CNS Drugs
DOI 10.1007/s40263-015-0267-6
ORIGINAL RESEARCH ARTICLE
Network Meta-Analysis and Cost-Effectiveness Analysis of New
Generation Antidepressants
Ai Leng Khoo1 • Hui Jun Zhou1 • Monica Teng1 • Liang Lin1 • Ying Jiao Zhao1
Lay Beng Soh2 • Yee Ming Mok3 • Boon Peng Lim1 • Kok Peng Gwee3
Ó Springer International Publishing Switzerland 2015
Abstract
Background Major depressive disorder (MDD) impacts
health, quality of life and workplace productivity. Antide-
pressant treatment is the primary therapeutic intervention.
This study assessed the efficacy and tolerability of new
generation antidepressants and their cost-effectiveness in
the Singapore healthcare system.
Methods We conducted a systematic search for head-to-
head randomised controlled trials on ten antidepressants
(agomelatine, duloxetine, escitalopram, fluvoxamine, flu-
oxetine, mirtazapine, paroxetine, sertraline, trazodone and
venlafaxine) employed as monotherapy in acute MDD
Electronic supplementary material The online version of this
article (doi:10.1007/s40263-015-0267-6) contains supplementary
material, which is available to authorized users.
& Ai Leng Khoo
ai_leng_khoo@nhg.com.sg
1
Pharmacy and Therapeutics Office, Group Corporate
Development, National Healthcare Group, 3 Fusionopolis
Link, #03-08 Nexus@one-north, Singapore 138543,
Singapore
2
Pharmacy Department, Institute of Mental Health, Singapore,
Singapore
3
Department of General Psychiatry, Institute of Mental Health,
Singapore, Singapore
•
management. We performed a network meta-analysis to
compare their relative efficacy. The outcome measures for
efficacy were response and remission rate, and mean
change in Hamilton Depression Rating Scale (HDRS)
score; and for tolerability, study withdrawal rates due to
adverse events. To evaluate their relative cost effective-
ness, a decision tree simulating a cohort of MDD patients
using antidepressant as monotherapy was constructed
from a societal perspective over 6 months. We used
effectiveness data from our network meta-analysis and
local data on resource use for depression in Singapore.
The incremental cost expected for each additional quality-
adjusted life-year (QALY) gained was calculated and
presented as the incremental cost-effectiveness ratio
(ICER).
Results We identified 76 relevant articles for the net-
work meta-analysis. Of the ten agents included in the
analysis, mirtazapine and agomelatine were most effica-
cious in achieving response and remission, respectively.
Mirtazapine and duloxetine resulted in the greatest mag-
nitude of change in the HDRS score. Agomelatine, esci-
talopram and sertraline were the best tolerated of the
drugs analysed, while duloxetine was the least well tol-
erated drug. Using a composite outcome of efficacy (re-
sponse and remission rates) and tolerability, agomelatine,
escitalopram and mirtazapine were the favoured treat-
ments. In the cost-effectiveness analysis, apart from
agomelatine, all the treatments were dominated by mir-
tazapine. Against mirtazapine, agomelatine was not cost
effective given that its ICER exceeded the threshold
value.
Conclusion Agomelatine, escitalopram and mirtazapine
had favourable balance between efficacy and tolerability.
In addition, mirtazapine was a cost-effective option in the
Singapore healthcare system.

Key Points
We evaluated the comparative efficacy and
tolerability of ten antidepressants and examined all
outcomes commonly reported in clinical studies,
namely response, remission and change in scores on
the depression scale using network meta-analysis.
Major depression is associated with significant
economic burden; using a decision-analytic model,
we compared the relative cost effectiveness of the
antidepressants in the Singapore healthcare system
using the effect estimates generated from the
network meta-analysis.
This extensive evaluation of new generation
antidepressants can help clinicians gain insights into
the relative efficacy, tolerability and cost
effectiveness of one treatment over another.
1 Introduction
Major depressive disorder (MDD) is a common mental
health problem affecting approximately 121 million people
worldwide according to a 2012 World Health Organisation
report. The estimated lifetime prevalence ranges from 1 to
20 %, varying among different cultures and countries [1,
2]. In Singapore, the lifetime prevalence of MDD was
estimated at 5.8 % in 2012 [3].
The main therapeutic modalities for MDD include
pharmacological treatment with antidepressants and psy-
chotherapy. Nonetheless, antidepressants remain the
mainstay of therapy for MDD [4]. Tricyclic antidepressants
and monoamine oxidase inhibitors were the earliest agents
used and have since been superseded by selective serotonin
reuptake inhibitors (SSRIs), which account for most
antidepressant prescriptions today. More recently, agents
with novel mechanisms of action, including serotonin
norepinephrine reuptake inhibitors (e.g. venlafaxine) and
other drugs that selectively target neurotransmitters (e.g.
mirtazapine) as well as melatonin agonists (e.g. agome-
latine), have broadened therapeutic choices. Some of these
newer agents also claimed to partially mitigate the negative
aspects of antidepressant therapy, such as reduced sexual
and cognitive function, and weight gain, which often lead
to treatment non-adherence. It is of interest to physicians
and decision makers to identify the most effective treat-
ment from a range of alternatives.
Although randomised controlled trials (RCTs) provide
the best available evidence for the relative treatment
effect of a particular pairwise comparison, sometimes
A. L. Khoo et al.
head-to-head RCTs may not be available. To gain
insights into the relative efficacy of one antidepressant
over another in such cases, we turn to indirect compar-
isons using network meta-analysis. Network meta-anal-
ysis is a method by which multiple meta-analyses of
different pairwise comparisons are performed simulta-
neously, from which evidence from both direct and
indirect comparisons across trials based on a common
comparator can be synthesised. In this regard, network
meta-analysis overcomes a major limitation of tradi-
tional pairwise meta-analysis.
Apart from efficacy, the costs of treatment alternatives
vary. The newly licensed antidepressants such as
agomelatine are more costly than SSRIs where the patents
of most agents in this class have expired. Having said that,
MDD represents a substantial economic burden beyond
the direct costs of its treatment. The indirect and intan-
gible costs (e.g. decreased productivity, morbidity and
increased mortality) account for 70–80 % of the total cost
[5]. By 2030, MDD is expected to become the leading
cause of years lost due to disability in developed countries
[6]. Depression is related to increased suicidal risk, hos-
pitalisations, impaired individual productivity and sub-
stantial loss of working days [7, 8]. The goal of treatment
is to attain remission, which can translate into improved
workplace productivity and increased quality of life for
patients with MDD [9].
In essence, there is great impetus to effectively manage
MDD for both health and economic reasons. Therefore, we
conducted a network meta-analysis and a model-based
cost-effectiveness analysis of ten widely used antidepres-
sants in the acute management of MDD. We aimed to
identify the most efficacious antidepressant for MDD
management and assess the cost effectiveness of these ten
pharmacological options considering local clinical practice
and economy in Singapore.
2 Methods
2.1 Search Strategy
A systematic search of PubMed, Embase, the Cochrane
Library and PsycINFO was conducted up to June 2015.
The Cochrane highly sensitive search strategy [10] was
employed to identify randomised trials, using a combina-
tion of medical subject headings (MeSH) and text words
related to the antidepressants of interest and the term
‘major depressive disorder’ (see Table S1 in the electronic
supplementary material). Reference lists from published
systematic reviews were hand searched. The searches were
limited to the English language.
NMA and CEA of New Generation Antidepressants
2.2 Study Selection
We included head-to-head RCTs of at least 6 weeks’
duration that compared the following ten antidepressants as
monotherapy in the acute treatment of MDD: agomelatine,
duloxetine, escitalopram, fluvoxamine, fluoxetine, mir-
tazapine, paroxetine, sertraline, trazodone and venlafaxine.
The agents were selected on the basis of local prescribing
practice and availability in the national mental health
institution. The study participants had to be 18 years or
older with a diagnosis of moderate to severe MDD
according to the Diagnostic and Statistical Manual of
Mental Disorders criteria (DSM-III, DSM-III-R, DSM-IV
or DSM-IV-TR). Studies conducted in inpatient and out-
patient settings were included. Studies recruiting children,
adolescents and pregnant women were excluded. In addi-
tion, studies that did not exclude patients with psychiatric
co-morbidities such as bipolar disorder, substance abuse or
psychosis were not eligible. Study selection was performed
by two reviewers (ALK and MT) and disagreements were
resolved through consensus.
2.3 Outcome Measure
The study endpoint of interest was 8 weeks, which is the
recommended acute treatment duration [11]. If 8-week data
were not available, we used data ranging between 6 to
12 weeks (depending on the study endpoint). Efficacy (as a
continuous outcome) was measured by the mean change in
score from baseline to study endpoint using the Hamilton
Depression Rating Scale (HDRS). Efficacy (as a dichoto-
mous outcome) was measured by the response and remis-
sion rate according to either the HDRS or Montgomery-
Åsberg Depression Rating Scale (MADRS). Response was
defined as a 50 % reduction in HDRS or MADRS score
from baseline. Remission was defined as an HDRS score of
7 and below on the 17-item version [12] or 8 and below for
the longer version, or a MADRS score of 12 and below.
Tolerability was measured by study withdrawal rates due to
adverse events (AEs).
2.4 Data Collection
Two reviewers (ALK and MT) independently collected the
following information using a customised evidence table:
year of publication, study population (sample size, age,
gender, severity of illness), intervention, comparator,
treatment effects (response and remission rates, mean
change in HDRS score and withdrawal due to AE), study
characteristics (study duration, time point of assessment,
care setting and location) and source of funding.
2.5 Risk of Bias Assessment
Risk of bias was assessed for each included study using the
Cochrane Collaboration risk of bias tool [10], based on six
domains: sequence generation, allocation concealment,
blinding of participants and personnel, blinding of outcome
assessors, incomplete outcome data and selective reporting.
We also considered other bias such as sponsorship. Judg-
ment on the risk of bias was made for each domain on the
basis of three categories: high risk, low risk and unclear
risk of bias.
2.6 Data Synthesis
2.6.1 Direct Treatment Comparisons
Pairwise meta-analyses using a random-effects model for
every treatment comparison with at least two studies was
performed in STATA software version 13.0 (Statacorp LP,
College Station, TX, USA).
2.6.2 Indirect and Mixed Treatment Comparisons
A frequentist network meta-analysis using the multivariate
meta-analysis model [13] (mvmeta command) [14] was
performed in STATA software version 13.0 (Statacorp LP,
College Station, TX, USA). Fluoxetine was used as the
reference treatment given that it was one of the first of the
new generation antidepressants to be marketed [15] and is
also commonly prescribed.
The summary treatment effect estimates for dichoto-
mous outcomes (response and remission rates, and study
withdrawal rate due to AEs) were presented as odds ratios
(ORs) with 95 % confidence intervals (CIs) for each
treatment comparison. The summary treatment effect esti-
mates for mean change in HDRS score were presented as
mean difference (MD) with 95 % CI for each treatment
comparison. We estimated the ranking probabilities for all
treatments of being at each possible rank and used the
Surface Under the Cumulative RAnking curve (SUCRA)
values to provide a hierarchy of treatments. Clustered rank
plots were used to examine measures of both efficacy and
tolerability simultaneously.
2.6.3 Assessment of Heterogeneity
The statistical heterogeneity within each pairwise com-
parison was evaluated using the Chi-square test at a sig-
nificance level of p \ 0.1 and I2 statistic. In the network
meta-analysis, a common heterogeneity variance was
assumed for every direct comparison [16].

2.6.4 Assessment of Inconsistency
The assumption of consistency (agreement between direct
and indirect sources of evidence), which underlies a net-
work meta-analysis, can be violated either in parts of the
network (loops of comparisons) or the entire network. We
conducted both local and global tests to assess inconsis-
tency. For the local test, we used the loop-specific approach
[17] where the inconsistency factor was evaluated, using
the ifplot command in STATA software [14], for every
closed loop formed by either three or four treatments in the
network. The magnitude of the inconsistency factors sig-
nified the difference between the direct and indirect esti-
mates and their 95 % CIs present in each loop. For the
global test, the design-by-treatment interaction model was
used to test the null hypothesis of consistency in the entire
network [18].
2.6.5 Network Meta-Regression
Network meta-regression was conducted using the fol-
lowing effect modifiers as possible sources of clinical and
study heterogeneity: (i) time point of analysis; (ii) age; (iii)
severity of illness; and (iv) care setting.
2.7 Cost-Effectiveness Analysis
2.7.1 Model Structure
A decision analytic model was developed to simulate
clinical management of patients with MDD over a time
horizon of 6 months (Fig. 1), using TreeAge Pro 2014
software (TreeAge Software Inc., Williamstown, MA,
USA). The target population was adults aged 18 and
above with moderate to severe MDD. In Singapore,
patients can gain direct and easy access to a psychiatrist
Fig. 1 Schematic representation of model structure. A decision-tree
analysis assessed ten antidepressants as monotherapy acute manage-
ment of major depressive disorder over a time horizon of 6 months.
When the initial treatment failed (no remission or relapse), patients
A. L. Khoo et al.
most of the time [19], therefore we did not distinguish
between primary care and secondary care but rather
simulated MDD management as a comprehensive clinical
process.
We adopted a societal perspective given that indirect
cost accounts for 80 % of total cost in the management of
MDD [5]. Major clinical events covered in the model were
remission, relapse and therapeutic change (augmentation
and switch therapy). The 6-month time horizon reflected
the standard care for MDD in Singapore [20], and this
duration was considered sufficient to capture important
clinical events that would determine the effectiveness of an
antidepressant.
2.7.2 Model Assumptions
Our model assumed an 8-week monotherapy with an
antidepressant (agomelatine, duloxetine, escitalopram, flu-
voxamine, fluoxetine, mirtazapine, paroxetine, sertraline,
trazodone or venlafaxine) titrated to its therapeutic dose
4 weeks after an initial recommended starting dose.
Patients who achieved remission during the initial treat-
ment period would continue medication for a 4-month
maintenance period. During this maintenance treatment,
patients could relapse or remain in remission. If patients
relapsed, it was assumed that the relapse occurred at
4 months after the start of treatment. Patients who relapsed
and did not achieve remission either switched to another
dual-action antidepressant (agomelatine, duloxetine, mir-
tazapine or venlafaxine) or received augmentation with one
of three agents (bupropion, lithium or quetiapine),
according to the local clinical guideline [17]. One-third of
the patients underwent a switch in therapy, and among the
two-thirds who received augmentation therapy, patients
had an equal chance of it being bupropion, lithium or
quetiapine.
would move to a second-line treatment, which could be either a
switch strategy or an augmentation strategy (with bupropion, lithium
or quetiapine)
NMA and CEA of New Generation Antidepressants
2.7.3 Model Inputs
The remission rates of the antidepressants were derived from
our network meta-analysis, which represented the compara-
tive clinical effectiveness of each treatment. The same dataset
was used to represent clinical effectiveness for switch therapy
since our network meta-analysis covered non-treatment naı̈ve
patients. The doses of three augmentation drugs and associ-
ated remission rates were obtained from the Sequenced
Treatment Alternatives to Relieve Depression study [21] and
a study conducted in Asia [22] (Table 1). The risk of relapse
after remission was 7.7 % [23] and was assumed to be similar
irrespective of initial treatment [24].
Cost included direct treatment costs (such as drug, clinical
visits, laboratory investigations and psychological therapy)
and indirect costs associated with sick leave and unemploy-
ment related to depression [25]. Cost for other healthcare
services concurrently received by MDD patients came from a
naturalistic prospective study on the same target population in
Singapore [25]. Utility weights are European Quality of Life-5
Dimensions scores representing utility for three MDD states:
before treatment, during treatment [26] and in remission [27].
2.7.4 Model Outcome
We estimated total societal cost and quality-adjusted life-
years (QALYs) for each comparator over 6 months. The
incremental cost-effectiveness ratio (ICER) per QALY
gained was computed. The willingness-to-pay (WTP)
threshold was set at 70,000 Singapore dollars (SGD)
(55,183 US dollars) per QALY gained, which corresponds
to the per capita gross domestic product (GDP) of Singa-
pore in 2014 [28].
2.7.5 Sensitivity Analyses
The uncertainties of key parameters were analysed using one-
way deterministic sensitivity analysis (DSA) and probabilistic
sensitivity analysis (PSA). The tests applied were guided by the
nature of data sources in order to better reflect their specific
uncertainties. For data associated with larger variation such as
drug costs, clinical visits, laboratory tests, relapse rate and
utilities, one-way DSA was performed across a wide but
clinically meaningful range to capture all possible scenarios.
Costs for other healthcare services, indirect costs and remission
rates were informed by prospective studies or network meta-
analysis; PSA was applied to reflect the impact of their
stochastic nature on the results. For each parameter subjected to
PSA, the best-fitting distributions (Table 1) were determined
and sampled through 10,000 Monte Carlo iterations. The PSA
results were presented as a cost-effectiveness acceptability
curve that indicated the likelihood of each drug being a cost-
effective treatment for MDD over a range of WTP values.
3 Results
3.1 Study Selection and Study Characteristics
The search of the published literature identified 6469 studies.
Review of each record by title and abstract resulted in 94
potentially relevant publications (Fig. 2). We eventually
included 76 trials from 1989 to 2014 for the analysis (Table 2),
totalling 16,389 participants (Table S2, see the electronic
supplementary material). Their mean ages ranged from 36 to
75 years and 67 % were female. Eight of the 76 studies
recruited exclusively elderly patients (age 55 or 65 and above).
The study duration ranged from 6 to 24 weeks, with the
majority of them being of 8 weeks’ duration. The time points
of analysis were 6, 7, 8 and 12 weeks for the included studies.
The majority of the studies were conducted in the Eur-
ope and North American continents, with only 10 % of the
studies involving Asian participants. The mean baseline
HDRS score ranged between 16 and 30. Five studies were
carried out in the severe MDD population, while most
studies recruited moderate to severe MDD participants; 19
studies reported the proportion of participants with severe
MDD, ranging from 5 to 60 %.
3.2 Risk of Bias Assessment
Majority of the studies were judged as having high or
unclear risk of bias in at least one domain using the
Cochrane Collaboration risk of bias tool (Figure S1, see the
electronic supplementary material). A large number of
trials did not report details about randomisation procedures
and allocation concealment. Almost 80 % of the studies
(61 out of 76) were funded by the manufacturers.
3.3 Indirect and Mixed Treatment Comparisons
Figure 3 shows the network of eligible comparisons for
response and remission in the network meta-analysis.
3.3.1 Response
There were 63 studies that reported response rates [29–91].
Agomelatine, escitalopram, mirtazapine and venlafaxine
were significantly more efficacious than fluoxetine in
achieving a 50 % reduction in baseline HDRS or MADRS
score (Fig. 4a). Compared with fluoxetine, mirtazapine had
the largest treatment effect on response rate (OR 1.56;
95 % CI 1.24–1.97), followed by agomelatine (OR 1.46;
95 % CI 1.18–1.81), venlafaxine (OR 1.45; 95 CI
1.24–1.69) and escitalopram (OR 1.33; 95 % CI
1.08–1.64). Mirtazapine and venlafaxine were also superior
to duloxetine, paroxetine and sertraline. Agomelatine was
significantly better than sertraline in achieving response.
 A. L. Khoo et al.

Table 1 Model inputs

Parameters Base case Uncertainty (distribution/range) Source

Drug costs
Treatment
Agomelatine SGD 155.68 77.84–155.68 Local hospital
Duloxetine SGD 212.8 106.40–212.80
Escitalopram SGD 89.88 59.92–119.84
Fluoxetine SGD 14.56 7.28–29.12
Fluvoxamine SGD 29.12 14.56–43.68
Mirtazapine SGD 16.24 8.12–24.36
Paroxetine SGD 22.12 11.06–55.30
Sertraline SGD 30.24 15.12–72.80
Trazodone SGD 97.83 48.72–194.88
Venlafaxine XR SGD 65.52 21.84–109.20
Augmentation strategy
Bupropion SR SGD 76.72 38.36–76.72
Lithium carbonate CR SGD 19.32 12.88–25.76
Quetiapine SGD 28.84 19.04–38.92
Psychiatrist visits
Treatment initiation SGD 240 160–320 Local hospital
Continuation SGD 240 160–320
Additional psychiatrist visits (relapse/switch/augmentation) SGD 320 240–400
Laboratory investigations
Full blood count SGD 24 24–72 Local hospital
Liver function test SGD 52.40 52.4–157.20
Thyroid function test SGD 49.22 49.22–147.66
Renal panel SGD 35.20 35.20–105.60
Serum lithium SGD 76.50 61.20–91.80
Other direct medical costs
Hospitalisation Ho [25]
Remission SGD 719 Gamma (SE 165)
Non-remission SGD 1161 Gamma (SE 300)
Psychotherapy
Remission SGD 35 Gamma (SE 11)
Non-remission SGD 45 Gamma (SE 14)
Alternative therapy
Remission SGD 6 Gamma (SE 5)
Non-remission SGD 155 Gamma (SE 124)
Direct non-medical costs
Transportation
Remission SGD 40 Gamma (SE 5)
Non-remission SGD 48 Gamma (SE 7)
Indirect costs
Sick leave Ho [25]
Remission SGD 843 Gamma (SE 288)
Non-remission SGD 2920 Gamma (SE 1816)
Unemployment related to depression
Remission SGD 2359 Gamma (SE 1300)
Non-remission SGD 3416 Gamma (SE 1581)
Remission rate
Treatment
Agomelatine 45.57 Normal (95 % CI 39.26–52.00) Network meta-analysis
Duloxetine 41.45 Normal (95 % CI 36.40–46.81)
Escitalopram 42.28 Normal (95 % CI 37.62–47.16)
Fluoxetine 38.10 Normal (95 % CI 36.00–40.20)
Fluvoxamine 41.02 Normal (95 % CI 33.27–48.17)
NMA and CEA of New Generation Antidepressants

Table 1 continued
Parameters Base case Uncertainty (distribution/range) Source

Mirtazapine 43.09 Normal (95 % CI 37.38–48.82)

Paroxetine 38.80 Normal (95 % CI 34.08–43.68)
Sertraline 38.19 Normal (95 % CI 32.99–43.48)
Trazodone 39.93 Normal (95 % CI 29.20–51.57)
Venlafaxine XR 43.48 Normal (95 % CI 39.26–47.67)
Augmentation strategy
Bupropion SR 29.75 Beta (95 % CI 24.45–35.49) Nierenberg [109]
Lithium carbonate CR 15.90 Beta (95 % CI 8.24–26.74) Nierenberg [109]
Quetiapine 36.04 Beta (95 % CI 32.24–39.97) Bauer [110]
Relapse rate 7.7 Deterministic (95 % CI 4.00–37.00) Rucci [23]
Utility
Utility before treatment 0.42 Deterministic (95 % CI 0.39–0.45) Sobocki [26]
Utility after treatment 0.64 Deterministic (95 % CI 0.53–0.75) Sobocki [26]
Utility in remission 0.84 Deterministic (95 % CI 0.78–0.89) Subramaniam [27]
Costs and resource use were computed for a period of 6 months
CI confidence interval, CR controlled release, SE standard error, SGD Singapore dollars, SR sustained release, XR extended release

Fig. 2 Study flow diagram.

PICO participants, intervention,
comparator and outcome, RCT
randomised controlled trial

3.3.2 Remission remission rates (Fig. 4b). Relative to fluoxetine, agome-

There were 50 studies [29, 30, 33, 34, 37–39, 41–64, 66,
67, 69–72, 74–80, 85, 89, 90, 92, 93] that reported remis-
sion rate as the outcome, but these data were not available
for fluvoxamine. Compared with fluoxetine and sertraline,
agomelatine and venlafaxine showed significantly better
latine had the largest treatment effect on remission rate
(OR 1.36; 95 % CI 1.05–1.76), followed by venlafaxine
(OR 1.25; 95 % CI 1.05–1.48), mirtazapine (OR 1.23;
95 % CI 0.97–1.55) and escitalopram (OR 1.19; 95 % CI
0.98–1.45). The results of mirtazapine and escitalopram
were not significant.
 A. L. Khoo et al.

3.3.3 Mean Change Fig. 4 Results derived from network meta-analysis on a responsec
rate, b remission rate, c change in Hamilton Depression Rating Scale
score and d tolerability. Treatments are reported in alphabetical order.
Sixty-five studies reporting the mean change in score on Significant results are in bold. a, b Results are the odds ratio (OR)
the HDRS were included in the analysis [29–34, 37–48, with 95 % confidence interval (CI) in the column-defining treatment
50–55, 57–73, 77, 80–89, 91, 93–104]. Duloxetine, esci- compared with the ORs in the row-defining treatment. ORs higher
talopram, mirtazapine, paroxetine and venlafaxine were than 1 favour the row-defining treatment. c Results are the mean
difference (MD) with 95 % CI in the column-defining treatment
significantly more efficacious in augmenting the score on compared with the MDs in the row-defining treatment. MDs higher
the HDRS than fluoxetine (Fig. 4c). Mirtazapine was sig- than 0 favour the row-defining treatment. d Based on study
nificantly better than agomelatine (MD 1.39; 95 % CI withdrawal rate due to adverse events, results are the OR with
0.13–2.65). Mirtazapine had the greatest treatment effect 95 % CI in the column-defining treatment compared with the ORs in
the row-defining treatment. ORs lower than 1 favour the row-defining
(i.e. magnitude in the MD) (MD 2.26; 95 % CI 1.45–3.08), treatment
followed by duloxetine (MD 1.46; 95 % CI 0.47–2.45),
escitalopram (MD 1.31; 95 % CI 0.23–2.38) and parox- except sertraline, where the effect was not significant (OR
etine (MD 1.21; 95 % CI 0.39–2.02). 1.58; 95 % CI 0.96–2.59) (Fig. 4d). Escitalopram and
sertraline were associated with significantly lower with-
3.3.4 Tolerability drawal rates than paroxetine and venlafaxine. Though
escitalopram (OR 0.92; 95 % CI 0.64–1.32) and sertraline
Agomelatine was associated with a significantly lower risk (OR 0.75; 95 % CI 0.52–1.08) were also better tolerated
of withdrawal due to AE compared with all other agents than fluoxetine, the difference did not reach statistical
significance. Compared with fluoxetine, treatment with
Table 2 Studies included in the network meta-analysis
duloxetine (OR 2.23; 95 % CI 1.52–3.28) was associated
Treatment Number of trials Year of publication with the highest risk of withdrawal due to AE, followed by
Earliest Latest Median venlafaxine (OR 1.41; 95 % CI 1.10–1.81). Duloxetine was
less well tolerated than all other agents, especially esci-
Agomelatine 8 2008 2014 2010 talopram, mirtazapine, paroxetine, sertraline and ven-
Duloxetine 10 2002 2008 2005 lafaxine, where significant results were shown.
Escitalopram 12 2004 2013 2007
Fluoxetine 35 1989 2014 2000 3.3.5 Ranking of Treatments on the Basis of Efficacy
Fluvoxamine 5 1994 2005 1997 and Tolerability
Mirtazapine 14 1995 2009 2003
Paroxetine 22 1993 2011 2003 The four most efficacious treatments (with their SUCRA
Sertraline 14 1993 2010 2000 values) were mirtazapine (89.6 %), venlafaxine (79.4 %),
Trazodone 8 1989 2006 1994 agomelatine (79.8 %) and escitalopram (64.5 %) in terms
Venlafaxine 25 1994 2012 2004 of response; and for remission, agomelatine (86.8 %),
The total number of arms is 153 and corresponds to 75 two-arm venlafaxine (74.1 %), mirtazapine (69.3 %) and esci-
studies and one three-arm study talopram (63.1 %) (Fig. 5).

Fig. 3 Network of available direct comparisons for the analysis on and size of the nodes are proportional to the number of studies and
a response rate and b remission rate. Connecting lines indicate the randomised participants (sample size) receiving each treatment,
direct comparisons between the two treatments. The width of the lines respectively
NMA and CEA of New Generation Antidepressants

(a)
Fluoxetine
1.46
(1.18 – 1.81) Agomelatine
1.14 0.78
(0.92 – 1.41) (0.59 – 1.03) Duloxetine
1.33 0.91 1.17
(1.08 – 1.64) (0.71 – 1.17) (0.95 – 1.44) Escitalopram
1.23 0.84 1.08 0.92
(0.78 – 1. 92) (0.52 – 1.37) (0.67 – 1.73) (0.57 – 1.49) Fluvoxamine
1.56 1.07 1.37 1.17 1.27
(1.24 – 1.97) (0.80 – 1.44) (1.05 – 1.80) (0.89 – 1.54) (0.78 – 2.06) Mirtazapine
1.15 0.79 1.01 0.87 0.94 0.74
(0.94 – 1.41) (0.60 – 1.03) (0.84 – 1.22) (0.69 – 1.08) (0.59 – 1.48) (0.58 – 0.94) Paroxetine
1.11 0.76 0.97 0.83 0.90 0.71 0.96
(0.90 – 1.37) (0.58 – 0.99) (0.75 – 1.26) (0.65 – 1.07) (0.57 – 1.44) (0.55 – 0.92) (0.76 – 1.22) Sertraline
1.06 0.73 0.93 0.80 0.87 0.68 0.92 0.96
(0.71 – 1.59) (0.47 – 1.13) (0.61 – 1.43) (0.52 – 1.23) (0.48 – 1.55) (0.46 – 1.00) (0.61 – 1.39) (0.64 – 1.45) Trazodone
1.45 0.99 1.27 1.09 1.18 0.93 1.25 1.30 1.36
(1.24 – 1.69) (0.79 – 1.24) (1.02 – 1.58) (0.88 – 1.34) (0.74 – 1.87) (0.72 – 1.19) (1.01 – 1.55) (1.04 – 1.63) (0.90 – 2.06) Venlafaxine

(b)
Fluoxetine
1.36
(1.05 – 1.76) Agomelatine
1.15 0.85
(0.93 – 1.43) (0.63 – 1.13) Duloxetine
1.19 0.88 1.04
(0.98 – 1.45) (0.67 – 1.15) (0.86 – 1.25) Escitalopram
1.23 0.91 1.07 1.03
(0.97 – 1.55) (0.66 – 1.24) (0.83 – 1.39) (0.80 – 1.33) Mirtazapine
1.03 0.75 0.89 0.86 0.83
(0.84 – 1.26) (0.57 – 1.00) (0.75 – 1.05) (0.71 – 1.03) (0.66 – 1.05) Paroxetine
1.00 0.73 0.87 0.83 0.81 0.97
(0.80 – 1.25) (0.55 – 0.97) (0.68 – 1.11) (0.66 – 1.06) (0.62 – 1.05) (0.77 – 1.22) Sertraline
1.08 0.79 0.94 0.91 0.88 1.05 1.09
(0.67 – 1.73) (0.47 – 1.33) (0.58 – 1.53) (0.56 – 1.47) (0.53 – 1.45) (0.66 – 1.69) (0.68 – 1.74) Trazodone
1.25 0.92 1.09 1.05 1.01 1.22 1.25 1.16
(1.05 – 1.48) (0.71 – 1.19) (0.88 – 1.33) (0.86 – 1.27) (0.79 – 1.30) (0.99 – 1.05) (1.00 – 1.57) (0.71 – 1.87) Venlafaxine

(c)
Fluoxetine
0.87
(-0.91 – 1.94) Agomelatine
1.46 0.59
(0.47 – 2.45) (-.0.73 – 1.91) Duloxetine
1.31 0.43 -0.16
(0.23 – 2.38) (-0.81 – 1.67) (-1.20 – 0.88) Escitalopram
1.49 0.61 0.02 0.18
(-0.04 – 3.02) (-1.22 – 2.44) (-1.69 – 1.73) (-1.62 – 1.98) Fluvoxamine
2.26 1.39 0.80 0.96 0.78
(1.45 – 3.08) (0.13 – 2.65) (-0.27 – 1.86) (-0.25 – 2.17) (-0.88 – 2.43) Mirtazapine
1.21 0.33 -0.26 -0.10 -0.28 -1.06
(0.39 – 2.02) (-0.91 – 1.57) (-1.06 – 0.55) (-1.22 – 1.02) (-1.85 – 1.29) (-1.88 – -0.23) Paroxetine
0.84 -0.04 -0.62 -0.47 -0.65 -1.42 -0.37
(-0.01 – 1.69) (-1.27 – 1.20) (-1.84 – 0.59 (-1.74 – 0.81) (-2.33 – 1.04) (-2.47 – -0.37) (-1.43 – 0.70) Sertraline
0.18 -0.69 -1.28 -1.12 -1.30 -2.08 -1.02 -0.66
(-1.46 – 1.83) (-2.60 – 1.22) (-3.11 – 0.55) (-3.02 – 0.77) (-3.51 – 0.91) (-3.84 – -0.32) (-2.74 – 0.70) (-2.46 – 1.15) Trazodone
1.15 0.27 -0.32 -0.32 -0.34 -1.12 -0.06 0.31 0.96
(0.49 – 1.80) (-0.83 – 1.37) (-1.39 – 0.75) (-1.39 – 0.75) (-1.97 – 1.28) (-1.99 – -0.24) (-0.98 – -0.24) (-0.62 – 1.23) (-0.71 – 2.63) Venlafaxine

(d)
Fluoxetine
0.48
(0.32 – 0.71) Agomelatine
2.23 4.69
(1.52 – 3.28) (2.88 – 7.63) Duloxetine
0.92 1.94 0.41
(0.64 – 1.32) (1.21 – 3.09) (0.29 – 0.59) Escitalopram
1.50 3.14 0.67 1.62
(0.49 – 3.79) (1.18 – 8.36) (0.26 – 1.72) (0.63 – 4.18) Fluvoxamine
1.05 2.21 0.47 1.14 0.70
(0.73 – 1.51) (1.34 – 3.63) (0.31 – 0.72) (0.74 – 1.75) (0.27 – 1.81) Mirtazapine
1.38 2.89 0.62 1.49 0.92 1.31
(0.96 – 1.98) (1.80 – 4.64) (0.43 – 0.87) (1.03 – 2.16) (0.38 – 2.25) (0.92 – 1.86) Paroxetine
0.75 1.58 0.34 0.81 0.50 0.71 0.55
(0.52 – 1.08) (0.96 – 2.59) (0.21 – 0.55) (0.51 – 1.30) (0.19 – 1.31) (0.45 – 1.12) (0.34 – 0.87) Sertraline
1.24 2.60 0.55 1.34 0.83 1.18 0.90 1.65
(0.71 – 2.14) (1.36 – 4.96) (0.30 – 1.03) (0.72 – 2.49) (0.29 – 2.37) (0.66 – 2.11) (0.49 – 1.64) (0.89 – 3.05) Trazodone
1.41 2.96 0.63 1.53 0.94 1.34 1.02 1.88 1.14
(1.10 – 1.81) (1.96 – 4.49) (0.44 – 0.90) (1.06- 2.20) (0.37 – 2.41) (0.94 – 1.92) (0.71 – 1.48) (1.27 – 2.78) (0.66 – 1.97) Venlafaxine
 A. L. Khoo et al.

(a) Agomelatine Duloxetine Escitalopram Fluoxetine

(c) Agomelatine Duloxetine Escitalopram Fluoxetine

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
79.8 33.6 64 .5 10.4 3 9 .1 68.8 60.4 5.9

Cumulative Probabilities
Cumulative Probabilities

1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Fluvoxamine Mirtazapine Paroxetine Sertraline Fluvoxamine Mirtazapine Paroxetine Sertraline

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
49.3 89.6 37.0 29.4 66.0 96.1 55.1 37.2
1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Trazodone Venlafaxine Trazodone Venlafaxine

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

26.9 79.4 18.6 52.9

1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Rank Rank
Graphs by Treatment Graphs by Treatment

(b) Agomelatine Duloxetine Escitalopram

(d) Agomelatine Duloxetine Escitalopram Fluoxetine

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

86 .8 53.5 6 3.1 99 .4 2.7 6 9.3 61.6

Cumulative Probabilities
Cumulative Probabilities

1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Fluoxetine Mirtazapine Paroxetine Fluvoxamine Mirtazapine Paroxetine Sertraline

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

18.5 69.3 23.5 30.0 56.5 28.9 84.1

1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Sertraline Trazodone Venlafaxine Trazodone Venlafaxine

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1
0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

0 .2 .4 .6 .8 1

19.5 41.8 74.1 40.8 26.5

1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Rank Rank
Graphs by Treatment Graphs by Treatment

Fig. 5 Ranking for a response rate, b remission rate, c change in treatment would be the best among the nine or ten treatments. The
Hamilton Depression Rating Scale score and d tolerability. The larger the SUCRA value, the better the rank of the treatment
Surface Under the Cumulative RAnking curves (SURCAs) are shown
with their values, which represent the cumulative probabilities that a

When response and remission rates were considered as effect estimates compared with the original analysis.
the efficacy measures with due consideration of tolerability Similarly, sensitivity analysis performed on study charac-
using clustered ranking plots, agomelatine, escitalopram teristics, i.e. risk of bias, did not lead to any important
and mirtazapine were the favoured treatments (Fig. 6a, b). changes in the results.
Using change in HDRS score as the efficacy measure, it
was not apparent that any of the treatments offered both 3.4 Direct Comparisons
superior efficacy and tolerability profile (Fig. 6c).
In Table 3, the pairwise ORs from the network meta-
3.3.6 Network Meta-Regression analysis were compared with ORs using traditional meta-
analysis for those comparisons where two or more studies
The network meta-regression analyses revealed that time were available. The results from the conventional pairwise
point of analysis (6, 7, 8 or 12 weeks) and care setting meta-analysis were generally consistent with those derived
(inpatient and outpatient) had no discernible impact on the from the network meta-analysis.
treatment effect estimates. To examine the impact of
patient characteristics on the results, exclusion of data on 3.5 Heterogeneity
response rate with exclusively elderly and severe MDD
(defined as baseline HDRS score or MADRS score of Overall, statistical heterogeneity was moderate. The 95 %
greater than 25 and 30, respectively) participants was CIs were wide for most comparisons and included values
analysed separately. There were no differences in treatment ranging from no to high heterogeneity, which could be
NMA and CEA of New Generation Antidepressants

(a) 100
(b)

100
Agomelatine Agomelatine

Sertraline Sertraline
80

80
Escitalopram
Escitalopram
Tolerability

Tolerability
Fluoxetine
60

60
Fluoxetine
Mirtazapine
Mirtazapine
40

Trazodone

40
Trazodone
Fluvoxamine
Paroxetine Venlafaxine
Paroxetine Venlafaxine
20

20
Duloxetine Duloxetine
0

0
0 20 40 60 80 100 20 40 60 80 100
Efficacy (response rate) Efficacy (remission rate)

(c)
100

Agomelatine

Sertraline
80

Escitalopram
Tolerability

Fluoxetine
60

Mirtazapine
40

Trazodone
Paroxetine Fluvoxamine
Venlafaxine
20

Duloxetine
0

0 20 40 60 80 100
Efficacy (change in HDRS score)

Fig. 6 Clustered ranking plot based on clustered analysis of Surface
Under the Cumulative RAnking curve (SUCRA) values for two
outcomes: tolerability and a response rate, b remission rate or
c change in Hamilton Depression Rating Scale (HDRS) score. The
probabilities of each treatment being ranked best among their
comparators in terms of tolerability (study withdrawal rates due to
adverse events) and efficacy (response or remission rates or change in
HDRS score) are represented by their Surface Under the Cumulative
RAnking curve (SURCA) values. Each colour represents a group of
treatments that belong to the same cluster. Treatments lying in the
upper right corner are more well tolerated and efficacious than the
other treatments

attributable to the small number of included studies for
each pairwise comparison. In the pairwise meta-analyses,
I2 values higher than 50 % were seen in the comparisons of
escitalopram versus duloxetine (I2 = 52.1 %) for response
rate and venlafaxine versus sertraline (I2 = 63.8 %) and
escitalopram versus paroxetine (I2 = 81.4 %) for remis-
sion rate. There were three studies in the first two com-
parisons and two studies in the latter.
3.6 Inconsistency
In the loop-specific test, high inconsistency between direct
and indirect comparisons was detected in two of the 67
loops for response rate (mirtazapine-sertraline-trazodone
and fluoxetine-agomelatine-venlafaxine) and two of 71
loops for mean change in HDRS score (agomelatine-sertra-
line-venlafaxine and agomelatine-escitalopram-sertraline).
We checked data extraction and found no apparent variables
that explained the inconsistency. We, however, noted that
there were few studies contributing to these loops. The
global test of the null hypothesis of consistency showed no
significant disagreement between the direct and indirect
evidence in the network: p = 0.445 for response rate and
p = 0.687 for remission rate.
3.7 Cost Effectiveness
Table 4 shows the costs and effectiveness of the ten drugs
in the base-case analysis. As projected by the decision tree,
MDD monotherapy with mirtazapine incurred SGD 6542
and created 0.2648 QALY in 6 months. Agomelatine cost
SGD 892 more and yielded an additional 0.0023 QALYs,
compared with mirtazapine. However, agomelatine was not
considered cost effective relative to mirtazapine, with an
 A. L. Khoo et al.

Table 3 Treatment effects using standard pairwise meta-analysis and network meta-analysis
Treatment comparison Number of trials in Treatment effect [OR (95 % CI)]
direct comparison
Pairwise meta-analysis Network meta-analysis

Response rate
Agomelatine vs. fluoxetine 2 1.20 (0.85–1.69) 1.46 (1.18–1.81)
Escitalopram vs. fluoxetine 2 1.31 (0.92–1.88) 1.33 (1.08–1.64)
Escitalopram vs. agomelatine 2 0.81 (0.52–1.26) 0.91 (0.71–1.17)
Escitalopram vs. duloxetine 3 1.24 (0.86–1.77) 1.17 (0.95–1.44)
Mirtazapine vs. fluoxetine 4 1.44 (1.01–2.04) 1.56 (1.24–1.97)
Paroxetine vs. fluoxetine 4 1.23 (0.73–2.07) 1.15 (0.94–1.41)
Paroxetine vs. duloxetine 4 0.99 (0.79–1.24) 1.01 (0.84–1.22)
Paroxetine vs. mirtazapine 4 0.74 (0.54–1.02) 0.74 (0.58–0.94)
Sertraline vs. fluoxetine 3 1.30 (0.89–1.89) 1.11 (0.90–1.37)
Trazodone vs. mirtazapine 2 0.52 (0.32–0.85) 0.68 (0.46–1.00)
Venlafaxine vs. fluoxetine 10 1.61 (1.34–1.92) 1.45 (1.24–1.69)
Venlafaxine vs. agomelatine 2 0.78 (0.54–1.15) 0.99 (0.79–1.24)
Venlafaxine vs. duloxetine 2 1.33 (0.97–1.84) 1.27 (1.02–1.58)
Venlafaxine vs. escitalopram 2 0.79 (0.46–1.37) 1.09 (0.88–1.34)
Venlafaxine vs. sertraline 3 1.45 (0.94–2.23) 1.30 (1.04–1.63)
Remission rate
Escitalopram vs. fluoxetine 2 1.25 (0.79–1.98) 1.19 (0.98–1.45)
Escitalopram vs. duloxetine 2 1.02 (0.76–1.38) 1.04 (0.86–1.25)
Mirtazapine vs. fluoxetine 4 1.07 (0.75–1.51) 1.23 (0.97–1.55)
Paroxetine vs. fluoxetine 2 1.20 (0.72–2.02) 1.03 (0.84–1.26)
Paroxetine vs. duloxetine 4 0.94 (0.77–1.14) 0.89 (0.75–1.05)
Paroxetine vs. escitalopram 2 0.87 (0.44–1.71) 0.86 (0.71–1.03)
Paroxetine vs. mirtazapine 5 0.74 (0.54–1.01) 0.83 (0.66–1.05)
Venlafaxine vs. fluoxetine 7 1.31 (1.06–1.63) 1.25 (1.05–1.48)
Venlafaxine vs. duloxetine 2 1.08 (0.80–1.46) 1.09 (0.88–1.33)
Venlafaxine vs. escitalopram 2 0.87 (0.59–1.27) 1.05 (0.86–1.27)
Venlafaxine vs. mirtazapine 3 1.45 (0.77–2.75) 1.01 (0.79–1.30)
Significant results are in bold
CI confidence interval, OR odds ratio

ICER of SGD 372,116 per QALY gained, which was much
higher than the WTP threshold of SGD 70,000 per QALY
gained. Other drugs were either dominated or extendedly
dominated by mirtazapine. After accounting for uncertainty
in adopting each parameter, the PSA found that the prob-
abilities of being cost effective were 57 and 20 % for
mirtazapine and fluvoxamine, respectively (Fig. 7).
4 Discussion
In the network meta-analysis, the most efficacious treat-
ments were mirtazapine and agomelatine on the basis of
response and remission rates, respectively. Agomelatine,
escitalopram and sertraline were the best tolerated of the
drugs analysed, while duloxetine and venlafaxine were the
least well tolerated. Using a composite outcome of efficacy
(response and remission rates) and tolerability, agome-
latine, escitalopram and mirtazapine were the favoured
treatments. In the cost-effectiveness analysis based on a
decision tree over a 6-month time frame, apart from
agomelatine, all the comparators were either dominated or
extendedly dominated by mirtazapine. However, agome-
latine was not cost effective as compared with mirtazapine,
given an ICER of SGD 372,116 per QALY, which
exceeded the WTP threshold value.
Among the SSRIs, escitalopram emerged as the most
efficacious agent. Newer agents such as agomelatine,
mirtazapine and venlafaxine also proved to be superior in
achieving response and remission. Using similar analytic
techniques, other studies have found that escitalopram is
most successful in achieving response [105] and remission
NMA and CEA of New Generation Antidepressants

Table 4 Cost and health outcomes per patient over 6 months

Treatment Cost (SGD) Incremental cost (SGD) Effectiveness (QALY) Incremental effectiveness ICER per QALY gained

Mirtazapine 6542 0.2648

Fluoxetine 6669 127 0.2601 – Dominated
Fluvoxamine 6682 140 0.2629 – Dominated
Paroxetine 6699 157 0.2608 – Dominated
Sertraline 6769 227 0.2602 – Dominated
Venlafaxine 6889 347 0.2652 – Extendedly dominated
Escitalopram 7054 512 0.2641 – Dominated
Trazodone 7159 617 0.2618 – Dominated
Agomelatine 7434 892 0.2671 0.0023 372,116
Duloxetine 7956 532 0.2633 – Dominated
QALY quality-adjusted life-year, ICER incremental cost-effectiveness ratio, SGD Singapore dollars

Fig. 7 Cost-effectiveness Escitalopram Fluoxene Fluvoxamine Paroxene Sertraline

acceptability curve. QALY Agomelane Duloxene Mirtazapine Trazodone Venlafaxine
1
quality-adjusted life-year, SGD
Probability that treatment is cost-Effecve

WTP threshold
Singapore dollars, WTP 0.9
willingness-to-pay 0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
20000 30000 40000 50000 60000 70000 80000 90000 100000
Willingness-to-pay per QALY gained (SGD)

[106]. What set apart our analysis from these older studies cost and dominance over all comparators except for esci-
was that agomelatine, recently approved by the European talopram. In one other local cost-effectiveness analysis, only
Medicines Agency for use in the EU, was being compared. three options were compared: escitalopram with venlafaxine
Agomelatine offered a good balance of efficacy and and fluvoxamine [19]. Our work sets itself apart from this
tolerability. study [19] by using QALY as an outcome and including
The network meta-analysis results showed that the dif- indirect costs, which are two important components in the
ference in effectiveness amongst the ten antidepressants was cost-effectiveness analysis of MDD management. Moreover,
small. However, the small difference in remission rates remission rates for each treatment were generated from
along with other input parameters had a significant impact simultaneous analysis of multiple studies and weighted by
on the cost effectiveness of the treatments. The sensitivity inverse variance weighting methods to improve the preci-
analyses showed that the results were most sensitive to sion of treatment effect estimates. This was not performed in
changes in utility values. Nonetheless, the cost-effectiveness previous studies, which obtained remission rates from a
ranking was robust to variation of the key model input single RCT or indirect estimate.
parameters. Our results were consistent with a cost-effec- Our study has several strengths. The review methods
tiveness study that compared ten new generation antide- were systematic and comprehensive. Given the large
pressants (citalopram, duloxetine, escitalopram, fluoxetine, number of treatment options, meta-analysis of direct
fluvoxamine, mirtazapine, paroxetine, reboxetine, sertraline comparisons becomes limited by the availability of head-
and venlafaxine) in the Swedish healthcare system [107], of to-head RCTs that assessed a particular pair of treatments.
which mirtazapine was associated with the lowest overall The advanced quantitative method of network meta-

analysis overcomes this issue by incorporating both direct
and indirect comparisons and providing more precise
summary treatment effects. A second advantage of such
analysis is that it provides an evidence-based treatment
hierarchy by considering both the efficacy and tolerability
of antidepressants.
Instead of relying on one outcome measure as previous
network meta-analyses have [105, 106], we studied three
measures: change in HDRS score, as well as response and
remission rates. First, assessment of response should be
based on change in score on the HDRS. Responder rate
analyses transform these continuous scores into a dichoto-
mous outcome, and this seems appropriate only when sig-
nificant differences in the change in score on the HDRS are
detected [108]. Next, we evaluated remission rate, which is
the ultimate goal of therapy [9] and also served as a data
input for our cost-effectiveness model. While other studies
employed overall study withdrawal rate to determine the
balance between benefits and harms, we felt that all-cause
attrition is not a specific measure of tolerability or safety.
Therefore, we used study withdrawal rate due to AE as a
proxy to tolerability to provide a better overview of the
benefits and harms of antidepressants. With multiple out-
come measures of efficacy and tolerability being studied,
this review offered more comprehensive insights into the
efficacy of antidepressants as compared with previous
reviews. Unlike a previous published economic model [5]
that derived effectiveness from several RCTs, our model
was populated using our network meta-analysis results that
simultaneously analysed both direct and indirect compar-
isons among multiple treatments across multiple studies.
This reinforced the robustness of present findings.
As with any systematic review, there are a number of biases
that may impact the results. Potential bias could arise from
study heterogeneity, such as study population (age and severity
of illness) and clinical trial design (time point of measurement).
To this end, we performed network meta-regression and found
that these had no significant impact on our results. The risk of
publication bias having an effect on our results cannot be ruled
out given that only English articles and studies with fully
published results were considered for inclusion. These are the
practical limitations in our work. Lastly, our study was not able
to tease out differences in patient population, that is, treatment-
naı̈ve and previously treated patients, as such detailed reporting
was not found in most trials.
There exist some limitations in the cost-effectiveness
analysis. By using similar treatment effects for the dual-
action antidepressants in the second-line treatment for
patients who relapsed or failed to achieve remission, we
may be overestimating the effectiveness of the treatments.
In addition, drug-specific AEs and non-adherence rates
were not considered. This may also result in treatment
effects being overestimated.
A. L. Khoo et al.
5 Conclusion
In this study, we evaluated the efficacy of various classes of
new antidepressants, using different outcome measures, as
well as in association with their tolerability profile, in a
network meta-analysis, and assessed their cost effective-
ness using data generated from our network meta-analysis
in a local context. The most efficacious treatments in
achieving response and remission were mirtazapine and
agomelatine, respectively. Among the SSRIs, escitalopram
offered superior efficacy and tolerability. The least toler-
ated treatment was duloxetine. Agomelatine and mirtaza-
pine were favoured using a composite outcome of efficacy
(response and remission rates) and tolerability. Mirtazapine
was considered cost effective in the Singapore healthcare
setting, but not agomelatine.
Acknowledgments The authors gratefully thank Ms Shu Hui Thng
and Ms Joanne Sng for identifying the unit costs in the cost-effec-
tiveness analysis, and Ms Emily Liew and Ms Celine Tan for sharing
their views.
Compliance with Ethical Standards
Funding None.
Conflict of interest YMM has received honorariums from and
served as an advisor for Lundbeck, Eli Lilly and Servier. The other
authors (ALK, HJZ, MT, YJZ, LL, LBS, BPL and KPG) declared no
conflict of interest.
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