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Original Article
Clinical Psychopharmacology and Neuroscience 2004; 2: 31-5
Comparison of Side Effect Profiles between Mirtazapine and
Selective Serotonin Reuptake Inhibitors; A Naturalistic Setting
Jeong-Ho Chae, Kyoung-Uk Lee, Yoon-Kyung Shin, Won-Myong Bahk,
Tae-Youn Jun, Kwang-Soo Kim, Tae-Yul Lew
Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
Since the efficacy of the various antidepressants is similar, their side effects, cost and overdose toxicity are preferentially considered when deciding which drug to use. Recently, selective serotonin reuptake inhibitors (SSRIs) have been more frequently
prescribed than tricyclic antidepressants, because of their less frequent side effects. Also, the use of noradrenergic and specific
serotonergic antidepressants (NaSSAs) is increasing. These new antidepressants have characteristic side effect profiles consisting
mainly of gastrointestinal side effects, weight gain and sexual dysfunction, which serve as a direct cause of noncompliance. In
the present study, we compared the drug side effects of patients with major depressive disorder who had taken either mirtazapine
or SSRIs. Patients with DSM-IV major depressive disorder who were treated with either mirtazapine or SSRI (fluoxetine, paroxetine)
monotherapy as an antidepressant were enrolled in this study. Subjects with physical illnesses or poor drug compliance were
excluded. A self-rating questionnaire was used to assess the drug side effects. A total of 86 patients (mirtazapine; 24, SSRIs;
62 [fluoxetine 18, paroxetine 44]) participated in this study. There was no difference in the mean age, sex ratio or mean duration
of administration between the two groups. Those patients taking mirtazapine experienced significantly less side effects than
those taking SSRIs in terms of decreased appetite, yawning, decreased libido and anorgasmia. Those patients taking SSRIs
had significantly less side effects in terms of peripheral edema than those taking mirtazapine. There were differences in some
of the side effects between mirtazapine and the SSRIs. Mirtazapine showed more favorable side effect profiles than the SSRIs
in terms of the gastrointestinal and sexual side effects. This data should help to establish useful guidelines for the selection of
antidepressants.
：Mirtazapine; SSRIs; Antidepressants; Side effects.
KEY WORDS：
INTRODUCTION
bitors, have the longest track record for the treatment of
depressive disorders.5 However, the problem with TCAs
is that they also block the acetylcholine and histamine
receptors, causing side effects such as anti-cholinergic
effects and weight gain, which in turn lead to poor drug
compliance.6
Of the newer classes of antidepressants, the selective
serotonin reuptake inhibitors (SSRIs), venlafaxine, mirtazapine and nefazodone, are known to have fewer side
effects than TCAs.7-10 SSRIs constitute one of the most
commonly prescribed groups of antidepressants for the
treatment of psychiatric illnesses, including affective disorders. Since fluoxetine was introduced as the first member of the SSRI family of drugs, a series of SSRIs such
as paroxetine, sertraline, fluvoxamine and citalopram were
followed. With fewer side effects, these SSRIs have opened a new chapter in the treatment of depressive disorders.5
These SSRIs have different chemical structures but similar
mechanisms of action and side effects, since they all act
by selectively inhibiting the reuptake of serotonin, while
Amid increasing understanding and knowledge about
the biological causes of depression, a slew of new antidepressants have been developed, with the focus of the
related research being placed on their biochemical mechanism of action. As there is little difference in the efficacy of the various antidepressants, their side effect profile,
cost and overdose toxicity are the factors that are mostly
considered when choosing antidepressant medication.1-4
Antidepressants have different side effect profiles depending on their receptor-affinity profiles. Among the
different antidepressant medications, tricyclic antidepressants (TCAs), which act as monoamine reuptake inhiAddress for correspondence: Kyoung-Uk Lee, MD, Department
of Psychiatry, College of Medicine, The Catholic University of
Korea, 65-1 Kumoh-dong, Uijeongbu 480-130, Korea
Tel: +82-31-820-3055, Fax: +82-31-847-3630
E-mail: [email protected]
This article is an English version of the one published in Korean J
Psychopharmacol 2004;15:30-6.
31
32·CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2004; 2: 31-5
leaving norepinephrine and dopamine relatively intact,
with the result that they have less anticholinergic effects.11
In several studies, more than half of the patients who
were treated with SSRIs did not complain of side effects
and eventually showed a lower drug discontinuation rate
than the TCA group, making SSRIs the first-line choice
of medication for the treatment of depression and anxiety
disorder.12-14 In the newer group of antidepressants, mirtazapine differs from the other drugs, because it is not a
reuptake inhibitor. Mirtazapine enhances both norepinephrine and serotonin activity by antagonizing the alpha
2-adrenaline receptors. By blocking the type 2 and 3
serotonin receptors, this drug has less of the adverse
effects observed with SSRIs, such as gastrointestinal problems and sexual dysfunction. However, mirtazapine has
side effects such as sleepiness, increased appetite and
consequent weight gain, since it also antagonizes the
type 1 histamine receptor, alpha 1-adrenergic receptor and
cholinergic receptor.15,16
The side effects of antidepressants have mainly been
reported through case studies, while placebo-controlled
studies have provided information about the efficacy and
safety of antidepressant drugs. The assessment of the
side effects of antidepressants relies on the patients’ selfreporting or instrument-assisted methods performed by
the physician, and instrument-assisted assessments are
widely used for the study of antidepressant side effects.
The downside to this kind of method lies in the difficulty of capturing data on the patients’ subjective experience of the side effects. Unlike in a controlled clinical
trial, patients’ complaints of side effects in a naturalistic
treatment setting are considered critical in clinical practice,
as they may directly influence the level of compliance.
The purpose of this study was to compare the frequencies of the side effects induced by mirtazapine and
various SSRIs, by using a self-rating instrument designed
to measure the subjective symptoms of patients in a naturalistic treatment setting.
A total of 86 patients participated in the study. Among
them, 24 (12 males and 12 females) were taking mirtazapine and the remaining 62 (24 males and 38 females)
were taking fluoxetine (18) or paroxetine (44), with a
mean age of 48.0±14.0 years in the mirtazapine group
and 43.3±15.6 years in the SSRI group. There were no
significant differences in age or sex between the two
groups. The mean durations of administration in the mirtazapine and SSRI groups were 20.2±21.5 weeks and
32.1±50.9 weeks, respectively, showing no significant
difference (Table 1). Those patients treated with mirtazapine showed a lower incidence of decreased appetite
(χ2=8.059, df=1, p=0.005), yawning (χ2=5.216, df=
1, p=0.022), reduced sexual desire (χ2=4.125, df=1,
p=0.042) and orgasmic dysfunction (χ2=4.125, df=1,
p=0.042), compared with those patients treated with
the SSRIs. On the other hand, those patients treated with
the SSRIs had a lower incidence of edema (χ2=4.064,
df=1, p=0.044). However, there were no significant
differences in the other side effects between the two
groups (Table 2).
SUBJECTS AND METHODS
DISCUSSION
The subjects were recruited from amongst the outpatients of the Department of Psychiatry, St. Mary’s Hospital, The Catholic University of Korea. The subjects
were diagnosed as major depressive disorders, meeting
DSM-IV criteria17 and taking either mirtazapine or SSRIs
monotherapy (fluoxetine or paroxetine) to treat their depression. The subjects used a self-rating instrument for
the assessment of the side effects of the antidepressant.
The assessment instrument was devised using drug package insert data on the most commonly observed side
A variety of antidepressant drugs are deemed to be
first-line choices for the treatment of depressive disorders,
effects of antidepressants (those with an incidence rate
of 3% or greater), released by the United States FDA.
The instrument comprised 42 items designed to measure
the antidepressant-induced side effects experienced by
the patients within the past one month. The type of medication, daily dose and administration duration were also
investigated. Those subjects with physical illnesses or
poor drug compliance were excluded from the study.
The data analysis was conducted using the t-test or
chi-square statistics depending upon the type of variable
being investigated. A probability (p) value of less than
0.05 was considered significant. SPSS 10.0 for Windows
(SPSS Inc., Chicago, USA) was employed for the statistical analysis.
RESULTS
Table 1. Demographic and clinical characteristics
Mirtazapine
SSRIs
(N=24)
(N=62)
Sex (male: female)
12 : 12
24 : 38
Age (years)
48.0±14.0
43.3±15.6
Duration of administration
20.2±21.5
32.1±50.9
(weeks)
SSRIs; selective serotonergic reuptake inhibitors
Values represent mean ±S.D.
P-value
NS
NS
NS
Side Effect Profiles; Mirtazapine and SSRIs·33
however there are still several obstacles which remain to
be addressed. For instance, in several previous studies,
around 30% of patients treated with antidepressants did
not respond to their treatment, and less than 40% of
those treated obtained complete relief from their symptoms.18-20 In other studies, among those who underwent
antidepressant treatment, approximately 44% stopped
taking their medications within three months, due to side
Table 2. Comparison of side effect profiles between groups taking mirtazapine and selective serotonin reuptake inhibitors
Side effects
Mirtazapine
SSRIs
P-value*
Not present
Present
Not present
Present
Headache
09 (37.5)
15 (62.5)
22 (36.1)
39 (63.9)0
Fatigue/asthenia
05 (21.7)
18 (78.3)
12 (19.7)
49 (80.3)0
NS
Flu syndrome
15 (62.5)
09 (37.5)
37 (60.7)
24 (39.3)0
NS
NS
Palpitation
10 (41.7)
14 (58.3)
15 (24.6)
46 (75.4)0
NS
Vasodilatation
11 (45.8)
13 (54.2)
23 (37.7)
38 (62.30)
NS
Orthostatic hypotension
21 (87.5)
03 (12.5)
53 (86.9)
08 (13.1)0
NS
Nausea
16 (66.7)
08 (33.3)
31 (50.0)
31 (50.0)0
NS
Dry mouth
09 (37.5)
15 (62.5)
17 (27.4)
45 (72.6)0
NS
Constipation
18 (75.0)
06 (25.0)
33 (53.2)
29 (46.8)0
NS
Diarrhea
13 (56.5)
10 (43.5)
31 (50.0)
31 (50.0)0
NS
Decreased appetite
14 (58.3)
10 (41.7)
16 (25.8)
46 (74.2)0
<0.05
Dyspepsia
13 (54.2)
11 (45.8)
22 (35.5)
40 (64.5)0
NS
Flatulence
10 (41.7)
14 (58.3)
28 (45.9)
33 (54.1)0
NS
Sweating
14 (58.30)
10 (41.7)
32 (51.6)
30 (48.4)0
NS
Rash
20 (83.3)
04 (16.7)
54 (87.1)
08 (12.9)0
NS
Pruritis
18 (75.0)
06 (25.0)
44 (71.0)
18 (29.0)0
NS
Yawn
13 (54.2)
11 (45.8)
17 (27.9)
44 (72.1)0
<0.05
Pharyngitis
19 (79.2)
05 (20.8)
45 (72.6)
17 (27.4)0
NS
Light headedness
14 (58.3)
10 (41.7)
31 (51.7)
29 (48.3)0
NS
Memory impairment
08 (33.3)
16 (66.7)
20 (33.3)
40 (66.7)0
NS
Decreased concentration
08 (33.3)
16 (66.7)
15 (24.6)
46 (75.4)0
NS
Blurred vision
09 (37.5)
15 (62.5)
32 (52.5)
29 (47.5)0
NS
Tinnitus
13 (54.2)
11 (45.8)
27 (44.3)
34 (55.7)0
NS
Peripheral edema
10 (41.7)
14 (58.3)
40 (65.6)
21 (34.4)0
<0.05
Weight change
09 (37.5)
15 (62.5)
32 (52.5)
29 (47.5)0
NS
Urinary frequency
12 (50.0)
12 (50.0)
26 (42.6)
35 (57.4)0
NS
Difficulty with micturition
13 (56.5)
10 (43.5)
40 (65.6)
21 (34.4)0
NS
Decreased libido
11 (64.7)
06 (35.3)
13 (35.1)
24 (64.9)0
<0.05
Anorgasmia
11 (64.7)
06 (35.3)
13 (35.1)
24 (64.9)0
<0.05
Satisfaction of sexual life
03 (18.8)
13 (81.3)
04 (10.8)
33 (89.2)0
NS
Delayed ejaculation
10 (76.9)
03 (23.1)
08 (47.1)
09 (52.9)0
NS
Erectile dysfunction
06 (46.2)
07 (53.8)
10 (66.7)
05 (33.3)0
NS
Increased cough
14 (58.3)
10 (41.7)
38 (61.3)
24 (38.7)0
NS
Somnolence
10 (41.7)
14 (58.3)
21 (33.9)
41 (66.1)0
NS
Dizziness
09 (37.5)
15 (62.5)
24 (39.3)
37 (60.7)0
NS
Insomnia
05 (20.8)
19 (79.2)
12 (19.7)
49 (80.3)0
NS
Tremor
09 (37.5)
15 (62.5)
29 (47.5)
32 (52.5)0
NS
Myoclonus/twitching
16 (66.7)
08 (33.3)
37 (60.7)
24 (39.3)0
NS
Nervousness
06 (25.0)
18 (75.0)
11 (18.0)
50 (82.0)0
NS
Anxiety
07 (29.2)
17 (70.8)
13 (22.0)
46 (78.0)0
NS
Abnormal dream
15 (62.5)
09 (37.5)
30 (50.0)
30 (50.0)0
NS
Paresthenia
15 (62.5)
09 (37.5)
30 (50.0)
30 (50.0)0
NS
SSRIs: selective serotonin reuptake inhibitors, NS: not specific. Values represent N (%). *Chi-square test with Fisher’s exact test
34·CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2004; 2: 31-5
effects or a lack of efficacy.21,22 The development of antidepressants, which are more effective, quicker acting
and have less side effects, remains the ultimate objective
of drug development. From this point of view, when compared with the diverse side effects of TCAs, the newer
antidepressants offer a milder side effect profile.23
Mirtazapine and SSRIs together constitute the most
commonly prescribed medication for controlling the symptoms of depression, due to their improved side effect
profiles, which have the effect of enhancing patient
compliance. Nevertheless, because of their different mechanisms of antidepressant action on the receptors, these
two groups of medication have different side effects.
SSRIs inhibit the reuptake of serotonin at the presynaptic neurons, while letting the amount of serotonin
increase in the synaptic cleft. By stimulating the serotonin
receptors at the postsynaptic neurons nonspecifically,
SSRIs cause a variety of adverse effects,25 including
decreased appetite, indigestion, nausea, diarrhea, anxiety,
agitation, and sexual dysfunction.26,27 Most SSRIs possess
similar side effects, but some differences do exist among
the various SSRIs. Decreased appetite is most commonly
seen in patients taking fluoxetine and weight loss is also
sometimes observed. In addition, fluoxetine may cause a
higher incidence of headache, anxiety and insomnia, than
the other SSRIs.12-14 SSRI-induced side effects tend to
be transient, although there is one case report in which
such symptoms occurred 10 years after the patient took
the medication.28 Paroxetine was associated with a higher
incidence of dry mouth and anticholinergic side effects,
such as constipation than fluoxetine. Among the SSRIinduced side effects, nausea and headache usually disappear in 2-4 weeks after onset, while sexual dysfunction
and somnolence tend to last for a considerable period of
time.
Mirtazapine is a presynaptic alpha-2 antagonist that
has a dual action, involving the enhancement of both serotonergic and noradrenergic neurotransmission. In addition,
it blocks histamine receptors, thereby increasing the
incidence of somnolence and weight gain, in a manner
which is more prominent than that observed in those
patients taking SSRIs. However, mirtazapine is less responsible for sexual dysfunction than SSRIs. In a previous
study, those patients taking mirtazapine showed a lower
incidence of side effects compared with both the amitriptyline group (87%) and the placebo group (76%).29
In this study, we compared the symptoms experienced
by patients taking mirtazapine and those taking SSRI
monotherapy to treat their major depressive disorders in
a naturalistic treatment setting. There were no significant
differences in the age, gender or administration period
between the two groups. A significantly lower incidence
of decreased appetite, yawning, reduced sexual desire
and orgasmic dysfunction was found in the mirtazapine
group. However, the incidence of edema was significantly higher in the mirtazapine group, than in the SSRI
group.
The higher incidence of decreased appetite observed
in this study for the patients treated with SSRIs is consistent with the findings of earlier studies.6,9,30,31 The
average 30-week period during which decreased appetite
was tracked after medication intake suggested the possibility that this effect might last for a long time. Based
on the package insert data released by the United States
FDA, the incidences of yawning for fluoxetine and paroxetine were 3% and 4%, respectively, whereas no incidence of yawning was reported for mirtazapine.32-34 There
was one case report of edema being observed in patients
treated with mirtazapine.35 Its incidence rate was reported
to be 2% in the FDA data, however no incidence rate of
edema was reported for patients treated with fluoxetine
or paroxetine. This study also demonstrated a greater
incidence of edema in the mirtazapine group than in the
SSRI group.
SSRI-induced sexual dysfunction is characterized by
a loss of sexual desire, impotence, delayed ejaculation
and orgasmic dysfunction.36 In the present study, a similar
level of sexual dysfunction was observed in patients treated with the two SSRIs, and the symptoms remained
constant throughout the duration of the treatment. Mirtazapine does not appear to be associated with the sexual
dysfunction caused by the blocking of the type 2 serotonin receptor or the gastrointestinal adverse effects,
such as nausea and vomiting, caused by the blocking of
the type 3 serotonin receptor.37 In the present study, we
also found a lower incidence of sexual problems and
gastrointestinal adverse effects in those patients taking
mirtazapine. This study has several limitations. Firstly,
the small sample size did not facilitate the comparison
between the low-incidence adverse effects. Since there
was a poor response rate for questions pertaining to sexual problems, caution is required in the interpretation
of the findings. Further studies with larger sample sizes
are needed in the future. Secondly, the subjects were
free to take medications other than those discussed in
the study. Therefore, the possibility that the incidence of
side effects might have been influenced by other medications that the patients were taking cannot be ruled out.
Thirdly, this study is a cross-sectional study in which
the data was collected at the same time for all of the
patients, rather than one in which individual side effects
were tracked over the administration period. Therefore,
Side Effect Profiles; Mirtazapine and SSRIs·35
it was difficult to distinguish the antidepressant-induced
side effects from the symptoms of depression that remained or were aggravated.
In summary, the present study provides evidence that
the incidence of adverse effects varies with the type of
antidepressant and that the side effects can remain constant during the period of time that the patient is taking
antidepressants. Considering the limited number of antidepressants and small sample size of the present study,
further studies need to be undertaken with larger sample
sizes and a broader range of antidepressants.
REFERENCES
1. Moller HJ. Are all antidepressants the same? J Clin Psychiatry
2000;61 Suppl 6:24-8.
2. Cohen LJ. Rational drug use in the treatment of depression.
Pharmacotherapy 1997;17:45-61.
3. Stahl SM. Selecting an antidepressant by using mechanism of
action to enhance efficacy and avoid side effects. J Clin Psychiatry 1998;59 Suppl 18:23-9.
4. Berndt ER, Bhattacharjya A, Mishol DN, Arcelus A, Lasky T.
An analysis of the diffusion of new antidepressants: variety,
quality, and marketing efforts. J Ment Health Policy Econ 2002;
5:3-19.
5. Nelson JC. Tricyclics and Tetracyclics. In: Sadock BJ, Sadock
VA. Comprehensive textbook of Psychiatry. 7th ed. Philadelphia: Lippincott Wiliams & Wilkins;2003. p.2491-502.
6. Fava M. Weight gain and antidepressants. J Clin Psychiatry
2000;61 Suppl 11:37-41.
7. Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry 1999;60 Suppl 4:4-11.
8. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 2000;355:911-8.
9. Nelson JC. Safety and tolerability of the new antidepressants. J
Clin Psychiatry 1997;58 Suppl 6:26-31.
10. Anderson IM. Selective serotonin reuptake inhibitors versus
tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000;58:19-36.
11. Vaswani M, Linda FK, Ramesh S. Role of selective serotonin
reuptake inhibitors in psychiatric disorders: a comprehensive
review. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:
85-102.
12. MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I. Efficacy and tolerability of
selective serotonin reuptake inhibitors compared with tricyclic
antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;326:1014.
13. Barbui C, Hotopf M, Freemantle N, Boynton J, Churchill R,
Eccles MP, Geddes JR, Hardy R, Lewis G, Mason JM. Selective
serotonin reuptake inhibitors versus tricyclic and heterocyclic
antidepressants: comparison of drug adherence. Cochrane Database Syst Rev 2000;4:CD002791.
14. Anderson IM, Tomenson BM. Treatment discontinuation with
selective serotonin reuptake inhibitors compared with tricyclic
antidepressants: a meta-analysis. BMJ 1995;310:1433-8.
15. de Boer T. The pharmacologic profile of mirtazapine. J Clin
Psychiatry 1996;57 Suppl 4:19-25.
16. Anttila SA, Leinonen EV. A review of the pharmacological and
clinical profile of mirtazapine. CNS Drug Rev 2001;7:249-64.
17. American Psychiatric Association. Diagnostic and statistical
manual of mental disorder. 4th ed. Washington DC: American
Psychiatric Association;1994.
18. Fawcett J, Barkin RL. Efficacy issues with antidepressants. J
Clin Psychiatry 1997;58 Suppl 6:32-9.
19. Richelson E. Treatment of acute depression. Psychiatr Clin
North Am 1993 Sep;16:461-78.
20. Thase ME, Entsuah AR, Rudolph RL. Remission rates during
treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001;178:234-41.
21. Lin EH, Von Korff M, Katon W, Bush T, Simon GE, Walker E,
Robinson P. The role of the primary care physician in patients’
adherence to antidepressant therapy. Med Care 1995;33:67-74.
22. Melfi CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S,
Sredl K. The effects of adherence to antidepressant treatment
guidelines on relapse and recurrence of depression. Arch Gen
Psychiatry 1998;55:1128-32.
23. Frazer A. Pharmacology of antidepressants. J Clin Psychopharmacol 1997;17 Suppl 1:2S-18S.
24. Thompson C. Mirtazapine versus selective serotonin reuptake
inhibitors. J Clin Psychiatry 1999;60 Suppl 17:18-22.
25. Masand PS, Gupta S. Selective serotonin-reuptake inhibitors:
an update. Harv Rev Psychiatry 1999;7:69-84.
26. Sommi RW, Crismon ML, Bowden CL. Fluoxetine: a serotoninspecific, second-generation antidepressant. Pharmacotherapy
1987;7:1-15.
27. Nemeroff CB. The clinical pharmacology and use of paroxetine,
a new selective serotonin reuptake inhibitor. Pharmacotherapy
1994;14:127-38.
28. Buchman N, Strous RD, Baruch Y. Side effects of long-term
treatment with fluoxetine. Clin Neuropharmacol 2002;25:55-7.
29. Sitsen JMA, Zivkov M. Mirtazapine: clinical profile. CNS Drugs
1995;4 Suppl 1:39-48.
30. Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with
paroxetine in major depression. J Clin Psychiatry 2000;61:
656-63.
31. Fava M, Dunner DL, Greist JH, Preskorn SH, Trivedi MH,
Zajecka J, Cohen M. Efficacy and safety of mirtazapine in
major depressive disorder patients after SSRI treatment failure:
an open-label trial. J Clin Psychiatry 2001;62:413-20.
32. http://www.fda.gov/cder/foi/label/2000/18936S58LBL.PDF
33. http://www.fda.gov/cder/foi/nda/99/20-936_Paxil_prntlbl.pdf
34. http://www.fda.gov/cder/foi/label/2002/20415S9lbl.pdf
35. Kutscher EC, Lund BC, Hartman BA. Peripheral edema associated with mirtazapine. Ann Pharmacother 2001;35(11):1494-5.
36. Gitlin MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J
Clin Psychiatry 1994;55:406-13.
37. Nutt DJ. Tolerability and safety aspects of mirtazapine. Hum
Psychopharmacol 2002;17 Suppl 1:S37-S41.