Safety and tolerablility of AD cotreatment published

Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=ieds20

Download by: [67.87.236.65] Date: 11 September 2015, At: 08:37

Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

Safety and tolerability of antidepressant co-treatment in acute major depressive disorder:results from a systematic review and exploratorymeta-analysis

Britta Galling MD, Amat Calsina Ferrer MD, Margarita Abi Zeid Daou MD,Dinesh Sangroula MD, Katsuhiko Hagi PhD & Christoph U Correll MD

To cite this article: Britta Galling MD, Amat Calsina Ferrer MD, Margarita Abi Zeid Daou MD,Dinesh Sangroula MD, Katsuhiko Hagi PhD & Christoph U Correll MD (2015): Safety andtolerability of antidepressant co-treatment in acute major depressive disorder: results from asystematic review and exploratory meta-analysis, Expert Opinion on Drug Safety

To link to this article: http://dx.doi.org/10.1517/14740338.2015.1085970

Published online: 10 Sep 2015.

Submit your article to this journal

View related articles

View Crossmark data

http://www.tandfonline.com/action/journalInformation?journalCode=ieds20

http://www.tandfonline.com/loi/ieds20

http://dx.doi.org/10.1517/14740338.2015.1085970

http://www.tandfonline.com/action/authorSubmission?journalCode=ieds20&page=instructions

http://www.tandfonline.com/action/authorSubmission?journalCode=ieds20&page=instructions

http://www.tandfonline.com/doi/mlt/10.1517/14740338.2015.1085970

http://www.tandfonline.com/doi/mlt/10.1517/14740338.2015.1085970

http://crossmark.crossref.org/dialog/?doi=10.1517/14740338.2015.1085970&domain=pdf&date_stamp=2015-09-10

http://crossmark.crossref.org/dialog/?doi=10.1517/14740338.2015.1085970&domain=pdf&date_stamp=2015-09-10

1. Introduction

2. Methods

3. Results

4. Conclusion

5. Expert opinion

Review

Safety and tolerability ofantidepressant co-treatment inacute major depressive disorder:results from a systematic reviewand exploratory meta-analysisBritta Galling, Amat Calsina Ferrer, Margarita Abi Zeid Daou,Dinesh Sangroula, Katsuhiko Hagi & Christoph U Correll†

†The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health

System, Glen Oaks, NY, USA

Introduction: Although antidepressant (AD) monotherapy is recommended

first-line for major depressive disorder (MDD), AD + AD co-treatment is

common.

Areas covered: We conducted the first systematic review searching PubMed/

MEDLINE/PsycInfo/Embase from database inception until 1 June 2015 for

acute randomized trials in ‡ 20 adults with MDD comparing AD monotherapy

with AD + AD co-treatment that reported quantitative data on adverse events

(AEs). Meta-analyzing 23 studies (n = 2435, duration = 6.6 weeks) AD mono-

therapy and AD + AD co-treatment were similar regarding intolerability-

related discontinuation (risk ratio [RR] = 1.38, 95% CI = 0.89 -- 1.10) and

frequency of ‡ 1 AE (RR = 1.19, 95% CI = 0.95 -- 1.49). Nevertheless, AD + AD

co-treatment was associated with significantly greater burden regarding

4/25 AEs (tremor: RR = 1.55, 95% CI = 1.01 -- 2.38; sweating: RR = 1.95, 95%

CI = 1.13 --3.38, ‡ 7% weight gain: RR = 3.15, 95% CI = 1.34 -- 7.41; weight

gain = 2.17, 95% CI = 0.71 -- 3.63 kg), but not more CNS, gastrointestinal,

sexual or alertness-related AEs. However, 11/25 AEs (44.0%) were reported

in only 1 -- 2 studies. Adding noradrenergic and specific serotonergic antide-

pressants (NaSSA) or tricyclic antidepressants (TCA) to selective serotonin

reuptake inhibitors (SSRIs) was specifically associated with more AEs.

Expert opinion: The potential for increased AEs with AD + AD co-treatment

needs to be considered vis-�a-vis unclear efficacy benefits of this strategy. In

particular, NaSSAs and TCAs should be added to SSRIs with caution. Clearly,

more data on side-effect burden of AD + AD co-treatment are needed.

Keywords: adverse effects, antidepressant, augmentation, combination, co-treatment,

depression, major depressive disorder, meta-analysis, safety, tolerability

Expert Opin. Drug Saf. [Early Online]

1. Introduction

For major depressive disorder (MDD), clinical guidelines suggest as first-linetreatment evidence-based, depression-focused psychotherapy with or withoutmonotherapy of an antidepressant (AD) [1-3]. Response rates to initial AD mono-therapy range between 50 and 75%, whereas remission rates are around 30% [4-9].For patients not responding to the initial treatment, optimization of the AD dose,a switch to another AD, augmentation with various non-ADs agents withantidepressant efficacy, or the co-treatment with two ADs are recommended [1-3].

10.1517/14740338.2015.1085970 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1All rights reserved: reproduction in whole or in part not permitted

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

http://informahealthcare.com/journal/EDS

In clinical care, AD + AD co-treatment is widespread [10,11],

although results regarding the efficacy and safety of this

strategy are heterogeneous [12-18].The use of more than one antidepressant agent is mostly

explained by attempts to increase or speed up efficacy, and

to reduce adverse effects (AEs) allowing for a dose reduction

of the first antidepressant [19]. However, whereas the avoid-

ance of specific AEs often influences the choice of a specific

antidepressant, concerns about drug--drug interactions rarely

influence the selection [20].Main concerns regarding AD + AD co-treatment include

higher cost, the potential for decreased treatment adherence

due to complex drug regimes, the risk of drug--drug interac-

tions, unclear efficacy advantages and, particularly, the

increased risk of AEs. In a meta-analysis of six studies,

AD + AD combination treatment used from the beginning

was shown to be better than monotherapy regarding remis-

sion (relative risk [RR] = 2.71, 95% CI = 1.69 -- 4.35) and

response (RR = 1.5, 95% CI = 1.21 -- 1.97) [21], whereas a

review of five studies of AD augmentation of inefficacious

AD monotherapy showed heterogeneous results [22].

However, these meta-analyses focused on efficacy outcomes

and despite the relatively large use of AD + AD co-treatment

in MDD [10,11], the AE burden of this treatment strategy has

not been comprehensively assessed [21-23].

In order to allow for a comprehensive risk--benefit analysis,detailed knowledge about the short-term and long-term toler-ability and safety of AD + AD co-treatment in MDD isneeded. Therefore, we conducted a systematic review andmeta-analysis of the frequency and severity of AEs in patientswith MDD treated with AD monotherapy comparedAD + AD co-treatment. We hypothesized that the riskof AEs would be significantly greater with AD + AD co-treatment compared with AD monotherapy.

2. Methods

2.1 Literature searchTwo authors (AF, MD) independently conducted a system-atic literature search in PubMed/MEDLINE, PsycInfo andEmbase from database inception through 1 June 2015 withoutlanguage restrictions, using the following search terms: (anti-depressant* OR ‘SSRI’ OR ‘selective serotonin reuptakeinhibitor’ OR ‘SNRI’ OR ‘serotonin norepinephrine reuptakeinhibitor’ OR ‘TCA’ OR ‘tricyclic antidepressant’ OR‘MAOI’ or ‘monoamine oxidase inhibitor’ OR mianserinOR mirtazapine OR vortioxetine OR vilazodone OR levimil-nacipran OR melitracene OR phenelzine OR isocarboxazidOR tranylcypromine OR moclobemide OR amitriptylineOR clomipramine OR dosulepin OR doxepin OR imipra-mine OR lofepramine OR nortriptyline OR trimipramineOR desvenlafaxine OR duloxetine OR venlafaxine OR citalo-pram OR escitalopram OR fluoxetine OR fluvoxamine ORparoxetine OR sertraline OR trazodone OR agomelatineOR reboxetine OR selegiline) AND (augmentation* ORenhancement OR add-on* OR addition* OR supplement*OR cotreatment* OR co-treatment* OR adjunctive* OR con-current* OR concomitant* OR simultaneous* OR polyphar-macy* OR polytherapy OR combin*) AND (depress* ORMDD) AND (random* OR placebo).

The electronic search was supplemented by a manualreview of reference lists from eligible publications and relevantreviews to identify additional studies. Whenever data weremissing for the meta-analysis, the authors were contacted foradditional information.

2.2 Inclusion criteriaInclusion criteria were: i) randomized controlled trials;ii) populations containing ‡ 20 adults; iii) current primarydiagnosis of MDD; iv) randomization to AD monotherapyor the co-treatment of the same AD with a different ADand v) reporting of quantitative data on the frequency orseverity of AEs.

Included were studies investigating either AD augmenta-tion, defined as the addition of a second AD to existing ADmonotherapy, and AD combination, defined as the simulta-neous initiation of two ADs from beginning of the trial afterwashout of previous medications. Excluded were studiesthat; i) aimed at reducing AEs of AD monotherapy by addinga second AD or ii) that compared AD augmentation with AD

Article highlights.

. Although we identified 23 randomized controlledstudies with a total of 2435 participants, global andspecific adverse event (AE) frequencies and, especially,severity are insufficiently and incompletely assessed orreported in the available randomized controlled studies,with only 14/25 (56.0%) AEs being reported in at leastthree studies.

. Co-treatment strategies do not appear to be associatedwith significantly greater intolerability-relateddiscontinuations and incidence of at least one AE, butwere associated with a significantly greater incidence orseverity of 4 of 25 specific reported AEs thanmonotherapy strategies.

. Specific AEs that were more common duringantidepressant (AD) + AD co-treatment included tremor,sweating, weight gain and clinically significant weightgain.

. Sparse data suggest clinically relevant AE differencesacross individual AD + AD class combinations,disfavoring the addition of noradrenergic and specificserotonergic antidepressants (NaSSA) or tricyclicantidepressants (TCA) to selective serotonin reuptakeinhibitors (SSRIs). AE types in the co-treatment groupsgenerally reflected the known AE profiles of individualAD classes.

. In clinical care, potential efficacy advantages ofantidepressant co-treatment strategies need to beevaluated in light of potential AE disadvantages.

This box summarizes key points contained in the article.

B. Galling et al.

2 Expert Opin. Drug Saf. (2015) 14(10)

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015


switch instead of continuation of the original ADmonotherapy.

2.3 Outcomes and data abstractionThis study focused solely on safety and tolerability-relatedoutcomes. The two co-primary outcomes were intolerability-related discontinuation and the proportion of patients withat least one AE. Secondary outcomes included; i) incidenceof any specific adverse effect and ii) severity of any specificadverse event (i.e., mean score ± standard deviation [SD], orpercent of patients with a certain level of severity). In addi-tion, we extracted data on the study design (e.g., blinding,duration, etc.), patient, illness and treatment characteristicsand co-medications.

Two authors (AF, DS) independently identified andextracted data from the eligible trials; inconsistencies wereresolved by consensus or involvement of a third reviewer(BG or CUC).

2.4 Data analysisWe conducted a meta-analysis of outcomes forwhich ‡ 2 studies contributed data, using ComprehensiveMeta-Analysis V3 (http://www.meta-analysis.com). Continu-ous outcomes were expressed as the standardized mean differ-ence (SMD) between the two groups in baseline to end pointchange scores (preferred) or end point scores (only preferred ifchange score results were skewed, that is, SD >twice themean), while dichotomous data were analyzed calculatingthe pooled risk ratio (RR) (Mantel-Haenszel RR), both withtheir 95% CI. Additionally, weighted mean difference(WMD) was calculated for weight change in kilograms. Tocombine studies, the random effects model by DerSimonianand Laird [24] was used, which is more conservative than fixedeffects models. We explored study heterogeneity using thechi-square test of homogeneity, with a p < 0.05 indicatingsignificant heterogeneity.

In the primary analyses, we pooled all studies thatcompared AD monotherapy with AD + AD co-treatment.In secondary analyses, we analyzed separately augmentationand combination studies as well as at individual AD combina-tions as long as data were reported in ‡ 2 trials. Forintolerability-related discontinuation, all randomized patientswere analyzed, including observed cases reports as long as thenumber of patients dropping out for adverse effects was men-tioned. For all other outcomes, we only abstracted data fromstudies reporting last observation carried forward data. Allanalyses were two-tailed with a = 0.05 and without adjust-ments for multiple comparisons. We used funnel plots toassess publication bias regarding the two co-primaryoutcomes, discontinuation due to AEs and patients with atleast one AE. To quantify whether publication bias couldhave influenced the results, we used Egger’s regressiontest [25] and the Duval and Tweedie’s trim and fill method [26],which is an interactive procedure to remove the most extremesmall studies from the positive side of the funnel plot or to

impute studies into the negative side of the funnel plot,re-computing the effect size at each iteration until the funnelplot is symmetric about the (new) effect size. In theory, thiswill yield an unbiased estimate of the effect size.

3. Results

The initial search resulted in 6474 hits. Altogether, 6410 stud-ies were excluded being duplicates and/or on the title/abstractlevel. Of the remaining 64 references plus 6 additional studiesfound reviewing reference lists, 47 articles were excluded afterfull text review, yielding 23 studies that were included in themeta-analysis (Figure 1). Reasons for excluding articles wereas follows: different articles on the same RCT/overlappingsample: n = 23, no combination group: n = 5, study includingbipolar depression: n = 4; MDD in remission: n = 3; studynot randomized: n = 3; no MDD diagnosis: n = 2, focus ontreatment of SSRI-induced AEs: n = 2, no analyzable data:n = 2, study not finished: n = 1; case report data: n = 1,only switch to medication as comparison: n = 1.

3.1 Pooled AD + AD co-treatment versus AD

monotherapy

3.1.1 Study, patient and treatment characteristics3.1.1.1 Study characteristicsOf the 23 meta-analyzed studies [12-15,27-45], most wereconducted in Europe (studies = 11, 47.8%; n = 950)[14,30,32,33,35-37,39,41,44,45], followed by the USA/Canada (stud-ies = 8, 34.8%; n = 1164) [12,13,15,28,29,31,40,43] and other partsof the world (studies = 4, 17.4%; n = 321) (Table 1)[27,34,38,42]. Most studies (78.3%) were double-blind (stud-ies = 18, n = 1692), three were open-label (13.0%, n = 238)and two were single-blind (8.7%, n = 505). The majority ofstudies (studies = 15, 65.2%; n = 1219) evaluated AD combi-nation treatment from baseline. While less studies focused onAD augmentation after insufficient effects of AD monother-apy (studies = 8, 34.8%), the number of included patientswas similar to that in the AD combination treatment studies(n = 1216, 49.9% of all patients). The mean study durationwas 6.6 ± 2.5 (range = 4 -- 12) weeks.

3.1.1.2 Patient characteristicsAltogether, 2435 patients with MDD were studied. The meanpatient age was 41.9 ± 3.8 (range = 18 -- 84) years, with aminority of male participants (34.7%, studies = 21,n = 815) (Table 1). The severity of depression was moderateto severe in most studies (studies = 18, n = 1767, 76.2% ofsubjects). Fewer studies included patients with severe or verysevere depression (studies = 2, n = 360) or patients whowere mildly to moderately ill (study = 1, n = 135). The major-ity of subjects were outpatients (studies = 12, n = 1820), sixstudies included inpatients (n = 248) and three wereconducted in both in- and outpatients (n = 165), while twostudies did not specify the treatment setting (n = 202)(Table 1).

Safety and tolerability of antidepressant co-treatment in acute MDD

Expert Opin. Drug Saf. (2015) 14(10) 3

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

http://www.meta-analysis.com


3.1.1.3 Treatment characteristicsMost studies compared monotherapy with a SSRI with co-treatment of an AD from another class (studies = 17,73.9%; n = 1405). The added non-SSRI ADs included norad-renergic and specific serotonergic antidepressants (NaSSA,studies = 7, n = 535), tricyclic antidepressants (TCA, stud-ies = 5, n = 139), norepinephrine-dopamine reuptake inhibi-tors (NDRI, studies = 3, n = 505) and norepinephrinereuptake inhibitors (NRI, studies = 2, n = 227). Other studiescompared TCA versus TCA + TCA (studies = 2, n = 173),TCA versus TCA + SSRI (studies = 2, n = 61), TCA versusTCA + monoamine oxidase inhibitor (MAOI, studies = 2,n = 135), MAOI versus MAOI + TCA (studies = 2,n = 79), TCA versus TCA + NaSSA (study = 1, n = 46),NDRI versus NDRI + SSRI (study = 1, n = 245),norepinephrine-reuptake inhibitor (NRI) versus NRI + SSRI(study = 1, n = 156), NaSSA versus NaSSA + SSRI (study = 1,n = 61), SNRI versus SNRI + NDRI (studies = 1, n = 48) andserotonin antagonist and reuptake inhibitors (SARI) versusSARI + SSRI (study = 1, n = 25) (Table 1).

3.1.2 AE risk with AD + AD co-treatment versus AD

monotherapyAll identified AE outcomes were reported by ‡ 2 studies,allowing meta-analytic calculations, but only 14/25 AEs(56.0%) were reported by ‡ 3 studies (Table 2).

There was no significant difference between AD monother-

apy and AD co-treatment regarding the two co-primary out-

comes, intolerability-related discontinuation (RR = 1.37,

95% CI = 0.89 -- 1.10, p = 0.80; heterogeneity: p = 0.80;

studies = 13, n = 1270) and frequency of ‡ 1 AE

(RR = 1.19, 95% CI = 0.95 -- 1.49, p = 0.14; heterogeneity:

p < 0.001; studies = 6, n = 1029) (Table 2).There was no indication of publication bias for the co-

primary outcomes across all meta-analyzable studies

(Figure 2A and B). The RRs remained virtually identical

even after applying the Duval and Tweedie’s trim and fill

method and after 4 missing studies for intolerability-related

discontinuation and two studies for frequency of ‡ 1 AE

were imputed.Regarding specific AEs, compared with AD monotherapy,

AD + AD co-treatment was associated with significantly

greater AE burden regarding 4/25 AEs. These four AEs

included tremor: RR = 1.55, 95% CI = 1.01 -- 2.38,

p = 0.044; sweating: RR = 1.95, 95% CI = 1.13 -- 3.38,

p = 0.017; ‡ 7% weight gain: RR = 3.15, 95%

CI = 1.34 -- 7.41, p = 0.009; body weight change:

SMD = 1.03, 95% CI = 0.27 -- 1.79, p = 0.008 and

WMD = 2.17, 95% CI = 0.71 -- 3.63 kg, p = 0.016) (Table 2).AD + AD co-treatment was not associated with greater AE

burden than AD monotherapy regarding CNS, gastrointesti-

nal, sexual and alertness-related AEs.

Unique articles identified and screened (n = 4796)

Articles excluded at abstract level (n = 4732)

Full text articles retrieved for evaluation of eligibility (n = 64)

Articles excluded (n = 47):• Overlapping sample (n = 23)• No combination group (n = 5)• Bipolar depression (n = 4)• MDD in remission (n = 3)• Not randomized (n = 3)• No MDD diagnosis (n = 2)• Study on SSRI-induced sexual dysfunction (n = 2)• Not analyzable data (n = 2)• Only switch as comparison (n = 1)• Case report data (n = 1)• Not finished studies (n = 1)

RCTs included in the meta-analysis (n = 23)

Potentially relevant articles (n = 6474)

Duplicate articles (n = 1678)

Individual hits in PubMed(n = 3847 )

Iden

tific

atio

nS

cree

ning

Elig

ibili

tyIn

clud

ed

Articles identified inreviews or meta-analyses (n = 6)

Individual hits in PsycINFO(n = 2319)

Individual hits in Embase(n = 308)

Figure 1. Flow chart for the systematic literature search.

B. Galling et al.


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015


Table

1.Design,patient,

illness

andtreatm

entch

aracteristics.

Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Augmentationstudies

Balletal.(2014)

(USA)[28]

--Double-blind

--Augmentation

--Outpatient

8227(226)

DSM-IV-TR

--NR

--Recurrent(‡

1episodein

last

5yrs)

--Partialresponders

onSSRI

‡2failures

torespond

toAD

incurrent

episode,BP,

PSY

45.1

±10.8

(18--65)

30.4

SSRI:

--Ongoingtx,

PBO

--n=115

SSRI+EDV:

--SSRI:ongoing

tx,EDV:12.7

(6--18)

--n=111

Hypnotics

forinsomnia

(<15d)

Fava

etal.(2002)

(USA)[15]

--Double-blind

--Augmentation

--Outpatient

--Multicenter

467(67)

DSM-III-R

--NR

--Resistant(partialor

nonresponders)to

openlabelFLU

--17-HDRS‡16

BP,PSY

40.3

±10.7

(18--65)

52.2

FLU:--N

R(40--60)

--n=33

FLU

+DES:

--FLU

:20(fixed

dose),DES:NR

(25--50)

--n=34

LRZ,over-

the-counter

medication

Fava

etal.(1994)

(USA)[31]

--Double-blind

--Augmentation

--Outpatient

--Multicenter

427(27)

DSM-III-R

--NR

--Refractory

toFLU

--17-HDRS‡16

NR

39.6§±9.9§

(18--65)§

39.0§

FLU:

--Ongoingtx:

NR(40--60)

--n=15

FLU

+DES:

--FLU

:20(fixed

dose),DES:NR

(25--50)

--n=12

NR

Ferrerietal.(2001)

(France)[32]

--Double-blind

--Augmentation

--In-andoutpatient

--Multi-center

670(70)

DSM-III-R

--7.3

±8.5

mo§

--Atleast

6wksoftx

withFLU

20mg/d

--17-HDRS‡25

PSY,

substance

abuse,

medical

illness

46.6

±12.7

§26.0

§FLU:

--20(fixeddose)

--n=38

FLU

+MIA:

--FLU

:20(fixed

dose),MIA:60

(fixeddose)

--n=32

BZP

Gulrezetal.(2012)

(India)[34]

--Single-blind(sub-

jects)

--Augmentation

--Outpatient

460(60)

DSM-IV-TR

--NR

--partialresponders

--NR

BP

41.2

±13.6

(18--75)

48.3

SSRIs:

--NR(NR)

--n=30

SSRI+BUP-SR:

--SSRIs:NR(NR),

BUP-SR:NR

(150--300)

--n=30

NR

Lichtetal.(2002)

(Denmark)[36]

--Double-blind

--Augmentation

--Outpatient

--Multicenter

5295(293)

DSM-IV

--NR

--NR

--17-HDRS‡18

PSY,

suicidality,

substance

abuse,psy-

chotic

features

40.3

±11.0

(19--65)

37.9

SER:ongoingtx

--100(fixed

dose)

--n=98

SER+MIA:

--SER:100(fixed

dose),MIA:30

(10--30)

--n=98

OXA,ZLP

SER:

--200(fixed

dose)

--n=97

*Numbers

basedonobservedcases.

z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle

(meanrange).**AMIstudyarm

:6weeks,

FLVandFLV+AMIstudyarm

s:4wks.

AD:Antidepressant;AMI:Amitriptyline;BP:Bipolardisorder;BUP:Bupropion;BUP-XL:

Bupropionextendedrelease;BUP-SR:Bupropionsustainedrelease;BZP:Benzodiazepine;CDP:Chlordiazepoxide;CLN

:Clonazepam;CLO

:Clomipramine;

CIT:Citaloprame;DCE:Durationofcurrentepisode;DEP:Depression;DES:Desipramine;DIA:Diazepam;d/o:disorder;d:day;

DSM-III:

TheDiagnostic

andStatisticalManualofMentalDisorders,ThirdEdition;DSM-IV(TR):TheDiagnostic

andStatisticalManualofMentalDisorders,FourthEdition(Text

Revised);DUL:

Duloxetine;ESC:Escitalopram;FLU:Fluoxetine;FLV:Fluvoxamine;HYP:Hypnotics;ISO:Isocarboxazid;IM

I:Im

ipramine;ITT:Intentionto

treat;LRZ:Lorazepam;

m:Month(s);MIA:Mianserin;MIR:Mirtazapine;Mono:Monotherapy;

N:Numberofstudies;

n:Numberofrandomizedsubjects;

NIT:Nitrazepam;NOR:Nortryptiline;NR:Notreported;OXA:Oxazepam;PAR:Paroxetine;PBO:Placebo;

PHE:Phenelzine;PSY:Psychosis;

REB:Reboxetine;SD:Standard

deviation;SER:Sertraline;SSRI:Selectiveserotonin

reuptakeinhibitor;TCA:Tricyclic

antidepressant;TCP:Tranylcypromine;TRI:Trimipramine;TRZ:Trazodone;tx:Treatm

ent;

wk:Week;yrs:

Years;ZLP:Zolpidem;ZOP:Zopiclone.

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

1.Design,patient,

illness

andtreatm

entch

aracteristics(continued).

Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Maesetal.(1996)

(Belgium)[37]

--Double-blind

--Augmentation

after10days

wash-out

--Inpatient

425(22)

DMS-III

--9.5

yrs

--NR

--17-HDRS‡18

OtherAxisI

d/o

52.8

±14.2

(25--70)*

50.0

TRZ:

--100(fixed

dose)

--n=10*

TRZ+FLU:

--TRZ:100(fixed

dose),FLU:20

(fixeddose)

--n=12*

NR

Rush

etal.(COMED)

(2011)(USA)[29]

--Single-blind

--Augmentation

--Outpatient

--Multicenter

12

445(445)

DSM-IV-TR

--NR

--Chronic,recurrent

--Moderatelysevere

BP,PSY

43.0

±13.3

(18--75)

34.4

ESC:

--NR(10--20)

--n=224

ESC

+BUP:

--ESC:NR(10--

20),BUP:NR

(150--400)

--n=221

None

Total:Studies=8,n

=1216,34.8%

of

totalstudies;

USA

andCanada:Studies

=4,n=766,

17.4%

oftotal

studies;

Europe:

Studies=3,n=

390,13.0%

oftotal

studies;

Rest

ofthe

world:Study=1,n

=60,4.3%

oftotal

studies

--Double-blind:

Studies=6,n=

711,26.1%

of

totalstudies;

Single-blind:Stud-

ies=2,n=505,

8.7%

oftotal

studies;

Open-label:

Study=0

--Outpatients:Stud-

ies=6,n=1121,

46.0

%oftotal

patients;In-and

outpatients:Study

=1,n=70,2.9

%oftotalpatients;

Inpatients:Study=

1,n=25,1%

of

totalpatients

5.9

(4--12)

1216(1210)

DSM-IV-TR:

Studies=

3,n=732;

DSM-IV:

Study=1,

n=295;

DSM-III-R:

Studies=

3,n=164;

DSM-III:

Study=1,

n=25;

17-HDRS‡16:

Studies=5,n=

826;17-HDRS‡18:

Studies=2,n=

320;17-HDRS‡25:

Study=1,n=70

Severity

of

depression:Moder-

ate

tosevere:

Studies=7,n=

1146,47%

oftotal

patients

Very

severe:

Studies=1,n=70,

2.9

%oftotal

patients

42.8

(18--

75)

36.1

SSRIvs

SSRI+NaSSA:

Studies=2,n(SSRI)=233,n

(SSRI+NaSSA)=251

SSRIvs

SSRI+NDRI:

Studies=2,n(SSRI)=254,n

(SSRI+NDRI)=251

SSRIvs

SSRI+NRI:

Study=1,n(SSRI)=115,n(SSRI

+NDRI)=111

SSRIvs

SSRI+TCA:

Studies=2,n(SSRI)=48,n(SSRI

+TCA)=46

SARIvs

SARI+SSRI:

Study=1,n(SARI)=10,n(SARI

+SSRI)=12

Co-treatm

entstudies

Akkaya

etal.(2010)

(Turkey)

[27]

--Openlabel

--Co-start

--NR

--Pooleddata

10

156(156)

DSM-IV-TR

NRNR

17-HDRS‡16

OtherAxisI

orIId/o,

PSY,

suicidality

40.5

±10.9

(19--65)*

16.7

REB:

--NR(4

--8)

--n=50*

REB+SER:

--REB:NR(4

--8

BID),SER:50

(fixeddose)

--n=52*

NR

SER:

--50(fixeddose)

--n=54*

*Numbers


z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle


:6weeks,


s:4wks.



:Clonazepam;CLO

:Clomipramine;


DSM-III:

TheDiagnostic



Revised);DUL:


I:Im




N:Numberofstudies;








ent;

wk:Week;yrs:


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

1.Design,patient,

illness

andtreatm

entch


Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Blieretal.(2009)

(Canada)[12]

--Double-blind

--Co-start

--Outpatient

861(61)

DSM-IV

--NR

--First

episode(63%

)or

recurrent(37%

),‡1

failedtx

(24.6%

)--1

7-HDRS‡18

BP

43.1

±10.5

54.1

MIR:

--NR(30--45)

--n=21

MIR

+PAR:

--MIR:NR

(30--45),

PAR:NR

(20--30)

--n=21

CLN

PAR:

--NR(20--30)

--n=19

Blieretal.(2010)

(Canada)[13]

--Double-blind

--Co-start

--Outpatients

--Multicenter

653(53)

DSM-IV

--NR

--Recurrent(68%

),‡

1failedtx

(50%

),‡

1yr

(43%

)--1

7-HDRS‡18

(Hypo)

mania,seiz-

ures,medical

illness

44.7

±2.3

NR

FLU:

--20(fixeddose)

--n=28

FLU

+MIR:

--FLU

:20(fixed

dose),MIR:30

(fixeddose)

--n=25

CLN

,ZOP,

ZLP

Dam

etal.(1998)

(Denmark)[30]

--Double-blind

--Co-start

--In-and

outpatients

634(34)

ICD-10,

DSM-III-R

--NR

--NR

--Moderate

tosevere,

--17-HDRS>16,

MES>14

Psychotic

DEP

NR(18--70)

*NR

FLU:

--20(fixeddose)

--n=18*

FLU

+MIA:

--FLU

:20(fixed

dose),MIA:30

(fixeddose)

--n=16*

NR

Fornaro

etal.(2014)

(Italy)[33]

--Double-blind

--Co-start

--Outpatient

648(45)

DSM-IV

--NR

--Currentepisode

withatypical

features

--NR

Epilepsy,

organicbrain

disease

39.0

±11.7

(19--65)

34.8

DUL:

--91.3

(60--

120)

--n=22

DUL+BUP:

--DUL:

86.1

(60

--120),BUP:

215.2

(150--

300)

--n=23

LRZ

Lauritzenetal.

(1992)(Denmark)

[35]

--Double-blind

--Co-start

after3

days

washout--N

R

646(40)

DSM-III

--NR

--17-HDRS>16

--Melancholia

scale

score:15--67

Current

episode‡12

m,suicidality

60z

(44--84)

25.0

IMI:

--NR(50--100)

--n=18

IMI+MIA:

--IMI:NR(50--

100),MIA:30

(fixeddose)

--n=22

OXA

Maesetal.(1999)

(Belgium)[37]

--Double-blind

--Co-start

--Inpatient

523(21)

DSM-III-R

--NR

--NR

--Allseveritiesof

MDD

(stages0--5)

OtherAxisI

d/o

49.1

±15.2

(25--70)

57.1

FLU:

--20(fixeddose)

--n=11

FLU

+MIA:

--FLU

:20(fixed

dose),MIA:30

(fixeddose)

--n=10

CDP,LRZ

*Numbers


z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle


:6weeks,


s:4wks.



:Clonazepam;CLO

:Clomipramine;


DSM-III:

TheDiagnostic



Revised);DUL:


I:Im




N:Numberofstudies;








ent;

wk:Week;yrs:


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

1.Design,patient,

illness

andtreatm

entch


Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Matreja

etal.(2012)

(India)[38]

--Openlabel

--Co-start

--Inpatient

660(60)

ICD-10,

DSM-IV

--3.7

±2.8

yrs

--Newlydiagnosed,

partialandnon-

responders

included

--17-HDRS‡18

BP,PSY

40.1

±12.9

(18--75)

50.0

SSRIs:

--NR(NR)

--n=30

SSRI+MIR:

--SSRI:NR(NR),

MIR:7.5

(fixed

dose)

--n=30

Concomitant

medication

allowed,but

notspecified

Murphyetal.(1977)

(UK)[39]

--Double-blind,

--Co-start

--Outpatient

--Multicenter

4173(173)

NR

--50.4

mo

--Endogenousand

reactivedepression

--Severe

enoughto

qualifyforTCAtx,

butbeanoutpatient

population

Medical

illness

and

pt.onother

psychotropic

medication

42.4

(18--65)

22.0

CLO

:--1

0TID

(fixeddose)

--n=57(57)

CLO

+DES:

--CLO

:10TID

(fixeddose),

DES:25TID

(fixeddose)

--n=58(58)

HYP

DES:

--25TID

(fixed

dose)

--n=58(58)

Nelsonetal.(2004)

(USA)[40]

--Double-blind

--Co-start

--Inpatient

--Multicenter

639(39)

DSM-IV

--NR

--MDD,sometx

resistantpatients,no

psychoticfeatures

--17-HDRSscore

‡18

BP,PSY,Sz,

SzA

,sub-

stance

abuse,clus-

terB

personality

d/o,medical

illness

44.8

±12.5

(>21)

43.6

DES:

--293.7

(100--350)

--n=12

DES+FLU:

--DES:98.1

(100

--350),FLU:20

(fixeddose)

--n=13

BZP

FLU:

--20(fixeddose)

--n=14

O’Brienetal.(1992)

(Ireland)[41]

--Double-blind

--Co-start

--Inpatient

679(79)

Research

diagnostic

criteria

(RDC)

--NR

--NR

--17-HDRSscore

‡16

Txresistant

DEP,other

medicalor

psychiatric

illness

41.4

±12.1

(18--65)*

43.0

TCP:

--18.5

(10--30)

--n=26*

TCP+AMI:

--TCP:19.7

(10

--30),AMI:

108.7

(50--150)

--n=25*

BZP

AMI:

--114.3

(50--

150)

--n=28*

*Numbers


z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle


:6weeks,


s:4wks.



:Clonazepam;CLO

:Clomipramine;


DSM-III:

TheDiagnostic



Revised);DUL:


I:Im




N:Numberofstudies;








ent;

wk:Week;yrs:


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

1.Design,patient,

illness

andtreatm

entch


Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Raisietal.(2006)

(Iran)[42]

--Double-blind

--Co-start

after

wash-out

--Outpatient

845(45)

DSM-IV

--10.6

±6.8

mo--N

R--1

7-HDRSscore

‡20

NR

33.0

±10.7

(18--54)

40

CIT:

--40(NR)

--n=22

CIT

+NOR:

--CIT:40(NR),

NOR:50(NR)

--n=23

None

Stewart

etal.(2014)

(USA)[43]

--Double-blind

--Co-start

--Outpatient

--Multicenter

12

245(245)

DSM-IV-TR

--DCE:80.1

±--1

31.1

mo

(6.7

±10.9)

--NR

--NR

BP,PSY

40.3

±10.7

(18--65)

33.5

BUP-XL:

--NR(150--450)

--n=83

BUP-XL+ESC:

--BUP-XL:

NR

(150--450),

ESC:NR

(10--40)

--n=78

NR

ESC:

--NR(10--40)

--n=84

Vezm

aretal.(2009)

(Serbia)[44]

--Openlabel

--Co-start

--Inpatient

4--6**

22(22)

DSM-IV

--NR--N

R--H

DRS

score

‡18

OtherAxisI

andIId/o

43.6

±11.4

31.8

AMI:

--75(fixeddose)

--n=9

AMI+FLV:

--AMI:75(fixed

dose),FLV:100

(fixeddose)

--n=7

NR

FLV:

--100(fixed

dose)

--n=6

Youngetal.(1979)

(UK)[45]

--Double-blind

--Co-start

--Outpatient

6135(135)

NR

--14.49m

--NR--M

ildto

moderate

OtherAxisI

orIId/o,

medical

illness

36.2

(20--70)

36.3

TRI:--1

06{

(50--150)

--n=34

TRI+PHE:

--TRI:102{

(50--150),PHE:

44(15--60)

--n=26

NIT,DIA

PHE:--4

5{

(15--60)

--n=25

TRI+ISO:

--TRI:96{

(50--150),ISO:

30(10--30)

--n=25

ISO

:--3

2{,#

(10--30)

--n=25

*Numbers


z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle


:6weeks,


s:4wks.



:Clonazepam;CLO

:Clomipramine;


DSM-III:

TheDiagnostic



Revised);DUL:


I:Im




N:Numberofstudies;








ent;

wk:Week;yrs:


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

1.Design,patient,

illness

andtreatm

entch


Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Total:Studies=15,

n=1219,65.2

%oftotalstudies;

Europe:Studies=8,

n=560,34.8

%of

totalstudies;

USA

andCanada:Studies

=4,n=398,17.4

%oftotalstudies;

Rest

oftheworld:

Studies=3,n=

261,13.0

%oftotal

studies

--Double-blind:

Studies=12,n=

981,52.2

%of

totalstudies;

Open-

label:Studies=3,

n=238,13.0%

of

totalstudies;

--Single-blind:Stud-

ies=0

--Outpatients:Stud-

ies=6,n=699,

28.7%

oftotal

patients;Inpatients:

Studies=5,n=

223,9.2

%of

totalpatients;--In-

andoutpatients:

Studies=2,n=

95,3.9

%oftotal

patients

--NR:

Studies=2,n=

202,8.3

%of

totalpatients

6.7

(4--

12)

1219(1209)

DSM-IV-TR:

Studies=

2,n=401;

NR:Studies

=2,n

=308;DSM-

IV:Studies

=6,n=

268;

Research

Diagnostic

Criteria:

Studies=

1,n=79;

ICD-10,

DSM-IV:

Studies=

1,n=60;

--NR:Studies=2,n

=308;17-HDRS‡

16:Studies=4,n=

292;MADRS‡22:

Study=1,n=245;

17-HDRS‡18:

Studies=3,n=

174;HDRS‡18:

Studies=2,n=61;

21-HDRS‡14:Study

=1,n=48;HDRS‡

16,MES>15:Study

=1,n=46;

17-HDRS‡20:Study

=1,n=45--Severity

ofdepression:

Moderate

tosevere:

Studies=11,n=

621,25.5%

oftotal

patients;Severe

tovery

severe:Studies

=2,n=290,11.9%

oftotalpatients;NR:

Studies=1,n=

173,7.1

%oftotal

patients;Mild

tomoderate:Studies=

1,n=135,5.5

%oftotalpatients

40.9

(18--84)

33.2

SSRIvs

SSRI+NaSSA:Studies=

5,n(SSRI)=106,n(SSRI+

NaSSA)=92

SSRIvs

SSRI+TCA:Studies=3,n

(SSRI)=42,n(SSRI+TCA)=34

SSRIvs

SSRI+NDRI:Study=1,n

(SSRI)=84,n(SSRI+NDRI)=39

SSRIvs

SSRI+NRI:Study=1,n

(SSRI)=54,n(SSRI+NRI)=26

TCA

vsTCA

+MAOI:Studies=2,

n(TCA)=62,n(TCA+MAOI)=

38

TCA

vsTCA

+NaSSA:Study=1,

n(TCA)=18,n(TCA+NaSSA)=

22

TCA

vsTCA

+SSRI:Studies=2,

n(TCA)=21,n(TCA+SSRI)=9

TCA

vsTCA

+TCA:Studies=2,

n(TCA)=115,n(TCA

+TCA)=

58

MAOIvs

MAOI+TCA:Studies=2,

n(M

AOI)=76,n(M

AOI+TCA)

=38

NaSSA

vsNaSSA

+SSRI:Study=

1,n(NaSSA)=21,n(NaSSA

+SSRI)=10

NDRIvs

NDRI+SSRI:Study=1,n

(NDRI)=83,n(NDRI+SSRI)=39

NRIvs

NRI+SSRI:Study=1,n

(NRI)=50,n(NRI+SSRI)=26

SNRIvs

SNRI+NDRI:Study=1,n

(SNRI)=23,n(SNRI+NDRI)=23

Summary

oftotalstudies

Total:Studies=23,

n=2435;USAand

Canada:Studies=8,

n=1164,34.8%

of

totalstudies;

Europe:

--Double-blind:

Studies=18,n=

1692,78.3%

of

totalstudies;;

Single-blind:

6.4

(4--

12)

2435(2419)

DSM-III:

Studies=

1,n=46;

ICD-10,

DSM-III:

17-HDRS‡16:

Studies=9,n=

1118;17-HDRS‡

18:Studies=5,n=

494;NR:studies=2,

41.9

(18--84)

34.7

SSRIvs

SSRI+NaSSA:Studies=

7,n(SSRI)=339,n(SSRI+

NaSSA)=222

SSRIvs

SSRI+TCA:Studies=5,n

(SSRI)=90,n(SSRI+TCA)=80

*Numbers


z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle


:6weeks,


s:4wks.



:Clonazepam;CLO

:Clomipramine;


DSM-III:

TheDiagnostic



Revised);DUL:


I:Im




N:Numberofstudies;








ent;

wk:Week;yrs:


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

1.Design,patient,illness

andtreatm

entch


Study(year)

Design:--B

linding

--Co-start/A

ug-

mentation

--Setting

--Multicenter

Trial

duration

(wks)

NRandom-

ized(ITT)

Diagnostic

criteria

MDD

MDD:

--Meanduration

(years)

--Illness

state

--Illness

severity

Exclusion

criteria

Age:years

±SD

(range)

Sex:

Male

(%)

Monotherapy:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Combination:

--Meandose,

range(m

g)

--Numberof

patients

(ITT)

Adjunctive

medication

allowed

Studies=11,n=

950,47.8%

oftotal

studies;

Rest

ofthe

world:Studies=4,n

=321,17.4%

of

totalstudies

Studies=2,n=

505,8.7%

oftotal

studies;;Open-

label:Studies=3,

n=238,13.0%

of

totalstudies;

--Co-

treatm

ent:Studies

=15,n=1219,

65.2%

oftotal

studies;

--Augmentation:

Studies=8,n=

1216,34.8%

of

totalstudies;

--Outpatients:Stud-

ies=12,n=1820,

74.7%

oftotal

patients;Inpatients:

Studies=6,

n=248,10.2%

of

totalpatients;NR:

Studies=2,n=

202,8.3%

oftotal

patients;In-and

outpatients:Studies

=3,n=165,

6.8%

oftotal

patients

Studies=

1,n=34;

DSM-III-R:

Studies=

1,n=23

n=308;17-HDRS‡

25:Study=1,n=

70;HDRS‡18:

Studies=2,n=61;

21-HDRS‡14:Study

=1,n=48;MADRS

‡22:Study=1,n=

245;HDRS‡16,

MES>15:Study=

1,n=46;17-HDRS

‡20:Study=1,n=

45;Severity

of

depression:Mild

tomoderate:Studies=

1,n=135,5.5%

of

totalpatients

Moderate

tosevere:

Studies=18,n=

1767,72.6%

of

totalpatients

Severe

tovery

severe:

Studies=2,n=

290,11.9%

oftotal

patients

Very

severe:

Studies=1,n=70,

2.9%

oftotal

patients,NR:studies

=1,n=173,7.1%

oftotalpatients

SSRIvs

SSRI+NDRI:Studies=3,

n(SSRI)=338,n(SSRI+NDRI)=

290

SSRIvs

SSRI+NRI:Studies=2,n

(SSRI)=169,n(SSRI+NRI)=137

TCAvs

TCA+MAOI:Studies=2,

n(TCA)=62,n(TCA+MAOI)=

38

TCAvs

TCA+NaSSA:Study=1,

n(TCA)=18,n(TCA+NaSSA)=

22

TCAvs

TCA+SSRI:Studies=2,

n(TCA)=21,n(TCA+SSRI)=9

TCAvs

TCA+TCA:Studies=2,

n(TCA)=115,n(TCA

+TCA)=

58

MAOIvs

MAOI+TCA:Studies=

2,n(M

AOI)=76,n(M

AOI+

TCA)=38

NaSSA

vsNaSSA

+SSRI:Study=

1,n(NaSSA)=21,n(NaSSA

+SSRI)=10

NDRIvs

NDRI+SSRI:Study=1,n

(NDRI)=83,n(NDRI+SSRI)=39

NRIvs

NRI+SSRI:Study=1,n

(NRI)=50,n(NRI+SSRI)=26

SNRIvs

SNRI+NDRI:Study=1,n

(SNRI)=23,n(SNRI+NDRI)=23

SARIvs

SARI+SSRI:Study=1,n

(SARI)=10,n(SARI+SSRI)=12

*Numbers


z Median.

§

Numbers

basedonwhole

studysample.{ M

eansofthelast

3weeksofthetrial.

#Asreportedin

thearticle


:6weeks,


s:4wks.



:Clonazepam;CLO

:Clomipramine;


DSM-III:

TheDiagnostic



Revised);DUL:


I:Im




N:Numberofstudies;








ent;

wk:Week;yrs:


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

3.1.3 AE risk with specific AD + AD class co-treatment

versus AD monotherapyRegarding individual AD co-treatment, addition of NaSSAs toSSRIs was associated with significantly more incidenceof ‡ 1 AE (RR = 1.63, 95% CI = 1.19 -- 2.23); sedation(RR = 3.22, 95% CI = 2.16 -- 4.081); ‡ 7% weight gain(RR = 3.81, 95% CI = 1.37 -- 10.55; SMD = 1.0, 95%CI = 1.03, 95% CI = 0.27 -- 1.79; WMD = 2.17, 95%CI = 0.71 -- 3.63 kg) than SSRI monotherapy (Table 3).Furthermore, TCA augmentation of SSRIs was associatedwith significantly greater incidence of dry mouth (RR = 1.96,95% CI = 1.17 -- 3.28) compared with SSRI monotherapy.

3.2 AD + AD augmentation versus AD monotherapy

3.2.1 Study, patient and treatment characteristics3.2.1.1 Study characteristicsIn total, 8 of the 23 studies (34.8%) with 16 treatment armsinvestigated AD augmentation, that is, the addition of a

second AD after insufficient response of AD monotherapy(Table 1) [15,28,29,31,32,34,36,37]. Augmentation studies weredouble-blind (75.0%, studies = 6, n = 1692) or single-blind(25%, studies = 2, n = 505). The mean study duration was6.1 ± 2.3 (range = 4 -- 12) weeks.

3.2.1.2 Patient characteristicsAltogether, 1216 patients with MDD were studied. The meanpatient age was 42.8 ± 4.5 (range = 18 -- 75) years, with aminority of male participants (36.1%, studies = 8, n = 439)(Table 1). All studies were conducted in patients who hadfailed prior antidepressant treatment or who were consideredtreatment resistant. The severity of depression was reportedto be moderate to severe in seven studies (n = 1146, 87.5%of subjects), while only one study included severely ill patients

(n = 70). The majority of subjects were outpatients (studies = 6,n = 1121), whereas one study was conducted with inpatients(n = 25), and one with in- and outpatients (n = 70).

-2.0

A.

B.

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

0.0

0.5

1.0

1.5

2.0

Sta

nd

ard

err

or

MH log risk ratio

Funnel plot of standard error by MH log risk ratio

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

Sta

nd

ard

err

or

MH log risk ratio

Funnel plot of standard error by MH log risk ratio0.0

0.2

0.4

0.6

0.8

1.0

Figure 2. (A) Funnel plot analysis for discontinuation due to adverse effect (all the studies are included). Observed RR (open

diamond) = 1.368 (95% CI: 0.894, 2.096); Egger’s test: p = 0.135. Adjusted RR (black diamond) after imputation of 4 missing

studies (black circles) = 1.204 (95% CI: 0.798 -- 1.815). (B) Funnel plot analysis for at least one adverse effect (only LOCF studies

are included). Observed RR (open diamond) = 1.180 (95% CI: 0.964, 1.444); Egger’s test: p = 0.344. Adjusted RR (black

diamond) after imputation of 2 missing studies (black circles) = 1.107 (95% CI: 0.904 -- 1.357)

B. Galling et al.


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015


Table

2.Adverseeffect

outcomesin

patients

onantidepressantmonotherapyversusantidepressantco

-treatm

ent(augmentationorco

mbination).

Outcome

Allstudies

Augmentation-studies

Combinationtreatm

ent-studies

Outcome

Nn

Riskratio/

SMD

95%

CI

p-

Value

p-Value

heterogeneity

Nn

Risk

ratio/

SMD

95%

CI

p-

Value

p-Value

heterogeneity

NN

Riskratio/

SMD

95%

CI

p-

Value

p-Value

heterogeneity

Co-primary

outcomes

Discontinuation

dueto

AE

18

1270

1.368

0.894,

2.096

0.149

0.797

3323

1.737

0.386,

7.807

0.471

0.220

15

947

1.434

0.887,

2.319

0.142

0.833

Atleast

oneAE

91029

1.185

0.945,

1.486

0.142

<0.001

3589

AD

mono"

1.498z

1.299,

1.726z

< 0.001§

0.406

6440

0.982

0.840,

1.149

0.824

0.140

Movementdisorder

Tremor

4576

AD

mono"

1.552z

1.012,

2.380z

0.044§

0.811

1293

1.327

0.383,

4.592

0.656

--3

283

AD

mono"

1.585z

1.006,

2.499z

0.047§

0.640

Anticholinergic

AE

Dry

mouth/

reduced

salivation

8839

1.516

0.910,

2.526

0.110

0.002§

3430

AD

mono"

2.082z

1.234,

3.513z

0.006§

0.403

5409

1.289

0.674,

2.465

0.443

0.002§

Blurredvision

265

2.265

0.556,

9.230

0.254

0.730

127

3.692

0.164,

83.268

0.411

--1

38

2.000

0.415,

9.650

0.388

--

Arousal-relatedAE

Sedation

5636

1.655

0.858,

3.194

0.133

0.023§

1293

AD

mono"

3.198z

2.134,

4.792z

< 0.001§

--4

343

1.149

0.700,

1.888

0.583

0.675

Fatigue/tired-

ness/drowsiness

5420

1.227

0.749,

2.010

0.418

0.445

2137

2.018

0.511,

7.975

0.317

0.251

3283

1.052

0.578,

1.915

0.867

0.431

Asthenia/lack

of

energy

2108

0.739

0.254,

2.150

0.579

0.325

170

0.297

0.035,

2.524

0.266

--1

38

1.000

0.292,

3.426

1.000

--

Insomnia

6702

0.855

0.566,

1.291

0.456

0.202

1293

1.279

0.574,

2.851

0.547

--5

409

0.778

0.481,

1.257

0.305

0.180

CardiovascularAE

Fainting/

Dizziness

8839

1.063

0.754,

1.498

0.729

0.998

3430

1.074

0.610,

1.892

0.804

0.791

5409

1.056

0.685,

1.627

0.805

0.990

Tachycardia

3164

0.836

0.192,

3.640

0.811

0.215

00

----

----

3164

0.836

0.192,

3.640

0.811

0.215

CNSAE

Confusion

3283

1.470

0.754,

2.867

0.258

0.419

00

----

----

3283

1.470

0.754,

2.867

0.258

0.419

Mania

4393

0.995

0.455,

2.176

0.990

0.549

00

----

----

4393

0.995

0.455,

2.176

0.990

0.549

Tension/inner

restlessness

3419

0.684

0.305,

1.536

0.358

0.932

1293

0.569

0.120,

2.686

0.476

--2

126

0.733

0.284,

1.891

0.521

0.799

*Averagechange,endpointonly

ifnoaveragechangeavailable.

z,§pvalues:

p<0.05;continuousdata

initalics.

":Superior;AD:Antidepressant;AE:Adverseevent;CNS:Centralnervoussystem;mono:Monotherapy;

N:Numberofstudies;

n:Numberofparticipants;SMD:Standardizedmeandifference;WMD:Weightedmeandifference.

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

2.Adverseeffect

outcomesin

patients

onantidepressantmonotherapyversusantidepressantco

-treatm

ent(augmentationorco

mbination)(continued).

Outcome

Allstudies

Augmentation-studies

Combinationtreatm

ent-studies

Outcome

Nn

Riskratio/

SMD

95%

CI

p-

Value

p-Value

heterogeneity

Nn

Risk

ratio/

SMD

95%

CI

p-

Value

p-Value

heterogeneity

NN

Riskratio/

SMD

95%

CI

p-

Value

p-Value

heterogeneity

Headache

7772

1.022

0.747,

1.400

0.890

0.797

2363

0.707

0.142,

3.514

0.671

0.227

5409

1.038

0.746,

1.445

0.823

0.819

GastrointestinalAE

Constipation

3164

0.951

0.190,

4.769

0.952

0.025§

138

1.000

0.474,

2.108

1.000

--2

126

1.430

0.025,

81.597

0.862

0.012

Diarrhea

2331

0.448

0.188,

1.065

0.069

0.771

1293

0.474

0.184,

1.218

0.121

--1

38

0.333

0.038,

2.925

0.322

--

Nausea

81007

0.918

0.683,

1.234

0.570

0.723

3589

1.411

0.643,

3.097

0.390

0.312

5418

0.840

0.604,

1.168

0.299

0.949

Abdominalpain/

GIdistress

2137

0.890

0.557,

1.421

0.625

0.377

2137

0.890

0.557,

1.421

0.625

0.377

00

----

----

Decreased

appetite

3283

0.827

0.521,

1.313

0.422

0.842

00

----

----

3283

0.827

0.521,

1.313

0.422

0.842

WeightchangeAE

Weight

gain

‡7%

or

reportedasside

effect

3401

AD

monosu-

perior3.148z

1.338,

7.405z

0.009§

0.511

2363

AD

monosu-

perior3.807z

1.374,

10.548z

0.010§

0.348

138

2.000

0.415,

9.650

0.388

--

Bodyweight

change(SMD)*

2346

AD

monosu-

perior1.033z

0.271,

1.794z

0.008§

0.019§

1293

AD

monosu-

perior0.692z

0.443,

0.941z

< 0.001§

--1

53

AD

monosu-

perior1.476z

0.868,

2.084z

< 0.001§

--

Bodyweight

change(W

MD:

kg)*

2346

AD

monosu-

perior2.170z

0.708,

3.631z

0.004§

0.016§

1293

AD

monosu-

perior1.500z

0.974,

2.026z

< 0.001§

--1

53

AD

monosu-

perior3.000z

1.904,

4.096z

< 0.001§

--

EndocrineAE

Sexualdysfunc-

tion(any)

5569

1.403

0.861,

2.287

0.174

0.378

1226

5.179

0.251,

106.673

0.287

--4

343

1.346

0.793,

2.284

0.271

0.323

OtherAEs

Paresthesia

2264

1.818

0.553,

5.973

0.325

0.720

1226

3.107

0.128,

75.472

0.486

--1

38

1.667

0.462,

6.008

0.435

--

Sweating/

Perspiration

7928

AD

monosu-

perior1.951z

1.127,

3.376z

0.017§

0.057

2519

2.530

0.398,

16.092

0.326

0.078§

5409

AD

monosu-

perior2.016z

1.017,

3.996z

0.045§

0.059


ifnoaveragechangeavailable.

z,§pvalues:


initalics.

":Superior;AD:Antidepressant;AE:Adverseevent;CNS:Centralnervoussystem;mono:Monotherapy;

N:Numberofstudies;

n:Numberofparticipants;SMD:Standardizedmeandifference;WMD:Weightedmeandifference.

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

3.Adverseeffect

outcomesin

patients

onantidepressantmonotherapyversussp

ecificantidepressantclass

co-treatm

ents.

SSRIvsSSRI+TCA

SSRIvsSSRI+NaSSA

SSRIvsSSRI+NDRI

MAOIvs

MAOI+TCA

TCA

vsTCA

+TCA

TCA

vsTCA

+SSRI

TCA

vsTCA

+MAOI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

Co-primary

outcomes

Numberofcomparisons

(OC/LOCF)

=5

Numberofcomparisons

(OC/LOCF)

=7

Numberof

comparisons

(OC/LOCF)

=3

Numberof

comparisons(OC/

LOCF)

=3

Numberof

comparisons(OC/

LOCF)

=2

Numberof

comparisons(OC/

LOCF)

=2

Numberof

comparisons(OC/

LOCF)

=3

Discontinuation

dueto

AE

1(27)

6.154

0.323,117.205

5(247)

1.339

0.413,4.342

1(123)

3.231

0.562,18.563

1(40)

6.692

0.292,153.546

2(173)

1.586

0.662,3.803

0(0)

--1(39)

1.000

0.100,10.037

Numberofcomparisons

(LOCF)

=5

Numberofcomparisons

(LOCF)

=6

Numberof

comparisons

(LOCF)

=3

Numberof

comparisons

(LOCF)

=2

Numberof

comparisons

(LOCF)

=2

Numberof

comparisons

(LOCF)

=2

Numberof

comparisons

(LOCF)

=2

Atleast

oneAE

1(10)

4.500

0.689,29.388

2(363)

AD

monosuperior

1.626

1.185,2.231z

1(123)

0.969

0.875,1.074

0(0)

--2(173)

0.688

0.446,1.061

1(12)

2.000

0.589,6.790

0(0)

--

Movementdisorder

Anyextrapyramidal

AE

0(0)

--0(0)

--1(123)

1.077

0.472,2.455

0(0)

--0(0)

--0(0)

--0(0)

--

Rigidity

0(0)

--0(0)

--1(123)

1.077

0.472,2.455

0(0)

--0(0)

--0(0)

--0(0)

--

Tremor

1(38)

3.000

0.342,26.327

1(293)

1.327

0.383,4.592

1(123)

1.846

0.944,3.612

0(0)

--0(0)

--0(0)

--0(0)

--

Anticholinergic

AE

Dry

mouth/reduced

salivation

2(105)

AD

monosuperior

1.962

1.172,3.284z

2(363)

3.118

0.477,20.388

1(123)

1.675

0.932,3.010

0(0)

--0(0)

--0(0)

--0(0)

--

Blurredvision

2(65)

2.265

0.556,9.230

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Arousal-relatedAE

Sedation

1(38)

1.167

0.481,2.829

2(353)

AD

monosuperior

3.224

2.159,4.813z

1(123)

0.887

0.401,1.962

0(0)

--0(0)

--0(0)

--0(0)

--

Fatigue/tiredness/

drowsiness

2(105)

1.630

0.782,3.398

1(70)

8.273

0.443,154.418

1(123)

0.718

0.281,1.835

0(0)

--0(0)

--0(0)

--0(0)

--

Asthenia/lack

of

energy

1(38)

1.000

0.292,3.426

1(70)

0.297

0.035,2.524

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Insomnia

1(38)

0.400

0.088,1.813

1(293)

1.279

0.574,2.851

1(123)

0.957

0.545,1.683

0(0)

--0(0)

--0(0)

--0(0)

--


ifnoaveragechange.

z p-values:


initalics.

AD:Antidepressant;AE:Adverseevent;MAOI:Monoamineoxidase

inhibitor;mono:Monotherapy;

N:Numberofcomparisons;

n:Numberofparticipants;NaSSA:Noradrenergic

andspecificserotonergic

antidepressant;NDRI:

Norepinephrine-dopaminereuptakeinhibitor;RR:Riskratio;SMD:Standardizedmeandifference;SSRI:Serotonin

reuptakeinhibitors;TCA:Tricyclic

antidepressant;WMD:Weightedmeandifference.

Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

3.Adverseeffect

outcomesin

patients



co-treatm

ents

(continued).

SSRIvsSSRI+TCA

SSRIvsSSRI+NaSSA

SSRIvsSSRI+NDRI

MAOIvs

MAOI+TCA

TCA

vsTCA

+TCA

TCA

vsTCA

+SSRI

TCA

vsTCA

+MAOI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

Agitation

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--Irritability

0(0)

--0(0)

--1(123)

0.862

0.175,4.247

0(0)

--0(0)

--0(0)

--0(0)

--

CardiovascularAE

Faintness/dizziness

2(105)

1.123

0.616,2.049

2(363)

0.908

0.336,2.452

1(123)

1.077

0.558,2.078

0(0)

--0(0)

--0(0)

--0(0)

--

Tachycardia

1(38)

1.000

0.230,4.343

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Sweating/

perspiration

1(38)

1.750

0.612,5.006

1(293)

1.257

0.636,2.482

1(123)

1.657

0.797,3.444

0(0)

--0(0)

--0(0)

--0(0)

--

Flush

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--CNSAE

Confusion

1(38)

2.000

0.198,20.244

0(0)

--1(123)

0.994

0.408,2.420

0(0)

--0(0)

--0(0)

--0(0)

--

Mania

0(0)

--1(30)

5.000

0.221,113.183

1(162)

1.346

0.375,4.833

0(0)

--0(0)

--0(0)

--0(0)

--

Concentration

difficulty

0(0)

--0(0)

--1(123)

1.256

0.536,2.943

0(0)

--0(0)

--0(0)

--0(0)

--

Tension/inner

restlessness

0(0)

--1(293)

0.569

0.120,2.686

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Vertigo

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--Headache

1(38)

0.800

0.253,2.529

2(363)

0.707

0.142,3.514

1(123)

1.077

0.642,1.806

0(0)

--0(0)

--0(0)

--0(0)

--

GastrointestinalAE

Constipation

1(38)

1.000

0.474,2.108

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Diarrhea

1(38)

0.333

0.038,2.925

1(293)

0.474

0.184,1.218

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Nausea

1(38)

0.500

0.049,5.061

2(363)

1.015

0.465,2.214

1(123)

0.875

0.520,1.473

0(0)

--0(0)

--0(0)

--0(0)

--

Abdominalpain/GI

distress

1(67)

0.863

0.537,1.385

1(70)

3.545

0.149,84.143

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Decreasedappetite

1(38)

0.600

0.166,2.163

0(0)

--1(123)

0.923

0.467,1.826

0(0)

--0(0)

--0(0)

--0(0)

--


ifnoaveragechange.

z p-values:


initalics.










Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

Table

3.Adverseeffect

outcomesin

patients



co-treatm

ents

(continued).

SSRIvsSSRI+TCA

SSRIvsSSRI+NaSSA

SSRIvsSSRI+NDRI

MAOIvs

MAOI+TCA

TCA

vsTCA

+TCA

TCA

vsTCA

+SSRI

TCA

vsTCA

+MAOI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

N(n)

RR/SMD,

95%

CI

WeightchangeAE

Weightgain

‡7%

orreportedasside

effects

1(38)

2.000

0.415,9.650

2(363)

AD

monosuperior

3.807

1.374,10.548z

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Bodyweight

change(SMD)*

0(0)

--2(346)

AD

monosuperior

1.033

0.271,1.794z

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

Bodyweight

change(W

MD:kg)

*

0(0)

--2(346)

AD

monosuperior

2.170

0.708,3.631z

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--

EndocrineAE

Sexualdysfunction

(any)

1(38)

0.800

0.253,2.529

1(60)

0.333

0.014,7.870

1(123)

1.197

0.610,2.346

0(0)

--0(0)

--0(0)

--0(0)

--

Erectile

dysfunction

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--OtherAEs

Exanthema/Rash

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--Paresthesia

1(38)

1.667

0.462,6.008

0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--0(0)

--


ifnoaveragechange.

z p-values:


initalics.










Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

3.2.1.3 Treatment characteristicsAll but one study compared SSRI monotherapy with AD aug-mentation from another class (studies = 7, 87.5% of studies,n = 1191), including NaSSAs (studies = 2, n = 365), TCAs(studies = 2, n = 94), NDRIs (studies = 2, n = 505) andNRIs (study = 1, n = 226). One study compared monother-apy with a SARI with augmentation by a SSRI (n = 22)(Table 1).

3.2.2 AE risk with AD + AD augmentation versus AD

monotherapyTen AE outcomes (40.0%) were reported by ‡ 2 studies,allowing meta-analytic calculations, but only 5/25 AEs(20.0%) were reported by ‡ 3 studies, and 4 AEs (16.0%)were not reported at all (Table 2).There was no significant difference between AD monother-

apy and AD augmentation regarding intolerability-relateddiscontinuation (RR = 1.74, 95% CI = 0.39 -- 7.81,p = 0.47; heterogeneity: p = 0.22; studies = 3, n = 323). Incontrast, AD augmentation was associated with a significantlygreater risk of ‡ 1 AE (RR = 1.50, 95% CI = 1.30 -- 1.73,p < 0.001; heterogeneity: p = 0.41; studies = 6, n = 589)(Table 2).Regarding specific AEs, compared with AD monotherapy,

adding a second AD to ongoing AD therapy was associatedwith significantly greater AE burden regarding meta-analyzable 3/25 AEs. These three AEs included ‡ 1 adverseeffect (RR = 1.498, 95% CI = 1.299 -- 1.726, p ‡ 0.001);dry mouth (RR = 2.08, 95% CI = 1.23 -- 3.51, p = 0.006);and ‡ 7% weight gain (RR = 3.81, 95% CI = 1.37 -- 10.55,p = 0.010). In one study each, AD augmentation treatmentwas also associated with significantly more sedation andweight gain (Table 2).

3.3 AD + AD combination versus AD monotherapy3.3.1 Study, patient and treatment characteristics3.3.1.1 Study characteristicsIn total, 15 out of the 23 studies (65.2%) with 25 treatmentarms investigated AD combination treatment, that is, the con-current initiation of 2 ADs at the beginning oftreatment [12,13,27,30,33,35,37,38,40-45]. Combination studieswere double-blind (80.0%, studies = 12, n = 981) or open-label studies (20.0%, studies = 3, n = 238). The mean studyduration was 6.7 ± 2.0 (range = 6 -- 12) weeks.

3.3.1.2 Patient characteristicsAltogether, 1219 patients with MDD were studied. The meanpatient age was 40.9 ± 4.2 (range = 18 -- 84) years, with aminority of male participants (33.2%, studies = 13,n = 376). The severity of depression was reported to be mod-erate to severe in eight studies (n = 352, 28.9% of subjects),while two studies included patients with a severe to very severedepression (n = 290, 23.8% of subjects) and one study was onmildly to moderately depressed patients (n = 135, 11.1% of

subjects). Severity of depression was not reported by one study(n = 173, 14.2% of subjects).

Studies were conducted in outpatients (studies = 6,n = 699) or inpatients (studies = 5, n = 223). Two studiesincluded both, in- and outpatients (n = 95) and two studiesdid not specify the setting (n = 202).

3.3.1.3 Treatment characteristicsMost studies compared SSRI monotherapy with combineduse of an AD from another class (studies = 10, 66.7% of stud-ies, n = 738), that is, NaSSAs (studies = 5, 33.3% of studies,n = 231), TCAs (studies = 3, 20% of studies, n = 106),NDRIs (study = 1, 6.7% of studies, n = 245) or NRIs(study = 1, 6.7% of studies, n = 156). Five studies with eighttreatment arms compared monotherapy with a TCA withcombined use of an AD from the same or another class, thatis, TCA (study = 1, study arms = 2, n = 173), SSRIs(studies = 2, n = 61), MAOIs (studies = 2, study arms = 3,n = 214) and NaSSAs (study = 1, n = 46). Other studiesfocused on the following combinations: MAOI versusMAOI + TCA (studies = 2, study arms = 3, n = 214),NDRI versus NDRI + SSRI (study = 1, n = 245), NRI versusNRI + SSRI (study = 1, n = 156), NaSSA versus NaSSA +SSRI (study = 1, n = 61) and SNRI versus SNRI + NDRI(studies = 1, n = 48).

3.3.2 AE risk with AD + AD combination versus AD

monotherapySixteen AE outcomes (64.0%) were reported by ‡ 2 studies,allowing meta-analytic calculations, but only 11/25 AEs(44.4.0%) were reported by ‡ 3 studies, and only 1 AE(4.0%) was not reported at all (Table 2).

There was no significant difference between AD monother-apy and AD co-treatment regarding the two co-primaryoutcomes, intolerability-related discontinuation (RR = 1.43,95% CI = 0.89 -- 2.32, p = 0.14; heterogeneity: p = 0.83;studies = 10, n = 947) and frequency of ‡ 1 AE (RR = 0.98,95% CI = 0.84 -- 1.15, p = 0.82; heterogeneity: p = 0.14;studies = 3, n = 440) (Table 2).

Regarding specific AEs, compared with AD monotherapy,AD + AD co-treatment was associated with significantlygreater AE burden regarding 2/25 meta-analyzable AEs.These two AEs included tremor (RR = 1.59, 95%CI = 1.01 -- 2.50, p = 0.047 and sweating: RR = 2.02, 95%CI = 1.0 -- 4.0, p = 0.045). In one study, AD combinationtreatment was also associated with significantly more weightgain (Table 2).

4. Conclusion

Results from this first systematic review and exploratory meta-analysis of AEs associated with AD + AD co-treatment com-pared with AD monotherapy studied in randomized con-trolled trials in adults with acute MDD indicate thefollowing: i) although we identified 23 randomized controlled

B. Galling et al.


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015


studies with a total of 2435 participants, global and specificAE frequencies and, especially, severity are insufficiently andincompletely assessed or reported in the available randomizedcontrolled studies, with only 14/25 (56.0%) AEs beingreported in at least three studies; ii) co-treatment strategiesdo not appear to be associated with significantly greaterintolerability-related discontinuations and incidence of atleast one AE, but were associated with a significantly greaterincidence or severity of 4 of 25 specific reported AEs thanmonotherapy strategies; iii) specific AEs that were more com-mon during AD + AD co-treatment included tremor, sweat-ing, weight gain and clinically significant weight gain;iv) sparse data suggest clinically relevant AE differences acrossindividual AD + AD class combinations, disfavoring theaddition of NaSSAs and TCAs to SSRIs and v) AE types inthe co-treatment groups generally reflect the known AE pro-files of individual AD classes.

5. Expert opinion

Studies comparing AD + AD co-treatment with AD mono-therapy in MDD are scare. Some studies have demonstratedsuperior efficacy regarding the reduction of depressive symp-toms [13,14,40,46], whereas others did not show a benefit ofAD co-treatment strategies compared with AD monother-apy [31,36,38,39]. Reflecting this situation, results from availablereviews and meta-analyses have been heterogeneous regardingthe efficacy of AD + AD co-treatment in patients withMDD [21-23]. Similar to the imbalance of reported and ana-lyzed efficacy versus safety and tolerability data concerningco-treatment versus monotherapy strategies in bipolar disor-der [47], AE data associated with AD + AD co-treatment com-pared with AD monotherapy have been barely and so far onlyincompletely reported or analyzed [21-23].

This systematic review and exploratory meta-analysis ofrandomized studies comparing AD + AD co-treatment toAD monotherapy indicates that AD co-treatment was notassociated with more frequent AE-related treatment discon-tinuations or incidences of at least one AE, but that some spe-cific AEs were more likely or more severe than in the ADmonotherapy groups. Based on the potential pharmacody-namically additive effects of ADs [16,48-51] as well as on poten-tial pharmacokinetic interactions [52-55], we expected morethan isolated disadvantages of the AD + AD co-treatmentgroups that would be reflected by greater dropout rates dueto intolerability and/or more patients suffering from at leastone AE. At least at that level, AD + AD co-treatment doesnot seem to have significant AE disadvantages over ADmonotherapy.

However, it is important to recognize that the data baseconsisted in the majority of studies (65.2%) of combinationtrials in which two ADs were started concurrently. The initi-ation of two ADs at once may have masked individual AEs ofthe second AD due to the fact that period incidence rates arereported and that AEs are most common in the beginning of

treatment. In other words, adverse effects, even mild in natureof the AD used also in the monotherapy arm could have beenmanifold, at least in the beginning, creating a ceiling effect.This idea is supported by the fact that when analyzing sepa-rately augmentation studies where AEs associated with theaddition of a second AD were assessed in greater isolation,AD + AD co-treatment was indeed associated with a higherincidence of at least one AE compared with AD monotherapy.Moreover, tremor, dry mouth, sedation, sweating and differ-ent measures of body weight gain seem to be more likelywhen combining ADs with each other.

While it was still surprising that only few specific AEs weremore likely with AD + AD co-treatment than AD monother-apy, one has to also bear in mind that only little more thanhalf (56%) of analyzable AEs were reported in at least threestudies, limiting the power greatly to show significant differ-ences. Moreover, studies did not compare AEs at differenttimes during the study to assess durability versus developmentof tolerance to certain AEs, and only weight gain was assessedas a scalable outcome, for which severity could be judged.Thus, although there was no difference in AEs leading tostudy discontinuation, it is still possible that AD + ADco-treatment could lead to more severe or impairing AEsthan AD monotherapy. This uncertainty about the degreeand relevance of specific AEs highlights the need for random-ized controlled studies to not only assess efficacy with detailedand frequently repeated rating sales that reflect changes overtime, but to also do the same for adverse effects that are cur-rently mostly assessed by use of global questioning and barely,if ever, analyzed with inferential statistical methods.

Nevertheless, based on the results of this review, potentialefficacy advantages of co-treatment strategies [19-21] need tobe evaluated in light of potential AE disadvantages [16], whichrequire that clinicians regularly asses and document bothefficacy and safety/tolerability of the frequently occurringcombination therapies in patients with MDD as part of rou-tine care [1-3]. Furthermore, although based on a very smallsubset of studies with data, our results of AD co-treatmentgrouped by AD class suggest that AE types reflect the knownprofiles of individual AD classes [56-64], such as sedation andweight gain when adding NaSSAs to SSRIs, and anticholiner-gic AEs when adding TCAs to SSRIs. Whether or not sweat-ing could have been a potential sign of low-grade serotoninsyndrome [48], is unclear based on the available data.

Clearly, the results of this study need to be interpretedwithin its limitations. In particular, this review is limited by:i) the low number of randomized studies comparing ADmonotherapies with AD + AD co-treatment in MDD report-ing AE data; ii) heterogeneous designs, especially with regardto blinding (double-blind: 78.3%, open label: 8.7%, single-blind: 13.0%), measurements and outcomes; iii) lack ofspecific AE rating scales in most studies and for most AEs,precluding a comprehensive assessment, including the evalua-tion of severity, clinical meaningfulness or patient impact aswell and time course of AEs and iv) selective reporting of



Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015


assessed AEs or a complete lack of reporting of quantitativeAE data in most of the published studies. Subsequently,subgroup and moderator analyses of individual AD combina-tions, dose levels, patient characteristics, illness phase/episodetype, etc., were not possible.Moreover, the role of pharmacogenetic effects and their

potential influence not only on efficacy, but also on AEswere not taken into account [65,66].To address these shortcomings, more acute trials in patients

with MDD are needed that concurrently assess efficacy andtolerability/safety of different AD co-treatment strategies,especially of agents associated with a low adverse effect burdenor, at least, those with complementary AE profiles. Addition-ally, both short- and long-term studies that report AEs atdifferent follow-up times and fundamental research on differ-ent mechanisms of action and their variability against thebackground of genetics and gene environment interactionsare needed.In summary, the results of this systematic review and

exploratory meta-analysis indicate that AD + AD co-treatment is associated with some increased AE risk that mightdiffer in clinically relevant ways among individual AD classes.Further research is needed in order to better understand theefficacy and safety/tolerability of specific combinations, ide-ally head-to-head and in long-term studies. In clinical care,

AD monotherapy should be considered as a first-line treat-ment and only be augmented with a second AD when mono-therapy is not sufficiently effective. AD + AD co-treatmentshould be restricted to combination treatments that haveproven efficacy, after adequate management of comorbiditiesand after considering co-treatment with non-pharmacologicinterventions, balancing benefits and associated risks carefullythrough ongoing monitoring and shared decision making.

Declaration of interest

CU Correll has been a consultant and/or advisor to or hasreceived honoraria from AbbVie, Acadia, Actavis, Alkermes,Bristol-Myers Squibb, Eli Lilly, Genentech, Gerson LehrmanGroup, IntraCellular Therapies, Janssen/J&J, Lundbeck,MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva,Roche, Sunovion, Supernus and Takeda. He has receivedgrant support from Bristol-Myers Squibb, Otsuka andTakeda. K Hagi is an employee of Dainippon SumitomoPharma. The authors have no other relevant affiliations orfinancial involvement with any organization or entity with afinancial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apart fromthose disclosed.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. American Psychiatric Association.

Practice guideline for the treatment of

patients with major depressive disorder

[Internet]. American Psychiatric

Association, Washington, DC;

2010. Available from: http://

psychiatryonline.com [Last accessed

8 May 2015]

2. National Institute for Health and

Clinical Excellence. Depression: The

treatment and management of depression

in adults (G90). National Institute for

Health and Care Excellence;

2009. Available from: https://www.nice.

org.uk/guidance/cg91/resources/guidance-

depression-in-adults-with-a-chronic-

physical-health-problem-pdf [Last

accessed 1 September 2015]

3. Harter M, Klesse C, Bermejo I, et al.

Unipolar depression: diagnostic and

therapeutic recommendations from the

current S3/National Clinical Practice

Guideline. Dtsch Arztebl Int

2010;107(40):700-8

4. Kennedy SH, Eisfeld BS, Meyer JH,

Bagby RM. Antidepressants in clinical

practice: limitations of assessment

methods and drug response.

Hum Psychopharmacol

2001;16(1):105-14

5. Nemeroff CB, Entsuah R, Benattia I,

et al. Comprehensive analysis of

remission (COMPARE) with venlafaxine

versus SSRIs. Biol Psychiatry

2008;63(4):424-34

6. Bowden CL, Schatzberg AF,

Rosenbaum A, et al. Fluoxetine and

desipramine in major depressive disorder.

J Clin Psychopharmacol

1993;13(5):305-11

7. Tignol J. A double-blind, randomized,

fluoxetine-controlled, multicenter study

of paroxetine in the treatment of

depression. J Clin Psychopharmacol

1993;13(6 Suppl 2):18S-22S

8. Ansseau M, Papart P, Troisfontaines B,

et al. Controlled comparison of

milnacipran and fluoxetine in major

depression. Psychopharmacology (Berl)

1994;114(1):131-7

9. Bennie EH, Mullin JM, Martindale JJ.

A double-blind multicenter trial

comparing sertraline and fluoxetine in

outpatients with major depression.

J Clin Psychiatry 1995;56(6):229-37

10. Valenstein M, McCarthy JF, Austin KL,

et al. What happened to lithium?

Antidepressant augmentation in clinical

settings. Am J Psychiatry

2006;163(7):1219-25

11. K€ohler S, Unger T, Hoffmann S, et al.

Comparing augmentation with non-

antidepressants over sticking to

antidepressants after treatment failure in

depression: a naturalistic study.

Pharmacopsychiatry 2013;46(2):69-76

12. Blier P, Gobbi G, Turcotte JE, et al.

Mirtazapine and paroxetine in major

depression: A comparison of

monotherapy versus their combination

from treatment initiation.

Eur Neuropsychopharmacol

2009;19(7):457-65

13. Blier P, Ward HE, Tremblay P, et al.

Combination of antidepressant

medications from treatment initiation for

major depressive disorder: a double-blind

randomized study. Am J Psychiatry

2010;167(3):281-8

14. Maes M, Libbrecht I, van Hunsel F,

et al. Pindolol and mianserin augment

the antidepressant activity of fluoxetine

in hospitalized major depressed patients,

including those with treatment resistance.

B. Galling et al.


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015

http://psychiatryonline.com

http://psychiatryonline.com

https://www.nice.org.uk/guidance/cg91/resources/guidance-depression-in-adults-with-a-chronic-physical-health-problem-pdf




http://www.ncbi.nlm.nih.gov/pubmed/21031129?dopt=Abstract











































1999;19(2):177-82

15. Fava M, Alpert J, Nierenberg A, et al.

Double-blind study of high-dose

fluoxetine versus lithium or desipramine

augmentation of fluoxetine in partial

responders and nonresponders to

fluoxetine. J Clin Psychopharmacol

2002;22(4):379-87

16. Dodd S, Horgan D, Malhi GS, Berk M.

To combine or not to combine?

A literature review of antidepressant

combination therapy. J Affect Disord

2005;89(1-3):1-11

17. Fleurence R, Williamson R, Jing Y, et al.

A systematic review of augmentation

strategies for patients with major

depressive disorder.

Psychopharmacol Bull 2009;42(3):57-90

18. Chang C-M, Sato S, Han C. Evidence

for the benefits of nonantipsychotic

pharmacological augmentation in the

treatment of depression. CNS Drugs

2013;27(Suppl 1):S21-7

19. De la Gandara J, Aguera L, Rojo JE,

et al. Use of antidepressant

combinations: which, when and why?

Results of a Spanish survey.

Acta Psychiatr Scand 2005;112:32-5

20. Zimmerman M, Posternak M,

Friedman M, et al. Which Factors

Influence Psychiatrists’ Selection of

Antidepressants? Am J Psychiatry

2004;161(7):1285-9

21. Rocha FL, Fuzikawa C, Riera R,

Hara C. Combination of antidepressants

in the treatment of major depressive

disorder: A systematic review and

meta-analysis. J Clin Psychopharmacol

2012;32(2):278-81

.. Latest systematic review and meta-

analysis on the efficacy of

combination/augmentation therapy in

major depressive disorder (MDD).

22. Lopes Rocha F, Fuzikawa C, Riera R,

et al. Antidepressant combination for

major depression in incomplete

responders–a systematic review.

J Affect Disord 2013;144(1-2):1-6

23. Connolly KR, Thase ME. If at first you

don’t succeed: a review of the evidence

for antidepressant augmentation,

combination and switching strategies.

Drugs 2011;71(1):43-64

.. Comprehensive review of different

antidepressant augmentation,

combination and switching strategies.

24. DerSimonian R, Laird N. Meta-analysis

in clinical trials. Control Clin Trials

1986;7(3):177-88

25. Egger M, Davey Smith G, Schneider M,

Minder C. Bias in meta-analysis detected

by a simple, graphical test. BMJ

1997;315(7109):629-34

26. Duval S, Tweedie R. A Nonparametric

“Trim and Fill” Method of Accounting

for Publication Bias in Meta-Analysis.

J Am Stat Assoc 2000;95(449):89-98

27. Akkaya C, Kirli S, Eker SS, et al.

Comparison of the efficacy and safety of

sertraline, reboxetine, and venlafaxine in

patients with major depressive disorder:

A pooled analysis of four randomized,

open-label trials. Klin Psikofarmakol Bul

Bull Clin Psychopharmacol

2010;20(4):274-87

28. Ball S, Dellva MA, D’Souza DN, et al.

A double-blind, placebo-controlled study

of edivoxetine as an adjunctive treatment

for patients with major depressive

disorder who are partial responders to

selective serotonin reuptake inhibitor

treatment. J Affect Disord

2014;167:215-23

29. Rush AJ, Trivedi MH, Stewart JW, et al.

Combining medications to enhance

depression outcomes (CO-MED): Acute

and long-term outcomes of a single-blind

randomized study. Am J Psychiatry

2011;168(7):689-701

. Largest placebo-controlled trial

combining medications in patients

with MDD.

30. Dam J, Ryde L, Svejsø J, et al. Morning

fluoxetine plus evening mianserin versus

morning fluoxetine plus evening placebo

in the acute treatment of major

depression. Pharmacopsychiatry

1998;31(2):48-54

31. Fava M, Rosenbaum JF, McGrath PJ,

et al. Lithium and tricyclic augmentation

of fluoxetine treatment for resistant

major depression: a double-blind,

controlled study. Am J Psychiatry

1994;151(9):1372-4

32. Ferreri M, Lavergne F, Berlin I, et al.

Benefits from mianserin augmentation of

fluoxetine in patients with major

depression non-responders to fluoxetine

alone. Acta Psychiatr Scand

2001;103(1):66-72

33. Fornaro M, Martino M, Mattei C, et al.

Duloxetine-bupropion combination for

treatment-resistant atypical depression:

a double-blind, randomized, placebo-

controlled trial.

Eur Neuropsychopharmacol J Eur

Coll Neuropsychopharmacol

2014;24(8):1269-78

34. Gulrez G, Badyal DK, Deswal RS,

Sharma A. Bupropion as an augmenting

agent in patients of depression with

partial response. Basic Clin

Pharmacol Toxicol 2012;110(3):227-30

35. Lauritzen L, Clemmesen L, Klysner R,

et al. Combined treatment with

imipramine and mianserin: A controlled

pilot study. Pharmacopsychiatry

1992;25(4):182-6

36. Licht RW, Qvitzau S. Treatment

strategies in patients with major

depression not responding to first-line

sertraline treatment: A randomised study

of extended duration of treatment, dose

increase or mianserin augmentation.

Psychopharmacology (Berl)

2002;161(2):143-51

37. Maes M, Vandoolaeghe E, Desnyder R.

Efficacy of treatment with trazodone in

combination with pindolol or fluoxetine

in major depression. J Affect Disord

1996;41(3):201-10

38. Matreja PS, Badyal DK, Deswal RS,

Sharma A. Efficacy and safety of add on

low-dose mirtazapine in depression.

Indian J Pharmacol 2012;44(2):173-7

39. Murphy JE. A comparative trial of

Anafranil, Pertofran and an Anafranil/

Pertofran combination. J Int Med Res

1977;5(1 Suppl):16-23

40. Nelson JC, Mazure CM, Jatlow PI, et al.

Combining norepinephrine and serotonin

reuptake inhibition mechanisms for

treatment of depression: a double-blind,

randomized study. Biol Psychiatry

2004;55(3):296-300

41. O’Brien S, McKeon P, O’Regan M,

et al. Blood pressure effects of

tranylcypromine when prescribed singly

and in combination with amitriptyline.


1992;12(2):104-9

42. Raisi FR, Habibi N, Nasehi AA,

Mohammadi MR. Combination of

Citalopram and Nortriptyline in

Treatment of Moderate to Severe Major

Depression: A Double-blind, Placebo-

controlled Trial. Iran J Psychiatry

2006;1(1):35-8

43. Stewart JW, McGrath PJ, Blondeau C,

et al. Combination antidepressant

therapy for major depressive disorder:



Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015
















































































speed and probability of remission.

J Psychiatr Res 2014;52:7-14

44. Vezmar S, Miljkovic B, Vucicevic K,

et al. Pharmacokinetics and efficacy of

fluvoxamine and amitriptyline in

depression. J Pharmacol Sci

2009;110(1):98-104

45. Young JP, Lader MH, Hughes WC.

Controlled trial of trimipramine,

monoamine oxidase inhibitors, and

combined treatment in depressed

outpatients. Br Med J

1979;2(6201):1315-17

46. Carpenter LL, Yasmin S, Price LH.

A double-blind, placebo-controlled study

of antidepressant augmentation with

mirtazapine. Biol Psychiatry

2002;51(2):183-8

47. Galling B, Garcia MA, Osuchukwu U,

et al. Safety and tolerability of

antipsychotic-mood stabilizer co-

treatment in the management of acute

bipolar disorder: results from a systematic

review and exploratory meta-analysis.

Expert Opin Drug Saf 2015;1-19

48. Boyer EW, Shannon M. The serotonin

syndrome. N Engl J Med

2005;352(11):1112-20

49. Decoutere L, De Winter S,

Vander Weyden L, et al. A venlafaxine

and mirtazapine-induced serotonin

syndrome confirmed by de- and

re-challenge. Int J Clin Pharm

2012;34(5):686-8

50. Talarico G, Tosto G, Pietracupa S, et al.

Serotonin toxicity: a short review of the

literature and two case reports involving

citalopram. Neurol Sci 2011;32(3):507-9

51. Schellander R, Donnerer J.

Antidepressants: clinically relevant drug

interactions to be considered.

Pharmacology 2010;86(4):203-15

. Comprehensive review of

drug interactions.

52. Paslakis G, Gilles M, Deuschle M.

Clinically relevant pharmacokinetic

interaction between venlafaxine and

bupropion: a case series.


2010;30(4):473-4

53. Hori H, Yoshimura R, Ueda N, et al.

A case with occurring adverse effects

when cross-over titration from

fluvoxamine to paroxetine associated with

increasing the plasma fluvoxamine level

in major depressive disorder. World J

Biol Psychiatry 2009;10(4 Pt 2):620-2

54. Vlase L, Leucuta A, Farcau D,

Nanulescu M. Pharmacokinetic

interaction between fluoxetine and

metoclopramide in healthy volunteers.

Biopharm Drug Dispos

2006;27(6):285-9

55. Sennef C, Timmer CJ, Sitsen JMA.

Mirtazapine in combination with

amitriptyline: a drug-drug interaction

study in healthy subjects.

Hum Psychopharmacol

2003;18(2):91-101

56. Purgato M, Papola D, Gastaldon C,

et al. Paroxetine versus other anti-

depressive agents for depression.

Cochrane Database Syst Rev

2014;4:CD006531

57. Magni LR, Purgato M, Gastaldon C,

et al. Fluoxetine versus other types of

pharmacotherapy for depression.


2013;7:CD004185

58. Cipriani A, Koesters M, Furukawa TA,

et al. Duloxetine versus other anti-



2012;10:CD006533

59. Cipriani A, Purgato M, Furukawa TA,

et al. Citalopram versus other anti-



2012;7:CD006534

60. Cipriani A, La Ferla T, Furukawa TA,

et al. Sertraline versus other

antidepressive agents for depression.


2010(4):CD006117

61. Omori IM, Watanabe N, Nakagawa A,

et al. Fluvoxamine versus other anti-



2010(3):CD006114

62. Watanabe N, Omori IM, Nakagawa A,

et al. MANGA (Meta-Analysis of New

Generation Antidepressants) Study

Group. Safety reporting and adverse-

event profile of mirtazapine described in

randomized controlled trials in

comparison with other classes of

antidepressants in the acute-phase

treatment of adults with depression:

systematic review and meta-analysis.

CNS Drugs 2010;24(1):35-53

63. Nakagawa A, Watanabe N, Omori IM,

et al. Milnacipran versus other

antidepressive agents for depression.


2009(3):CD006529

64. Cipriani A, Furukawa TA, Salanti G,

et al. Comparative efficacy and

acceptability of 12 new-generation

antidepressants: a multiple-treatments

meta-analysis. Lancet Lond Engl

2009;373(9665):746-58

65. Kovacs D, Gonda X, Petschner P, et al.

Antidepressant treatment response is

modulated by genetic and environmental

factors and their interactions.

Ann Gen Psychiatry 2014;13:17

66. Fabbri C, Porcelli S, Serretti A. From

pharmacogenetics to pharmacogenomics:

the way toward the personalization of

antidepressant treatment. Can J

Psychiatry Rev Can Psychiatr

2014;59(2):62-75

AffiliationBritta Galling1 MD, Amat Calsina Ferrer2 MD,

Margarita Abi Zeid Daou3 MD,

Dinesh Sangroula1 MD,

Katsuhiko Hagi1,4 PhD &

Christoph U Correll†1,5,6,7 MD†Author for correspondence1The Zucker Hillside Hospital, Psychiatry

Research, North Shore - Long Island Jewish

Health System, Glen Oaks, NY, USA

Tel: +1 71 84 70 48 12;

Fax: +1 71 83 43 16 59;

E-mail: [email protected] d’Assistencia Sanit�aria, Hospital de Santa

Caterina, Salt, Spain3Vanderbilt Psychiatric Hospital, Nashville, TN,

USA4Dainippon Sumitomo Pharma Co, Ltd, Osaka,

Japan5Hofstra North Shore LIJ School of Medicine,

Hempstead, NY, USA6The Feinstein Institute for Medical Research,

Manhasset, NY, USA7Albert Einstein College of Medicine, Bronx, NY,

USA

B. Galling et al.


Dow

nloa

ded

by [

67.8

7.23

6.65

] at

08:

37 1

1 Se

ptem

ber

2015























































mailto:[email protected]


Documents

Safety and tolerablility of AD cotreatment published