Journal of

Personalized
Medicine

Article
Antidepressant Treatment and Manic Switch in Bipolar I
Disorder: A Clinical and Molecular Genetic Study
Chih-Ken Chen 1,2,† , Lawrence Shih-Hsin Wu 3,† , Ming-Chyi Huang 4,5 , Chian-Jue Kuo 4,5 and
Andrew Tai-Ann Cheng 3,6, *

1 Community Medicine Research Center & Department of Psychiatry, Chang Gung Memorial Hospital,
Keelung 204, Taiwan; [email protected]
2 College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
3 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan;
[email protected]
4 Taipei City Psychiatric Center, Department of General Psychiatry, Taipei City Hospital, Taipei 10341, Taiwan;
[email protected] (M.-C.H.); [email protected] (C.-J.K.)
5 Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University,
Taipei 106, Taiwan
6 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
* Correspondence: [email protected]; Tel.: +886-2-27899119; Fax: +886-2-27823047
† These authors contributed equally to this work.

Abstract: Affective switch is an important clinical issue when treating bipolar disorder. Though
commonly seen in clinical practice, the benefits of prescribing antidepressants for bipolar depression
are still controversial. To date, there have been few genetic studies and no genome-wide association
study (GWAS), focusing on manic switch following bipolar depression. This study aims to investigate





 the effects of individual genomics and antidepressant medication on the risk of manic switch in
Citation: Chen, C.-K.; Wu, L.S.-H.; bipolar I disorder (BPI). A total of 1004 patients with BPI who had at least one depressive episode with
Huang, M.-C.; Kuo, C.-J.; Cheng, complete data on antidepressant treatment and outcome were included. Clinical assessment of mania
A.T.-A. Antidepressant Treatment and depression was performed by trained psychiatric nurses and psychiatrists using the Chinese
and Manic Switch in Bipolar I version of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), and the diagnosis of
Disorder: A Clinical and Molecular
BPI was made according to DSM-IV criteria. Manic switch was defined as a manic episode occurring
Genetic Study. J. Pers. Med. 2022, 12,
within eight weeks of remission from an acute depressive episode. The age at first depressive episode
615. https://doi.org/10.3390/
of the study patients was 30.7 years (SD 12.5) and 56% of all patients were female. GWAS was
jpm12040615
carried out in a discovery group of 746 patients, followed by replication in an independent group
Academic Editors: Chia-Hsiang Chen of 255 patients. The top SNP rs10262219 on chromosome 7 showed the strongest allelic association
and Yu-Shu Huang with manic switch (p = 2.21 × 10−7 ) in GWAS, which was however not significantly replicated.
Received: 11 March 2022 Antidepressant treatment significantly (odds ratio 1.7; 95% CI 1.3–2.2; p < 0.001) increased the risk
Accepted: 31 March 2022 of manic switch. In logistic regression analysis, the CC genotype of rs10262219 (odds ratio 3.0; 95%
Published: 11 April 2022 CI 1.7–5.2) and antidepressant treatment (odds ratio 2.3; 95% CI 1.4–3.7) significantly increased the
risk of manic switch with a joint effect (odds ratio 5.9; 95% CI 3.7–9.4). In conclusion, antidepressant
Publisher’s Note: MDPI stays neutral
medication and rs10262219 variants jointly increased the risk of manic switch after bipolar depression.
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Keywords: bipolar I disorder; bipolar depression; antidepressant treatment; manic switch; genome-
wide association study

Copyright: © 2022 by the authors.

Licensee MDPI, Basel, Switzerland. 1. Introduction
This article is an open access article
Bipolar disorder is characterized by episodic recurrent mania or hypomania and major
distributed under the terms and
depression, associated with great morbidity and mortality [1]. Bipolar depressive episodes
conditions of the Creative Commons
are more pervasive with greater burden in terms of economic costs, functioning, caregiver
Attribution (CC BY) license (https://
burden, and suicide than manic episodes, and their treatments are more challenging
creativecommons.org/licenses/by/
than those in manic episodes [2]. Patients with bipolar disorder average 45% of time ill
4.0/).

J. Pers. Med. 2022, 12, 615. https://doi.org/10.3390/jpm12040615 https://www.mdpi.com/journal/jpm

J. Pers. Med. 2022, 12, 615 2 of 12

during long-term follow-up, and depression accounts for 72% of time ill [3]. In addition,
patients with bipolar disorder typically require long-term pharmacological treatment to
prevent recurrent episodes of depression and mania [4]. Treatment of bipolar depression
remains unsatisfactory although some modern antipsychotics (particularly lurasidone,
olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine are available.
The value and safety of antidepressants remain controversial [5]. However, evidence-based
guidelines are often not followed by prescribers, and, in some countries, the most common
form of treatment is antidepressant monotherapy [6–8].
Manic switch is an important clinical issue when treating bipolar depression. Com-
pared with giving a mood stabilizer alone, short-term administration of an additional
antidepressant yielded neither major protection from depression nor a substantial increase
in the risk of mania [9–11]. However, prolonged use is associated with an increased risk of
treatment-emergent mania or hypomania [7,12,13]. Retrospective data obtained from pa-
tients hospitalized between 1920 and 1959 show a rate of 29% for naturalistic switching from
depression to hypomania or mania [14]. The frequency of mood switching associated with
acute antidepressant therapy is 27% in a trial with small samples [15]. Hypomanic/manic
switches occur in 14.0~19.3% of the acute treatment trials and in 33.0~36.7% of continuation
trials of adjunctive treatment with antidepressants in bipolar depression [16–18]. However,
a naturalistic study on bipolar disorder concludes that the use of antidepressants does not
influence the daily rate of switching from depression to mania [19].
So far, the progress of uncovering single nucleotide polymorphisms (SNPs) underpin-
ning treatment efficacy in bipolar disorder is encouraging [20,21]. For example, genome-
wide association study (GWAS) has identified specific SNPs associated with response to
lithium treatment in bipolar disorder to be replicated [22–25]. To date, however, there
have been few genetic studies [26], and no GWAS focusing on manic switch following
bipolar depression has been reported. In the present report, we will first clarify whether
antidepressants can increase the risk of manic episodes and examine differential risks of
switching from depression to mania among various antidepressants in Taiwanese Han
patients with bipolar I (BPI) disorder. Then, results of a GWAS for manic switch after
bipolar depression will be presented.

2. Results
2.1. Demographic and Clinical Characteristics
Case selection profile was showed in Figure 1, and 1004 BPI patients were selected
to further analyses. Durations of antidepressant treatment ranged from 1 to 168 weeks
(median: 9.0 weeks). Durations between remissions from bipolar depression to a manic
switch ranged from 0 to 8 weeks (median: 3.0 weeks). Table 1a shows the demographic and
clinical characteristics of the study patients. The mean age of the first depressive episode
was 30.7 years old. There was no significant gender difference in rates of antidepressant
treatment (44.0% in males, 56.0% in females). The overall rate of manic switch was 39.7%,
with no significant gender difference (male 39.4%, female 40.0%). Following their first
depressive episode, 76.2% of study patients had a subsequent manic episode. There was no
significant difference in rates of a subsequent manic episode between patients with and
without antidepressant treatment. However, the former were significantly (p < 0.001) more
likely to have a manic switch after remission of depression than the latter (46.2% and 33.1%,
respectively) or recurrence of mania within one year. The types of antidepressants for the
first depressive episode included SSRI (Selective Serotonin Reuptake Inhibitor) (25.7%),
TCA (Tricyclic Antidepressants) (9.3%), SNRI (Serotonin and Norepinephrine Reuptake
Inhibitor) (6.3%), and other antidepressants (9.7%) (Table 1b). There was no significant
association between rates of manic switch and types of antidepressants. Of all patients,
28.7% received lithium treatment, 40.2% received antipsychotics, and 31.6% received other
mood stabilizers (including valproate 17.6%). The most commonly used antipsychotics
were sulpiride (7.1%) and quetiapine (5.9%). The use of lithium, antipsychotics, or other
mood stabilizers was not associated with the risk of manic switch.
J. Pers. Med. 2022, 12, x FOR PEER REVIEW 3 of 12

ceived other mood stabilizers (including valproate 17.6%). The most commonly used an-
J. Pers. Med. 2022, 12, 615 tipsychotics were sulpiride (7.1%) and quetiapine (5.9%). The use of lithium, antipsychot-
3 of 12
ics, or other mood stabilizers was not associated with the risk of manic switch.

Figure 1.
Figure 1. Case selection
selection profile.
profile.

Table1.1.Demographic
Table Demographicand
andclinical
clinicalcharacteristics,
characteristics,comparing
comparingstatistics
statisticsofof study
study patients
patients with
with bipo-
bipolar
lar I disorder.
I disorder.
(a) Antidepressant Treatment
(a) Antidepressant Treatment
Total Treatment with antidepressants
Total Treatment with antidepressants
N = 1004 No (N = 493) Yes (N = 511) p Value
N = 1004 No (N = 493) Yes (N = 511) p Value
Female gender, N (%) 562 (56.0) 262 (53.1) 300 (58.7) 0.086
Female gender, N (%) 562 (56.0) 262 (53.1) 300 (58.7) 0.086
Age at first depressive episode, mean (SD) 30.7 (12.5) 29.7 (12.0) 31.6 (12.8) 0.017
Age at first depressive episode, mean (SD) 30.7 (12.5) 29.7 (12.0) 31.6 (12.8) 0.017
Subsequentmanic
Subsequent manic episode,
episode, N (%)
N (%) 765
765 (76.2)
(76.2) 384384 (77.9)
(77.9) 381
381 (74.6)
(74.6) 0.215
0.215
Manic
Manic switch
switch ororrecurrence
recurrence within
within 1 year,
1 year, N (%)
N (%) 603
603 (60.1)
(60.1) 259259 (52.5)
(52.5) 344
344 (67.3)
(67.3) <0.001
<0.001
Manic switch, N (%)
Manic switch, N (%) 399 (39.7)
399 (39.7) 163163
(33.1)
(33.1) 236 (46.2)
236 (46.2) <0.001
<0.001
(b) Manic (b)Switch
Manic Switch
Manic
Manic switch
switch
NoNo
(N(N
= 605)
= 605) Yes (N(N
Yes = 399)
= 399)
Femalegender,
Female gender, N (%)
N (%) 562
562 (56.0)
(56.0) 336336 (55.5)
(55.5) 226
226 (56.6)
(56.6) 0.730
0.730
Age at first depressive episode,
Age at first depressive episode, mean (SD)(SD)
mean 30.7 (12.5)
30.7 (12.5) 30.9 (12.2)
30.9 (12.2) 30.4 (12.9)
30.4 (12.9) 0.017
0.017
Types of antidepressants
Types of antidepressants
SSRI 258 (25.7) 138 (22.8) 120 (30.1) 0.244
SSRI
TCA 258
93 (25.7)
(9.3) 44138 (22.8)
(7.3) 49120 (30.1)
(12.3) 0.244
TCA
SNRI 6393 (9.3)
(6.3) 33 44 (7.3)
(5.5) 3049 (12.3)
(7.5)
Other antidepressants
SNRI 9763
(9.7)
(6.3) 60 33
(9.9)
(5.5) 3730
(9.3)
(7.5)
Lithium, N (%)
Other antidepressants 27097
(28.7)
(9.7) 163 60
(28.6)
(9.9) 10737(28.7)
(9.3) 0.990
Other mood stabilizers, N (%) 317 (31.6) 185 (30.6) 132 (33.1) 0.403
Lithium, N (%)
Antipsychotics, N (%)
270 (28.7)
404 (40.2)
163 (28.6)
249 (41.2)
107 (28.7)
155 (38.8)
0.990
0.465
Other mood stabilizers, N (%) 317 (31.6) 185 (30.6) 132 (33.1) 0.403
SD: standard deviation; SSRI: selective serotonin reuptake inhibitors; TCA: tricyclic antidepressants; SNRI:
Antipsychotics,serotonin
N (%) and norepinephrine reuptake
404 (40.2)
inhibitors. 249 (41.2) 155 (38.8) 0.465
SD: standard deviation; SSRI: selective serotonin reuptake inhibitors; TCA: tricyclic antidepressants;
SNRI:Among
serotonin
theand norepinephrine
subjects, 156 (39.1%reuptake inhibitors.
of those with manic switch) had a manic switch within
one week after remission of bipolar depression. Figure 2a shows the survival curves of
manic switch or recurrence of manic episode after remission of the first depressive episode.
Patients treated with antidepressants were more likely than those without to turn into a
manic switch after the first depressive episode.
 Among the subjects, 156 (39.1% of those with manic switch) had a manic switch
within one week after remission of bipolar depression. Figure 2a shows the survival
curves of manic switch or recurrence of manic episode after remission of the first depres-
sive episode. Patients treated with antidepressants were more likely than those without
to turn into a manic switch after the first depressive episode.
J. Pers. Med. 2022, 12, 615 4 of 12

(a) (b)
Figure
Figure 2. 2. Survival
Survival functions
functions of of manic
manic switch
switch or
or recurrence
recurrence after
after remission
remission ofof the
the first
first depressive
depressive
episode among bipolar I patients. (a) Among patients with bipolar I disorder (N = 1004), 511 re-
episode among bipolar I patients. (a) Among patients with bipolar I disorder (N = 1004), 511 received
ceived antidepressant treatments, while 493 did not for their first depressive episodes. Median sur-
antidepressant treatments, while 493 did not for their first depressive episodes. Median survival
vival time to manic switch or recurrence following remission of the first depressive episode was
time(95%
12.0 to manic switch orweeks
CI 8.5–15.5) recurrence following
and 52.0 (95% CIremission
39.9–64.1) ofweeks
the first
fordepressive
those withepisode was 12.0
and without (95%
antide-
CI 8.5–15.5) weeks and 52.0 (95% CI 39.9–64.1) weeks for those with and without
pressant treatment, respectively (chi-square = 68.2, p < 0.001). (b) Among patients who had antide- antidepressant
treatment,
pressant respectively
treatments (chi-square
for the first depressive p < 0.001).
= 68.2, episode (N (b) Among
= 511), patientssurvival
the median who had antidepressant
time to the manic
episode
treatments for for
those
thetreated with SSRIepisode
first depressive (N = 257),
(NSNRI (Nthe
= 511), = 62), TCA (N
median = 93), and
survival timeother
to theantidepressants
manic episode
(N
for =those
99) were 12.0with
treated (95% CI 7.9–16.1)
SSRI (N = 257),weeks,
SNRI 10.0
(N =(95% CI 0.0–21.2)
62), TCA (N = 93),weeks, 8.0 (95%
and other CI 4.5–11.5)(N
antidepressants weeks,
= 99)
and 20.0 (95% CI 7.9–32.1) weeks, respectively. Patients treated with TCA had a lower
were 12.0 (95% CI 7.9–16.1) weeks, 10.0 (95% CI 0.0–21.2) weeks, 8.0 (95% CI 4.5–11.5) weeks, and 20.0 mean survival
time
(95% than patientsweeks,
CI 7.9–32.1) treated with other antidepressants
respectively. (Generalized
Patients treated with TCA hadWilcoxon test chi-square
a lower mean survival time= 4.6,
thanp
= 032). SSRI: Selective serotonin reuptake inhibitors; SNRI: Serotonin and norepinephrine reuptake
patients treated with other antidepressants (Generalized Wilcoxon test chi-square = 4.6, p = 0.032).
inhibitors; TCA: Tricyclic antidepressants.
SSRI: Selective serotonin reuptake inhibitors; SNRI: Serotonin and norepinephrine reuptake inhibitors;
TCA: Tricyclic antidepressants.
Among the first depressive episodes with antidepressant treatments (N = 511), the
meanAmong
survivalthe time
firstfor those withepisodes
depressive antidepressant monotherapy treatments
with antidepressant and those with(N =concomi-
511), the
tant mood stabilizers or antipsychotics was 8.0 (95% CI 2.9–13.1) weeks
mean survival time for those with antidepressant monotherapy and those with concomitant and 13.0 (95% CI
8.1–17.9) weeks, respectively.
mood stabilizers There was
or antipsychotics was no
8.0 significant difference
(95% CI 2.9–13.1) in survival
weeks and 13.0time to the
(95% CI
next manic episode between those with antidepressant monotherapy
8.1–17.9) weeks, respectively. There was no significant difference in survival time and those with con-
to
comitant mood episode
the next manic stabilizers or antipsychotics
between (chi-square = 0.1,
those with antidepressant p = 0.744). Among
monotherapy patients
and those with
whose first depressive
concomitant episode
mood stabilizers was treated with
or antipsychotics antidepressants
(chi-square = 0.1, p =(N = 511),
0.744). as shown
Among in
patients
Figure
whose 2b,
firstthe median survival
depressive episodetime
was to the manic
treated withepisode for those(N
antidepressants treated with
= 511), as SSRI
shown (Nin=
257),
FigureSNRI (N =median
2b, the 62), TCA (N = 93)
survival andtoother
time antidepressants
the manic episode for(N those
= 99) were 12.0
treated (95%
with CI
SSRI
7.9–16.1)
(N = 257),weeks,
SNRI 10.0
(N =(95% 62), CI
TCA0.0–21.2) weeks,
(N = 93) and 8.0 (95%
other CI 4.5–11.5) weeks,
antidepressants (N = and 20.0 (95%
99) were 12.0
CI 7.9–32.1) weeks, respectively. Patients treated with TCA had a
(95% CI 7.9–16.1) weeks, 10.0 (95% CI 0.0–21.2) weeks, 8.0 (95% CI 4.5–11.5) weeks,lower mean survival
and
time than CI
20.0 (95% patients
7.9–32.1)treated
weeks,with other antidepressants
respectively. Patients treated(Generalized
with TCAWilcoxon
had a lower testmean
chi-
square
survival= time
4.6, pthan
= 0.032).
patients treated with other antidepressants (Generalized Wilcoxon test
chi-square = 4.6, p = 0.032).

2.2. Genome-Wide Association Study

The principal component analysis did not find substantial population stratification and
cryptic relationship among the 746 GWAS patients (Figure S1). Manhattan plot constructed
by the allelic model showed no SNP associated with manic switch after bipolar depressive
episodes at genome-wide significance (Figure 3). Q-Q plot of the allelic model p values is
shown in the Supplementary Materials (Figure S2). The top-ten significant SNPs are listed
in the Supplementary Materials (Table S1). The Top SNP rs10262219 on chromosome 7,
located in the intergenic region between leucine zipper protein 6 (LUZP6) and cholinergic
J. Pers. Med. 2022, 12, 615 5 of 12

receptor muscarinic 2 (CHRM2), showed the strongest allelic association with manic switch
(p = 2.21 × 10−7 ). A few SNPs near the rs10262219 also showed suggestive association
(p < 10−5 ) (Figure S3). The replication did not reach a significant association (p = 0.40), and
all samples (combined GWAS and replication) showed p = 6.44 × 10−7 in the allelic model.
We further analyzed the dominant model for rs10262219 and found an increased risk for
manic switch with the CC genotype (odds ratio 2.5; 95% CI 1.7–3.6) (Table 2). The genotypic
association for rs10262219 in the replication group did not reach statistical significance.
However, logistic regression analysis showed that the CC genotype of rs10262219 (odds
ratio 3.0; 95% CI 1.7–5.2) and antidepressant treatment (odds ratio 2.3; 95% CI 1.4–3.7)
increased the risk of manic switch with a joint effect of odds ratio 5.9 (95% CI 3.7–9.4).

Table 2. Effects of antidepressants treatment and rs10262219 genotypes on manic switch after bipolar
depression.

Switch (+) Switch (−) Odds Ratio (95% CI) p Value

GWAS cohort, N = 746(%)
CC 301 (85.3%) 275 (70.0%) 2.5 (1.7–3.6) 6.6 × 10−7
TT + TC 52 (14.7%) 118 (30.0%)
Replication cohort, N = 255(%)
CC 77 (72.6%) 100 (67.1%) 1.3 (0.8–2.2) 0.36
TT + TC 29 (27.4%) 49 (32.9%)
Combined, N = 1001(%)
CC 378 (82.4%) 375 (69.2%) 2.1 (1.5–2.8) 1.96 × 10−6
TT + TC 81 (17.6%) 167(30.8%)
Antidepressants X rs10262219 *
Antidepressants(−) × CT + TT (ref.) 1
Antidepressants(+) × CC 5.9 (3.7–9.4) <10−6
Antidepressants(+) × CT + TT 2.3 (1.4–3.7) 7.0 × 10−4
Antidepressants(−) × CC 3.0 (1.7–5.2) 1.2 × 10−4
Ref. reference group * Joint effect of antidepressant medication and rs10262219 genotypes from logistic regression
analysis.
J. Pers. Med. 2022, 12, x FOR PEER REVIEW 6 of 12

J. Pers. Med. 2022, 12, 615 6 of 12

Figure
Figure 3.
3. Genome-wide
Genome-wideassociation
associationbetween
between single-nucleotide polymorphisms
single-nucleotide polymorphisms (SNPs)
(SNPs)andand
manic switch
manic afterafter
switch bipolar depressive
bipolar episodes.
depressive Results
episodes. from the
Results fromasso-
the
ciation between individual SNPs and manic switch after depressive episodes treated with antidepressants in 746 patients with bipolar I disorder. The negative log
association between individual SNPs and manic switch after depressive episodes treated with antidepressants in 746 patients with bipolar I disorder. The negative
of the P value for the association, as calculated by means of the chi-square test for the dominant model, is plotted against the chromosomal location across the
log of the P value for the association, as calculated by means of the chi-square test for the dominant model, is plotted against the chromosomal location across the
genome. The horizontal line indicates the significance level of 1.0 × 10−6, which was achieved by a few SNPs. The highest SNPs on chromosome 7 are located in the
genome. The horizontal line indicates the significance level of 1.0 × 10−6 , which was achieved by a few SNPs. The highest SNPs on chromosome 7 are located in the
intergenic region between LUZP6 and CHRM2.
intergenic region between LUZP6 and CHRM2.
J. Pers. Med. 2022, 12, 615 7 of 12

3. Discussion
In this retrospective cohort study, we have demonstrated that antidepressant treatment
significantly increased the risk of manic switch after remission of depression. The SNP
rs10262219 on chromosome 7 showed the strongest allelic association with manic switch
though not reaching the level of significance after a Bonferroni correction. To our knowl-
edge, this is the first GWAS searching for the genetic marker of manic switch following
bipolar depressive episodes.
Our study found that manic switch after remission of first depressive episode was
more frequently observed in patients treated with antidepressants than those without.
The overall manic switch rate (39.7%) is in line with the figure reported from a multi-
center study (a lifetime prevalence of 44.4%) [27]. Among the subjects with manic switch,
39.1% had a manic episode within one week after remission of the previous depressive
episode. The possibility that some mixed affective episodes were classified into manic
switch after bipolar depression could be ruled out. The manic switch rate in this study
might be inflated in this way. Our study enrolled patients with BPI only and that could
have contributed partly to the high switch rate in this study. An analysis of randomized
trials of adjunctive treatment with antidepressants in bipolar depression concludes that
hypomanic/manic switch rate is higher in patients with BPI (30.8%) than those with bipolar
II disorder (18.6%) [18]. The manic switch rate in our study was higher than that among
patients with BPI by Leverich et al. (2006), which was a prospective clinical trial with all
study subjects receiving mood stabilizers under close monitoring of drug adherence [18].
Definitions of manic switch are different between these studies.
Although antidepressant-associated manic switch was reported to be more commonly
observed in female than in male patients in some previous studies [28,29], no such gender
difference was observed in our study. Methodological differences may account for this
dissimilarity. For example, in the study by Truman et al. (2007), manic switch is defined as a
report of mania, hypomania, or mixed episodes within the first 12 weeks of treatment with
an antidepressant. This definition entirely excludes patients without any antidepressant
treatment. We defined manic switch in this study as a manic episode occurring within eight
weeks of remission from an acute depressive episode, according to the recommendations
of the International Society for Bipolar Disorder (ISBD) Task Force [30].
Our finding that antidepressant treatment is associated with an increased risk of manic
episode after remission of depression in bipolar patients is in line with previous studies and
reviews [27,31]. In previous studies [28,32] including a meta-analysis [33], manic switch
from depression was found to occur more frequently during treatment with TCA than
with non-TCA drugs in bipolar inpatients. Our study revealed that TCA drugs were more
commonly associated with manic switch than other antidepressants in bipolar I disorder.
These findings were in line with the conclusions from the International Society for Bipolar
Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders [34]. The
mechanism behind the significant association between the type of antidepressants used and
the risk of experiencing a manic switch needs further exploration. Two retrospective natu-
ralistic studies separately reported that mood stabilizers as an adjunct to antidepressants
in bipolar depression significantly reduced the risk of antidepressant-associated manic
switch [7,35]. However, a meta-analysis on mania associated with antidepressant treatment
did not find a clear-cut benefit of adjunct mood stabilizers with antidepressant treatment
in the prevention of antidepressant-associated manic switch [33]. Our study found that
concurrent use of mood stabilizer or antipsychotics did not reduce the risk of manic switch.
Our manic switch GWAS revealed several SNPs reaching the significance level of
1.0 × 10−6 . The highest SNPs on chromosome 7 are located in the intergenic region between
LUZP6 and CHRM2. The SNP rs10262219 is located in the intergenic region between
LUZP6 and CHRM2 genes and has no known biological function. The CHRM2, one of
the muscarinic receptors, involves the cholinergic system and plays an important role in
the pathophysiology of mood disorders [36,37]. Positron emission tomography studies
have reported a decrease in the CHRM2 selective agonist [18F]FP-TZTP in the anterior
J. Pers. Med. 2022, 12, 615 8 of 12

cingulate cortex of individuals with bipolar disorder [36]. Decreased CHRM2 receptor
binding and expression have been noted in the prefrontal cortex of the post-mortem tissue
from individuals with bipolar disorder [37]. The imbalance between central cholinergic
and adrenergic neurotransmitter activity may contribute to inducing mania and depression.
It is suggested that a hypocholinergic-hyperadrenegic state may cause mania, whereas a
hypercholinergic-hypoadrenegic state may contribute to the symptoms of depression [38].
In a rat model, the increasing levels of CHRM2 protein may be involved in the mechanisms
of action of mood stabilizers and tricyclic antidepressants [39]. The role of CHRM2 in
depression-mania switch phenomenon in bipolar disorder patients and the mechanisms
behind warrant further investigation.
The phenotype of manic switch has raised great concerns. In many studies aiming to
investigate treatment emergent switch to mania, they only include patients on antidepres-
sants. If the aim is to analyze the naturally occurring switch to mania in bipolar disorder,
then patients on antidepressants should be excluded. This study analyzed switch to mania
within eight weeks after remission from bipolar depression rather than treatment emergent
switch. Due to consideration of the sample size for GWAS, we did not exclude subjects
on antidepressant treatment or analyze those on antidepressant treatment exclusively.
Manic switch in this study may include naturally occurring switch and treatment-emergent
switch.
Among patients with manic switch, 39.1% had a manic episode within one week after
remission of the previous depressive episode. The possibility that some mixed affective
episodes were classified into manic switch after bipolar depression could not be ruled out.
The manic switch rate in this study might be inflated in this way.
There are limitations to this study. First, the sample size was relatively small, which
might be responsible, at least in part, for our findings of no statistically significant asso-
ciation for several SNPs after correction for multiple testing. However, the frequency of
risk genotype CC was higher in patients with manic switch than those without in both
discovery and replication groups (Table 2). Second, our study only included patients of
Han ancestry, which has the important advantage of reducing the likelihood of confound-
ing by population structure but also limits the generalizability of our results. Third, the
retrospective nature of the study indicates that our findings can only suggest an association.
Fourth, there might be selection bias as treated patients in this study are more likely to have
a higher severity in symptoms of depression, and those treated with antidepressants and
concomitant mood stabilizers or antipsychotics might be more prone to manic episodes
than their counterparts treated with antidepressant monotherapy.
In conclusion, antidepressant treatment for bipolar depressive episodes significantly
increased the risk of manic switch. The top SNPs identified from the GWAS for manic
switch may deserve further investigation in the future.

4. Materials and Methods

4.1. Study Patients
Study patients were selected from a total of 1807 patients with a BPI diagnosis with
a complete history of disease course and treatment, recruited from 52 psychiatric depart-
ments of general hospitals and psychiatric institutions in the Taiwan Bipolar Consortium
(TBC) [40] up to December 2018. The TBC aims to understand genetic vulnerability of BPI
and to conduct a pharmacogenetic study of mood stabilizers. All of them were diagnosed
according to DSM-IV [41] criteria for BPI disorder. Patients with other psychotic and
affective disorders were excluded. For the analyses of manic switch, we first identified
1310 patients with BPI with a complete history of disease course and treatment (see case
selection profile in Figure 1). Among the 1310 patients with BPI, 1004 had had at least
one major depressive episode and were included in the analyses of manic switch. The
study was approved by the institutional review board of all the participating hospitals and
Academia Sinica, Taiwan. All the study subjects provided a written informed consent.
J. Pers. Med. 2022, 12, 615 9 of 12

4.2. Assessments
Clinical assessment of mania and depression was performed by trained psychiatric
nurses and psychiatrists using the Chinese version of the Schedules for Clinical Assessment
in Neuropsychiatry (SCAN) [42], supplemented by available medical records and reports
from key family members and in-charge psychiatrists. The assessment of affective switch
and antidepressant treatment in BPI disorder was based on a life chart with graphical
presentation of lifetime clinical course prepared for every patient recruited by the TBC.
This life chart included all manic, hypomanic, and depressive episodes with onset year and
month, duration, and severity, all doses of and duration of treatment with psychotropic
drugs and mood stabilizers ever prescribed, drug adherence recorded in medical charts
during treatment at outpatient clinics, all recorded blood levels of mood stabilizers, and any
adverse drug reactions. Mixed episodes were categorized into manic episodes in this study.
This graphical life chart was presented on the basis of integrated information gathered from
direct interviews with patients and their key family members, interviews with in-charge
psychiatrists, and a thorough medical chart review.

4.3. Antidepressant Treatment and Affective Switch

We then compared frequencies of affective switches from depression to mania be-
tween those with and without antidepressant treatments. The first documented depressive
episode was selected as the index episode. Antidepressant treatments with doses less
than 1/2 defined daily dose recommended by the WHO Collaborating Center for Drug
Statistics Methodology and with a duration of less than two weeks were included in the
“no antidepressant treatment” group unless these treatments were apparently associated
with a manic switch. Affective switches or other courses and outcomes in bipolar disorder
were defined according to the recommendations of the International Society for Bipolar
Disorder Task Force [30]. A manic switch and a manic recurrence were defined as a manic
episode occurring within and >8 weeks, respectively, of remission from an acute depressive
episode.

4.4. Genome-Wide Association Study (GWAS)

Genotyping was performed using the Illumina HumanOmni1-Quad BeadChip (N = 936)
and the HumanOmni2.5-Quad BeadChip (N = 575) by Chun-Tai Co. (Taipei, Taiwan).
For this study, we integrated the two genome-wide SNP data sets through imputation
with 1000 Genomes. To bridge the two sets, we also genotyped 82 of the first 936 patients
using the HumanOmni2.5-Quad BeadChip. The two gene chips shared about 750 K
common SNPs, thus we could check the genotyping consistency of the two sets. Genotype
calling for the two data sets was determined by Beadstudio (Illumina) using default
parameters. The genotype imputation method, IMPUTE2 [43–45], was performed under
default setting to estimate the genotypes of SNPs not on array. In the imputation process,
reference haplotypes were curated from 1000 Genomes Project Phase III [46]. To improve
the efficiency, we performed whole genome imputation in every 5 Mb chunk, respectively.
ANNOVAR [47] was used to annotate the functional consequences of single nucleotide
variants found in our dataset. The imputation dataset included genotyping information
from 1429 subjects of the TBC. Among the 1004 patients, 746 with genotyping data were
included in the GWAS for affective switch. The following quality control of the genotype
data was implemented for each data set to exclude SNPs and individuals before the
imputation: (1) Individuals with a call rate <98%, (2) p < 1.0 × 10−4 for Hardy-Weinberg
violation, (3) SNPs with MAF <5%, (4) samples with first-degree cryptic relationships, (5)
samples that were potentially contaminated. The imputation dataset included genotyping
information from 1429 subjects of the Taiwan Bipolar Consortium. Among the 1004 patients,
746 with genotyping data were included in the GWAS for this study.
Except for 3 patients with no DNA available, the remaining 255 of the 1004 subjects
without genotyping information were used for replication. We used the TaqMan SNP
Genotyping Assays (ABI: Applied Biosystems Inc. Foster City, CA, USA) for replication.
J. Pers. Med. 2022, 12, 615 10 of 12

The primers and probes of the replicated SNP(s) were from an ABI assay on demand (AOD)
kit. Reactions were carried out according to the manufacturer’s protocol (TaqMan SNP
Genotyping Assays, protocol, Part Number 4,332,856 Rev. C). The probe fluorescence signal
detection was performed using an ABI Prism 7900 Real-Time PCR System.

4.5. Statistical Analysis

Variables were presented as either mean (± standard deviation) or frequency (%). Chi-
square test or t test was used to compare the differences between depressive episodes with
or without affective switch for categorical or continuous variables, respectively. Logistic
regression was used to analyze multivariate risk factors of affective switches. Survival
curves of affective switches from depressive to manic episodes were analyzed using Kaplan-
Meier cumulative survival analyses. The statistical software package IBM SPSS Statistics
ver. 21.0 (IBM Co., Armonk, NY, USA) was utilized for statistical analyses. All tests were
two-tailed, and p values < 0.05 were considered significant.
Principal component analysis for all study subjects based on the genome-wide IBS
(identical by state) pairwise distances was performed using PLINK v. 1.9 (https://www.
cog-genomics.org/plink2, accessed on 10 March 2022) [48]. GWAS was carried out for the
discovery groups by comparing allele/genotype frequencies between patients with BPI
with and without a history of manic switch. The threshold P value was set at 1.05 × 10−8
after a Bonferroni correction for the number of SNPs (4,750,978). When no SNP reached the
significance level after Bonferroni correction, top SNP was considered for further examina-
tions. Quantile-quantile (Q-Q) plots were then used to examine P-value distributions. The
calculation was performed using PLINK v. 1.9 [48]. Top SNP identified in the GWAS were
replicated in the replication group. The χ2 test for replication and evaluation of diagnostic
tests were performed by SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jpm12040615/s1. Figure S1. The principal component analysis
plot of the 1306 GWAS samples, Figure S2. Q-Q plot of the fisher’s test for allelic model p values of
GWAS cohort (N = 746), Figure S3. Regional plots of genetic variants in genomic location encompass
rs10262219 (±10 kbp) with genotyping data and association p values (−log10 p). Table S1. Top-ten
significant SNPs in GWAS at allelic model.
Author Contributions: Conceptualization: C.-K.C., L.S.-H.W. and A.T.-A.C., Acquisition, analysis, or
interpretation of data: C.-K.C., L.S.-H.W., M.-C.H., C.-J.K. and A.T.-A.C., Drafting of the manuscript:
C.-K.C., L.S.-H.W. and A.T.-A.C., Statistical analysis: C.-K.C. and L.S.-H.W., Funding acquisition: A.T.-
A.C. and C.-K.C., Supervision: A.T.-A.C. Critical revision of the manuscript for important intellectual
content: All authors. All authors have read and agreed to the published version of the manuscript.
Funding: The study were supported by a grant (AS 23-23, 52102310023C) from Academia Sinica,
grants (NSC100-2325-B-001-026, NSC101-2325-B-001-023, and NSC102-2325-B-001-023) from Ministry
of Science and Technology, Taiwan, and China Medical University (CMU107-Z-06). CKC was
supported in this work by Chang Gung Memorial Hospital, Keelung, Taiwan (CRRPG2K0013 and
CLRPG2L0052) and grants MOST103-2314-B-182-011-MY3, MOST107-2314-B-182 -065.
Institutional Review Board Statement: The study was conducted according to the guidelines of
the Declaration of Helsinki, and approved by the Institutional Review Boards at each of all the
participating hospitals and at Academia Sinica, Taiwan.
Informed Consent Statement: All the study subjects provided a written informed consent.
Data Availability Statement: The datasets generated during and/or analyzed during the current
study are not publicly available due to the limitation of study consent documents with repository
deposition but are available from the corresponding author upon reasonable request.
Conflicts of Interest: The authors declare no competing interests.
J. Pers. Med. 2022, 12, 615 11 of 12

References
1. Muller-Oerlinghausen, B.; Berghofer, A.; Bauer, M. Bipolar disorder. Lancet 2002, 359, 241–247. [CrossRef]
2. Miller, S.; Dell’Osso, B.; Ketter, T.A. The prevalence and burden of bipolar depression. J. Affect. Disord. 2014, 169 (Suppl. S1),
S3–S11. [CrossRef]
3. Forte, A.; Baldessarini, R.J.; Tondo, L.; Vazquez, G.H.; Pompili, M.; Girardi, P. Long-term morbidity in bipolar-I, bipolar-II, and
unipolar major depressive disorders. J. Affect. Disord. 2015, 178, 71–78. [CrossRef] [PubMed]
4. Grunze, H.; Vieta, E.; Goodwin, G.M.; Bowden, C.; Licht, R.W.; Möller, H.J.; Kasper, S.; WFSBP Task Force on Treatment Guidelines
for Bipolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment
of Bipolar Disorders: Update 2010 on the treatment of acute bipolar depression. World J. Biol. Psychiatry 2010, 11, 81–109.
[CrossRef] [PubMed]
5. Baldessarini, R.J.; Tondo, L.; Vázquez, G.H. Pharmacological treatment of adult bipolar disorder. Mol. Psychiatry 2019, 24, 198–217.
[CrossRef]
6. Baldessarini, R.J.; Leahy, L.; Arcona, S.; Gause, D.; Zhang, W.; Hennen, J. Patterns of psychotropic drug prescription for U.S.
patients with diagnoses of bipolar disorders. Psychiatric Serv. 2007, 58, 85–91. [CrossRef]
7. Viktorin, A.; Lichtenstein, P.; Thase, M.E.; Larsson, H.; Lundholm, C.; Magnusson, P.K.; Landén, M. The risk of switch to mania in
patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am. J.
Psychiatry 2014, 171, 1067–1073. [CrossRef]
8. Lyall, L.M.; Penades, N.; Smith, D.J. Changes in prescribing for bipolar disorder between 2009 and 2016: National-level data
linkage study in Scotland. Br. J. Psychiatry 2019, 215, 415–421. [CrossRef]
9. Ghaemi, S.N.; Wingo, A.P.; Filkowski, M.A.; Baldessarini, R.J. Long-term antidepressant treatment in bipolar disorder: Meta-
analyses of benefits and risks. Acta. Psychiatr. Scand. 2008, 118, 347–356. [CrossRef]
10. Sachs, G.S.; Nierenberg, A.A.; Calabrese, J.R.; Marangell, L.B.; Wisniewski, S.R.; Gyulai, L.; Friedman, E.S.; Bowden, C.L.; Fossey,
M.D.; Ostacher, M.J.; et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N. Engl. J. Med. 2007, 356,
1711–1722. [CrossRef]
11. Sidor, M.M.; Macqueen, G.M. Antidepressants for the acute treatment of bipolar depression: A systematic review and meta-
analysis. J. Clin. Psychiatry 2011, 72, 156–167. [CrossRef] [PubMed]
12. Perlis, R.H.; Ostacher, M.J.; Goldberg, J.F.; Miklowitz, D.J.; Friedman, E.; Calabrese, J.; Thase, M.E.; Sachs, G.S. Transition to mania
during treatment of bipolar depression. Neuropsychopharmacology 2010, 35, 2545–2552. [CrossRef]
13. McGirr, A.; Vohringer, P.A.; Ghaemi, S.N.; Lam, R.W.; Yatham, L.N. Safety and efficacy of adjunctive second-generation
antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: A systematic review and
meta-analysis of randomised placebo-controlled trials. Lancet Psychiatry 2016, 3, 1138–1146. [CrossRef]
14. Angst, J. Switch from depression to mania, or from mania to depression: Role of psychotropic drugs. Psychopharmacol. Bull. 1987,
23, 66–67. [PubMed]
15. Henry, C.; Sorbara, F.; Lacoste, J.; Gindre, C.; Leboyer, M. Antidepressant-induced mania in bipolar patients: Identification of risk
factors. J. Clin. Psychiatry 2001, 62, 249–255. [CrossRef] [PubMed]
16. Post, R.M.; Altshuler, L.L.; Frye, M.A.; Suppes, T.; Rush, A.J.; Keck, P.E., Jr.; McElroy, S.L.; Denicoff, K.D.; Leverich, G.S.; Kupka,
R.; et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to
mood stabilizers. Bipolar Disord. 2001, 3, 259–265. [CrossRef]
17. Post, R.M.; Leverich, G.S.; Nolen, W.A.; Kupka, R.W.; Altshuler, L.L.; Frye, M.A.; Suppes, T.; McElroy, S.; Keck, P.; Grunze, H.;
et al. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: Data from the Stanley Foundation
Bipolar Network. Bipolar Disord. 2003, 5, 396–406. [CrossRef]
18. Leverich, G.S.; Altshuler, L.L.; Frye, M.A.; Suppes, T.; McElroy, S.L.; Keck, P.E., Jr.; Kupka, R.W.; Denicoff, K.D.; Nolen, W.A.;
Grunze, H.; et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and
continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am. J. Psychiatry 2006, 163, 232–239.
[CrossRef]
19. Bauer, M.; Rasgon, N.; Grof, P.; Glenn, T.; Lapp, M.; Marsh, W.; Munoz, R.; Suwalska, A.; Baethge, C.; Bschor, T.; et al. Do
antidepressants influence mood patterns? A naturalistic study in bipolar disorder. Eur. Psychiatry 2006, 21, 262–269. [CrossRef]
20. Rybakowski, J.K. Genetic influences on response to mood stabilizers in bipolar disorder: Current status of knowledge. CNS Drugs
2013, 27, 165–173. [CrossRef]
21. Amare, A.T.; Schubert, K.O.; Baune, B.T. Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for
personalized psychiatry. EPMA J. 2017, 8, 211–227. [CrossRef] [PubMed]
22. Perlis, R.H.; Smoller, J.W.; Ferreira, M.A.; McQuillin, A.; Bass, N.; Lawrence, J.; Sachs, G.S.; Nimgaonkar, V.; Scolnick, E.M.;
Gurling, H.; et al. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am. J.
Psychiatry 2009, 166, 718–725. [CrossRef] [PubMed]
23. Squassina, A.; Manchia, M.; Borg, J.; Congiu, D.; Costa, M.; Georgitsi, M.; Chillotti, C.; Ardau, R.; Mitropoulos, K.; Severino, G.;
et al. Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar
disorder. Pharmacogenomics 2011, 12, 1559–1569. [CrossRef] [PubMed]
24. Chen, C.H.; Lee, C.S.; Lee, M.T.M.; Ouyang, W.C.; Chen, C.C.; Chong, M.Y.; Wu, J.Y.; Tan, H.K.L.; Lee, Y.C.; Chuo, L.J.; et al.
Variant GADL1 and response to lithium therapy in bipolar I disorder. N. Eng. J. Med. 2014, 370, 119–128. [CrossRef]
J. Pers. Med. 2022, 12, 615 12 of 12

25. Hou, L.; Heilbronner, U.; Degenhardt, F.; Adli, M.; Akiyama, K.; Akula, N.; Ardau, R.; Arias, B.; Backlund, L.; Banzato, C.E.M.;
et al. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. Lancet
2016, 387, 1085–1093. [CrossRef]
26. Biernacka, J.M.; McElroy, S.L.; Crow, S.; Sharp, A.; Benitez, J.; Veldic, M.; Kung, S.; Cunningham, J.M.; Post, R.M.; Mrazek, D.; et al.
Pharmacogenomics of antidepressant induced mania: A review and meta-analysis of the serotonin transporter gene (5HTTLPR)
association. J. Affect. Disord. 2012, 136, e21–e29. [CrossRef]
27. Truman, C.J.; Goldberg, J.F.; Ghaemi, S.N.; Baldassano, C.F.; Wisniewski, S.R.; Dennehy, E.B.; Thase, M.E.; Sachs, G.S. Self-reported
history of manic/hypomanic switch associated with antidepressant use: Data from the Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD). J. Clin. Psychiatry 2007, 68, 1472–1479. [CrossRef]
28. Koszewska, I.; Rybakowski, J.K. Antidepressant-induced mood conversions in bipolar disorder: A retrospective study of tricyclic
versus non-tricyclic antidepressant drugs. Neuropsychobiology 2009, 59, 12–16. [CrossRef]
29. Fela-Thomas, A.L.; Olotu, O.S.; Esan, O. Risk of manic switch with antidepressants use in patients with bipolar disorder in a
Nigerian neuropsychiatric hospital. S. Afr. J. Psychiatry 2018, 24, 1215. [CrossRef]
30. Goldberg, J.F.; Truman, C.J. Antidepressant-induced mania: An overview of current controversies. Bipolar Disord. 2003, 5, 407–420.
[CrossRef]
31. Mundo, E.; Cattaneo, E.; Russo, M.; Altamura, A.C. Clinical variables related to antidepressant-induced mania in bipolar disorder.
J. Affect. Disord. 2006, 92, 227–230. [CrossRef] [PubMed]
32. Tondo, L.; Vazquez, G.; Baldessarini, R.J. Mania associated with antidepressant treatment: Comprehensive meta-analytic review.
Acta Psychiatr. Scand. 2010, 121, 404–414. [CrossRef] [PubMed]
33. Pacchiarotti, I.; Bond, D.J.; Baldessarini, R.J.; Nolen, W.A.; Grunze, H.; Licht, R.W.; Post, R.M.; Berk, M.; Goodwin, G.M.; Sachs,
G.S.; et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am.
J. Psychiatry 2013, 170, 1249–1262. [CrossRef] [PubMed]
34. Serretti, A.; Artioli, P.; Zanardi, R.; Rossini, D. Clinical features of antidepressant associated manic and hypomanic switches in
bipolar disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2003, 27, 751–757. [CrossRef]
35. Cannon, D.M.; Carson, R.E.; Nugent, A.C.; Eckelman, W.C.; Kiesewetter, D.O.; Williams, J.; Rollis, D.; Drevets, M.; Gandhi, S.;
Solorio, G.; et al. Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder. Arch. Gen. Psychiatry 2006, 63,
741–747. [CrossRef]
36. Gibbons, A.S.; Scarr, E.; McLean, C.; Sundram, S.; Dean, B. Decreased muscarinic receptor binding in the frontal cortex of bipolar
disorder and major depressive disorder subjects. J. Affect. Disord. 2009, 116, 184–191. [CrossRef]
37. Janowsky, D.S.; El-Yousef, M.K.; Davis, J.M.; Sekerke, H.J. A cholinergic-adrenergic hypothesis of mania and depression. Lancet
1972, 2, 632–635. [CrossRef]
38. Gibbons, A.S.; Jeon, W.J.; Scarr, E.; Dean, B. Changes in muscarinic m2 receptor levels in the cortex of subjects with bipolar disorder
and major depressive disorder and in rats after treatment with mood stabilisers and antidepressants. Int. J. Neuropsychopharmacol.
2016, 19, pyv118. [CrossRef]
39. Lee, M.T.; Chen, C.H.; Lee, C.S.; Chen, C.C.; Chong, M.Y.; Ouyang, W.C.; Chiu, N.Y.; Chuo, L.J.; Chen, C.Y.; Tan, H.K.L.; et al.
Genome-wide association study of bipolar I disorder in the Han Chinese population. Mol. Psychiatry 2011, 16, 548–556. [CrossRef]
40. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed.; American Psychiatric Association:
Washington, DC, USA, 1994.
41. Cheng, A.T.; Tien, A.Y.; Chang, C.J.; Brugha, T.S.; Cooper, J.E.; Lee, C.S.; Compton, W.; Liu, C.Y.; Yu, W.Y.; Chen, H.M. Cross-
cultural implementation of a Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) in Taiwan. Br.
J. Psychiatry 2001, 178, 567–572. [CrossRef]
42. Tohen, M.; Frank, E.; Bowden, C.L.; Colom, F.; Ghaemi, S.N.; Yatham, L.N.; Malhi, G.S.; Calabrese, J.R.; Nolen, W.A.; Vieta, E.;
et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in
bipolar disorders. Bipolar Disord. 2009, 11, 453–473. [CrossRef] [PubMed]
43. Howie, B.N.; Donnelly, P.; Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-
wide association studies. PLoS Genet. 2009, 5, e1000529. [CrossRef] [PubMed]
44. Howie, B.; Marchini, J.; Stephens, M. Genotype imputation with thousands of genomes. G3 Genes Genomes Genet. 2011, 1, 457–470.
[CrossRef] [PubMed]
45. Marchini, J.; Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 2010, 11, 499–511. [CrossRef]
46. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 2015, 526, 68–74.
47. Wang, K.; Li, M.; Hakonarson, H. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data.
Nucleic Acids Res. 2010, 38, e164. [CrossRef]
48. Purcell, S.; Neale, B.; Todd-Brown, K.; Thomas, L.; Ferreira, M.A.; Bender, D.; Maller, J.; Sklar, P.; de Bakker, P.I.; Daly, M.J.; et al.
PLINK: A tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 2007, 81, 559–575.
[CrossRef]