Newer antidepressant drug use in East Asian psychiatric
treatment settings: REAP (Research on East Asia
Psychotropic Prescriptions) Study
Kang Sim, N. B. Lee, Hong C. Chua, Rathi Mahendran, Senta Fujii,1Shu-yu Yang,2Mian-Yoon Chong,2Tianmei Si,3
Yan L. He,4Min S. Lee,5Kil M. Sung,6Eun K. Chung,7Yiong H. Chan,8Naotaka Shinfuku,1Chay H. Tan,8
Norman Sartorius9& Ross J. Baldessarini10
Institute of Mental Health/Woodbridge Hospital, Singapore,1Kobe University, Kobe, Japan,2Kaoshiung Medical University, Kaoshiung,
Taiwan,3Beijing Medical University, Beijing and4Shanghai Mental Health Centre, Shanghai, China,5Korea University College of
Medicine, Korea,6Yonsei University College of Medicine, Korea,7Seoul National Hospital, Seoul, Korea,8National University of
Singapore, Singapore,9University of Geneva, Geneva, Switzerland and10Department of Psychiatry, Harvard Medical School;
Psychopharmacology Program, McLean Division of Massachusetts General Hospital, Belmont, MA, USA
Dr Kang Sim, Woodbridge
Hospital/Institute of Mental Health,
10 Buangkok View, Singapore
Tel.: + 65 6389 2000
Fax: + 65 6385 5900
antidepressant, diagnosis, East Asia,
27 January 2006
2 August 2006
31 October 2006
Antidepressant use in East Asia is poorly documented. We compared patients given
newer and older antidepressants to test the hypothesis, suggested in the literature,
that use of newer antidepressants is associated with treatment settings rather than
specific diagnostic categories.
We compared rates of use of older (pre1990) vs. newer antidepressants among 1898
patients identified as antidepressant treated at 21 centres in five East Asian countries
(China, Japan, Korea, Singapore, Taiwan) in 2003. Demographics, treatment setting
and clinical factors associated with preferential use of newer drugs were tested in
univariate and multivariate analyses.
Newer antidepressants were included in the treatment regimens of 67.5% (N = 1282/
1898) of study subjects. Prescription for newer antidepressants was significantly
associated with younger age (z = -4.55, d.f. = 1888, P < 0.001), hospitalization [odds
ratio (OR) 1.32, 95% confidence interval (CI) 1.07, 1.64, P < 0.01] and treatment
within psychiatric hospitals (OR 1.59, 95% CI 1.27, 2.00, P < 0.001). On multivariate
analyses, treatment with newer antidepressants was independently associated with
younger age (P < 0.001), country (P < 0.001) and treatment within private hospitals
(P < 0.001), but not with sex or diagnosis of affective or anxiety disorders (all P > 0.1).
Demographic factors and treatment settings appear to influence antidepressant choice
more than clinical factors such as diagnosis.
British Journal of Clinical Pharmacology
© 2006 The Authors
Journal compilation © 2006 Blackwell Publishing Ltd
Br J Clin Pharmacol
63:4 431–437 431
Some population-based studies have found increased
use of antidepressants in some countries or regions over
the years [1, 2], particularly in primary-care settings 
and following the introduction of modern antidepres-
sants in the 1990s . Increased use of modern antide-
inhibitors (SSRIs), has been associated specifically with
younger patient age , ethnicity , type of clinical
setting, including the presence of counselling within
surgery consultations , availability of treatment
guidelines  and pharmaceutical promotional activity
, whereas association of modern antidepressant use
with particular psychiatric diagnoses has been inconsis-
tent . In addition, antidepressant selection within
and between clinical settings has been highly variable
[7, 11]. Overall, such findings indicate considerable
clinical and sociological complexity in the selection of
specific types of antidepressants, and that the choice
may not necessarily be based on clinical indications.
There is increasing awareness of the potential value of
documenting sometimes major disparities between clini-
cal practice and recommended treatment guidelines
based on research and expert opinion . Antidepres-
sant selection may affect the effectiveness of clinical
treatment and patient outcome , but most reported
research evidence suggests only minor differences in
efficacy among dissimilar antidepressants, at least in
major depressive disorder, leaving other factors to influ-
ence drug selection . We perceive a need to clarify
practice patterns with modern and older drugs in areas
that have been little studied, particularly in East Asia.
Accordingly, in this study we examined differences
between EastAsian patients given newer antidepressants
introduced after 1990 vs. older agents, in relation to
demographic and clinical factors, and particular treat-
ment settings. Based on the literature just cited, we
hypothesized that preferential use of newer antidepres-
sants is associated with treatment settings rather than
specific diagnostic categories.
Study sample and design
We conducted an international, cross-sectional, case-
record and drug-centred study using a standardized data
collection procedure within a 1-month period in Novem-
ber 2003. The study sample involved 1898 consecutive
patients treated with antidepressants and seen at 21 psy-
chiatric centres in five East Asian countries (The Peo-
ple’s Republic of China, Japan, Republic of Korea,
Singapore and Taiwan), with no specific exclusion cri-
teria applied in terms of age or diagnosis. We collected
data from representative psychiatric units serving
defined populations within geographical catchment
areas and which were affiliated with the Institute of
Mental Health: Beijing Medical University (Beijing,
China); the Department of Psychiatry, Kobe University
School of Medicine (Kobe, Japan); the Seoul National
Hospital (Seoul, Korea); the Institute of Mental Health
(Singapore); and Department of Psychiatry, Kaoshiung
University (Kaoshiung County, Taiwan). The study was
approved by research and ethics committees of each of
the collaborating sites.
Two consensus meetings were held before the study to
discuss methodological details, including uniformity of
case selection, data collection, arrangement and data-
entry procedures to assure comparability across sites and
countries. Socio-demographic and clinical information
collected from medical records and held confidential
included age, sex, ICD-10 diagnosis, treatment setting
(inpatient vs. outpatient, public vs. private psychiatric
hospital or clinic, psychiatric hospital vs. psychiatric
units in general hospitals) and the type and dose of
Older antidepressants, developed prior to 1990,
included tricyclic antidepressants (TCAs: amitripty-
line, clomipramine, doxepin, imipramine, nortriptyline);
monoamine oxidase (MAO) inhibitors (phenelzine, tra-
nylcypromine) as well as a reversible MAO inhibitor
(moclobemide). Newer antidepressants included SSRIs
(citalopram, escitalopram, fluoxetine, fluvoxamine, par-
oxetine, sertraline); a serotonin and noradrenaline
serotonergic antidepressant (mirtazapine); a selective
noradrenaline reuptake inhibitor (NRI; reboxetine); and
agents with serotonin receptor-antagonist and weak
monoamine transport effects (trazodone, nefazodone).
Diagnoses were grouped into the major, standard,
ICD-10 categories: organic mental disorders (F1);
primary psychotic disorders (F2: schizophrenia, schizo-
typal and delusional disorders); mood disorders (F3);
(anxiety-related conditions, F4); behavioural syndromes
associated with physiological disturbance and physical
factors (F5); disorders of adult personality and behav-
iour (F6); mental retardation (F7); disorders of psycho-
logical development (F8); behavioural and emotional
disorders with onset in childhood and adolescence (F9).
Averages are reported as means ? standard deviation
(SD) and relative risks are reported as odds ratios (OR)
with 95% confidence intervals (95% CI). Normality of
K. Sim et al.
Br J Clin Pharmacol
distributions of continuous measures was checked with
the Kolmogorov–Smirnov one-sample test. Differences
between groups were tested by Student’s t-test and
one-way anova for normally distributed data, nonpara-
metric Mann–Whitney U and Kruskal–Wallis tests
for non-normally distributed continuous data, and
by contingency tables (c2) for categorical variables.
Sociodemographic and clinical variables were included
in the univariate analyses and significant variables in the
initial analyses were then considered for multivariate
analyses. Multiple logistic regression was carried out to
adjust for relevant covariates and to determine predictors
(age, gender, country, different treatment settings,
ICD-10 diagnoses) of selecting newer antidepressants.
Statistical significance was set at two-tailed P < 0.05.
All analyses were performed using the Statistical
Package for Social Sciences (SPSS®), version 11.0
(SPSS Inc, Chicago, IL, USA).
Demographic and clinical characteristics
Medical records of 1898 adult subjects were examined
for demographic and clinical characteristics of the
sample (Table 1). Overall, age averaged 46.7 ? 16.9
years, 59.1% were women, 68.9% were treated as outpa-
psychiatric unit within a general hospital rather than to a
psychiatric specialty hospital. Treatment settings varied
considerably among countries sampled (Table 1). Anti-
(mood disorders) or F4 (anxiety-associated disorders or
neuroses) ICD-10 diagnoses in 78.8% of all subjects.
Newer antidepressants were included in the treatment
regimens of 67.5% of the 1898 patients sampled. Pref-
erential use of modern agents ranked: Taiwan ?
Singapore > China ? Korea > Japan (Table 1). With
Japan as reference, the use of newer antidepressants was
greatest in Taiwan (OR 1.78, 95% CI 1.63, 1.95), fol-
lowed by Singapore (OR 1.76, CI 1.56, 1.99), China
(OR 1.44, CI 1.31, 1.59) and Korea (OR 1.42, CI 1.27,
1.59; all P < 0.001).
The most commonly prescribed older antidepressants
in specific countries were: China (amitriptyline, clomi-
pramine, maprotiline); Japan (amitriptyline, clomi-
pramine, mianserin); Korea (amitriptyline, imipramine);
Singapore (clomipramine, imipramine); Taiwan (clomi-
pramine, imipramine, moclobemide), making amitrip-
employed older drugs across countries. The most com-
monly prescribed modern antidepressants, by country,
were: China (fluoxetine, paroxetine, sertraline); Japan
(fluvoxamine, paroxetine, trazodone); Korea (citalo-
Characteristics of 1898 East Asian patients treated with antidepressants, by country
Japan n = 609 Korea n = 293 China n = 536Singapore n = 73Taiwan n = 387
Public hospital (%)
Private hospital (%)
Psychiatric hospital (%)
General hospital (%)
ICD-10 F3 (%)
ICD-10 F4 (%)
Newer antidepressants (%)
Columns in ascending rank order of usage of modern antidepressants. *P-values derived from Kruskal–Wallis test. †P-values
derived from c2test.
Newer antidepressant use in East Asia
Br J Clin Pharmacol
pram, paroxetine, sertraline); Singapore (fluoxetine,
fluvoxamine, mirtazapine); and Taiwan (paroxetine, tra-
zodone, venlafaxine), indicating that various SSRIs
were, by far, the most popular modern drugs in 2003.
Overall prescription numbers of separate antidepres-
sants by class and country are shown in Table 2.
Correlates of antidepressant use
Patients given newer antidepressants were several years
younger but included the same proportion of women as
were given older agents (Table 3). Patients given newer
antidepressants were also more likely to be treated in a
psychiatric institution when hospitalized, somewhat less
likely to be diagnosed with a mood disorder, and more
likely to have a disorder other than a neurotic or anxiety-
related condition (Table 3).
Using multivariate logistic regression modelling with
antidepressant type (newer/older) as the dependent
outcome variable and adjusting for covariates (age, sex,
country, treatment settings and ICD-10 diagnostic cat-
Overall prescription numbers of antidepressants by class
Japan N (%)Korea N (%)China N (%) Singapore N (%) Taiwan N (%)
SSRI, Selective serotonin reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor; NASSA, noradrenergic and
specific serotonergic agent; SARI, serotonin antagonist reuptake inhibitor; TCA, tricyclic antidepressant; RIMA, reversible inhibitor
of monoamine oxidase.
Characteristics of East Asian patients given either older or newer antidepressants
Older (n = 616) Newer (n = 1282)
Test statistics z or OR
Age (mean ? SD, years)
Treatment settings (N,%)*
(b) Public units
(c) General hospital
49.3 ? 16.4
45.5 ? 17.0
z = -4.55
1.32 (1.07, 1.64)
0.63 (0.50, 0.79)
0.71 (0.58, 0.87)
1.65 (1.28, 2.12)
*Treatment setting comparisons involve 2 ¥ 2 contrasts for drug type and: (a) inpatients vs. outpatients; (b) public vs. private
settings; (c) general vs. psychiatric hospital sites for inpatients; unstated are the proportion of subjects in each contrasting setting
(in each category, the difference between the stated proportion and 100%).
K. Sim et al.
Br J Clin Pharmacol
egory; Table 4), factors that were significantly associ-
ated with greater use of newer antidepressants were:
younger age, country (Singapore > Taiwan > China
> Korea) and treatment setting (private hospitals vs.
This is the first large-scale, multicentre, international
study of antidepressant use within psychiatric treatment
settings in East Asia. Newer antidepressants, especially
SSRIs, were prescribed in a majority of the treatment
regimens in late 2003. However, despite wide availabil-
ity of older and newer types of antidepressants in all 21
participating sites and five countries, we found major
international variations in antidepressant selection. Use
of modern antidepressants was more likely to occur in
all four other East Asian countries studied compared
with Japan. Based on multivariate analysis, selection of
newer antidepressants was associated with younger
patients, especially in private hospitals, whether general
or psychiatric, as well as being less likely to occur in
Japan compared with other countries. These relation-
ships are consistent with our hypothesis that preferential
use of newer antidepressants is associated with demo-
graphic profiles and treatment settings rather than spe-
cific diagnostic categories.
In this study, 67.5% of all antidepressant prescriptions
were for modern agents, particularly the SSRIs. The
only exception to this preference for modern antidepres-
sants was Japan, which continued to prefer older antide-
pressants by a slight majority (51.1%; Table 1). Large
international differences in antidepressant selection also
have been found recently between Australia, Brazil,
Israel, Russia, Spain and the USA . Even within a
single country, there were sixfold variations in the types
of antidepressants used recently in specific regions and
healthcare settings within Denmark . Preferential and
increased use of modern antidepressants, and particu-
larly the SSRIs, has been reported in recent studies con-
ducted in countries as diverse as Australia  and Italy
, as well as among elderly, young adult and juvenile
patients [15, 16]. Reasons for this trend may include
vigorous promotion of SSRIs and other newer antide-
pressants , improved safety and patient tolerability
of modern agents  and a broadening range of
approved and empirical indications for the versatile
SSRIs , which are about as effective in a number of
anxiety-related disorders as in major depression .
The lack of empirical support of superior efficacy of
one antidepressant over another in major depression 
suggests that factors associated with local preferences in
specific treatment settings  may contribute to anti-
depressant selection. We found that selection of modern
antidepressants was associated with hospitalization,
especially in specialized psychiatric institutions as well
as in private general and psychiatric hospitals. Reasons
for such choices are not entirely clear, but social expec-
tations of patients and physicians, access, affordability
and economic factors may play a role, including whether
relatively expensive modern drugs are allowed by
managed-care policies and supported by third-party pay-
ments in particular settings .
Greater use of modern antidepressants by younger
patients has been observed in some [21, 22] but not other
Multivariate logistic regression values for
factors associated with greater use of
modern* vs. older antidepressants in five
East Asian countries
P-valueOR 95% CI
ICD-10 F3/F4 diagnoses
B, logit estimate; SE, standard error of logit estimate; OR, odds ratio. *Of the total
of 1898 subjects, 1282 (67.5%) were given modern antidepressants. †Compared
Newer antidepressant use in East Asia
Br J Clin Pharmacol
recent studies [4, 5]. The inconsistencies may be related
to the region-specific demographic profile of patients
involved, and whether they have been sampled since the
early 1990s, during which world-wide preference for the
newer antidepressants became established. Preferential
use of modern antidepressants with younger age may
also reflect apparent growth in the recognition and phar-
macological treatment of children and adolescents with
emotional problems in many countries , their pref-
erence for better-tolerated treatments  and the fact
that only fluoxetine, and no older antidepressant, has
been approved by some international regulatory bodies
for use in juvenile depression .
Conversely, the association of older antidepressants
with advanced age calls for critical re-evaluation of indi-
cations for these medications, and close medical moni-
toring during their use, especially long-term, in elderly
patients owing to their potential toxicity. The TCAs, in
particular, are associated with adverse cardiac depres-
sant, hypotensive, central intoxicating and other anticho-
linergic autonomic effects. Such effects can compound
existing medical or neurological problems, including
cardiac disorders and even dementia [25, 26].
The lack of association of preferential use of modern
antidepressants with gender which we found agrees with
the findings of Olfson et al. . In other reports [5, 12]
women were over-represented among patients given all
types of antidepressants, perhaps related to the higher
prevalence of depressive disorders among women, their
greater likelihood of seeking treatment for emotional
distress and a proposed superiority of SSRIs over TCAs
in depressed women compared with men .
Antidepressant use was not strongly associated with
specific diagnoses and, indeed, preferential use of
modern antidepressants was slightly less likely among
patients diagnosed with mood disorders (ICD-10 F3
cluster). Lack of strong association of antidepressant use
with affective disorder diagnoses seems paradoxical, but
has been noted in other settings . The lack of a
strong and consistent preference for modern antidepres-
sants for use in affective disorders in East Asian centres
is not readily explained.As suggested by the data, it may
be related to the use of antidepressants, especially
SSRIs, in conditions other than purely affective disor-
ders such as anxiety spectrum disorders, comorbid
depression in chronic psychotic disorders, as well as in
patients with alcohol or drug use disorders and coexist-
ing depression . In addition, clinician factors such as
patient mix and experience may further influence anti-
depressant prescribing practices.
There are several limitations of this study. First, its
cross-sectional sampling does not allows a longitudinal
comparison of expected recent changes of antidepres-
sant use within and between countries over time.
Second, some potentially highly relevant factors were
not evaluated, particularly provider preferences and
economic factors, including local reimbursement and
funding policies. Third, as this is a drug-centred case
record study, more elaborate assessment of individual
patient variables using rating scales was not included.
Fourth, the study population was restricted to patients
attending psychiatric treatment centres, hence the find-
ings may not be generalizable to primary healthcare
In conclusion, we found that greater use of modern
antidepressants in 21 centres in five EastAsian countries
was associated with being a relatively young adult
patient and with particular treatment settings (especially
psychiatric inpatient settings and in private hospitals),
and in countries other than Japan, but not with psychi-
atric diagnosis or sex. These findings add to a growing
international research literature on factors associated
with selection of particular treatments in specific
Supported by research funds from (i) Institute of Mental
Health, Department of Research, Singapore (K.S.), (ii)
International Centre for Medical Research, Japan (S.F.,
N.Sh.), (iii) Bureau of National Health Insurance,
Taiwan (S-Y.Y., M-Y.C.) and (iv) Bruce J. Anderson
Foundation, and the McLean Private Donors Psychop-
harmacology Research Fund (R.J.B.).
1 Ciuna A, Andretta M, Corbari L. Are we going to increase the
use of antidepressants up to that of benzodiazepines? Eur J Clin
Pharmacol 2004; 60: 629–34.
2 McManus P, Mant A, Mitchell P. Length of therapy with selective
serotonin reuptake inhibitors and tricyclic antidepressants in
Australia. Aust NZ J Psychiatry 2004; 38: 450–4.
3 Lawrenson RA, Tyrer F, Newson RB. The treatment of
depression in UK general practice: selective serotonin reuptake
inhibitors and tricyclic antidepressants compared. J Affect Disord
2000; 59: 149–57.
4 Percudani M, Barbui C, Fortino I. Antidepressant drug use in
Lombardy, Italy: a population-based study. J Affect Disord 2004;
5 Barbui C, Broglio E, Laia AC. Cross-sectional database analysis of
antidepressant prescribing in Italy. J Clin Psychopharmacol
2003; 23: 31–4.
6 Blazer DG, Hybels CF, Simonsick EM. Marked differences in
antidepressant use by race in an elderly community sample:
1986–1996. Am J Psychiatry 2000; 157: 1089–94.
K. Sim et al.
Br J Clin Pharmacol
7 Hansen DG, Sondergaard J, Vach W. Antidepressant drug use in Download full-text
general practice: inter-practice variation and association with
practice characteristics. Eur J Clin Pharmacol 2003; 59:
8 Hamed A, Lee A, Ren XS. Use of antidepressant medications:
are there differences in psychiatric visits among patient
treatments in the Veterans Administration? Med Care 2004; 42:
9 De Las Cuevas C, Sanz EJ, De La Fuente JA. Variations in
antidepressant prescribing practice: clinical need or market
influences? Pharmacoepidemiol Drug Saf 2002; 11: 515–22.
10 Bouhassira M, Allicar MP, Blachier C. Which patients receive
antidepressants? A ‘real world’ telephone study. J Affect Disord
1998; 49: 19–26.
11 Simon GE, Fleck M, Lucas R. Prevalence and predictors of
depression treatment in an international primary care study. Am
J Psychiatry 2004; 161: 1626–34.
12 Pietraru C, Barbui C, Poggio L. Antidepressant drug prescribing
in Italy, 2000: analysis of a general practice database. Eur J Clin
Pharmacol 2001; 57: 605–9.
13 van Eijk ME, Avorn J, Porsius AJ. Reducing prescribing of highly
anticholinergic antidepressants for elderly people: randomised
trial of group versus individual academic detailing. BMJ 2001;
14 Anderson IM. Selective serotonin reuptake inhibitors versus
tricyclic antidepressants: a meta-analysis of efficacy and
tolerability. J Affect Disord 2000; 58: 19–36.
15 Mamdani MM, Parikh SV, Austin PC. Use of antidepressants
among elderly subjects: trends and contributing factors. Am J
Psychiatry 2000; 157: 360–7.
16 Murray ML, de Vries CS, Wong IC. A drug utilisation study of
antidepressants in children and adolescents using the General
Practice Research Database. Arch Dis Child 2004; 89:
17 Depont F, Rambelomanana S, Le Puil S. Antidepressants:
psychiatrists’ opinions and clinical practice. Acta Psychiatr Scand
2003; 108: 24–31.
18 Baldessarini RJ. Drug therapy of depression and anxiety
disorders. Chapter 17. In: Goodman and Gilman’s The
Pharmacological Basis of Therapeutics, 11th edn, eds Brunton
LL, Lazo JS, Parker KL. New York: McGraw-Hill 2005: 429–59.
19 MacGillivray S, Arroll B, Hatcher S. 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.
20 Olfson M, Marcus SC, Druss B. National trends in the outpatient
treatment of depression. JAMA 2002; 287: 203–9.
21 Hansen DG, Sondergaard J, Vach W. Socio-economic
inequalities in first-time use of antidepressants: a
population-based study. Eur J Clin Pharmacol 2004; 60: 51–5.
22 Olfson M, Marcus SC, Pincus HA. Antidepressant prescribing
practices of outpatient psychiatrists. Arch Gen Psychiatry 1998;
23 Zito JM, Safer DJ. Recent child pharmacoepidemiological
findings. J Child Adolesc Psychopharmacol 2005; 15: 5–9.
24 Hemels ME, Koren G, Einarson TR. Increased use of
antidepressants in Canada: 1981–2000. Ann Pharmacother
2002; 36: 1375–9.
25 Glassman A, Shapiro PA, Ford DE. Cardiovascular health and
depression. J Psychiatr Pract 2003; 9: 409–21.
26 Jiang W, Davison JR. Antidepressant therapy in patients with
ischemic heart disease. Am Heart J 2005; 151: 871–81.
27 Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender
differences in treatment response to sertraline versus
imipramine in patients with nonmelancholic depressive
disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004;
28 Zimmerman M, Posternak M, Friedman M. Which factors
influence psychiatrists’ selection of antidepressants? Am J
Psychiatry 2004; 161: 1285–9.
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