ORIGINAL PAPER

Efficacy and tolerability of mirtazapine in treating major

depressive disorder with anxiety symptoms: an 8-week
open-label randomised paroxetine-controlled trial
J. E. Kim,1 S. J. Yoon,2,3 J. Kim,1 J. Y. Jung,1 H. S. Jeong,1 H. B. Cho,1 E. Shin,4 I. K. Lyoo,1
T. S. Kim2

1
Departments of Psychiatry and
SUMMARY
What’s known Neuroscience, Seoul National
Aims: Prominent anxiety symptoms are related to poor clinical course and out- Patients with major depressive disorder (MDD) University College of Medicine,
Seoul, South Korea
come in major depressive disorder (MDD). The aim of this randomised, open-label, often suffer from anxiety symptoms, and prominent 2
Department of Psychiatry,
controlled study is to compare the efficacy and tolerability of mirtazapine in the anxiety accompanied in MDD is known to be a risk
Catholic University of Korea
factor for poor clinical outcome. Mirtazapine has
form of orally disintegrating tablets against paroxetine in treating MDD patients College of Medicine, Seoul,
shown its superior efficacy in improving anxiety South Korea
with anxiety symptoms. Methods: A total of 60 MDD patients with a score above
symptoms compared with placebo. However, there 3
St. Paul’s Hospital, Catholic
18 on the Hamilton Anxiety Rating Scale (HARS) were randomly assigned to have not been any studies that assessed the University of Korea College of
8 weeks of fixed dosing treatment with mirtazapine (15–30 mg ⁄ day) and paroxe- efficacy of mirtazapine in reducing anxiety Medicine, Seoul, South Korea
4
tine (10–20 mg ⁄ day). Efficacy was primarily assessed with the HARS and with the symptoms in MDD patients compared with other Department of Chemistry, New
17-item Hamilton Depression Rating Scale (HDRS) at weeks 1, 2, 4 and 8 after newer antidepressants. York University, New York, NY,
USA
treatment. Tolerability was assessed from adverse events. Results: The generalised
What’s new
estimating equations (GEE) models showed that the rates of improvement in HDRS For reducing anxiety symptoms, mirtazapine was Correspondence to:
scores from baseline to week 8 were similar between mirtazapine and paroxetine more effective than paroxetine for the first 2 weeks T. S. Kim, Department of
groups. However, patients with mirtazapine exhibited earlier improvement in HARS Psychiatry, Catholic University
of treatment in MDD patients with the high-level
of Korea College of Medicine,
scores at weeks 1 and 2. Week-by-week GEE models showed that these significant anxiety. For improving depressive symptoms,
505 Banpo-Dong, Seocho-Gu,
differences in improvement of HARS scores between the two treatment groups mirtazapine and paroxetine were equally effective Seoul 137-701, South Korea.
were detectable from the first evaluation after the treatment (week 1) and main- and well tolerated. These findings suggest that Tel.: + 82 2 2258 6085
tained through week 2. There was no difference in the overall frequency of mirtazapine can be considered for the treatment of Fax: + 82 2 594 3870
MDD with anxiety symptoms for fast relieving the Email: bluenote@catholic.ac.kr
adverse events experienced between the two treatment groups. The most common
anxiety, which is an important factor for successful
adverse event in the mirtazapine group was somnolence (n = 8), whereas that in treatment of anxious depression. Disclosures
the paroxetine group was gastrointestinal discomfort (n = 9). Conclusions: Mirt- Dr Lyoo has received research
azapine and paroxetine were equally effective and well tolerated for the depressive support from Organon, Eli Lilly,
GlaxoSmithKline, Lundbeck and
symptoms in MDD patients with the high level of anxiety symptoms. Mirtazapine AstraZeneca. Other authors
was, however, more effective in reducing the anxiety symptoms than paroxetine in report no conflict of interest.
the early weeks of treatment, suggesting that mirtazapine may have an earlier-
onset action for the anxiety symptoms in MDD patients.

course or outcome including chronic course of ill-

Introduction
Patients with major depressive disorder (MDD) fre-
quently experience anxiety symptoms as well as cogni-
tive and affective ones (1). Approximately 50–70% of
depressed patients suffer from moderate anxiety, and
20–25%, severe anxiety (2). The prevalence of anxious
depression, as defined as MDD with moderate or
higher level of anxiety, was 46% of MDD patients (3).
It has been reported that individuals with anxious
depression were likely to be in a more severe spec-
trum of illness and be more functionally impaired
(4). Furthermore, anxious depression has been
reported to be associated with the unfavourable
ness (5), delayed treatment response (6), increased
suicide risk (7), and lower response rate to antide-
pressants (8,9). Remaining anxiety symptoms after
treatment have been reported to be associated with
higher concomitant use of anxiolytics ⁄ hypnotics (3)
and higher relapse rate (10,11).
Given the high prevalence of anxiety symptoms in
MDD and the unfavourable outcome of MDD
patients with anxiety symptoms, proper treatment of
anxiety in MDD may be crucial. However, there have
been only a few reports regarding the efficacy of spe-
cific antidepressants in MDD patients with anxiety
symptoms (12–14).

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329
doi: 10.1111/j.1742-1241.2010.02624.x 323
324 Efficacy and tolerability of mirtazapine in treating MDD
Mirtazapine (Remeron; Organon, Oss, The Neth-
erlands) is a newer antidepressant with a novel
mechanism of action enhancing both norepinephrine
and serotonin levels (15). This was reported to occur
via antagonisation of the a-autoreceptors and a-het-
eroreceptors and the blockade of 5-HT2 and 5-HT3
receptors, which may exert anxiolytic effects (16). It
has also been reported that mirtazapine may have a
faster onset of action compared with other antide-
pressants (17,18). A meta analysis found that mirt-
azapine was superior to placebo and comparable to
amitriptyline for the treatment of depressed patients
with anxiety symptoms (2,19). Mirtazapine has also
been reported to be effective in various anxiety disor-
ders including post-traumatic stress disorder (20),
generalised anxiety disorder (21), panic disorder (22)
and social anxiety disorder (23). Despite these
reports that show the potential of mirtazapine to be
a treatment of choice in MDD patients with anxiety
symptoms, there have not been any studies, to our
best knowledge, that assessed the efficacy of mirtaza-
pine in reducing anxiety symptoms in MDD patients
compared with other newer antidepressants fre-
quently used in the clinical setting.
Mirtazapine has been reported to reduce the need
for additional medications (24) and to be cost effec-
tive (25) compared with other antidepressants. Mirt-
azapine may prevent polypharmacy, which is
frequently needed in treating patients with anxious
depression, and thus may help avoid additional
adverse effects in depressed patients with anxiety (26).
In the present study, we compared the efficacy and
tolerability of mirtazapine in the form of orally dis-
integrating tablets (ODTs) against paroxetine in
treating MDD patients with anxiety symptoms. The
aim of this study was to assess whether there would
be the faster and greater anxiety and depressive
symptom reduction in MDD patients treated with
mirtazapine than those treated with paroxetine. The
primary outcome measure was the change in the 17-
item Hamilton Depression Rating Scale (HDRS) and
the Hamilton Anxiety Rating Scale (HARS) scores,
compared between treatment groups.
Methods
The present study was an 8-week, prospective, open-
label, randomised comparison of the efficacy and tol-
erability of mirtazapine ODTs and paroxetine in
MDD patients with anxiety symptoms. The diagnosis
was made on the consensus between two board-cer-
tificated psychiatrists at screening and baseline,
according to the Diagnostic and Statistical Manual of
Mental Disorders-IV (DSM-IV) criteria of MDD (1).
The Structured Clinical Interview, DSM-IV Axis I
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329
Disorder-Clinician Version (SCID-IV) (27) was per-
formed in all subjects. Inclusion criteria were (i) age
18–59 years and (ii) MDD, as determined by the
SCID-IV, (iii) depressive episodes at the time of both
screening and baseline interviews, as defined by
above 17 on the HDRS (28) and (iv) presentation of
anxiety symptoms at the time of both screening and
baseline interviews, determined as above 18 on the
HARS (29). Exclusion criteria were (i) major medical
or neurological disorders or conditions, (ii) active
substance abuse or dependence in the preceding
3 months, (iii) other comorbid axis I psychiatric
diagnosis requiring psychotropic medications, (iv)
pregnancy or breastfeeding or (viii) comorbid antiso-
cial or borderline personality disorders assessed by
the International Personality Disorder Examination
(30).
Written informed consent was obtained from each
subject prior to study enrolment. The protocol of the
present study was critically reviewed and approved
by the institutional review board in the Catholic
University College of Medicine, Seoul, Korea.
The study period was 8 weeks with fixed dosing
schedule. Subjects who met the inclusion and exclu-
sion criteria were assigned to either the mirtazapine
group or the paroxetine group by simple randomisa-
tion. Starting doses were 15 mg ⁄ day for mirtazapine
group and 10 mg for paroxetine group, respectively,
at bedtime for the first 3 days. For the next 53 days,
30 mg ⁄ day and 20 mg ⁄ day at bedtime were main-
tained for the mirtazapine and paroxetine groups,
respectively. Zolpidem (a maximum dose of 10 mg)
was allowed for sleep control purposes during the
study period. Other concomitant psychotropic medi-
cations, however, were not permitted. Medication
adherence was monitored by a self-rating visual ana-
logue scale and an inquiry about status of medica-
tion administration by a trained clinician to ensure
greater than 80% of the medication adherence rate.
Subjects were assessed at baseline, weeks 1, 2, 4
and 8 (end-point). The primary outcome measure of
the study was the changes in the HDRS and the
HARS at 1 week and study end-point to test poten-
tial effects of mirtazapine on the faster (at 1 week)
and greater (at study end-point) anxiety and depres-
sive symptom reduction in MDD patients with anxi-
ety symptoms. The secondary efficacy measures
included responder (defined as ‡ 50% reduction in
the HDRS and HARS scores at end-point compared
with baseline) and remission (defined as the HDRS
score £ 7). All structured interviews including the
SCID-IV, the HDRS and the HARS were conducted
by one experienced board-certified psychiatrist (Dr S.
J. Yoon) who was blind to the treatment assignment.
Inter-rater reliability measures for total scale scores

of the HDRS and the HARS, as assessed by the intra-
class correlation coefficients, were 0.94 and 0.93,
respectively. Kappa coefficient values for the reliabil-
ity for the diagnosis of MDD were 0.9 or greater.
Safety and tolerability were evaluated on the basis
of self-reported adverse events and specific inquires
regarding potential health problems on appetite,
weight, sleep, sensorimotor and gastrointestinal sys-
tems at each visit. Vital signs and physical examina-
tions were also performed at each visit. Standard
laboratory tests and electrocardiography were con-
ducted at baseline and end-point.
Based on the analysis of previous drug trial in
MDD patients comparing the effects of mirtazapine
with other antidepressants (31), the current sample
of 58 subjects had the statistical power of a = 0.91
to detect an effect size of 0.50 for the group differ-
ence of change in HDRS or HARS scores at study
end-point. With an effect size of 0.60 for the group
difference of change in HDRS or HARS scores at
1 week after treatment, the statistical power of
a = 0.98 could be assumed.
Group differences in demographic variables
involving continuous data were computed using
unpaired t-test. The response, remission and adverse
event rates were compared between the two groups
using chi-square test. Efficacy analyses were con-
ducted for the intent-to-treat (ITT) patients. Gener-
alised estimating equations (GEE) regression
modelling (32) was used for the primary efficacy
outcomes of changes in HDRS and HARS scores.
Age, gender and baseline HDRS or HARS scores
were included as covariates. This modelling method
is tolerant of missing data, so long as the available
data for any subject unbiasedly represent the sub-
ject’s data path over the entire trial period. Interac-
tions will be checked for significance in models in
which there are multiple explanatory factors. Regres-
sion modelling was conducted according to the
model building strategies recommended (33). Statis-
tical significance was defined at an alpha level of
< 0.05 and two tailed. Stata 7.0 (Stata corp., College
Station, TX, USA) for Windows was used for all
computations.
Results
Study population
Sixty outpatients with MDD have been enrolled in
the study. Patients were randomly assigned to receive
mirtazapine or paroxetine. Fifty-eight patients of
enrolled patients (mirtazapine group, n = 29; paroxe-
tine group, n = 29) had at least one postrandomisa-
tion assessment and were included in analyses for
efficacy in ITT populations. Six subjects receiving the
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329
Efficacy and tolerability of mirtazapine in treating MDD 325
mirtazapine dropped out of an 8-week study at
weeks 1 (n = 1), 2 (n = 1), 4 (n = 2) and 8 (n = 2).
Dropouts within the paroxetine group were 7 [at
weeks 1 (n = 1), 2 (n = 2), 4 (n = 2) and 8 (n = 2)].
There were no significant differences in age
(t = 0.82, p = 0.417), gender composition (v2 = 0.25,
p = 0.56), or the proportion of subjects who had pre-
viously treated with either mirtazapine (p = 0.50) or
paroxetine (p = 0.69) between groups at baseline. One
patient on the mirtazapine treatment group and two
patients on the paroxetine treatment group used zolpi-
dem for sleep control during the study period.
No statistically significant difference between the
two groups at baseline was noted on the HDRS
(t = 0.09, p = 0.93) and HARS scores (t = 0.95,
p = 0.35). Baseline demographic and clinical charac-
teristics of IIT sample are presented in Table 1.
Efficacy
Figure 1 demonstrates results for the HDRS and
HARS changes by the treatment groups from base-
line to weeks 1, 2, 4 and 8. A significant improve-
ment in HDRS and HARS scores between baseline
and 8-week follow-up occurred in both groups
(p-value for time effect < 0.001 and < 0.001 for
HDRS and HARS scores, respectively).
The GEE models for HDRS scores with a treat-
ment group by weeks interaction term, showed that
the rates of improvement in HDRS scores from base-
line were similar between mirtazapine and paroxetine
groups (Figure 1A; p-value for interaction effect
between time and group at each study week > 0.5;
p-value for group effect = 0.946). However, week-by-
week GEE models showed that there were significant
differences in the improvement of HARS scores
between two treatment groups, which were detectable
from the first evaluation (week 1) and maintained
through week 2 (Figure 1B). Patients with mirtaza-
pine administration exhibited earlier improvement in
HARS scores at week 1 (z = )3.39, p-value for inter-
action effect between time and group = 0.001; mean
and SD for HARS scores at week 1; 20.9 ± 4.3 and
23.8 ± 5.2 for mirtazapine and paroxetine treatment
groups, respectively) and 2 (z = )2.18, p-value for
interaction effect between time and group = 0.029;
mean and SD for HARS scores at week 2; 18.5 ± 4.3
and 20.8 ± 4.4 for mirtazapine and paroxetine treat-
ment groups, respectively). This greater improvement
in HARS scores in patients treated with mirtazapine
than those treated with paroxetine was not observed
after week 4 (week 4; z = )0.25, p-value for interac-
tion effect between time and group = 0.805;
16.8 ± 4.7 and 17.9 ± 4.1 for mirtazapine and par-
oxetine treatment groups, respectively; week 8;
z = )0.65, p-value for interaction effect between time
326 Efficacy and tolerability of mirtazapine in treating MDD

Table 1 Demographic and clinical characteristics of patients

Intent-to-treat sample Randomised sample

Mirtazapine Paroxetine Mirtazapine Paroxetine

group (n = 29) group (n = 29) p-Value group (n = 30) group (n = 30) p-Value

Age, year, mean (SD) 42.6 (9.6) 44.6 (9.0) 0.42 42.4 (9.5) 43.9 (9.5) 0.56
Female, N (%) 22 (75.9) 20 (69.0) 0.56 23 (76.7) 20 (66.7) 0.39
Body weight, kg, mean (SD) 61.8 (7.8) 63.8 (8.2) 0.36 61.5 (8.2) 64.1 (8.2) 0.23
Major depression diagnosis, N (%)
Single episode 13 (44.8) 14 (48.3) 0.79 13 (43.3) 14 (46.7) 0.80
Recurrent episodes 16 (55.2) 15 (51.7) 17 (56.7) 16 (53.3)
Baseline HDRS, mean (SD) 22.9 (2.9) 23.0 (2.9) 0.93 22.9 (2.9) 23.0 (2.9) 0.89
Baseline HARS, mean (SD) 24.4 (4.5) 25.5 (4.1) 0.35 24.2 (4.5) 25.3 (4.2) 0.36
Prior mirtazapine use history 1 (3.5) 0 (0.0) 0.50 1 (3.3) 0 (0.0) 0.50
Prior paroxetine use history 4 (13.8) 3 (10.3) 0.69 4 (13.3) 3 (10.0) 0.69

Data are mean (SD) or number (%). HARS, Hamilton Anxiety Rating Scale; HDRS, 17-item Hamilton Depression Rating Scale.

A 25 and group = 0.513, 13.3 ± 4.6 and 15.3 ± 4.1 for

Mirtazapine group (n = 29)
Paroxetine group (n = 29)
mirtazapine and paroxetine treatment groups, respec-
tively).
20
In particular, the mean decrease in scores of
HDRS scores

insomnia (item 4 on HARS) was greater for the

15
mirtazapine group than for the paroxetine group at
week 1 (z = )2.45, p-value for interaction effect
between time and group = 0.014; 1.35 ± 0.75 and
10 1.74 ± 0.45 for mirtazapine and paroxetine treatment
groups, respectively) and week 2 (z = )2.44, p-value
0
for interaction effect between time and
Baseline Week 1 Week 2 Week 4 Week 8 group = 0.015; 1.21 ± 0.50 and 1.58 ± 0.64 for mirt-
Study week
azapine and paroxetine treatment groups, respec-
B 30 tively). Scores of tension (item 2 on HARS) showed
p = 0.001
a similar pattern of improvement difference between
25
Mirtazapine group (n = 29)
Paroxetine group (n = 29) groups at week 1 (z = )2.13, p-value for interaction
p = 0.029 effect between time and group = 0.033; 1.46 ± 0.76
HARS scores

and 1.85 ± 0.46 for mirtazapine and paroxetine

20
15
10
0
Baseline Week 1 Week 2 Week 4
Study week
Figure 1 Mean total scores on Hamilton Depression Rating
Scale (A) and Hamilton Anxiety Rating Scale (B*) during
the 8-week trial in the mirtazapine and paroxetine-
treatment groups values are expressed as mean (grey and
blue squares) with 95% confidence interval (bar).
*Significant differences between treatment groups in rates
of improvement in HARS scores at weeks 1 (z = )3.39,
p-value for interaction = 0.001) and 2 (z = )2.18, p-value
for interaction = 0.029) with generalised estimating
equations modelling. HDRS, 17-item Hamilton Depression
Rating Scale; HARS, Hamilton Anxiety Rating Scale
treatment groups, respectively).
In an effort to rule out the possibility that the cur-
rent results may be affected by the prior treatment his-
tory with the study drugs (34), the main analysis was
repeated including this prior study drug history as a
potential covariate. The results remained unchanged
Week 8 (HARS scores at week 1, z = )3.39, p-value for inter-
action effect between time and group = 0.001; HARS
scores at week 2, z = )2.19, p-value for interaction
effect between time and group = 0.028).
The proportion of subjects achieving remission by
HDRS criteria (total scores £ 7 on HDRS) at study
end-point were 20.1% (six subjects) in the mirtaza-
pine group and 24.1% (seven subjects) in the par-
oxetine group. There was no significant difference in
proportion of remission at the end-point between
the groups [v2 (1) = 0.10, p = 0.75]. The results of
the responder analysis (more than 50% reduction in

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329
 Efficacy and tolerability of mirtazapine in treating MDD 327

80 p = 0.78
Mirtazapine group
seven patients who discontinued, three withdrew as a
Paroxetine group result of adverse experience [agitation (n = 1) and
69.0%
60 65.5% (20/29) p = 0.104
gastrointestinal discomfort (n = 2)], two had follow-
(19/29)
% responders

up loss, one retracted consents and one had non-

40 48.3%
(14/29)
20 27.6%
(8/29)
0
HDRS HARS
Figure 2 Response rate in HDRS and HARS scores after 8
weeks of treatment with mirtazapine (Blue bars) and
paroxetine (gray bars)*. Response was defined as ‡ 50%
reduction in HDRS and HARS scores at end-point
compared with baseline. *Response rates of both treatment
groups were calculated in data with the last observation
carried forward. Although the level of group differences in
these outcome measures did not reach statistical
significance [v2 (1) = 2.636, p = 0.104], the proportion of
responders for HARS scores was greater in the mirtazapine
(48.3%, 14 subjects among 29 mirtazapine-treated subjects)
than in paroxetine (27.6%, 8 subjects among 29
paroxetine-treated subjects) treatment groups. HDRS, 17-
item Hamilton Depression Rating Scale; HARS, Hamilton
Anxiety Rating Scale
HDRS and HARS scores at the end-point) showed
that there were no differences in proportion of treat-
ment responders for depression [v2 (1) = 0.078,
p = 0.780] and anxiety [v2 (1) = 2.636, p = 0.104]
between treatment groups. Mirtazapine group
showed 65.5% (19 among 29 mirtazapine-assigned
study subjects) and 48.3% (14 among 29 mirtaza-
pine-assigned study subjects) response rates in HDRS
and HARS scores, respectively. These were not statis-
tically different from that observed with paroxetine
but numerically the proportion of HARS responders
for mirtazapine was higher than that for paroxetine
(HDRS 69.0%, 20 among 29 paroxetine-assigned
study subjects; HARS 27.6%, 8 among 29 paroxe-
tine-assigned study subjects) (Figure 2).
Safety
compliance to the treatment.
Overall, the mirtazapine and paroxetine treatments
were well tolerated. No serious adverse events were
reported in any of the treatment groups. All side
effects were mild-to-moderate. 43.3% (n = 13) of
mirtazapine group and 40.0% (n = 12) of paroxetine
group experienced at least one adverse event. Five
patients (8.3%) discontinued the trial prematurely
because of adverse events, two in mirtazapine group
and three in paroxetine group. The frequency of
adverse events did not differ between two groups.
The cumulative number of adverse events since
the onset of trial was 31 and 34 in the mirtazapine
and the paroxetine groups, respectively (Table 2).
Thirteen subjects in mirtazapine group had somno-
lence (n = 8), headache (n = 1), increased appetite
(n = 7), weight gain (n = 3), dizziness (n = 7), dry
mouth (n = 4) and gastrointestinal discomfort
(n = 1). Twelve patients in paroxetine group had tre-
mor (n = 2), somnolence (n = 3), headache (n = 5),
dizziness (n = 3), constipation (n = 2), gastrointesti-
nal discomfort (n = 9), dry mouth (n = 5) and agita-
tion (n = 5). However, all above adverse events
excluding five dropouts because of adverse events
(two in mirtazapine and three in paroxetine groups)
were mild.
Discussion
To our knowledge, this is the first controlled trial
to compare the efficacy of mirtazapine against par-
Table 2 Adverse events experienced by patients in
either treatment group (all subjects treated population)
Mirtazapine Paroxetine
group group
(n = 30) (n = 30)

The safety analysis included 60 subjects who were Subjects experienced 13 (43.3) 12 (40)
selected for random assignment. Dropouts within the any adverse events
mirtazapine group were six at weeks 1, 2, 4 and 8 Headache 1 (3.3) 5 (16.7)
(n = 1, n = 1, n = 2 and n = 2, respectively). Rea- Dizziness 7 (23.3) 3 (10.0)
sons for non-completion were adverse experience Agitation – 5 (16.7)
(n = 2; two subjects of mirtazapine group were Somnolence 8 (26.7) 3 (10.0)
dropped out as a result of somnolence and weight Gastrointestinal discomfort 1 (3.3) 9 (30)
gain, respectively), loss to follow-up (n = 2), non- Constipation – 2 (6.7)
adherence to the protocol (n = 1) and retraction of Increased appetite 7 (23.3) –
Weight gain 3 (10.0) –
consent (n = 1). Seven subjects receiving paroxetine
Dry mouth 4 (13.3) 5 (16.7)
dropped out of the study at weeks 1, 2, 4, and 8
Tremor – 2 (6.7)
(n = 1, n = 2, n = 2 and n = 2, respectively). Of

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329
328 Efficacy and tolerability of mirtazapine in treating MDD
oxetine in treating MDD patients with anxiety
symptoms. As the recovery from a depressive epi-
sode is less than optimal in patients with coexisting
anxiety symptoms, effective and fast reduction of
anxiety is of great importance (2). In the present
study, mirtazapine was superior to paroxetine in
improving the HARS scores at week 1 through week
2, although this greater rate of improvement in
HARS scores was not observed from week 4. These
results indicate that the mirtazapine group demon-
strated a significantly greater improvement in anxi-
ety symptoms than the paroxetine group in the first
2 weeks of treatment. The current study results may
provide clinical evidence favouring the use of the
mirtazapine in the treatment of MDD with anxiety
symptoms.
Considering the suffering from the remaining anx-
iety symptoms in MDD patients for the first few
weeks of treatment can cause substantial distress to
patients, sometimes leading to treatment non-com-
pliance (35); the use of mirtazapine may be favoured
in choosing the first drug of choice to treat MDD
with anxiety symptoms. This also would have benefi-
cial effects in reducing the distress of MDD patients
with anxiety symptoms for the earlier course of the
treatment.
Mirtazapine is known to enhance both norepi-
nephrine (a-autoreceptor and a-heteroreceptor
antagonism) and serotonin (the blockade of 5-HT2
and 5-HT3 receptors) levels without reuptake inhibi-
tion (15). Although speculative, considering that the
dysfunctional states of noradrenergic and serotoner-
gic system are known as the neurochemical aetiolo-
gies of pathological anxiety, the simultaneous
increase in noradrenergic and serotonergic transmis-
sion as well as the selective antagonism of both
5-HT2 and 5-HT3 receptors may account for the
early relief of anxiety symptoms (16). In addition, in
animal models, mirtazapine had the anxiolytic action
via the activation of postsynaptic 5-HT1A receptor
and a1 adenoreceptor (36). This unique pharmaco-
logical profile of mirtazapine may also account for
faster onset of action for anxiety relief than other
antidepressants. Selective serotonin reuptake inhibi-
tors may cause transient increase in anxiety symp-
toms including agitation when treatment is initiated
(37). In the present study, paroxetine group patients
had agitation (n = 5), but mirtazapine group patients
had no agitation. This result may, in part, add to the
difference of early response of anxiety reduction
between the two groups.
In the present study, both mirtazapine and par-
oxetine were equally effective in reducing the overall
depressive symptoms measured by the HDRS in
MDD patients for 8 weeks. This finding was similar
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329
to those in previous comparisons between mirtaza-
pine and paroxetine in adult MDD patients (17,38).
However, the previous results of the greater antide-
pressant effect of mirtazapine in early treatment per-
iod (weeks 1 and 2) compared with paroxetine were
not found in the present study. The discrepancy in
the early treatment response between the current and
previous studies (17,38) may be attributed to the
presence of comorbid anxiety symptoms, the differ-
ence in gender composition, dosing schedules and
study designs (17,38).
It has been reported that the prior exposure to the
study drug before the study enrolment, may in part
influence the efficacy outcomes (12). In our study,
only minor portion of the patients has ever been
treated with mirtazapine or paroxetine. In addition,
when the analyses were repeated with this prior med-
ication history as a potential covariate, the results
remained unchanged.
Both mirtazapine and paroxetine treatments were
well tolerated in the present study. However, there
were some differences in the adverse event profiles
of the two antidepressants, which were in line with
their respective pharmacological profiles. Mirtaza-
pine was associated with more somnolence, dizzi-
ness and increased appetite, whereas paroxetine
had more frequent incidences of tremor, headache,
gastrointestinal discomfort, constipation and agita-
tion.
The following limitations should be considered in
interpreting the current results. A placebo group was
not included in the present study. It cannot be ruled
out that non-specific placebo effect might have
affected the efficacy and safety of mirtazapine and
paroxetine. Third, this study had the open-label
design that may raise the possibility of biased obser-
vations. Future studies in larger samples, with dou-
ble-blind, placebo-controlled head-to-head
comparison designs would be needed to draw more
confirmative conclusions.
In conclusion, mirtazapine and paroxetine were
equally effective and well tolerated for the treatment
of anxiety symptoms as well as for the treatment of
overall depressive symptoms in MDD patients with
anxiety symptoms. However, mirtazapine was signifi-
cantly more effective in reducing the anxiety symp-
toms than paroxetine for the first weeks of
treatment, suggesting that mirtazapine might have an
earlier-onset action for the anxiety symptoms in
MDD patients.
Author contributions
All authors participated in the design, conduct, and
analysis of the study and were involved in drafting
 Efficacy and tolerability of mirtazapine in treating MDD 329

the manuscript and its revision. The final submitted and the Organon Inc. (GL184, Dr IK Lyoo). Funding
manuscript was approved by all authors. sources had no role in study design, data collection,
data analysis, manuscript preparation and ⁄ or publi-
cation decisions.
Funding and acknowledgements
This work was in part supported by the National
Research Foundation of Korea (KRF-2008-331-
E00169, Dr TS Kim and 2009-0074584, Dr JE Kim)

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ª 2011 Blackwell Publishing Ltd Int J Clin Pract, March 2011, 65, 3, 323–329