JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 24, Number 10, 2014

Mary Ann Liebert, Inc.
Pp. 551561
DOI: 10.1089/cap.2014.0028

Risk of Manic Switch Associated with Antidepressant

Therapy in Pediatric Bipolar Depression
Debajyoti Bhowmik, PhD,1,2 Rajender R. Aparasu, MPharm, PhD, FAPhA,1 Suja S. Rajan, MS, PhD, MPA,3
Jeffrey T. Sherer, PharmD, MPH,1 Melissa Ochoa-Perez, MD,4 and Hua Chen, MD, PhD1

Abstract

Objective: The purpose of this study was to assess the risk of manic switch associated with antidepressants in Medicaidenrolled pediatric patients with bipolar depression.
Methods: This retrospective cohort study involved 20032007 Medicaid Analytic eXtract (MAX) data from four geographically diverse states. The study sample included children and adolescents (ages 618 years) who had received a
diagnosis of bipolar disorder on two or more separate occasions or during a hospital discharge, followed by a diagnosis of
depression. According to the pharmacotherapy received by these patients in the 30 days around the index bipolar depression
diagnosis, patients were categorized into five mutually exclusive groups. Manic switch was defined as having received a
diagnosis of mania within 6 weeks after the initiation of bipolar depression treatment. Relative risks of manic switch between
antidepressant monotherapy/polytherapy and their alternatives were assessed using Cox proportional hazards model. The
robustness of the conventional Cox proportional hazards model toward possible bias caused by unobserved confounders was
tested using instrumental variable analysis, and the uncertainty regarding manic switch definition was tested by altering the
duration of follow-up.
Results: After applying all the selection criteria, 179 antidepressant monotherapy, 1047 second-generation antipsychotic
(SGA) monotherapy, 570 mood stabilizer monotherapy, 445 antidepressant polytherapy, and 1906 SGAmood stabilizer
polytherapy users were identified. In Cox proportional hazard analyses, both antidepressant monotherapy and polytherapy
exhibited higher risk of manic switch than their alternatives (antidepressant monotherapy vs. SGA monotherapy, hazard ratio
[HR] = 2.87 [95% CI: 1.107.49]; antidepressant monotherapy vs. mood stabilizer monotherapy, HR = 1.41 [95% CI: 0.52
3.80); antidepressant polytherapy vs. SGA-mood stabilizer polytherapy, HR = 1.61 [95% CI: 0.902.89]). However, only the
comparison between antidepressant monotherapy and SGA monotherapy was statistically significant. The instrumental
variable analysis did not detect endogeneity of the treatment variables. Extending the follow-up period from 6 weeks to 8 and
12 weeks generated findings consistent with the main analysis.
Conclusions: Study findings indicated a higher risk of manic switch associated with antidepressant monotherapy than with
SGA monotherapy in pediatric patients with bipolar depression. The finding supported the clinical practice of cautious
prescribing of antidepressants for brief periods.

Introduction

ipolar disorder is a form of mood disorder characterized

by the presence of episodes of highly elevated mood (manic)
and episodes of depression. The lifetime prevalence of the depressive phase among bipolar disorder patients is threefold higher
than that of the mania phase (Post et al. 2003). Among the phases of
bipolar disorder, untreated bipolar depression, particularly in
children and adolescents, is associated with the highest risk of
suicidality (Tondo et al. 1998), substance abuse, functional dis-

ability, and poor academic and social performance (Angst et al.

2002; Frye et al. 2006; Thase 2006; Dutta et al. 2007; Huxley and
Baldessarini 2007; Tondo et al. 2007; Baldessarini et al. 2008).
Until 2002, antidepressant monotherapy had been recommended
as the first-line treatment for bipolar depression in all treatment
guidelines for adults (Baldessarini et al. 2007; Amit and Weizman
2012). That year, the American Psychiatric Association (APA)
treatment guidelines relegated antidepressants to second-line use
after initial treatment with mood stabilizer monotherapy (Hirschfeld et al. 2002). However, there has been debate over whether

Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, Texas.
Global Health Economics, Amgen Inc., Thousand Oaks, California.
3
Division of Management, Policy and Community Health, School of Public Health, The University of Texas Health Science Center, Houston, Texas.
4
Department of Psychiatry, Legacy Community Health Services, Houston, Texas.
2

551

552
antidepressants are safe and effective medications for the condition,
both before and after the APA revision. Multiple observational
studies including patients self-reports and naturalistic studies reported a higher risk of manic switch associated with the use of
antidepressants in adults with bipolar depression (Peet 1994; Altshuler et al. 1995; Boerlin et al. 1998; Henry et al. 2001; Ghaemi
et al. 2003; Truman et al. 2007). However, most of the clinical trials
included in the review by Licht et al. (2008) and in the metaanalysis by Gijsman et al. (2004) did not find statistically significant differences between antidepressants and placebo regarding the
risk of manic switch.
Critical evaluation of these clinical trials suggested that it is
difficult to make a confirmatory conclusion based on available
evidence, because of the presence of biases in the existing trials
(Licht et al. 2008). For example, in some of the randomized controlled trials (RCTs) that compared the risk of manic switch between antidepressants and placebo, 75% of the patients were
concomitantly treated with mood stabilizers or second-generation
antipsychotics (SGAs). Also, these trials captured manic switch
during various follow-up times, and did not report whether the
switch occurred during acute treatment for depression or after remission, thereby drawing inconclusive evidence for manic switch
risk with antidepressants (Licht et al. 2008).
Bipolar disorder with childhood onset seems to be more severe
than the form that first appears in adults (Perlis et al. 2004; Birmaher
et al. 2006). Although there are no empirical data available to clarify
the association between antidepressant monotherapy and the risk of
manic switch in this subgroup, some indirect evidence suggests that
children and adolescents with bipolar disorder may have symptoms
more often and switch moods more frequently than adults with the
illness. In a recent study conducted among a cohort of youth (920
years) with depressive and anxiety disorders, and with at least one
parent with bipolar I disorder, 21% had been treated with antidepressants. Among these antidepressant recipients, 57% had had an
adverse reaction in the form of manic symptoms (irritability, aggression, impulsivity, or hyperactivity), leading to antidepressant
discontinuation (Strawn et al. 2014). Therefore, the existing pediatric guidelines for bipolar disorder tend to be more conservative in
recommending the use of antidepressants. Antidepressant monotherapy was never recommended, and the use of antidepressants as
an adjunct treatment was mentioned as may not be necessary unless
the depressed phase persists or becomes severe (McClellan et al.
1997) and caution must be taken because antidepressants may
destabilize the patients mood or incite a manic episode (McClellan
et al. 2007). However, our previous research using Medicaid data
revealed that antidepressants were used in nearly half (48.17%) of
children and adolescents with bipolar depression, of whom 42.40%
received it as an adjunct treatment and 5.77% received is as a
monotherapy (Bhowmik et al. 2013).
Almost all existing clinical trials assessing manic switch associated with the use of antidepressants compared them to placebo
(Mendlewicz and Youdim 1980; Himmelhoch et al. 1982; Cohn
et al. 1989; Nemeroff et al. 2001; Tohen et al. 2003). However, in
practice, the more clinically relevant issue is the risk from antidepressants versus their alternatives. Head-to-head comparison data
between antidepressant monotherapy and SGA/mood stabilizer
monotherapy, or between antidepressant polytherapy and SGA/
mood stabilizer polytherapy, are needed. Therefore, the objectives
of this study were to evaluate the comparative risk of manic switch
associated with 1) antidepressant monotherapy versus SGA
monotherapy, 2) antidepressant monotherapy versus mood stabilizer monotherapy, and 3) antidepressant polytherapy (with SGA or

BHOWMIK ET AL.
mood stabilizer) versus SGA-mood stabilizer polytherapy in
Medicaid-enrolled children and adolescents with bipolar depression. We hypothesized that an antidepressant, when used alone or in
combination with a mood stabilizer/SGA in children with bipolar
depression, was associated with increased risk of manic switch
compared with corresponding SGA and mood stabilizer monotherapies or combination.
Methods
Data source
In this retrospective cohort study, 20032007 Medicaid Analytic
eXtract (MAX) files from the Center for Medicare and Medicaid
Services (CMS) were used to achieve the study objectives. The
MAX is a set of person-level claims data files containing information on Medicaid eligibility, demographics, service utilization,
and payments. We used data from four geographically diverse
states with large Medicaid enrolments of children and adolescents
(CA, TX, IL, and NY).
Pharmacotherapy for bipolar depression
The pharmacotherapies for bipolar depression assessed in this
study were mood stabilizers (lithium, sodium divalproex/valproate,
oxcarbazepine, topiramate, lamotrigine, and gabapentin); SGA
(risperidone, aripiprazole, olanzapine, quetiapine, clozapine, and
ziprasidone); newer antidepressants (serotonin reuptake inhibitor
[SSRI] antidepressants and others, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, and bupropion); and other antidepressants (amitriptyline, clomipramine,
desipramine, doxepin, imipramine, nortriptyline, mirtazapine, nefazodone, and trazodone) (Bhowmik et al. 2013).
Study population
The study design and cohort identification process are presented
in Figure 1. Children and adolescents with bipolar depression were
identified based on the following algorithm (Bhowmik et al. 2013):
1) 618 years of age (children and adolescents), 2) having received
a minimum of two diagnoses of bipolar disorder other than bipolar
depression (International Classification of Diseases, 9th version,
Clinical Modification [ICD-9-CM]: 296.0, 296.1, 296.4-296.8,
301.11, 301.13) on different service dates, or only one diagnosis of
bipolar disorder that came from hospital discharge, followed by a
diagnosis of depression (ICD-9-CM: 296.5, 296.2, 296.3) (Busch
et al. 2008) any time between January 2003 and December 2007;
and 3) having received antidepressants, SGA, or mood stabilizers
within 30 days of the depression diagnosis. The date on which the
first prescription of these medications was filled was defined as the
index date.
Exclusion criteria
Patients who received diagnoses of schizophrenia (ICD-9-CM:
295.0-295.9) or epilepsy (ICD-9-CM: 345.xx) were excluded from
the cohort, to increase the likelihood that the prescriptions were
used for the treatment of bipolar disorder. Patients without continuous Medicaid eligibility 2 months prior to and 3 months after
the index date were also excluded. Finally, for identification of new
users of antidepressants, patients who had received antidepressant
prescriptions during the 2 month pre-index period were excluded.
The bipolar depression patients identified were then divided
into five mutually exclusive groups based on their medication

ANTIDEPRESSANTS ASSOCIATED WITH MANIC SWITCH IN CHILDREN

553

Medicaid enrolees 6-18 years of age

with any mental disorder diagnosis or
received any psychotropic drug =
4,216,094
Excluded patients having diagnoses
of epilepsy or schizophrenia = 8,731
Patients with two distinctive bipolar
disorder diagnoses or one diagnosis
from hospital discharge followed by a
depression diagnosis at any time
during Jan2003-Dec2007 = 14,009

Patients filled an antidepressant,

an atypical antipsychotic or a mood
stabilizer during 30 days before or 30
days after the bipolar depression
diagnosis = 8,397

Excluded patients with

antidepressant use during the 2
months pre-index period = 2,051

Follow-up = 6
weeks

Cohort : To observe the short term

manic switch associated with
antidepressant exposure = 4,147

Monotherapy
cohort = 1,796

Antidepressant
monotherapy =
179

Excluded Patients without

continuous eligibility 2 months
before and 3 months after the index
pharmacotherapy for bipolar
depression treatment = 589

Atypical
antipsychotic
monotherapy
= 1,047

Excluded patients for computing

physician prescribing preference =
4,250

Polytherapy
cohort = 2,351

Mood
stabilizer
monotherapy
= 570

FIG. 1.

Antidepressant
polytherapy =
445

Atypical
antipsychoticmood
stabilizer
polytherapy =
1,906

Consort diagram.

use during 30 days around the index bipolar depression diagnosis: 1) Antidepressant monotherapy, 2) SGA monotherapy,
3) mood stabilizer monotherapy, 4) antidepressantSGA or
antidepressantmood stabilizer polytherapy, and 5) SGAmood
stabilizer polytherapy. Monotherapy was defined as receiving
medications from a single therapeutic class only, whereas
polytherapy was defined as receiving medications from different therapeutic classes within 30 days of the depression diagnosis and with a minimum of 14 day overlap between the
prescriptions.
Manic switch
Manic switch events were identified from the combined inpatient and other therapy MAX files, using the ICD-9-CM codes of
mania (296.0, 296.1, 296.4, 296.81) during the 6 week follow-up
period after the index date. The follow-up window was restricted to
6 weeks to differentiate manic events as being treatment emergent
rather than the natural progression of bipolar disorder itself (Salvadore et al. 2010).

Statistical analyses
Descriptive analysis was conducted to describe the demographics, treatment utilization, comedications, and comorbidities
during the 2 month pre-index period for the monotherapy and
polytherapy users, respectively. Time to manic switch was analyzed using a multivariable Cox proportional hazards regression
model to assess the risk of manic switch associated with bipolar
depression treatment. The analyses evaluated antidepressant
monotherapy versus mood stabilizer or SGA monotherapy and
antidepressant polytherapy versus SGAmood stabilizer polytherapy. KaplanMeier plot, log-minus-log survival plot, and
Schoenfeld residual test were performed to test the proportionality
of hazard assumption. Patients were censored in the model upon: 1)
Discontinuation of the index treatment regimen, 2) augmentation
with a newer medication other than the index regimen, or 3) end of
follow- up. SAS 9.3 was used for the entire analyses and p < 0.05
was considered to be statistically significant.
Covariates included in the Cox model were patient demographics, comedications, and comorbidities that were measured at 2

554
months pre-index date. Comorbidities included previous manic
episodes identified by diagnosis codes of mania, substance abuse
disorder (SUD), attention-deficit/hyperactivity disorder (ADHD),
oppositional defiant disorder (ODD), anxiety, adjustment disorder,
and psychotic disorder at baseline. Comedications included stimulants, sedatives, hypnotics, anticholinergics, SGAs, or mood stabilizers at baseline. Uses of psychotherapy and hospital admissions
at baseline were identified as measures of disease severity. Patient
demographic characteristics included were age (categorized as
children if <13 years of age and adolescent if 13 years of age),
gender, race (white, black, or other) and state of residence (TX, NY,
CA, or IL). Medicaid eligibility categories such as Temporary
Assistance for Needy Families (TANF) and foster children were
also identified, as these variables may indicate socioeconomic
characteristics of patients. Duration of disease was computed as
days between the first bipolar disorder diagnosis identified in the
data and the index bipolar depression diagnosis date, as longer
duration of disease may influence the future symptomatic outcomes, such as mood destabilization. Finally, number of physicians
available in each zip code was measured to adjust for psychiatric
care availability for patients.
Sensitivity analysis on unobserved confounding
The robustness of the conventional Cox proportional hazards
model toward possible bias caused by unobserved confounders
such as the responsiveness to previous treatment for bipolar disorders was tested using instrumental variable (IV) analysis. In this
study, physicians preference, misdiagnosis of index bipolar
depression as unipolar depression (ICD-9-CM code: 296.2,
296.3), and year of cohort entry were identified as instruments.
Among these IVs, the physician prescribing preference has been
established as a valid instrument for explaining psychotropic
treatment variation in the literature (Brookhart et al. 2006, 2007;
Rassen et al. 2009).
Physician prescribing preference was operationalized as the treatment prescribed to the previous eligible patient of the same physician
(Brookhart et al. 2006). According to this approach, if the last prescription written by a physician for a child with bipolar depression was
for an antidepressant, then for the next patient the physician was
classified as an antidepressant prescriber. Otherwise, that physician
was classified as a non-antidepressant prescriber. Confirmed bipolar disorder patients (those with two consecutive bipolar disorder
diagnoses) experiencing a depressive episode and given a major depressive disorder (unipolar depression) diagnosis instead of a bipolar
depression diagnosis (ICD-9-CM: 296.5) suggested a misdiagnosis
(Stensland et al. 2008). The year patients entered into the cohort,
computed based on their index date, explains secular changes in
Medicaid policy and formularies, which may predict treatment selection between antidepressant and its alternates.
Conceptually, physicians preference for a drug is a strong
predictor for treatment selection. A prior history of treating bipolar
depression with antidepressants over mood stabilizers or SGAs
may predict future use of antidepressants by those physicians while
treating subsequent patients. Similarly, misdiagnosing bipolar depression as major depression leads to a higher likelihood of
prescribing antidepressants. The availability and coverage of
medications at different years also predicts the utilization. However, these factors do not directly result in a manic switch or affect a
patients clinical profile or sociodemographic characteristics;
hence, they cannot predict the risk of manic switch, except through
its influence on the type of treatment administered.

BHOWMIK ET AL.
Apart from these conceptual justifications, we also performed
specification tests to validate the instruments. Strength of association between the instruments and the binary treatment variables
were assessed by computing a partial F test and partial R2 (Rassen
et al. 2009; Hadley et al. 2010). Change in observed covariate
imbalance was determined by comparing the covariate distribution
across the treatment groups and the instruments. Fractional change
in distribution (Rassen et al. 2009) of each covariate between
the treatment groups and the instruments was computed. Test to
detect the presence of endogeneity was also performed by testing
the statistical significance of the coefficient on the residual computed from the first stage and included in the second stage of the
regression.
The IV analysis that was used in this study is called the twostage residual inclusion (2SRI) estimation (Terza et al. 2008). In
the first-stage model, binary continuous treatment variables were
regressed on all the covariates and the instruments using a linear
probability model (Humphreys et al. 2011). Residual (r) for each
patient was computed as the difference between the binary treatment variable and the predicted treatment variable from the linear
probability model.
In the second-stage model, time to manic switch associated with
the treatment variables was assessed using a conventional Cox
proportional hazards regression model adjusting for all the previously measured covariates and r computed from the first stage. The
standard errors in the second stage were bootstrapped to avoid
using the ones generated from the manual computation of the 2SRI.
Association between the outcome and the treatment variable and all
other covariates were reported as hazard ratios (HRs) with 95% CIs.
Statistical insignificance of r in the second stage regression might
be the result of the exogeneity of the treatment variable, thereby
making the IV analysis unnecessary.
Sensitivity analysis on the duration of follow-up
Although 6 weeks is a commonly used follow-up period for
assessing short-term manic switch, the medical community has not
yet reached a consensus on the duration of follow-up. According to
the nomenclature of the course and outcome of bipolar disorder
defined by the International Society for Bipolar Disorders (ISBD)
task force (Tohen et al. 2009), a manic event 8 weeks after
treatment is a definite measure of manic switch, whereas one
during the 12 week window is a likely or possible. To test
the robustness of our findings toward the variations in the follow-up
period, sensitivity analyses were conducted by extending the follow-up to 8 weeks and 12 weeks, respectively.
Results
As presented in Figure 1, 4147 children and adolescents with
bipolar depression were identified after imposing all inclusion and
exclusion criteria. Most of these patients were adolescents (13
years), white, and male. Approximately 25% of these patients
were foster children. The most common comorbid conditions
were ADHD, ODD, anxiety, and adjustment disorder, and common comedications were stimulants and sedatives. More than
50% of the monotherapy and polytherapy users received psychotherapy, and 1630% had been hospitalized during the preindex period. The average duration between the first bipolar
disorder diagnosis presented in the data and the index bipolar
depression was 300 days.
Of 4147 patients identified, 1796 received monotherapy and
2351 received polytherapy. These patients were further categorized

ANTIDEPRESSANTS ASSOCIATED WITH MANIC SWITCH IN CHILDREN

as recipients of antidepressant monotherapy (n = 179), SGA
monotherapy (n = 1047), mood stabilizer monotherapy (n = 570),
antidepressantmood stabilizer or antidepressantSGA polytherapy (n = 445), or SGAmood stabilizer polytherapy (n = 1906).
Descriptive statistics
As presented in Tables 1 and 2, antidepressant (both monotherapy and polytherapy) recipients were older, more likely to be
female, less likely to be foster children, and less likely to have
comorbid ADHD or to receive stimulants than SGA and mood
stabilizer recipients. During the 6 week follow-up period, the
highest incidence of manic switch was observed in children and
adolescents receiving SGAmood stabilizer polytherapy (n = 218,
11.44%), followed by mood stabilizer monotherapy (n = 62,
10.88%), antidepressant monotherapy (n = 17, 9.50%), SGA
monotherapy (n = 95, 9.07%) and antidepressant polytherapy
(n = 136, 8.09%). Using antidepressant monotherapy as the reference, log rank tests found that there were no statistically significant

555

differences in the risk of manic switch between antidepressant

monotherapy recipients and the recipients of all other regimens.
Multivariable Cox proportional hazards regression
analysis
Tables 35 present the findings of three traditional Cox proportional hazard analysis models that compared the risk of manic
switch between antidepressant monotherapy and SGA monotherapy, antidepressant monotherapy and mood stabilizer monotherapy, and antidepressant polytherapy and SGAmood stabilizer
polytherapy after controlling for all observable confounders. Antidepressant monotherapy was associated with a higher risk
of manic switch than SGA monotherapy (HR = 2.87 [95% CI:
1.107.49]). However, similar results were not found when antidepressant monotherapy was compared with mood stabilizer
monotherapy (HR = 1.41 [95% CI: 0.523.80]), and when antidepressant polytherapy was compared with SGAmood stabilizer
polytherapy (HR = 1.61 [95% CI: 0.902.89]).

Table 1. Descriptive Results for the Monotherapy Cohort (n = 1796)

Covariates
Demographics
Age category
Children (613 years)
Adolescents (1418 years)
Race
White
Black
Gender (Male)
State
TX
CA
IL
NY
Number of physicians in ZIP codes
Proxy measurements of severity
Duration of disease
Prior hospitalization
Medicaid eligibility groups
Foster care
TANF
Comorbidity
Substance abuse disorder
ADHD
Suicidality
Oppositional defiant disorder
Anxiety
Adjustment disorder
Psychotic disorder
Mania
Comedication
Stimulant
Sedative
Hypnotic
Anticholinergic
Psychotherapy
SGA
Mood stabilizer

Antidepressant
monotherapy (n = 179)
n (%) or Mean ( SD)

SGA monotherapy
(n = 1047)
n (%) or Mean ( SD)

Mood stabilizer
monotherapy (n = 570)
n (%) or Mean ( SD)

36 (20.45)
140 (79.55)

437 (42.55)
590 (57.45)

177 (31.83)
379 (68.17)

< 0.0001

89 (50.28)
32 (18.08)
71 (40.11)

461 (44.58)
291 (28.14)
650 (62.86)

260 (46.43)
157 (28.04)
321 (57.32)

0.0630

76
36
51
14
23

320
206
340
168
31

164
124
201
71
29

(42.94)
(20.34)
(28.21)
(7.91)
( 23)

(30.95)
(19.92)
(32.88)
(16.25)
( 29)

p value

< 0.0001

(29.29)
(22.14)
(35.89)
(12.68)
( 28)

0.0025

0.0007

328 ( 364)
41 (22.91)

334 ( 372)
211 (20.15)

295 ( 338)
101 (17.72)

0.1012
0.2574

32 (17.88)
14 (7.82)

322 (30.75)
80 (7.64)

160 (28.07)
48 (8.42)

0.0019
0.8562

15
35
9
27
26
16
5
23

(8.38)
(19.55)
(5.03)
(15.08)
(14.53)
(8.94)
(2.79)
(12.85)

73
339
22
262
95
123
81
134

(6.97)
(32.38)
(2.10)
(25.02)
(9.07)
(11.75)
(7.74)
(12.80)

44
150
9
123
61
65
23
87

(7.72)
(26.32)
(1.58)
(21.58)
(10.70)
(11.40)
(4.04)
(15.26)

0.7363
0.0004
0.0221
0.0090
0.0712
0.5488
0.0018
0.3676

29
48
4
4
102
12
9

(16.20)
(26.82)
(2.23)
(2.23)
(56.98)
(6.70)
(5.03)

209
177
50
71
543
539
61

(19.96)
(16.91)
(4.78)
(6.78)
(51.86)
(51.48)
(5.83)

105
102
16
22
309
38
276

(18.42)
(17.89)
(2.81)
(3.86)
(54.21)
(6.67)
(48.42)

0.4389
0.0063
0.0711
0.0065
0.3661
< 0.0001
< 0.0001

SGA, second-generation antipsychotic; ADHD, attention-deficit/hyperactivity disorder; TANF, Temporary Assistance for Needy Families.

556

BHOWMIK ET AL.
Table 2. Descriptive Results for the Polytherapy Cohort (n = 2351)

Covariates
Demographics
Age category
Children
Adolescents
Race
White
Black
Gender: Male
State
TX
CA
IL
NY
Number of physicians in ZIP codes
Proxy measurements of severity
Duration of disease
Prior hospitalization
Medicaid eligibility groups
Foster care
TANF
Comorbidity
Substance abuse disorder
ADHD
Suicidality
Oppositional defiant disorder
Anxiety
Adjustment disorder
Psychotic disorder
Mania
Comedication
Stimulant
Sedative
Hypnotic
Anticholinergic
Psychotherapy
SGA
Mood stabilizer

Antidepressant polytherapy (n = 445) SGA/Mood stabilizer polytherapy (n = 1906)

n (%) or Mean ( SD)
n (%) or Mean ( SD)

p value

156 (36.03)
277 (63.97)

808 (43.49)
1050 (56.51)

0.0046

209 (47.83)
86 (19.68)
236 (54.00)

885 (47.33)
487 (26.04)
1268 (67.81)

0.0061
< 0.0001

(39.95)
(17.97)
(25.94)
(16.15)
( 29)

< 0.0001

295 ( 369)
139 (31.24)

392 ( 377)
322 (16.89)

< 0.0001
< 0.0001

83 (18.65)
49 (11.01)

651 (34.16)
90 (4.72)

< 0.0001
< 0.0001

228
75
112
22
26

(52.17)
(17.16)
(25.63)
(5.03)
( 24)

747
336
485
302
33

< 0.0001

28
128
10
87
65
58
32
56

(6.29)
(28.76)
(2.25)
(19.55)
(14.61)
(13.03)
(7.19)
(12.58)

97
602
31
487
145
238
149
296

(5.09)
(31.58)
(1.63)
(25.55)
(7.61)
(12.49)
(7.82)
(15.53)

0.3085
0.2470
0.3677
0.0080
< 0.0001
0.7542
0.6554
0.1169

61
109
20
27
286
151
67

(13.71)
(24.49)
(4.49)
(6.07)
(64.27)
(33.93)
(15.06)

442
440
93
175
1071
1375
1323

(23.19)
(23.08)
(4.88)
(9.18)
(56.19)
(72.14)
(69.41)

< 0.0001
0.5269
0.7325
0.0348
0.0019
< 0.0001
< 0.0001

SGA, second-generation antipsychotic; ADHD, attention-deficit/hyperactivity disorder; TANF, Temporary Assistance for Needy Families.

Among all three models, a prior manic episode was a very strong
predictor of short-term manic switch with an HR of 14.00 (95% CI:
8.9921.78) for the comparison between antidepressant monotherapy and SGA monotherapy, 17.80 (95% CI: 10.2930.81) for
the comparison between antidepressant monotherapy and mood
stabilizer monotherapy, and 10.96 (95% CI: 8.3614.37) when
antidepressant polytherapy was compared with SGAmood stabilizer polytherapy.
IV analysis
Table 6 presents the statistical validation of instrumental variables. The F statistic for all three comparisons ranged from 149 to
285, and the partial R2 ranged from 0.27 to 0.40 which were well
above the widely used rule of thumb (i.e., 10 for F statistic) indicated by Staiger and Stock (1997). These measures implied that the
instrumental variables selected for the study were strong predictors
of treatment selection.

Tables 35 present the findings of IV analysis using 2SRI

models. It was found that the residuals (r) generated from the first
stage regressions were not statistically significant in the second
stage model in all three comparisons, which might imply exogeneity of the treatment selection for bipolar depression.
Sensitivity analysis on duration of follow-up
As presented in Tables 35, the associations between the treatment regimens and the risk of short-term manic switch remained
consistent when the follow-up period was extended from 6 weeks to
8 and 12 weeks.
Discussion
Consistent with existing adult data (Yatham et al. 2005; Bond
et al. 2008; Frye et al. 2009; Perlis et al. 2010), previous manic
episode was identified in our study as the most important predictor
(HR ranged from 11 to 18 for the three comparisons) for short-term

ANTIDEPRESSANTS ASSOCIATED WITH MANIC SWITCH IN CHILDREN

Table 3. Cox Proportional Hazards Regression Analysis
Results (Antidepressant Monotherapy vs.
Second-Generation Antipsychotic [SGA] Monotherapy)

Variables

Hazard ratio
(95% CI) from
conventional Cox
proportional hazard
regression model

Hazard ratio
(95% CI)
from instrumental
variable analysis

Table 4. Cox Proportional Hazards Regression

Analysis Results (Antidepressant Monotherapy vs.
Mood Stabilizer Monotherapy)

Variables

Follow-up: 6 weeks
Antidepressant
monotherapy (ref:
SGA monotherapy)
Prior mania
Stimulant
Oppositional defiant
disorder
Residual (r)
Antidepressant
monotherapy
Stimulant
Oppositional defiant
disorder
Prior mania
Residual (r)
Antidepressant
monotherapy
Stimulant
Anticholinergic
Oppositional defiant
disorder
Prior mania
Residual (r)

557

Hazard ratio
(95% CI) from
conventional Cox
proportional hazard
regression model

Hazard ratio
(95% CI) from
instrumental
variable analysis

Follow-up: 6 weeks

2.87 (1.10-7.49)

2.34 (0.41-13.30)

14.00 (8.99-21.78)
1.86 (1.07-3.23)
1.78 (1.09-2.90)

16.01 (9.58-26.77)
1.86 (1.04-3.35)
1.80 (1.07-3.04)

N/A
Follow-up: 8 weeks

1.38 (0.21-8.89)

2.69 (1.10-6.60)

2.35 (0.51-10.75)

1.87 (1.11-3.15)
1.85 (1.17-2.93)

1.89 (1.09-3.29)
1.88 (1.16-3.03)

12.47 (8.18-18.99) 13.93 (8.69-22.32)

N/A
1.27 (0.25-6.40)
Follow-up: 12 weeks
2.44 (1.09-5.46)

1.49 (0.34-6.58)

1.97 (1.19-3.25)
0.25 (0.06-0.95)
1.80 (1.16-2.79)

2.04 (1.21-3.46)
0.17 (0.004-6.57)
1.78 (1.12-2.83)

13.34 (8.91-19.96)
N/A

14.90 (9.41-23.59)
2.11 (0.44-10.20)

Only statistically significant variables at p < 0.05 are included in the

table. Complete list of variables included in the models was as follows:
demographics (age category, gender, race, state, number of physicians in
the ZIP codes), proxy measurements of severity (duration of disease, prior
hospitalization), Medicaid eligibility groups (foster care, Temporary
Assistance to Needy Families), comorbidity (substance abuse disorder,
attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety, adjustment disorder, psychotic disorder, prior mania), comedications
(stimulant, sedative, hypnotic, anticholinergic, psychotherapy, SGA, mood
stabilizer).

manic switch in children and adolescents with bipolar depression.

The finding is consistent with the general belief that polarity switch
may be a part of the natural course of bipolar disorder itself. Irrespective of antidepressant treatment status, subjects who had had a
manic episode prior to the treatment initiation were more likely to
transition to a manic phase than were those without the previous
episode. Consequently, previous manic history should be an important consideration in treatment decisions.
After adjusting for previous manic episode and other covariates,
the Cox proportional hazard analysis suggested that antidepressant
monotherapy was associated with increased risk of manic switch
compared with SGA monotherapy (HR = 2.63). The higher risk of
manic switch associated with antidepressants versus SGA could be
explained by the psychotropics mechanism of action, as described
in previous literature. Previous animal and genetic studies have
explored the potential role of many neurotransmitters in manic
switch, including serotonin, noradrenergic, dopamine, and cate-

Antidepressant
monotherapy (ref:
mood stabilizer
monotherapy)
Prior mania
Residual (r)
Antidepressant
monotherapy
Anticholinergic
History of mood
stabilizer
Prior mania
Residual (r)
Antidepressant
monotherapy
History of mood
stabilizer
Prior mania
Residual (r)

1.41 (0.52-3.80)

1.17 (0.24-5.57)

17.80 (10.29-30.81)
N/A
Follow-up: 8 weeks

24.06 (11.32-51.15)
1.34 (0.23-7.67)

1.68 (0.67-4.21)

1.32 (0.30-5.84)

3.73 (1.14-12.16)
2.21 (1.17-4.20)

3.84 (0.88-16.69)
2.30 (0.96-5.53)

18.16 (10.59-31.15) 24.24 (11.64-50.44)

N/A
1.56 (0.29-8.40)
Follow-up: 12 weeks
1.44 (0.63-3.29)

1.19 (0.28-5.13)

1.90 (1.02-3.55)

1.95 (0.83-4.60)

17.74 (10.42-30.20)
N/A

23.27 (11.54-46.95)
1.45 (0.25-8.33)

Only statistically significant variables at p < 0.05 are included in the

table. Complete list of variables included in the models was as follows:
demographics (age category, gender, race, state, number of physicians in
the ZIP codes), proxy measurements of severity (duration of disease, prior
hospitalization), Medicaid eligibility groups (foster care, Temporary
Assistance to Needy Families), comorbidity (substance abuse disorder,
attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety, adjustment disorder, psychotic disorder, prior mania), comedications
(stimulant, sedative, hypnotic, anticholinergic, psychotherapy, history of
second generation antipsychotics, history of mood stabilizers).

cholaminergic activity (Salvadore et al. 2010). The mechanism that

helps to explain the different effects of antidepressants and SGA on
manic switch is the effect of these medications on regulating synaptic plasticity and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor trafficking in the hippocampus region
of brain that is associated with SGA. The exposure to antidepressants (such as imipramine) known for triggering manic switch has
been reported earlier to increase AMPA synaptic expression in the
hippocampus (Du et al. 2003; Gray et al. 2003). Other research
suggests that treatment of rodents with antipsychotics can reduce
the expression of some AMPA receptor subunit mRNA and protein
expression (Fitzgerald et al. 1995; Healy and Meador-Woodruff
1997; Fumagalli et al. 2008). Given the opposing effect of SGA and
antidepressant drugs on the AMPA GluR1 receptor, AMPA receptor trafficking has been strongly suggested to play a key role in
the mechanism of manic switching.
Existing research suggests that mood stabilizers such as lithium
and valproate have similar effects as SGA on reducing glutamate
AMPA receptor (GluR1) synaptic expression in the hippocampus
(Du et al. 2004). However, statistically significant differences in the

558

BHOWMIK ET AL.
Table 5. Cox Proportional Hazards Regression
Analysis Results (Antidepressant Polytherapy
vs. SGAMood Stabilizer Polytherapy)

Variables

Hazard ratio (95% CI)

Hazard ratio
from conventional
(95% CI)
Cox proportional
from instrumental
hazard regression
variable analysis
model
Follow-up: 6 weeks

Antidepressant
polytherapy (ref:
SGA polytherapy)
Prior mania
Residual (r)
Antidepressant
polytherapy
History of SGA
Prior mania
Residual (r)
Antidepressant
polytherapy
Prior mania
Residual (r)

1.61 (0.90-2.89)

1.23 (0.52-2.89)

10.96 (8.36-14.37)
N/A
Follow-up: 8 weeks

11.33 (8.48-15.12)
1.44 (0.58-3.59)

1.70 (0.97-2.98)

1.22 (0.54-2.76)

1.39 (1.01-1.91)
10.51 (8.10-13.63)
N/A
Follow-up: 12 weeks

1.36 (0.97-1.92)
10.85 (8.24-14.28)
1.22 (0.64-3.75)

1.17 (0.71-1.92)

0.69 (0.32-1.49)

9.37 (7.35-11.96)
N/A

9.68 (7.46-12.56)
2.03 (0.88-4.68)

Only statistically significant variables at p < 0.05 are included in the

table. Complete list of variables included in the models was as follows:
demographics (age category, gender, race, state, number of physicians in
the ZIP codes), proxy measurements of severity (duration of disease, prior
hospitalization), Medicaid eligibility groups (foster care, Temporary
Assistance to Needy Families), comorbidity (substance abuse disorder,
attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety,
adjustment disorder, psychotic disorder, prior mania), comedications (stimulant, sedative, hypnotic, anticholinergic, psychotherapy, SGA, mood stabilizer).
SGA, second-generation antipsychotic.

risk of manic switch were not observed when antidepressant

monotherapy was compared with mood stabilizer monotherapy
(HR = 1.41 [95% CI: 0.523.80]) in our study. The finding could be
explained by the slower and weaker antimanic effect of mood
stabilizers compared with SGA (Delbello et al. 2006; Macmillan
et al. 2008; Pavuluri et al. 2010; Geller et al. 2012), and also by the
relatively small sample available for the comparison between MS
and antidepressant monotherapy recipients.
Both mood stabilizers and SGA are recommended for acute and
prophylactic treatment of the manic phase. Therefore, antimanic
medications (mood stabilizers and SGA) are believed to treat or prevent
an antidepressant-induced manic switch when antidepressantSGA/
mood stabilizer combination therapy is used. Literature suggests that
Table 6. Association between Instruments
and Treatment Cohorts
F statistics

R2

SGA monotherapy

149

0.28

mood stabilizer
monotherapy
SGA-mood stabilizer
polytherapy

150

0.40

285

0.27

Treatment groups

Comparison groups

Antidepressant
monotherapy
Antidepressant
monotherapy
Antidepressant
polytherapy

SGA, second-generation antipsychotic.

concomitant therapy with a mood stabilizer may reduce antidepressantinduced manic switch (Ghaemi et al. 2003). Our analysis confirmed
that the combination of antidepressant and SGA/mood stabilizer has a
comparable risk of manic switch as SGA and mood stabilizer.
Our study is the first that assessed the risk of manic switch in
children and adolescents with bipolar depression, and it is also the
first head-to-head comparison study between antidepressant
monotherapy and polytherapy and their alternatives. Given that
making such comparisons in children using an experimental design
is highly unlikely because of ethical concerns, an observational
study such as this can provide valuable data for clinical practice.
Despite these advantages, existence of unobserved confounders
is always a concern in observational studies, regardless of how
refined the statistical methods and adjustment of the confounding
factors are. Although particular patient characteristics were taken
into account by adjusting for clinical and sociodemographic variables, geographic location, comorbidities, and past use of somatic
and psychotropic medications, data on some potentially important
confounding variables, such as responsiveness to the previous
treatment, were unavailable. Literature suggests that responsiveness to previous psychopharmacotherapy is an important predictor
of the risk of manic switch associated with an antidepressant
(Salvadore et al. 2010). It is likely that there is a severity difference,
and that patients who did not respond well to mood stabilizer and
SGA were switched to antidepressants. To test the robustness of the
conventional Cox proportional hazards model for possible unobserved confounding, the analysis was conducted again using an IV
approach. The statistical insignificance of the residual r in the IV
analysis probably implies that unobserved confounding was not a
concern in the three models. Hence, the conventional Cox proportional hazards model used in the main analysis might provide
sufficient statistical justification for the association between psychotropic treatment and the risk of manic switch.
Another concern about the studies of manic switch is the lack of
agreement on the duration of follow-up (Salvadore et al. 2010).
Ideally, in order for results to be comparable across studies, a single
a priori definition of the time frame (e.g., 6 weeks) from the beginning of antidepressant treatment in patients experiencing a depressive episode, is required. Our present lack of consensus
regarding temporal criteria may dilute the biological underpinnings
of this phenomenon, because subjects who develop affective switch
within very different time frames from the start of antidepressant
treatments are considered equivalent. This methodological issue
has been emphasized by a task force of the ISBD (Grunze 2008). To
test the robustness of our findings against the different definitions of
switching, and to understand the effect of possible misclassification, we conducted a sensitivity analysis by extending the follow-up
period from 6 weeks to 8 and 12 weeks. The sensitivity analysis
confirmed the higher risk of manic switch with antidepressant
monotherapy versus SGA monotherapy.
In addition to the two main concerns that have been addressed in
the sensitivity analysis, our study has other limitations because of
the nature of claims data. For example, prescription claims for
antidepressants, SGAs, and mood stabilizers were captured and
deemed bipolar depression treatment without documented indications from physicians notes. To ensure that those medications were
prescribed to treat bipolar depression, other common indications
for prescribing SGA or mood stabilizers (epilepsy, schizophrenia)
were removed from the cohort, and a strict rule requiring initiation
of the antidepressant within 30 days of depression diagnosis was
also applied. Also, bipolar depression cases and manic switch
events were identified based on ICD-9 diagnosis codes rather than

ANTIDEPRESSANTS ASSOCIATED WITH MANIC SWITCH IN CHILDREN

structured clinical evaluation using depression and mania rating
scales. To negate possible misclassification of bipolar cases, a strict
algorithm was applied, and only patients who had had a minimum
of three bipolar disorder diagnoses were included in the analysis.
Manic switch associated with medication use is an emergent, onetime event that cannot be ascertained by repeated coding; therefore,
misclassification of outcome caused by misdiagnosis or miscoding
cannot be completely ruled out. However, there is no practical
reason to believe that misclassification of disease in the claims data
would have affected treatment groups differently and, therefore, it
should not affect the studys conclusions.
Lastly, subcategories and individual drugs within the broad antidepressant class could have varying degrees of risk of manic switch.
Tricyclic antidepressants (TCA) have been reported to have higher
risk of manic switch than newer antidepressants, such as SSRIs
(Salvadore et al. 2010). However, in our study cohort, *90% of
children and adolescents in the antidepressant monotherapy group
were on an SSRI antidepressant. It would be valuable, in future
analysis, to further assess the relative risk between individual SSRI
antidepressants in terms of manic switch.
Conclusions
In conclusion, antidepressant monotherapy was associated with
an increase in the risk of short-term manic switch compared with
SGA monotherapy. However, a similar association was not found
between antidepressant monotherapy and mood stabilizer monotherapy, or between antidepressant polytherapy and SGAmood
stabilizer combination. Overall, the study findings support the
current guidelines that antidepressant monotherapy should be always avoided, because of its potential for causing manic switch
Clinical Significance
Our study is the first that assessed the risk of manic switch in
children and adolescents with bipolar depression, and it is also the
first head-to-head comparison study between antidepressant
monotherapy, and combinations and their alternatives. Given that
making such comparisons in children using an experimental design
is highly unlikely because of ethical concerns, observational studies
such as this can provide valuable data for clinical practice.
Disclosures
No competing financial interests exist.
References
Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A,
Ackerman L: Antidepressant-induced mania and cycle acceleration:
A controversy revisited. Am J Psychiatry 152:11301138, 1995.
Amit BH, Weizman A: Antidepressant treatment for acute bipolar
depression: An update. Depress Res Treat 2012:684725, 2012.
Angst F, Stassen HH, Clayton PJ, Angst J: Mortality of patients with
mood disorders: Follow-up over 3438 years. J Affect Disord 68:
167181, 2002.
Baldessarini RJ, Henk H, Sklar A, Chang J, Leahy L: Psychotropic
medications for patients with bipolar disorder in the United
States: Polytherapy and adherence. Psychiatr Serv 59:1175
1183, 2008.
Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J:
Patterns of psychotropic drug prescription for US patients with
diagnoses of bipolar disorder. Psychiatr Serv 58:8591, 2007.
Bhowmik D, Aparasu RR, Rajan SS, Sherer JT, OchoaPerez M,
Chen H: The utilization of psychopharmacological treatment and

559

medication adherence among Medicaid enrolled children and adolescents with bipolar depression. J Affect Disord 150:424429,
2013.
Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiappetta L,
Ryan N, Leonard H, Hunt J, Iyengar S, Keller M: Clinical course of
children and adolescents with bipolar spectrum disorders. Arch Gen
Psychiatry 63:175183, 2006.
Boerlin HL, Gitlin MJ, Zoellner LA, Hammen CL: Bipolar depression
and antidepressant-induced mania: a naturalistic study. J Clin
Psychiatry 59:374379, 1998.
Bond DJ, Noronha MM, KauerSantAnna M, Lam RW, Yatham LN:
Antidepressant-associated mood elevations in bipolar II disorder
compared with bipolar I disorder and major depressive disorder: A
systematic review and meta-analysis. J Clin Psychiatry 69:1589
1601, 2008.
Brookhart MA, Rassen JA, Wang PS, Dormuth C, Mogun H,
Schneeweiss S: Evaluating the validity of an instrumental variable
study of neuroleptics: Can between-physician differences in prescribing patterns be used to estimate treatment effects? Med Care
45:S116S122, 2007.
Brookhart MA, Wang PS, Solomon DH, Schneeweiss S: Evaluating
short-term drug effects using a physician-specific prescribing
preference as an instrumental variable. Epidemiology 17:268275,
2006.
Busch AB, Frank RG, Sachs G: Bipolar-I depression outpatient
treatment quality and costs in usual care practice. Psychopharmacol
Bull 41:2439, 2008.
Cohn JB, Collins G, Ashbrook E, Wernicke JF: A comparison of
fluoxetine imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol 4:313322, 1989.
Delbello MP, Kowatch RA, Adler CM, Stanford KE, Welge JA,
Barzman DH, Nelson E, Strakowski SM: A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent
mania. J Am Acad Child Adolesc Psychiatry 45:305313, 2006.
Du J, Feng L, Zaitsev E, Je H, Liu X, Lu B: Regulation of TrKB
receptor tyrosine kinase and its internalization by neuronal activity
and calcium influx. J Cell Biol 163:385395, 2003.
Du J, Quiroz JA, Gray NA, Szabo ST, Zarate CA Jr, Manji HK:
Regulation of cellular plasticity and resilience by mood stabilizers:
the role of AMPA receptor trafficking. Dialogues Clin Neurosci
6:143155, 2004.
Dutta R, Boydell J, Kennedy N, VAN Os J, Fearon P, Murray RM:
Suicide and other causes of mortality in bipolar disorder: Longitudinal study. Psychol Med 37:839847, 2007.
Fitzgerald LW, Deutch AY, Gasic G, Heinemann SF, Nestler EJ:
Regulation of cortical and subcortical glutamate receptor subunit
expression by antipsychotic drugs. J Neurosci 15:24532461, 1995.
Frye MA, Calabrese JR, Reed ML, Hirschfeld RM: Healthcare resource utilization in bipolar depression compared with unipolar
depression: Results of a United States population-based study. CNS
Spectr 11:704719, 2006.
Frye MA, Helleman G, McElroy SL, Altshuler LL, Black DO, Keck
PE Jr, Nolen WA, Kupka R, Leverich GS, Grunze H, Mintz J, Post
RM, Suppes T: Correlates of treatment-emergent mania associated
with antidepressant treatment in bipolar depression. Am J Psychiatry 166:164172, 2009.
Fumagalli F, Frasca A, Racagni G, Riva MA: Dynamic regulation of
glutamatergic postsynaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs. Mol Pharmacol 73:
14841490, 2008.
Geller B, Luby JL, Joshi P, Wagner KD, Emslie G, Walkup JT,
Axelson DA, Bolhofner K, Robb A, Wolf DV, Riddle MA, Birmaher B, Nusrat N, Ryan ND, Vitiello B, Tillman R, Lavori P: A
randomized controlled trial of risperidone, lithium, or divalproex

560
sodium for initial treatment of bipolar I disorder, manic or mixed
phase, in children and adolescents. Arch Gen Psychiatry 69:515
528, 2012.
Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK: Antidepressants in
bipolar disorder: the case for caution. Bipolar Disord 5:421433,
2003.
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM:
Antidepressants for bipolar depression: A systematic review of
randomized, controlled trials. Am J Psychiatry 161:15371547,
2004.
Gray N, Du J, Falke C, Yuan P, Manji H: Lithium regulates total and
synaptic expression of the AMPA glutamate receptor GluR2
in vitro and in vivo. Ann N Y Acad Sci 1003:402404, 2003.
Grunze HC: Switching, induction of rapid cycling, and increased
suicidality with antidepressants in bipolar patients: Fact or overinterpretation? CNS Spectr 13:790795, 2008.
Hadley J, Yabroff KR, Barrett MJ, Penson DF, Saigal CS, Potosky
AL: Comparative effectiveness of prostate cancer treatments:
Evaluating statistical adjustments for confounding in observational
data. J Natl Cancer Inst 102:17801793, 2010.
Healy D, MeadorWoodruff J: Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in
rat cortex and striatum. Brain Res Mol Brain Res 47:331338,
1997.
Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M: Antidepressantinduced mania in bipolar patients: identification of risk factors. J
Clin Psychiatry 62:249255, 2001.
Himmelhoch JM, Fuchs CZ, Symons BJ: A double-blind study of
tranylcypromine treatment of major anergic depression. J Nerv
Ment Dis 170:628634, 1982.
Hirschfeld RMA, Bowden CL, Gitlin M, Keck PE, Perlis RH, Suppes
T, Thase ME, Wagner KD. American Psychiatric Association.
Practice guideline for the treatment of patients with bipolar disorder
(revision). Am J Psychiatry159 (Suppl):150, 2002.
Humphreys B, Nyman J, Ruseski J: The effect of gambling on health:
Evidence from Canada. Working Paper no. 201118. Available at:
http://www.economics.ualberta.ca/*/media/economics/Faculty
AndStaff/WPs/WP2011-18-Humphreys-Ruseski.pdf. Accessed
November 18, 2014.
Huxley N, Baldessarini RJ: Disability and its treatment in bipolar
disorder patients. Bipolar Disord 9:183196, 2007.
Licht RW, Gijsman H, Nolen WA, Angst J: Are antidepressants safe
in the treatment of bipolar depression? A critical evaluation of their
potential risk to induce switch into mania or cycle acceleration.
Acta Psychiatr Scand 118:337346, 2008.
Rfer SR, Tilley CA, Mrakotsky
Macmillan CM, Withney JE, KorndO
C, GonzalezHeydrich JM: Comparative clinical responses to risperidone and divalproex in patients with pediatric bipolar disorder.
J Psychiatr Pract 14:160169, 2008.
McClellan J, Kowatch R, Findling RL, The Work Group on Quality
Issues: Practice parameter for the assessment and treatment of
children and adolescents with bipolar disorder. J Am Acad Child
Adolesc Psychiatry 46:107125, 2007.
McClellan J, Werry J, The Work Group on Quality Issues: Practice
parameters for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry
36:138157, 1997.
Mendlewicz J, Youdim MB: Antidepressant potentiation of 5-hydroxytryptophan by L-deprenyl in affective illness. J Affect Disord
2:137146, 1980.
Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel
IP, Oakes R, Pitts CD: Doubleblind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 158:906912, 2001.

BHOWMIK ET AL.
Pavuluri MN, Henry DB, Findling RL, Parnes S, Carbray JA, Mohammed T, Janicak PG, Sweeney JA: Double-blind randomized
trial of risperidone versus divalproex in pediatric bipolar disorder.
Bipolar Disord 12:593605, 2010.
Peet M: Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 164:549550,
1994.
Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M,
DelBello MP, Bowden CL, Sachs GS, Nierenberg AA: Long-term
implications of early onset in bipolar disorder: Data from the first
1000 participants in the systematic treatment enhancement program
for bipolar disorder (STEP-BD). Biol Psychiatry 55:875881, 2004.
Perlis RH, Ostacher MJ, Goldberg JF, Miklowitz DJ, Friedman E,
Calabrese J, Thase ME, Sachs GS: Transition to mania during
treatment of bipolar depression. Neuropsychopharmacology 35:
25452552, 2010.
Post RM, Denicoff KD, Leverich GS, Altshuler LL, Frye MA, Suppes
TM, Rush AJ, Keck PE Jr, McElroy SL, Luckenbaugh DA, Pollio
C, Kupka R, Nolen WA: Morbidity in 258 bipolar outpatients
followed for 1 year with daily prospective ratings on the NIMH life
chart method. J Clin Psychiatry 64:680690; quiz 738739, 2003.
Rassen JA, Brookhart MA, Glynn RJ, Mittleman MA, Schneeweiss S:
Instrumental variable II: Instrumental variable applicationin 25
variations, the physician prescribing preference generally was
strong and reduced covariate imbalance. J Clin Epidemiol 62:1233
1241, 2009.
Salvadore G, Quiroz JA, MachadoVieira R, Henter ID, Manji HK,
Zarate CA Jr: The neurobiology of the switch process in bipolar
disorder: a review. J Clin Psychiatry 71:14881501, 2010.
Staiger D, Stock JH: Instrumental variable regression with weak instruments. Econometrica 65:557586, 1997.
Stensland MD, Schultz JF, Frytak JR: Diagnosis of unipolar depression following initial identification of bipolar disorder: A common
and costly misdiagnosis. J Clin Psychiatry 69:749758, 2008.
Strawn JR, Adler CM, McNamara RK, Welge JA, Bitter SM, Mills
NP, Barzman DH, Cerullo MA, Chang KD, Strakowski SM, DelBello MP: Antidepressant tolerability in anxious and depressed
youth at high risk for bipolar disorder: A prospective naturalistic
treatment study. Bipolar Disord 16:52330, 2014.
Terza JV, Basu A, Rathouz PJ: Two-stage residual inclusion estimation: Addressing endogeneity in health econometric modeling. J
Health Econ 27:531543, 2008.
Thase ME: Pharmacology of bipolar depression: an update. Curr
Psychiatry Rep 8:478488, 2006.
Tohen M, Frank E, Bowden CL, Colom F, Ghaemi SN, Yatham
LN, Malhi GS, Calabrese JR, Nolen WA, Vieta E, Kapczinski F,
Goodwin GM, Suppes T, Sachs GS, Chengappa KR, Grunze H,
Mitchell PB, Kanba S, Berk M: The International Society for Bipolar
Disorders (ISBD) Task Force report on the nomenclature of course
and outcome in bipolar disorders. Bipolar Disord 11:453473, 2009.
Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C,
Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A: Efficacy of olanzapine and
olanzapinefluoxetine combination in the treatment of bipolar I
depression. Arch Gen Psychiatry 60:10791088, 2003.
Tondo L, Lepri B, Baldessarini RJ: Suicidal risks among 2826 Sardinian major affective disorder patients. Acta Psychiatr Scand 116:
419428, 2007.
Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M:
Lithium treatment and risk of suicidal behavior in bipolar disorder
patients. J Clin Psychiatry 59:405414, 1998.
Truman CJ, Goldberg JF, Ghaemi SN, Baldassano CF, Wisniewski
SR, Dennehy EB, Thase ME, Sachs GS: Self-reported history of
manic/hypo associated with antidepressant use: Data from the

ANTIDEPRESSANTS ASSOCIATED WITH MANIC SWITCH IN CHILDREN

Systematic Treatment Enhancement Program for Bipolar Disorder
(STEP-BD). J Clin Psychiatry 68:14721479, 2007.
Yatham LN, Kennedy SH, ODonovan C, Parikh S, MacQueen G,
McIntyre R, Sharma V, Silverstone P, Alda M, Baruch P, Beaulieu S,
Daigneault A, Milev R, Young LT, Ravindran A, Schaffer A, Connolly M, Gorman CP; Canadian Network for Mood and Anxiety
Treatments: Canadian Network for Mood and Anxiety Treatments
(CANMAT) guidelines for the management of patients with bipolar
disorder: consensus and controversies. Bipolar Disord 7:569, 2005.

561

Address correspondence to:

Hua Chen, MD, PhD
Department of Pharmaceutical Health Outcomes and Policy
College of Pharmacy
University of Houston
1441 Moursund St.
Houston, TX 77030
E-mail: hchen20@uh.edu