Newer antidepressant drug use in East Asian psychiatric treatment settings: REAP (Research on East Asia Psychotropic Prescriptions) Study.
ABSTRACT 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.
- SourceAvailable from: Brijesh Sathian[Show abstract] [Hide abstract]
ABSTRACT: Background: According to WHO, it is estimated that major depression would be the second most leading cause of disability in the world by 2020. Drug utilization study is defined as study of the marketing, distribution, prescription and use of drugs in a society highlighting on the resulting medical, social and economic consequences. The main objective of this study was to find the utilization pattern of antidepressants prescribed in a tertiary care centre with major depression in hospitalized patients of Western Nepal. Methods: A hospital based observational study was done between 1st October 2009 and 31st March 2010 at Psychiatry Ward of Manipal Teaching Hospital, Nepal. Both qualitative and quantitative data was collected from bed side. The outcome variables were essential drug, generic and trade, treatment, groups of antidepressants and antidepressants used. The explanatory variables were age, gender, monthly income, employment of the patient. Z test and logistic regression was used for the analysis. P-value < 0.05 was considered to be statistically significant. This is the first study done to understand the utilization pattern of antidepressant drugs in hospitalized patients in Nepal. Results: Among the 240 psychiatric patients studied, 38 (15.8%) cases were suffering from major depression. Male and female patients were 44.7% and 55.3% respectively, 95% CI [28.9, 60.5 and 39.5, 71.1]. Depression was more common in housewives (42.1%) followed by teachers 18.4% and students 10.5%. Fluoxetine was the commonest antidepressants to be prescribed 42.1% followed by Amitriptyline 26.3%, Trazodone 21.1% etc. Psychiatrists has a tendency of prescribing essential drugs if monthly income <10000, 1.063 times as compared to monthly income >10000, 2.63 times more in Hindus and 1.197 times more in Brahmins than any other ethnic groups. 9.179 times more tendency of prescribing antidepressants by trade names in case of unemployed patients as compared to employed patients in Nepal. Conclusion: According to the utilization pattern of antidepressants it was found that among the Selective serotonin reuptake inhibitors Fluoxetine was used relatively higher than conventional drugs like Tricyclic antidepressants, recommend that there is a trend of using Typical antidepressants drugs for depression rather than Newer antidepressants. Keywords: Depression, Drug utilization study, Psychiatry, Nepal.Nepal Journal of Epidemiology. 01/2011; 1(5):144-152.
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ABSTRACT: This systematic review evaluated Chinese trials examining the efficacy of venlafaxine in the treatment of depression. Chinese databases CNKI and VIP and western databases were searched for blinded randomized controlled trial publications comparing venlafaxine to other antidepressants or placebo (in English or Chinese). Trials had to establish diagnosis of depression according to the Chinese Classification of Mental Disorders, Diagnostic and Statistical Manual of Mental Disorders, or International Classification of Diseases. Studies were excluded if more than 20% of participants had a primary diagnosis of dysthymia or if more than 15% had a primary diagnosis of bipolar disorder. Effect sizes were calculated as Hedges' g for rating scale scores and Mantel-Haenszel risk ratios (MH RR) for response and remission data. Effect sizes were combined in a fixed-effects model. A total of 25 studies were included. Nine trials compared venlafaxine to selective serotonin reuptake inhibitor; placebo-controlled trials were lacking. Quality was at best modest, and all trials were underpowered. There were more responders (MH RR, 1.08; 95% confidence interval [CI], 1.02-1.15) and remitters (MH RR, 1.12; 95% CI, 1.02-1.24) in venlafaxine groups compared with those in tricyclic antidepressant group. Hamilton Depression Rating Scale end point scores in the venlafaxine groups were lower (Hedges' g = 0.16; 95% CI, 0.04-0.27), and venlafaxine was better tolerated than tricyclic antidepressant (Hedges' g = 0.56; 95% CI, 0.37-0.74). There were no significant differences between venlafaxine and selective serotonin reuptake inhibitor on any of these parameters. Analyses of publication bias were inconclusive. Chinese researchers have published a number of randomized controlled trials comparing venlafaxine to active comparators, but study quality was found to be low. To make optimal use of their research potential Chinese, researchers will have to improve trial reporting and the peer-review process.Journal of clinical psychopharmacology 02/2011; 31(2):194-200. · 5.09 Impact Factor
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 = 609Korea n = 293China n = 536Singapore n = 73 Taiwan 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-value OR95% 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.).
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