2013. Vol.4, No.3, 174-177
Published Online March 2013 in SciRes (
Copyright © 2013 SciRes.
Prospective Observation of Switching Rate of Antidepressants in
Management of Depressive Episode in 3 Months*
Weidong Jin#, Naixin Wang, Yongchun Ma, Zhenhua Tong
Tongde Hospital of Zhejiang Province, Hangzhou, China
Received June 25th, 2012; revised January 5th, 2013; accepted February 7th, 2013
Objective: to observe prospectively of switching rate of antidepressants in management of depressive
episode. Methods: 190 patients with depressive episode treated by antidepressants were observed for 3
months and switching rate were assessed under “best natural therapy”. And switching criteria was fol-
lowing: 1) manic or hypomanic episode; or 2) promoting rapid cycling; or 3) YMRS 11 or irritability or
aggravation in YMRS 3. 4) Psychiatrist thinks that the patients should be stopped to take antidepressants
and should be placed by mood stabilizer or antipsychotics or their combination. Results: 1) 18 of 190 pa-
tients was found to switch in 3 month therapy. The switching rate was 9.47%. 2) 4 of 61 males was found
and 14 females was found to switch, their switching rate was not significant (6.56%, 10.85%, X2 = 0.89, P
> 0.05). 3) 10 of 170 unipolar depression and 8 of bipolar depression was found to switch, their switching
rate was very significant (5.88%, 40%, X2 = 24.29, P < 0.01). 4) 5 of 36 patients token mood stabilizer
and 13 patients not token mood stabilizer was found to switch, their switching rate was not significant
(13.8%, 8.44%, X2 = 1.47, P > 0.05). 5) 7 of 54 patients token more two antidepressants and 11 patients
token single antidepressant was found to switch, their switching rate was not significant (12.96%, 8.08%,
X2 = 1.07, P > 0.05). 6) 7 of 38 patients with family history of mood disorder and 11 of patients without
family history of mood disorder was found to switch, their switching rate was significant (18.4%, 7.23%,
X2 = 4.43, P < 0.05). 7) The switching often carried out at one month after treatment with antidepressants.
8) The significant difference in switching rate among various antidepressants were not found. Conclusion:
Some depressive patients may switch during treatment with antidepressant, it should be stressed on.
Keywords: Antidepressants; Switching; Bipolar Depression; Family History; Mood Stabilize
The concept of bipolar disorder has expanded from one in
which there are major pathological variations in mood of a
severe, extreme form ,to one in which more subtle variation are
found, which merger imperceptibly with “normal” mood varia-
tion. These milder forms appear to be common. They may be-
come more severe under some circumstances and show some
degree of progression. The triggers for such progression can be
socially, or hormonally, or pharmacologically, especially anti-
depressants mediated (Ferrier, Macmillan, & Yong, 2011).
These patients can belong to bipolar spectrum disorder, which
is bigger diagnostic fields consisting of many disorder (Akiskal,
1996). And it also can be thought as soft bipolar (Jin, Chen, &
Xing, 2005; Jin, Chen, & Xing, 2007a), which have been stud-
ied and discussed by Akiskal and others. The relation of these
clues to bipolarity also documented in some Chinese literatures
(Jin et al., 2005, 2007). Several studies have advocated includ-
ing patients with antidepressant-induced mania or hypomania in
the bipolar spectrum (Ghaemi, Ko, & Goodwin, 2002). Akiskal
has also note that ,when followed prospectively, many adults
patients with antidepressant-associated hypomania are found to
progress to bipolar states with spontaneous mania or hypoma-
nia months or years later. In fact, treatment-induced hypomania
was 100% specific for the eventual endpoint of bipolar disorder,
closely followed by a family history of bipolar disorder, which
was 98% specific. Consequently, we give greater weight to
these 2 factors as predictive of a bipolar illness (Ghaemi, Ko, &
Goodwin, 2002).
The nature of depressive episode determines the diversity of
effects of antidepressant treatment variability, particularly sig-
nificant reaction differences often appear between unipolar
depression and bipolar depression Therapy differences were
apparent, so many depression treatment guidelines emphasize
the distinction .Because some patients with depression present
exciting performance in the role of antidepressants, the so-
called “switching”, in which case there’s change we call turn to
manic state, such as antidepressants cause mania or hypomania,
also so called BP-III patients, Bipolar III disorder (pseudo-
unipolar bipolar disorder) refer to a more heterogeneous
grouping of people who experience recurrent episodes of uni-
polar depression and also show clinical features suggesting that
they may go on to development a hypomanic or manic episode.
Such people may have a family history of bipolar disorder,
experienced antidepressant-induced hypomanic switching, or
have hyperthymic, dysthymic or cyclothymic, premorbid tem-
peraments (Ferrier, Macmillan, & Yong, 2011; Akiskal, 1996;
Jin, Chen, & Xing, 2007b). However, it has been controversial
that how much prevalence of antidepressants triggering switch
during treatment. Because this switching involved the unmber
of chance in the end, such as definition of switching (Jin, Chen,
& Xing, 2007a), time of administration (Jin, Chen, & Xing,
2007b), drug type (Jin X. G. & Jin W. D., 2007), type of dis-
*Supported by Medicine study Medicine fund of Zhejiang Province (No
2006A017), China.
#Corresponding author.
ease and to investigate or research methods (Jin X. G. & Jin W.
D., 2007).Most of current studies is a retrospective investiga-
tion (Akiskal, 1996; Jin, Chen, & Xing, 2007a; Jin X. G. & Jin
W. D., 2007), and prospective studies is less, which can be
right investigating un-controlling factors of duration of therapy,
combination therapy problems in the nature of the care status.
Prospective study that we apply may be effective in controlling
certain variables, in order to more accurately at same time ob-
served certain drugs trigger or induce switching and it’s inci-
dence. We conducted research in this area, and will report is as
As episode of depression ,especially first episode depression,
was difficult to distinguished as unipolar or bipolar, and be-
cause 2/3 bipolar disorder always had depression episode as
first onset, and most depression was common clinical phase
during all of bipolar disorder, and also unipolar and bipolar
depression was similar in psychopathology. So whereas unipo-
lar or bipolar depression, only depression episode, was com-
panied mania, which was induced by antidepressants or natu-
rally appearance, as has significant clinical role. This means
that patients should be diagnosed as bipolar disorder. So put-
ting stress on switching is very important. The same case is
caring switching rate in clinical. During median follow-up of 41
weeks (range, 8 - 251 weeks), manic conversion occurred in
4786 patients (5.4%). Multivariate analyses using time-de-
pendent Cox proportional hazards models indicated that an
increased risk of manic conversion was associated with antide-
pressant category vs no antidepressant exposure (hazard ratios:
2.1 for selective serotonin reuptake inhibitors, P < .001; 3.8 for
“other” antidepressants, P < .001; and 3.9 for tricyclic antide-
pressants, P = .002)
Material and Methods
Study of 190 cases met the American standards of classifica-
tion and diagnosis of mental disorders fourth edition (DSM-IV)
and the Chinese classification and diagnostic criteria for mental
disorders third edition (CCMD-3) in the depressive episode or
bipolar depression diagnostic criteria. Male patients was 61
cases, female was 129 cases, aged was from 16 to 62 years old,
age mean was 25.6 ± 19.9 years. There were 170 cases of de-
pression, bipolar depression, 20 cases in 190 patients; a posi-
tive family history of mood disorder were 38 cases and 152
patients without family history of mood disorders.
Switching criteria: 1) to appear manic or hypomanic episode;
or 2) to become quicker circulation of the originals; or 3)
Young Mania Rating Scale 11 points or one of irritability and
destruction attacks 3 points; or 4) therapists believe that the
use of antidepressants should be discontinued antipsychotics or
mood stabilizers or change their therapeutic methods.
Treatment: Each patient diagnosed with depression or bipolar
depression was managed by psychiatrists with the most natural
treatment. The most natural is the so-called that doctors use of
antidepressant drugs for the patient based on the diagnosis and
their own treatment experience of adding or not adding mood
stabilizers. However, the patient wasn’t observed that added
typical or atypical antipsychotics. Duration observed continue
for 3 months. In 3 months was continuous treatment, without
interruption and not to change antidepressants.
Evaluation: Three scales were sued. There were Hamilton
Depression Rating Scale (HAMD), Hamilton Anxiety Rating
Scale (HAMA) Young Mania Rating Scale (YMRS). Patients
were assessed before treatment and after 1 week, 1 month, 2
months, in March. No matter how the ratings, 3 require a scale
of assessment. When a patient at some time within 3 months is
considered the switching, the subsequent assessment of the
interruption and as a “positive” patients treated.
Application of Chi-square test in SPSS10.0 for X2 test.
1) Switching rate: There were 18 patients switching to mania
during therapy for 3 months. The switching rate was 9.47%.
2) Switching time: The time to switching during treatment
was from shortest 3 days to longest 81 days, and average was
28.4 ± 24.5 day. And there was no difference between male and
female patients (30.8 ± 19.5 vs 26.9 ± 13.1 day), but it’s was
longer of unipolar patients than that of bipolar patients (45.9 ±
8.1 vs 20.4 ± 10.6 day),and it’s shorter of patients with family
history of bipolar disorder than that without family history of
bipolar disorder (23.5 ± 12.8 vs 33.7 ± 20.1 day).
3) Comparison relatively as following.
4) Comparison between different antidepressants.
There were 136 patients treated by only one antidepressant and
11 cases switched. The number of 80 patients treated with SSRI
switched was 5 (6.25%), of 26 patients with SNRI switched
was 3 (11.5%), of 25 patients with TCA switched was 2 (8%),
of 5 patients with others switched was 1 (20%). No differences
in switching rate was found (X2 = 2.21, P > .05). If TCA was
thought as dual action mechanism antidepressant as SNRI, no
difference in switching rate between SSRI and dual action
mechanism antidepressants (TCA + SNRI, X2 = 0.55, P > .05).
Table 1.
Comparison relative factors.
Factors Cases
Cases of
rate X2 P
Male 61 4 6.56% 0.89 >.05
Female 129 14 10.85%
Unipolar 170 10 5.88% 24.29 <.01
Bipolar 20 8 40.00%
Family Historyof Mood Disorders
Positive 38 7 18.40% 4.43 <.05
Negative 152 11 7.23%
Only One 136 11 8.08%1.07
Two And More 54 7 12.96%
Mood Stabilizer
Yes 36 5 13.80% 1.47 >.05
No 154 13 8.44%
Copyright © 2013 SciRes. 175
On the antidepressant drug-induced phase conversion of
most of the data are retrospective, and therefore to some extent
there may be partial differences. Therefore, prospective obser-
vation may avoidance this partial differences, which can find
real switching rate under certain the conditions specified or
natural treatment condition in a certain time period of antide-
pressant therapy and can find risks related to switching. Our
results show that about 10% depressive episode patients may
switch and it often appear at about 1 month after beginning of
Clinicians managing depression in patients with bipolar
disorder or patients who we don’t know its trait face two chal-
lenges. First, major depression is a handicapping disease and is
associated with a high risk of suicide in bipolar patients. Sec-
ond, in bipolar patients, antidepressant drugs are associated
with a high risk of antidepressant-induced mania (AIM) and
rapid cycling. The definition of predictors of AIM is a key issue
for the therapeutic management of bipolar patients. Clinical
studies on bipolar patients with and without AIM have identi-
fied characteristics with poor sensitivity and low specificity.
Many factors related to switching was found, such as family
history of bipolar disorder, early onset of disorder, hyperthemia
of Temperament, extreme personality, history of switching, and
some biological factors, such as Hypothyroidism, functional
polymorphism of the serotonin transporter (5-HTT) gene
(Rousseva et al., 2003). Also findings suggesting gender, some
clinical features (Jin et al., 2006), dysthmia and cyclothmia, or
borderline personality disorder (Ghaemi, Ko, & Goodwin,
2002,) maybe related to switching. But all these refer to bipolar
disorder. In fact, some depressive patients diagnosed as unipo-
lar depression maybe switched during treatment with antide-
Tondo L. (2009) review available data pertaining to risk of
mania—hypomania among bipolar (BPD) and major depressive
disorder (MDD) patients with vs. without exposure to antide-
pressant drugs (ADs) and consider effects of mood stabilizers,
They computerized searching yielded 73 reports (109 trials,
114,521 adult patients); 35 were suitable for random effects
meta-analysis, and multivariate-regression modeling included
all available trials to test for effects of trial design, AD type,
and mood-stabilizer use. And found that overall risk of mania
with/without ADs averaged 12.5%/7.5%. The AD-associated
mania was more frequent in BPD than MDD patients (Tondo,
Vázquez, & Baldessarini, 2010). We also had some results. 10
of 170 unipolar depression had switched during antidepressants
therapy. It indicated that there is greater difference in switching
rate between bipolar and unipolar disorder, which was most
significant risk for switching. These patients can not be diag-
nosed as bipolar disorder by model criteria. when followed
prospectively, many adults patients with antidepressant-associ-
ated hypomania are found to progress to bipolar states with
spontaneous mania or hypomania months or years later
(Ghaemi, Ko, & Goodwin, 2002; Gao et al., 2008). So the pa-
tients with switching of mania could be diagnosed bipolar dis-
order only depending on modification of model bipolar dis-
order diagnose criteria (Jin et al., 2006; Chun & Dunner, 2004;
Gao et al., 2008).
In General, Combination usage of antidepressant may one
risk for switching (Jin, Chen, & Xing, 2007a; Gao et al., 2008),
but we don’t found this conclusion, which may be related to
short duration of observation and less cases. Many results sup-
ported that 2 or more AD combination for treatment of depres-
sive episode promoted risk of switching to mania or rapid cy-
cling. But this switching can be interrupted or reduced by mood
stabilizers, it’s risk can be reduced 50% (Bottlender et al.,
2001). In past we also found lithium carbonate can significantly
reduced switching risk in bipolar disorder (Jin X. G. & Jin W.
D., 2007). But our result can not show the same result, which
may be related more “nulpolar” depression patients who be
treated less mood stabilizer and all patient be treated less mood
stabilizer. Only 5 patients in our studied patients were con-
gratulated with mood stabilizes, which reflected therapy status
of psychiatrist in china.
Treatment of bipolar depression patients is caused for con-
cern, In general, antidepressants do not need the participation of
many bipolar depression treatment Many guidelines also em-
phasize this point. But most of the cases, the risk of bipolar
depression phase conversion was significantly higher than uni-
polar depression, almost close to half of depression may con-
verse to drug-related mania or hypomania, even rapid cycling.
Our previous study found that bipolar depression is occurred
during treatment with probability close to 40% (Song et al.,
2008), this study also suggest a similar discovery.
Different antidepressants maybe had a various switching rate
for patients with depressive episode. In general, TCA and SNRI
had more promotion to mania than that of SSRIs for depressive
patients. So bipolar depressive patients shouldn’t be treated
with antidepressants except special conditions, in which only
SSRIs was used. Some studies found that TCA and SNRI is
more than motivational than SSRI, especially for bipolar de-
pression on the types of antidepressant drugs (Peet, 1994; Ba-
rak, Kimhi, & Weizman, 2000). The switching rate of TCA was
12 times compare to citalopram (Barak, Kimhi, & Weizman,
2000), SNRI’s switching rate of SSRI 3 times compare to par-
oxetine (Peet, 1996), we do not have similar findings, which
may be and fewer cases and the observation time is short. But
more of concern is the type of depression.
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