholinergic properties of
the drug. No rebound insomnia was observed at either 4 or
14 days following drug discontinuation. A 4-week study84 of
trimipramine (mean dose=100 mg) in 55 insomnia patients
found significant improvements in sleep efficiency but no
impact on total sleep time. Adverse effects were deemed minimal and no rebound insomnia was observed.
One open label study85 of nefazodone in primary insomnia
has been reported. Patients (N=32) were treated with 100
mg nefazodone at bedtime. Over the 4-week period evaluated, this dose could be titrated up to 400 mg depending
on treatment response. At the end of the treatment period
sleep latency was prolonged and there was less SWS relative
to baseline values. The duration of REM sleep was greater
and improvements were seen in subjective Pittsburgh Sleep
Quality Index scores, but overall sleep effects were decidedly
mixed. Furthermore, 12 of 32 participants dropped out of the
study citing either lack of efficacy or intolerable side effects.
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