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REVIEW ARTICLE

Insomnia and Somnolence Associated With


Second-Generation Antidepressants During the Treatment
of Major Depression
A Meta-Analysis
Siegfried Alberti, MD,* Alberto Chiesa, MD,* Costanza Andrisano, MD,* and Alessandro Serretti, MD, PhD*

According to current guidelines, the so-called second-


Background: Sleep reduction or enhancement is frequently observed
generation antidepressants have played in the last 2 decades an
with second-generation antidepressant treatments, and they can be benefi-
cial or harmful depending on the symptom profile of each subject. Never- increasingly important role for the treatment of MD.7,8 Although
theless, relatively little attention has been given so far to rank those effects there is no complete consensus as to which antidepressants should
across compounds. The aim of this meta-analysis is to provide quanti- be included under the label of second-generation antidepres-
tative data about short-term rates of insomnia and somnolence associ- sants, there is general consensus that they broadly include selective
ated with 14 second-generation antidepressants during the treatment serotonin reuptake inhibitors (SSRIs), serotonin and norepineph-
of major depression. rine reuptake inhibitors, and other drugs with related mechanisms
Methods: A literature search and a search of unpublished documents of action that usually selectively target neurotransmitter receptors
were performed. Eligible studies focusing on MD patients treated with and reuptake.911 Second-generation antidepressants have been
second-generation antidepressants were entered in the analysis. Our pri- found to be effective and generally well tolerated.1216 For this rea-
mary outcome measures were insomnia and somnolence rates induced son, they are considered the first-line treatment in clinical settings.
by antidepressants as compared with those associated with placebo. Sensi- Despite their positive balance of efficacy and side effects,
tivity analyses were carried out as well.
second-generation antidepressants are often associated with mild-
Results: Ten second-generation antidepressants showed higher rates of
to-moderate side effects that, although unrelated to risks of mortal-
insomnia than placebo. The highest incidence was found for bupropion
ity, can undermine compliance with treatment and impair quality
and desvenlafaxine. Agomelatine was the only antidepressant with a lower
likelihood of inducing insomnia than placebo. Eleven antidepressants were
of life. In fact, these side effects including, among others, sex-
associated with higher rates of somnolence than placebo. Fluvoxamine and
ual dysfunction, weight gain, gastrointestinal disorders, and sleep
mirtazapine showed the highest frequency of somnolence. Bupropion in- disorders have been found to represent the main reason for drop-
duced somnolence to a lower extent than placebo. Sensitivity analyses out during antidepressant treatment, in particular during the first
showed a degree of variation of those findings. 3 months of treatment.17,18
Discussion: Antidepressants are associated with different insomnia and Of note, recent meta-analyses showed that significant dif-
somnolence rates, mainly depending on their mechanisms of action. ferences exist among different antidepressants in terms of, for
Despite some limitations, we underscore that the treatment-emergent in- instance, the incidence of drug-related sexual dysfunction19 and
somnia and/or somnolence are frequent, and they could be used in clinical weight gain,20 mainly depending on the underpinning pharmaco-
practice to face the specific needs of each patient. logical mechanisms of each specific drug. On the other hand, it is
less clear so far the extent to which second-generation antidepres-
Key Words: depression, antidepressants, tolerability, individualized
sants have an impact on sleep aspects in patients treated with these
therapy
drugs. Sleep-related issues are of particular importance as they
(J Clin Psychopharmacol 2015;35: 296303) may influence quality of life of subjects and also the risk of re-
lapse.21 Depression presents with a variable of sleep-related symp-
toms ranging from the most frequent insomnia to somnolence.
M ajor depression (MD) is one of the most relevant health-care
problems. Indeed, it is thought to affect about 121 million
people throughout the world,1 it has an estimated lifetime pre-
Therefore, it is of particular importance to use the most appropri-
ate compound for each specific symptom profile, for example,
valence of 13.2% in the United States,2 and it is associated with a patient with insomnia and/or anxiety will benefit more from
significant disability,3 mortality,4,5 and costs for both affected in- a sleep-inducing antidepressant. In particular, although some re-
dividuals and the health-care system.6 views have been published that provide a qualitative comparison
of the modifications on sleep induced by different antidepressants,
for example,22 a comprehensive meta-analysis comparing the
rates of insomnia and daytime somnolence among these antide-
From the *Department of Biomedical and Neuromotor Science, University
of Bologna, Bologna; and Department of Clinical and Experimental Medicine
pressants has not been performed thus far.
and Pharmacology, University of Messina, Messina, Italy. Accordingly, the aim of the present work is to provide quanti-
Received June 19, 2014; accepted after revision March 4, 2015. tative data about the short-term rates of insomnia and somnolence
Reprints: Alessandro Serretti, MD, PhD, Department of Biomedical and associated with second-generation antidepressants during the
Neuromotor Science, University of Bologna, Viale Carlo Pepoli 5, 40123
Bologna, Italy (email: alessandro.serretti@unibo.it). treatment of MD. In particular, we investigated the extent to which
Supplemental digital contents are available for this article. Direct URL citation 14 second-generation antidepressants, including agomelatine,
appears in the printed text and is provided in the HTML and PDF versions bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram,
of this article on the journals Web site (www.psychopharmacology.com). fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine,
Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0271-0749 reboxetine, sertraline, and venlafaxine impact insomnia and som-
DOI: 10.1097/JCP.0000000000000329 nolence over the short-term period in patients with MD.

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Journal of Clinical Psychopharmacology Volume 35, Number 3, June 2015 Insomnia, Somnolence, and Antidepressants

MATERIALS AND METHODS sponsorship, and concomitant therapies on the outcomes of inter-
est (see below).
Literature Research
A literature research was undertaken using MEDLINE, Outcome Measures
ISI Web of Science, the Cochrane database, and references Our 2 primary outcome measures were short-term insomnia
of retrieved articles (this is not a Cochrane Collaboration Study). and somnolence rates reported during the treatment period with
The research included articles written in English and published up a second-generation antidepressant in patients with MD. In partic-
to January 2013. The main key words were agomelatine, bupro- ular, whenever it was possible, we referred to side effects emerg-
pion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluox- ing within the first 8 weeks of treatment. If 8-week data were
etine, fluvoxamine, milnacipran, mirtazapine, paroxetine, not available, we focused, in the following order, on the emer-
reboxetine, sertraline, and venlafaxine in combination with ma- gence of insomnia and somnolence rates within the 10th or the
jor depression or major depressive disorder. A research of un- 12th week of treatment, as reported by the authors of original stud-
published documents was performed as well. More in detail, ies, or alternatively, in case of studies with a shorter duration,
documents were requested to the following pharmaceutical on the same outcome measures emerged within the first sixth
companies: Eli Lilly, Lundbeck, Organon, Solvay, Pfizer, week of treatment. We included data about insomnia and somno-
GlaxoSmithKline, Bristol-Myers Squibb, and Pierre Fabre, and lence rates only if these data were described as treatment-related
to the main Medical Control Agencies, including the Food and side effects and labeled with the following words: insomnia,
Drug Administration, the European Medicines Agency, the Phar- reduced time of sleep, or sleep difficulty for the insomnia
maceuticals and Medical Devices Agency and the Therapeutic rates and somnolence drowsiness or sleepiness for the som-
Goods Administration. nolence rates. It is worth noting that, whether a study reported
overlapping data for a given side effect (eg, somnolence and drows-
Selection of Trials iness), we included that associated with the largest incidence.
Of note, in case of overlapping samples, the decision to
Two reviewers independently searched eligible articles for
include a given study was based on the following algorithm:
inclusion (A.C. and S.A.). Included studies had to do the follow-
(1) whether no difference existed between two studies in terms
ing: focus on patients aged 18 or older with MD according to
of outcome measures, we considered the study with the largest
the Diagnostic and Statistical Manual for Mental Disorders,
sample size, and (2) whether the studies provided different out-
Fourth Edition, Text Revision, criteria, with or without further psy-
comes, we choose the study whose outcomes were more in line
chiatric comorbidities; investigate the use of one or more of the
with the criteria of the present meta-analysis.
above-mentioned antidepressants; provide dichotomous measures
of drug-related insomnia and/or somnolence rates within the 12th
week of treatment; and have a minimum duration of 6 weeks. In- Data Extraction and Analysis
somnia and somnolence are broad definitions, which may range Data were independently extracted from original reports by
to mild-to-severe symptoms. In the present analysis, we reported 2 reviewers (A.C. and S.A.). Quality of included articles was inde-
their rates as present in included papers, to which we refer. Usu- pendently assessed by the 2 reviewers using validated quality
ally, these symptoms have been assessed with specific rating scales: the Jadad Scale25 for controlled studies and a modified ver-
scales or using clinical criteria. sion of the New Ottawa Scale26 for uncontrolled studies for the re-
We also included data of a sample of patients with MD re- maining studies. For controlled trials, a score of 3 or higher was
ported in 2 previously published studies.23,24 However, from those considered to be indicative of high quality,25 whereas for uncon-
studies, which included also bipolar disorder, we selected only trolled ones, a score of 4 or higher was considered as indicative
data of patients with MD from the original datasets and included of high quality.26 All disagreements were resolved through dis-
these data as if they were derived from a single uncontrolled study. cussion and, in case of persistent disagreement, with the involve-
Excluded were as follows: 1) case reports and case series, ment of a third reviewer (A.S.). The agreement rates between the
2) review articles and meta-analyses, 3) long-term studies (lasting 2 main reviewers were high (94%). After the involvement of the
more than 12 weeks) that did not provide information about the third reviewer, no final disagreement was observed.
emergence of drug-related insomnia and/or somnolence rates in All data were referred to the intention-to-treat populations,
the short-term period (612 weeks); 4) studies providing data on when available. Otherwise, the completers sample was analyzed.
patients with and without MD joined together; 5) studies focusing In addition, whether one study included 2 (or more) treatment
on depressed patients taking other psychotropic drugs at study en- arms of patients treated with the same antidepressant at different
try (ie, patients treated with other psychotropic drugs in the days dosages, we separately considered each treatment arm as if they
before the entry in the study who switched to the antidepressant were 2 (or more) independent studies.
without a washout period); 6) studies focusing on patients in re- Data extracted from the included studies were entered into
mission at study entry; 7) studies focusing on the combination the Cochrane Collaboration Review Management Software
of a pharmacological treatment with a nonpharmacological ther- (RevMan version 5.1; Cochrane Collaboration, Oxford, UK) and
apy of any kind; And 8) studies providing data on more antide- analyzed by RevMan analysis 1.01. For insomnia and somnolence
pressants or more psychoactive drugs joined together. A notable rates, odds ratios and their 95% confidence intervals were calcu-
exception was represented by studies investigating the association lated, using a random effect model, which takes into account
between a single antidepressant and anxiolytics (a benzodiazepine possible differences in the implementation of intervention and
or a benzodiazepine-like drug), although this was considered in characteristics of participants included. Heterogeneity across the
sensitivity analyses. The concomitant treatment with cardiovascu- studies was assessed by the 2 and 2 statistics and by visual in-
lar drugs was allowed only if the authors specified that the admin- spection of the results. The 2 statistic P < 0.05 and the 2 statistic
istration of these drugs was stable at study entry and remained higher than 50% were taken to be suggestive of heterogeneity.
stable during the study period. Studies with different methodolog- Moreover, for studies that did not include a placebo control
ical designs were included. However, sensitivity analyses were group, we calculated the weighted mean of the placebo samples
performed so as to estimate the possible impact of study design, for the considered variable from placebo-controlled studies that

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Alberti et al Journal of Clinical Psychopharmacology Volume 35, Number 3, June 2015

investigated the same variable and applied it to studies not includ- Sensitivity Analyses
ing a placebo group according to a previously reported methodol-
ogy.20,27 In such cases, the sample size of the virtual placebo Short-Term Insomnia Rates
group was considered as equal to the number of patients treated When data derived from randomized, double-blind, placebo-
with antidepressants in the specific studies that did not include a controlled studies were separately analyzed, the main results of
placebo group to limit the estimate inflation. the general analysis were overall confirmed. However, citalopram
We also performed additional sensitivity analyses focus- was associated with a higher likelihood of inducing insomnia,
ing on the following: 1) double-blind, randomized placebo- whereas fluvoxamine and sertraline were associated with insom-
controlled studies, 2) antidepressants monotherapy studies, and nia to a lower extent than that they were in the general analysis.
3) nonsponsored studies (studies were considered as sponsored Furthermore, fluvoxamine was the only antidepressant that
if they were funded, also in part, by a pharmaceutical company showed no significant difference from placebo in terms of insom-
or if at least one of the authors was member of a pharmaceutical nia rates (Fig. 2).
company) to investigate whether the incidence of insomnia and In addition, when we focused only on studies providing data
somnolence varied as a function of these variables. to be included about antidepressant monotherapy, duloxetine proved to be the
in a sensitivity analysis; each drug was required to be investigated antidepressant associated with the highest rates of insomnia
in at least 2 studies providing data about the specific outcome (Supplementary Figure 1, Supplemental Digital Content 2,
measure of interest. http://links.lww.com/JCP/A283). Finally, when we considered
only nonsponsored studies, we found that fluoxetine was the drug as-
sociated with the highest risk of insomnia, whereas fluvoxamine was
RESULTS
the drug associated with the lowest risk (Supplementary Figure 2,
Supplemental Digital Content 3, http://links.lww.com/JCP/A284).
Search Result
The original research identified about 7000 published pa-
pers. About 5220 studies were not considered for inclusion be- Short-Term Somnolence Rates
cause they were review, meta-analyses, case reports, case series, When we focused only on double-blind, randomized placebo-
and studies conducted on animal models. After the inclusion controlled studies, the highest rates of somnolence were found for
and the exclusion criteria were applied to the remaining 1780 stud- mirtazapine, followed by fluovoxamine. Another remarkable dif-
ies, 1535 studies were excluded and 245 studies could be included ference from the general analysis was the significantly higher
in the present meta-analysis. incidence of somnolence associated with citalopram (Fig. 2).
In addition, 3 of 8 pharmaceutical companies, as well as 3 of The remaining results were consistent with those observed in
4 Medical Control Agencies, replied to us. Appropriate docu- the primary analysis.
ments providing information about one or both our outcomes When we specifically focused on antidepressants mono-
of interest were provided by one pharmaceutical company and therapy studies, we found that bupropion was no longer asso-
by 2 Medical Control Agencies. The inclusion and the exclusion ciated with a lower rate of somnolence than placebo and did
criteria were also applied to these documents: 345 studies were not differ significantly from placebo (Supplementary Figure 1,
excluded, and 30 could be included in our meta-analysis. Supplemental Digital Content 2, http://links.lww.com/JCP/A283).
Overall, we used the data of 276 trials (4 concerning Finally, when data derived from nonsponsored studies were
agomelatine, 21 bupropion, 24 citalopram, 10 desvenlafaxine, 32 separately analyzed, mirtazapine showed a higher association with
duloxetine, 26 escitalopram, 60 fluoxetine, 8 fluvoxamine, 10 somnolence than fluvoxamine and showed the highest somnolence
milnacipran, 23 mirtazapine, 44 paroxetine, 8 reboxetine, 37 rate among all included antidepressants (Supplementary Figure 2,
sertraline, and 52 venlafaxine). Among included studies, 223 Supplemental Digital Content 3, http://links.lww.com/JCP/A284).
studies used a randomized controlled, 7 studies used a non- Details of all analyses are reported in Supplementary Table 2,
randomized controlled design, and 46 studies used an uncon- Supplemental Digital Content 4, http://links.lww.com/JCP/A285.
trolled design. A summary of included studies is shown
in Supplementary Table 1, Supplemental Digital Content 1,
http://links.lww.com/JCP/A282. DISCUSSION
The aim of the present work was to quantify and compare for
Primary Outcome Measures the first time the short-term rates of insomnia and somnolence
Ten of 14 antidepressants showed significantly higher rates associated with 14 second-generation antidepressants during MD
of short-term insomnia than placebo, with the following increas- treatment. Our analysis showed several important findings. First,
ing order of incidence: escitalopram, duloxetine, venlafaxine, parox- bupropion, desvenlafaxine, duloxetine, escitalopram, fluoxetine,
etine, reboxetine, fluoxetine, fluvoxamine, sertraline, desvenlafaxine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine
and bupropion. On the other hand, agomelatine was the only anti- were associated with significantly higher rates of insomnia as com-
depressant that had a lower likelihood of inducing insomnia than pared with placebo. These findings can be considered consistent
placebo. Mirtazapine, milnacipran, and citalopram did not differ with current knowledge of the mechanisms of action of these
from placebo in terms of insomnia rates (Fig. 1). drugs. Indeed, all these drugs directly affect brain levels of neuro-
Pertaining to the short-term somnolence rates, 11 antide- transmitters involved in the regulation of the sleep-wake cycle. In
pressants were associated with a higher likelihood of inducing particular, bupropion is the only antidepressant that selectively
this side effect than placebo, with the following increasing inhibits the reuptake of dopamine and noradrenaline. More in
order of incidence: escitalopram, citalopram, fluoxetine, sertraline, detail, it has been well documented that the dopaminergic stimula-
venlafaxine, duloxetine, desvenlafaxine, paroxetine, reboxetine, tion in the substantia nigra and ventral tegmental area is involved
mirtazapine, and fluvoxamine. The only drug that was associated in arousal.28,29 Furthermore, norepinephrine has been found to
with a significantly lower risk of inducing somnolence than pla- promote waking through the stimulation of 1-adrenoreceptors,
cebo was bupropion. Milnacipran and agomelatine did not differ as well as through the activation of other wake-promoting systems,
from placebo in terms of somnolence rates (Fig. 1). and the inhibition of systems involved in sleep stimulation.30

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Journal of Clinical Psychopharmacology Volume 35, Number 3, June 2015 Insomnia, Somnolence, and Antidepressants

FIGURE 1. General analysis. CIs are reported for each drug.

These mechanisms of action could explain our observation that Pertaining to sertraline, the high incidence of insomnia asso-
bupropion is the antidepressant associated with the highest rates ciated with this drug could be the consequence of its mechanism
of insomnia. It is also remarkable that the strong association be- of action. Indeed, sertraline has a weak dopaminergic action in the
tween bupropion and insomnia is consistent with findings re- striatum and the nucleus accumbens,40 thus promoting arousal.
ported by previous reviews.3133 Desvenlafaxine was the second Another important finding of our work is that agomelatine
drug associated with insomnia following bupropion. The pharma- proved to be the only second-generation antidepressant associated
codynamic properties of this drug could partially explain this re- with a lower likelihood of inducing insomnia compared with pla-
sult: indeed, both the noradrenergic and the serotonergic activity cebo. This seems to be linked to its peculiar action of inhibiting
of this drug have a reverse relationship with sleep duration,30,34,35 serotonin 5-HT(2C) receptors and stimulating melatonin M1 and
possibly leading to the usually higher risk of insomnia observed M2 receptors.4144 However, this effect may not be related to the
in association with serotonin and norepinephrine reuptake inhibi- overall antidepressant effect.
tors in comparison with SSRIs. However, this does not explain It is also worth noting that escitalopram and citalopram
the reason behind our observation that desvenlafaxine could be were associated with lower rates of insomnia in comparison
more likely to induce insomnia as compared with its racemic with the remaining SSRIs. As to escitalopram, this could be
form, venlafaxine. One could hypothesize that this finding could linked to the highest selectivity and peculiar mechanism of ac-
be the result of the dosage of this drug used in included studies tion on the serotonergic transporter compared with the other
or pharmacokinetics issues, although we were not able to test this SSRIs.45 Pertaining to citalopram, our finding could be related
hypothesis.3639 to its weak antagonist action on histamine1 receptor that has

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Alberti et al Journal of Clinical Psychopharmacology Volume 35, Number 3, June 2015

FIGURE 2. Sensitivity analysis I: Double-blind, randomized placebo-controlled studies. CIs are reported for each drug.

been associated to the higher rates of sedation usually associ- Finally, also in the sensitivity analysis focusing on non-
ated with this drug.46 sponsored studies, the overall results were confirmed, although
In the sensitivity analysis focusing on double-blind random- with some differences.
ized placebo controlled studies, results were mainly similar but Pertaining to somnolence, we found that the following de-
probably closer to what is observed in clinical practice regarding creasing order of incidence: fluvoxamine, mirtazapine, reboxetine,
the rank of compounds. paroxetine, desvenlafaxine, duloxetine, venlafaxine, sertraline,
When we focused on monotherapy studies only, the results citalopram, fluoxetine, and escitalopram. As to fluvoxamine, this
of the general analysis were largely confirmed. However, association was already reported by the review of Wagner et al.
duloxetine and fluoxetine were associated with higher rates that classified somnolence as the second most frequent side effect
of insomnia than those observed in the general analysis. A of fluvoxamine over the short-term period.53 This effect could be
possible explanation for these findings could be related to probably related to the inhibition of melatonin degradation asso-
the notion that the concomitant use of benzodiazepines and ciated with this drug.54,55 Nevertheless, it is worth noting that a
benzodiazepine-like drugs could interfere with the result ob- reduction of melatonin levels has been associated with depressed
served of the general analysis. As an example, it has been well mood and sleep disorders.56,57 Therefore, the influence on
documented that fluoxetine, beside its serotonergic action, in- melatonin metabolism could be useful for the treatment of
creases also dopamine and norepinephrine levels in prefrontal MD by improving both mood and insomnia associated with this
cortex4749 to higher levels than other SSRIs, thus being more disease.58,59 Moreover, fluvoxamine confidence intervals were
likely to induce insomnia.4852 very large, indicating much heterogeneity across studies, this

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Journal of Clinical Psychopharmacology Volume 35, Number 3, June 2015 Insomnia, Somnolence, and Antidepressants

was the case also for insomnia. In fact, in RCT studies and par- changes in insomnia and somnolence associated with antide-
ticularly in nonsponsored studies, fluvoxamine had the lowest pressants as continuous measures. However, our choice derived
insomnia rates compared to the other compounds. Therefore, from the observation that the majority of studies reported in lit-
fluvoxamine may be beneficial in depressed subjects presenting erature provided dichotomous data. Furthermore, studies applied
insomnia but with attention on the individual reaction, which may different methods for detecting these symptoms, ranging from
vary considerably. side effect rating scales to clinical observation; this may have in-
Pertaining to mirtazapine, the main reason that could explain troduced a bias. Finally, a more detailed analysis including inten-
the association between this drug and high levels of somnolence sity, duration, necessity of a specific treatment, and so on would
could be its high affinity for histamine H1 receptors with a conse- add more from a clinical point of view. However, this information
quent antihistaminic effect,60 thus resulting in a higher somno- is not available in literature or to a very low extent.
lence rates than several SSRIs.61 Fourth, we included studies with a small sample size,
Reboxetine was the third drug associated with somnolence which limits their power to detect differences among different
after mirtazapine. This finding seems at odds with the mechanism treatment options.
of action of reboxetine but could be due to a rebound effect of noc- Fifth, our analyses focused only on the acute-phase treatment
turnal insomnia, given its REM sleep disruption. However, we un- of MD and cannot be generalized to periods longer than 12 weeks.
derscore the dearth of studies reporting the incidence of this side Also, multiple-treatments meta-analysis methods have been
effect during treatment with reboxetine. As a consequence, this re- recently used to simulate head-to-head comparisons. However,
sult should be considered with caution. criticisms have been raised against those methods; therefore, we
A further relevant finding was that bupropion was the only followed a more conservative approach.
drug associated with a lower incidence of this side effect than pla- Finally, we did not consider the impact of the adminis-
cebo. This result is in agreement with the aforementioned bio- tered dosage in the outcomes of our interest, and we included
chemical activity of the drug and with its more activating effects. groups of patients treated with different dosages for the
The results of the sensitivity analysis focusing on double- same antidepressant.
blind randomized placebo controlled studies confirmed the over-
all results of the general analysis. However, it is worth noting that, CONCLUSION
unlike the general analysis, mirtazapine showed a higher likeli- In conclusion, the results of the present meta-analysis indi-
hood of inducing insomnia than fluvoxamine. This result seems cate that the majority of second-generation antidepressants are as-
to be consistent with the aforementioned pharmacodynamic sociated to a higher risk than placebo of inducing insomnia and/or
properties, especially if one considers that the inhibition of hista- somnolence during the short-term treatment of MD. Knowledge
minergic receptors could be more relevant in inducing a sedative of the specific sleep modulation properties of each drug is impor-
state than fluvoxamine's melatonergic action. Furthermore, a re- tant for compliance and may also be beneficial to treat specific de-
cent study demonstrated that fluvoxamine has no significant pression profiles were insomnia or somnolence are predominant.
effect on histaminergic system, whereas mirtazapine has a high Moreover, for an effective individualized treatment, other proper-
affinity for H1 receptors,62 thus explaining the higher impact of ties of the compounds, such as on weight gain or on sexual dys-
mirtazapine on weight gain. When we focused on antidepressants function, should be considered.
monotherapy studies only and on nonsponsored studies, overall Desspite the potential clinical usefulness of these findings,
findings were mainly confirmed. we suggest that data about several antidepressants should be con-
The reviewed findings are noteworthy and could have impor- sidered with caution, pointing to the need for larger properly
tant clinical implications. Indeed, patients with MD may present powered randomized controlled studies aimed at exploring the dif-
various forms of sleep disturbances, ranging from insomnia to ferences between placebo and antidepressants in terms of insom-
hypersomnia. So it is important to carefully consider each antide- nia and somnolence rates.
pressants effect on sleep-wake rhythm as a criterion for choosing
the most appropriate treatment on the basis of the individual
symptom profile. AUTHOR DISCLOSURE INFORMATION
However, several limitations should be considered before firm This study was partially supported by Abbott Laboratories.
conclusions are drawn from the results of the present meta-analysis. The authors have no other relevant affiliations or financial in-
First, we included both controlled and uncontrolled studies volvement with any organization or entity in conflict with the sub-
as well as both double-blind, single-blind, and open trials, al- ject matter or materials discussed in this manuscript apart from
though double-blind randomized controlled studies showed those disclosed.
superiority to other study designs and are usually preferred for Dr Serretti is or has been consultant/speaker for Abbott,
meta-analytic purposes.63,64 Note, however, that we performed a Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol-Myers
sensitivity analysis focusing on randomized, double-blind placebo Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco,
controlled studies, finding overall results that largely overlap Janssen, Lundbeck, Pfizer, Sanofi, and Servier. Dr Chiesa is
those observed in the general analysis, although with interesting or has been consultant/speaker for Abbott, Innovapharma.
differences. However it has been suggested that outpatients may Dr Andrisano and Dr Alberti have no conflict of interest to
show a reduced response (and compliance) in outpatient settings; disclose.
this is another possible bias in the present analysis.
Second, for studies that did not include a placebo control group, REFERENCES
we calculated a virtual placebo. Nevertheless, it is worth mentioning 1. World Health Organization WHO: The world health report 2001Mental
that in previous meta-analyses, an analysis aimed at comparing the re- Health: New Understanding, New Hope 2001. Available from:
sults observed in placebo-controlled trials separately analyzed with http://www.who.int/whr/2001/en/. 2001. Accessed April 14, 2014.
those derived including virtual placebo samples found no significant 2. Hasin DS, Goodwin RD, Stinson FS, et al. Epidemiology of major
differences between the 2 inclusion criteria.20 depressive disorder: results from the National Epidemiologic Survey on
Third, we decided to evaluate the outcomes of our interest Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005;62:
with dichotomous measures, although some studies reported 10971106.

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Alberti et al Journal of Clinical Psychopharmacology Volume 35, Number 3, June 2015

3. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of 25. Jadad AR, Moore RA, Carroll D. Assessing the quality of reports of
disease and risk factors, 2001: systematic analysis of population health randomized clinical trials: is blinding necessary? Controlled Clinical
data. Lancet. 2006;367:17471757. Trials. 1996;17:112.
4. Blair-West GW, Mellsop GW, Eyeson-Annan ML. Down-rating lifetime 26. Wells GA, Shea B, OConnell D. The Newcastle-Ottawa Scale (NOS) for
suicide risk in major depression. Acta Psychiatr Scand. 1997;95:259263. assessing the quality of nonrandomised studies in meta-analysis. 2005;
5. Murray CJ, Lopez AD. Alternative projections of mortality and disability Available from: http://www.ohri.ca/programs/clinical_epidemiology/
by cause 19902020: Global Burden of Disease Study. Lancet. 1997;349: oxford.asp. Accessed April 14, 2014.
14981504. 27. Durrleman S, Chaikin P. The use of putative placebo in active control trials:
6. Gensichen J, Petersen JJ, Von Korff M, et al. Cost-effectiveness of two applications in a regulatory setting. Stat Med. 2003;22:941952.
depression case management in small practices. Br J Psychiatry. 2013;202: 28. Jones BE. From waking to sleeping: neuronal and chemical substrates.
441446. Trends Pharmacol Sci. 2005;26:578586.
7. American Psychiatric Association Practice Guideline For The Treatment 29. Smith Y, Kieval JZ. Anatomy of the dopamine system in the basal ganglia.
of Patients With Major Depressive Disorder, 3rd edition. 2010. Trends Neurosci. 2000;23:S2833.
http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/
30. Osaka T, Matsumura H. Noradrenaline inhibits preoptic sleep-active
mdd.pdf. Accessed April 14, 2014.
neurons through alpha 2-receptors in the rat. Neurosci Res. 1995;21:
8. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines. 323330.
10th Edition. London: Informa Health Care; 2009.
31. Dhillon S, Yang LP, Curran MP. Bupropion: a review of its use in the
9. Gartlehner G, Hansen RA, Morgan LC, et al. Comparative benefits management of major depressive disorder. Drugs. 2008;68:653689.
and harms of second-generation antidepressants for treating major
32. Stahl SM, Pradko JF, Haight BR, et al. A review of the neuropharmacology
depressive disorder: an updated meta-analysis. Ann Intern Med.
of bupropion, a dual norepinephrine and dopamine reuptake inhibitor.
2011;155:772785.
Prim Care Companion J Clin Psychiatry. 2004;6:159166.
10. Spina E, Santoro V, DArrigo C. Clinically relevant pharmacokinetic
33. Richelson E. Synaptic effects of antidepressants. J Clin Psychopharmacol.
drug interactions with second-generation antidepressants: an update.
1996;16:1S7S; discussion 7S9S.
Clin Ther. 2008;30:12061227.
34. Penalva RG, Lancel M, Flachskamm C, et al. Effect of sleep and sleep
11. Thaler KJ, Morgan LC, Van Noord M, et al. Comparative effectiveness of
deprivation on serotonergic neurotransmission in the hippocampus:
second-generation antidepressants for accompanying anxiety, insomnia,
a combined in vivo microdialysis/EEG study in rats. Eur J Neurosci.
and pain in depressed patients: a systematic review. Depress Anxiety.
2003;17:18961906.
2012;29:495505.
35. Bjorvatn B, Gronli J, Hamre F, et al. Effects of sleep deprivation on
12. Cheeta S, Schifano F, Oyefeso A, et al. Antidepressant-related deaths
extracellular serotonin in hippocampus and frontal cortex of the rat.
and antidepressant prescriptions in England and Wales, 19982000.
Neuroscience. 2002;113:323330.
Br J Psychiatry. 2004;184:4147.
36. Clayton AH, Kornstein SG, Rosas G, et al. An integrated analysis of the
13. Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other
safety and tolerability of desvenlafaxine compared with placebo in the
antidepressant drugs: analysis of United Kingdom mortality data.
treatment of major depressive disorder. CNS Spectr. 2009;14:183195.
BMJ. 2002;325:13321333.
37. Nichols AI, Focht K, Jiang Q, et al. Pharmacokinetics of venlafaxine
14. Henry JA, Alexander CA, Sener EK. Relative mortality from overdose
extended release 75 mg and desvenlafaxine 50 mg in healthy CYP2D6
of antidepressants. BMJ. 1995;310:221224.
extensive and poor metabolizers: a randomized, open-label, two-period,
15. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: parallel-group, crossover study. Clin Drug Investig. 2011;31:155167.
cardiovascular toxicity. Toxicol Rev. 2005;24:205214.
38. Preskorn SH, Nichols AI, Paul J, et al. Effect of desvenlafaxine on the
16. Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic cytochrome P450 2D6 enzyme system. J Psychiatr Pract. 2008;14:
antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 368378.
2000;58:1936.
39. McAlpine DE, Biernacka JM, Mrazek DA, et al. Effect of cytochrome
17. Bull SA, Hunkeler EM, Lee JY, et al. Discontinuing or switching selective P450 enzyme polymorphisms on pharmacokinetics of venlafaxine.
serotonin-reuptake inhibitors. Ann Pharmacother. 2002;36:578584. Ther Drug Monit. 2011;33:1420.
18. Maddox JC, Levi M, Thompson C. The compliance with antidepressants 40. Kitaichi Y, Inoue T, Nakagawa S, et al. Sertraline increases extracellular
in general practice. J Psychopharmacol. 1994;8:4852. levels not only of serotonin, but also of dopamine in the nucleus accumbens
19. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to and striatum of rats. Eur J Pharmacol. 2010;647:9096.
antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29: 41. Zupancic M, Guilleminault C. Agomelatine: a preliminary review of a
259266. new antidepressant. CNS Drugs. 2006;20:981992.
20. Serretti A, Mandelli L. Antidepressants and body weight: a comprehensive 42. Racagni G, Riva MA, Popoli M. The interaction between the internal
review and meta-analysis. J Clin Psychiatry. 2010;71:12591272. clock and antidepressant efficacy. Int Clin Psychopharmacol.
21. Wirz-Justice A, Benedetti F, Berger M, et al. Chronotherapeutics 2007;22(Suppl 2):S9S14.
(light and wake therapy) in affective disorders. Psychol Med. 43. Quera-Salva MA, Lemoine P, Guilleminault C. Impact of the novel
2005;35:939944. antidepressant agomelatine on disturbed sleep-wake cycles in depressed
22. Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. patients. Hum Psychopharmacol. 2010;25:222229.
Hum Psychopharmacol. 2005;20:533559. 44. Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep
23. Serretti A, Cusin C, Benedetti F, et al. Insomnia improvement during in major depressive disorder with a novel antidepressant, agomelatine:
antidepressant treatment and CLOCK gene polymorphism. Am J Med randomized, double-blind comparison with venlafaxine. J Clin Psychiatry.
Genet B Neuropsychiatr Genet. 2005;137:3639. 2007;68:17231732.
24. Serretti A, Olgiati P, Liebman MN, et al. Clinical prediction of 45. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human
antidepressant response in mood disorders: linear multivariate vs. neural monoamine transporter binding profile of escitalopram and R-fluoxetine.
network models. Psychiatry Res. 2007;152:223231. Biol Psychiatry. 2001;50:345350.

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46. Sanchez C, Gruca P, Bien E, et al. R-citalopram counteracts the effect of cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin.
escitalopram in a rat conditioned fear stress model of anxiety. Pharmacol Eur J Clin Pharmacol. 2000;56:123127.
Biochem Behav. 2003;75:903907.
56. Mendlewicz J, Linkowski P, Branchey L, et al. Abnormal 24 hour pattern
47. Jordan S, Kramer GL, Zukas PK, et al. In vivo biogenic amine efflux of melatonin secretion in depression. Lancet. 1979;2:1362.
in medial prefrontal cortex with imipramine, fluoxetine, and fluvoxamine.
57. Rahman SA, Marcu S, Kayumov L, et al. Altered sleep architecture
Synapse. 1994;18:294297.
and higher incidence of subsyndromal depression in low endogenous
48. Pozzi L, Invernizzi R, Garavaglia C, et al. Fluoxetine increases extracellular melatonin secretors. Eur Arch Psychiatry Clin Neurosci. 2010;260:
dopamine in the prefrontal cortex by a mechanism not dependent on 327335.
serotonin: a comparison with citalopram. J Neurochem. 1999;73:
10511057. 58. Sunami E, Usuda K, Nishiyama Y, et al. A preliminary study of
fluvoxamine maleate on depressive state and serum melatonin levels
49. Tanda G, Carboni E, Frau R, et al. Increase of extracellular dopamine in the in patients after cerebral infarction. Intern Med. 2012;51:11871193.
prefrontal cortex: a trait of drugs with antidepressant potential?
Psychopharmacology (Berl). 1994;115:285288. 59. Dalery J, Honig A. Fluvoxamine versus fluoxetine in major depressive
episode: a double-blind randomised comparison. Hum Psychopharmacol.
50. Bymaster FP, Zhang W, Carter PA, et al. Fluoxetine, but not other selective
2003;18:379384.
serotonin uptake inhibitors, increases norepinephrine and dopamine
extracellular levels in prefrontal cortex. Psychopharmacology (Berl). 60. de Boer TH, Maura G, Raiteri M, et al. Neurochemical and autonomic
2002;160:353361. pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770
and its enantiomers. Neuropharmacology. 1988;27:399408.
51. Clark RN, Ashby CR Jr, Dewey SL, et al. Effect of acute and chronic
fluoxetine on extracellular dopamine levels in the caudate-putamen and 61. Behnke K, Sogaard J, Martin S, et al. Mirtazapine orally disintegrating
nucleus accumbens of rat. Synapse. 1996;23:125131. tablet versus sertraline: a prospective onset of action study. J Clin
52. Ichikawa J, Meltzer HY. Effect of antidepressants on striatal and Psychopharmacol. 2003;23:358364.
accumbens extracellular dopamine levels. Eur J Pharmacol. 1995; 62. Sato H, Ito C, Tashiro M, et al. Histamine H receptor occupancy by the
281:255261. new-generation antidepressants fluvoxamine and mirtazapine: a positron
53. Wagner W, Plekkenpol B, Gray TE, et al. Review of fluvoxamine safety emission tomography study in healthy volunteers. Psychopharmacology
database. Drugs. 1992;43(Suppl 2):4853; discussion 5354. (Berl). 2013;230:227234.
54. Hartter S, Wang X, Weigmann H, et al. Differential effects of fluvoxamine 63. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias.
and other antidepressants on the biotransformation of melatonin. Dimensions of methodological quality associated with estimates of
J Clin Psychopharmacol. 2001;21:167174. treatment effects in controlled trials. JAMA. 1995;273:408412.
55. von Bahr C, Ursing C, Yasui N, et al. Fluvoxamine but not citalopram 64. Colditz GA, Miller JN, Mosteller F. How study design affects outcomes
increases serum melatonin in healthy subjects an indication that in comparisons of therapy. I Medical Stat Med. 1989;8:441454.

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