Risk of Manic Switch Associated With Antidepressant Therapy in Pediatric Bipolar Depression...

Risk of Manic Switch Associated with AntidepressantTherapy 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 Medicaid-enrolled pediatric patients with bipolar depression.

Methods: This retrospective cohort study involved 20032007 Medicaid Analytic eXtract (MAX) data from four geo-graphically 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: 0.523.80); antidepressant polytherapy vs. SGA-mood stabilizer polytherapy, HR = 1.61 [95% CI: 0.902.89]). However, only thecomparison 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 withSGA monotherapy in pediatric patients with bipolar depression. The finding supported the clinical practice of cautious

prescribing of antidepressants for brief periods.

Introduction

Bipolar disorder is a form of mood disorder characterizedby the presence of episodes of highly elevated mood (manic)and episodes of depression. The lifetime prevalence of the de-

pressive 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 (Hirsch-

feld et al. 2002). However, there has been debate over whether

1Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, Texas.2Global Health Economics, Amgen Inc., Thousand Oaks, California.3Division of Management, Policy and Community Health, School of Public Health, The University of Texas Health Science Center, Houston, Texas.4Department of Psychiatry, Legacy Community Health Services, Houston, Texas.

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 24, Number 10, 2014 Mary Ann Liebert, Inc.Pp. 551561DOI: 10.1089/cap.2014.0028

551

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 re-

ported a higher risk of manic switch associated with the use of

antidepressants in adults with bipolar depression (Peet 1994; Alt-

shuler 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 meta-

analysis by Gijsman et al. (2004) did not find statistically signifi-

cant 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 con-

trolled trials (RCTs) that compared the risk of manic switch be-

tween 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 re-

mission, 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 anti-

depressants. Among these antidepressant recipients, 57% had had an

adverse reaction in the form of manic symptoms (irritability, ag-

gression, impulsivity, or hyperactivity), leading to antidepressant

discontinuation (Strawn et al. 2014). Therefore, the existing pedi-

atric guidelines for bipolar disorder tend to be more conservative in

recommending the use of antidepressants. Antidepressant mono-

therapy 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 asso-

ciated 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 antide-

pressants 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 stabi-

lizer monotherapy, and 3) antidepressant polytherapy (with SGA or

mood stabilizer) versus SGA-mood stabilizer polytherapy in

Medicaid-enrolled children and adolescents with bipolar depres-

sion. 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 mono-

therapies 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 infor-

mation 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, flu-

oxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, and bu-

propion); and other antidepressants (amitriptyline, clomipramine,

desipramine, doxepin, imipramine, nortriptyline, mirtazapine, ne-

fazodone, 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 con-

tinuous 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

552 BHOWMIK ET AL.

use during 30 days around the index bipolar depression diag-

nosis: 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 differ-

ent therapeutic classes within 30 days of the depression di-

agnosis and with a minimum of 14 day overlap between the

prescriptions.

Manic switch

Manic switch events were identified from the combined inpa-

tient 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 (Sal-

vadore et al. 2010).

Statistical analyses

Descriptive analysis was conducted to describe the demo-

graphics, treatment utilization, comedications, and comorbidities

during the 2 month pre-index period for the monotherapy and

polytherapy users, respectively. Time to manic switch was ana-

lyzed 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 poly-

therapy. 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 < 0.05was considered to be statistically significant.

Covariates included in the Cox model were patient demo-

graphics, comedications, and comorbidities that were measured at 2

Excluded Patients without continuous eligibility 2 months

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

Excluded patients with antidepressant use during the 2

months pre-index period = 2,051

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 having diagnoses of epilepsy or schizophrenia = 8,731

Medicaid enrolees 6-18 years of age with any mental disorder diagnosis or

received any psychotropic drug = 4,216,094

Cohort : To observe the short term manic switch associated with

antidepressant exposure = 4,147

Follow-up = 6 weeks

Monotherapy cohort = 1,796

Polytherapy cohort = 2,351

Antidepressant monotherapy =

179

Atypical antipsychotic monotherapy

= 1,047

Antidepressant polytherapy =

445

Atypical antipsychotic-

mood stabilizer

polytherapy = 1,906

Mood stabilizer

monotherapy = 570

Excluded patients for computing physician prescribing preference =

4,250

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

FIG. 1. Consort diagram.

ANTIDEPRESSANTS ASSOCIATED WITH MANIC SWITCH IN CHILDREN 553

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 stim-

ulants, sedatives, hypnotics, anticholinergics, SGAs, or mood sta-

bilizers 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

as recipients of antidepressant monotherapy (n = 179), SGAmonotherapy (n= 1047), mood stabilizer monotherapy (n = 570),antidepressantmood stabilizer or antidepressantSGA polyther-

apy (n = 445), or SGAmood stabilizer polytherapy (n= 1906).

Descriptive statistics

As presented in Tables 1 and 2, antidepressant (both mono-

therapy 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%), SGAmonotherapy (n= 95, 9.07%) and antidepressant polytherapy(n = 136, 8.09%). Using antidepressant monotherapy as the refer-ence, log rank tests found that there were no statistically significant

differences in the risk of manic switch between antidepressant

monotherapy recipients and the recipients of all other regimens.

Multivariable Cox proportional hazards regressionanalysis

Tables 35 present the findings of three traditional Cox pro-

portional hazard analysis models that compared the risk of manic

switch between antidepressant monotherapy and SGA mono-

therapy, antidepressant monotherapy and mood stabilizer mono-

therapy, and antidepressant polytherapy and SGAmood stabilizer

polytherapy after controlling for all observable confounders. An-

tidepressant 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 anti-

depressant monotherapy was compared with mood stabilizer

monotherapy (HR = 1.41 [95% CI: 0.523.80]), and when antide-pressant 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)

Antidepressantmonotherapy (n = 179)

SGA monotherapy(n = 1047)

Mood stabilizermonotherapy (n= 570)

Covariates n (%) or Mean ( SD) n (%) or Mean ( SD) n (%) or Mean ( SD) p value

DemographicsAge category

Children (613 years) 36 (20.45) 437 (42.55) 177 (31.83) < 0.0001Adolescents (1418 years) 140 (79.55) 590 (57.45) 379 (68.17)

RaceWhite 89 (50.28) 461 (44.58) 260 (46.43) 0.0630Black 32 (18.08) 291 (28.14) 157 (28.04)

Gender (Male) 71 (40.11) 650 (62.86) 321 (57.32) < 0.0001State

TX 76 (42.94) 320 (30.95) 164 (29.29) 0.0025CA 36 (20.34) 206 (19.92) 124 (22.14)IL 51 (28.21) 340 (32.88) 201 (35.89)NY 14 (7.91) 168 (16.25) 71 (12.68)

Number of physicians in ZIP codes 23 ( 23) 31 ( 29) 29 ( 28) 0.0007Proxy measurements of severity

Duration of disease 328 ( 364) 334 ( 372) 295 ( 338) 0.1012Prior hospitalization 41 (22.91) 211 (20.15) 101 (17.72) 0.2574

Medicaid eligibility groupsFoster care 32 (17.88) 322 (30.75) 160 (28.07) 0.0019TANF 14 (7.82) 80 (7.64) 48 (8.42) 0.8562

ComorbiditySubstance abuse disorder 15 (8.38) 73 (6.97) 44 (7.72) 0.7363ADHD 35 (19.55) 339 (32.38) 150 (26.32) 0.0004Suicidality 9 (5.03) 22 (2.10) 9 (1.58) 0.0221Oppositional defiant disorder 27 (15.08) 262 (25.02) 123 (21.58) 0.0090Anxiety 26 (14.53) 95 (9.07) 61 (10.70) 0.0712Adjustment disorder 16 (8.94) 123 (11.75) 65 (11.40) 0.5488Psychotic disorder 5 (2.79) 81 (7.74) 23 (4.04) 0.0018Mania 23 (12.85) 134 (12.80) 87 (15.26) 0.3676

ComedicationStimulant 29 (16.20) 209 (19.96) 105 (18.42) 0.4389Sedative 48 (26.82) 177 (16.91) 102 (17.89) 0.0063Hypnotic 4 (2.23) 50 (4.78) 16 (2.81) 0.0711Anticholinergic 4 (2.23) 71 (6.78) 22 (3.86) 0.0065Psychotherapy 102 (56.98) 543 (51.86) 309 (54.21) 0.3661SGA 12 (6.70) 539 (51.48) 38 (6.67) < 0.0001Mood stabilizer 9 (5.03) 61 (5.83) 276 (48.42) < 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 mono-

therapy 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 stabi-

lizer polytherapy.

IV analysis

Table 6 presents the statistical validation of instrumental vari-

ables. 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) indi-

cated 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 exo-

geneity of the treatment selection for bipolar depression.

Sensitivity analysis on duration of follow-up

As presented in Tables 35, the associations between the treat-

ment 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

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

Antidepressant polytherapy (n = 445) SGA/Mood stabilizer polytherapy (n = 1906)Covariates n (%) or Mean ( SD) n (%) or Mean ( SD) p value

DemographicsAge category

Children 156 (36.03) 808 (43.49) 0.0046Adolescents 277 (63.97) 1050 (56.51)

RaceWhite 209 (47.83) 885 (47.33) 0.0061Black 86 (19.68) 487 (26.04)

Gender: Male 236 (54.00) 1268 (67.81) < 0.0001State

TX 228 (52.17) 747 (39.95) < 0.0001CA 75 (17.16) 336 (17.97)IL 112 (25.63) 485 (25.94)NY 22 (5.03) 302 (16.15)

Number of physicians in ZIP codes 26 ( 24) 33 ( 29) < 0.0001Proxy measurements of severity

Duration of disease 295 ( 369) 392 ( 377) < 0.0001Prior hospitalization 139 (31.24) 322 (16.89) < 0.0001

Medicaid eligibility groupsFoster care 83 (18.65) 651 (34.16) < 0.0001TANF 49 (11.01) 90 (4.72) < 0.0001

ComorbiditySubstance abuse disorder 28 (6.29) 97 (5.09) 0.3085ADHD 128 (28.76) 602 (31.58) 0.2470Suicidality 10 (2.25) 31 (1.63) 0.3677Oppositional defiant disorder 87 (19.55) 487 (25.55) 0.0080Anxiety 65 (14.61) 145 (7.61) < 0.0001Adjustment disorder 58 (13.03) 238 (12.49) 0.7542Psychotic disorder 32 (7.19) 149 (7.82) 0.6554Mania 56 (12.58) 296 (15.53) 0.1169

ComedicationStimulant 61 (13.71) 442 (23.19) < 0.0001Sedative 109 (24.49) 440 (23.08) 0.5269Hypnotic 20 (4.49) 93 (4.88) 0.7325Anticholinergic 27 (6.07) 175 (9.18) 0.0348Psychotherapy 286 (64.27) 1071 (56.19) 0.0019SGA 151 (33.93) 1375 (72.14) < 0.0001Mood stabilizer 67 (15.06) 1323 (69.41) < 0.0001

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

556 BHOWMIK ET AL.

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. Irre-

spective 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 im-

portant 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 ofmanic 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-

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 syn-

aptic plasticity and a-amino-3-hydroxy-5-methyl-4-isoxazole pro-pionic acid (AMPA) receptor trafficking in the hippocampus region

of brain that is associated with SGA. The exposure to antidepres-

sants (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 re-

ceptor 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

Table 3. Cox Proportional Hazards Regression AnalysisResults (Antidepressant Monotherapy vs.

Second-Generation Antipsychotic [SGA] Monotherapy)

Variables

Hazard ratio(95% CI) from

conventional Coxproportional hazardregression model

Hazard ratio(95% CI)

from instrumentalvariable analysis

Follow-up: 6 weeks

Antidepressantmonotherapy (ref:SGA monotherapy)

2.87 (1.10-7.49) 2.34 (0.41-13.30)

Prior mania 14.00 (8.99-21.78) 16.01 (9.58-26.77)Stimulant 1.86 (1.07-3.23) 1.86 (1.04-3.35)Oppositional defiant

disorder1.78 (1.09-2.90) 1.80 (1.07-3.04)

Residual (r) N/A 1.38 (0.21-8.89)

Follow-up: 8 weeks

Antidepressantmonotherapy

2.69 (1.10-6.60) 2.35 (0.51-10.75)

Stimulant 1.87 (1.11-3.15) 1.89 (1.09-3.29)Oppositional defiant

disorder1.85 (1.17-2.93) 1.88 (1.16-3.03)

Prior mania 12.47 (8.18-18.99) 13.93 (8.69-22.32)Residual (r) N/A 1.27 (0.25-6.40)

Follow-up: 12 weeks


2.44 (1.09-5.46) 1.49 (0.34-6.58)

Stimulant 1.97 (1.19-3.25) 2.04 (1.21-3.46)Anticholinergic 0.25 (0.06-0.95) 0.17 (0.004-6.57)Oppositional defiant

disorder1.80 (1.16-2.79) 1.78 (1.12-2.83)


Only statistically significant variables at p< 0.05 are included in thetable. Complete list of variables included in the models was as follows:demographics (age category, gender, race, state, number of physicians inthe ZIP codes), proxy measurements of severity (duration of disease, priorhospitalization), Medicaid eligibility groups (foster care, TemporaryAssistance to Needy Families), comorbidity (substance abuse disorder,attention-deficit/hyperactivity disorder, oppositional defiant disorder, anx-iety, adjustment disorder, psychotic disorder, prior mania), comedications(stimulant, sedative, hypnotic, anticholinergic, psychotherapy, SGA, moodstabilizer).

Table 4. Cox Proportional Hazards RegressionAnalysis Results (Antidepressant Monotherapy vs.

Mood Stabilizer Monotherapy)

Variables

Hazard ratio(95% CI) from

conventional Coxproportional hazardregression model

Hazard ratio(95% CI) frominstrumental

variable analysis

Follow-up: 6 weeks

Antidepressantmonotherapy (ref:mood stabilizermonotherapy)

1.41 (0.52-3.80) 1.17 (0.24-5.57)


Follow-up: 8 weeks


1.68 (0.67-4.21) 1.32 (0.30-5.84)

Anticholinergic 3.73 (1.14-12.16) 3.84 (0.88-16.69)History of mood

stabilizer2.21 (1.17-4.20) 2.30 (0.96-5.53)


Follow-up: 12 weeks


1.44 (0.63-3.29) 1.19 (0.28-5.13)

History of moodstabilizer

1.90 (1.02-3.55) 1.95 (0.83-4.60)


Only statistically significant variables at p < 0.05 are included in thetable. Complete list of variables included in the models was as follows:demographics (age category, gender, race, state, number of physicians inthe ZIP codes), proxy measurements of severity (duration of disease, priorhospitalization), Medicaid eligibility groups (foster care, TemporaryAssistance to Needy Families), comorbidity (substance abuse disorder,attention-deficit/hyperactivity disorder, oppositional defiant disorder, anx-iety, adjustment disorder, psychotic disorder, prior mania), comedications(stimulant, sedative, hypnotic, anticholinergic, psychotherapy, history ofsecond generation antipsychotics, history of mood stabilizers).


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 beexplained 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

concomitant therapy with a mood stabilizer may reduce antidepressant-

induced 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 vari-

ables, 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 responsive-

ness 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 unob-

served 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 pro-

portional hazards model used in the main analysis might provide

sufficient statistical justification for the association between psy-

chotropic 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 be-

ginning of antidepressant treatment in patients experiencing a de-

pressive 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 misclassifica-

tion, 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 indica-

tions 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

Table 5. Cox Proportional Hazards RegressionAnalysis Results (Antidepressant Polytherapy

vs. SGAMood Stabilizer Polytherapy)

Variables

Hazard ratio (95% CI)from conventionalCox proportionalhazard regression

model

Hazard ratio(95% CI)

from instrumentalvariable analysis

Follow-up: 6 weeks

Antidepressantpolytherapy (ref:SGA polytherapy)

1.61 (0.90-2.89) 1.23 (0.52-2.89)


Follow-up: 8 weeks

Antidepressantpolytherapy

1.70 (0.97-2.98) 1.22 (0.54-2.76)

History of SGA 1.39 (1.01-1.91) 1.36 (0.97-1.92)Prior mania 10.51 (8.10-13.63) 10.85 (8.24-14.28)Residual (r) N/A 1.22 (0.64-3.75)

Follow-up: 12 weeks


1.17 (0.71-1.92) 0.69 (0.32-1.49)


Only statistically significant variables at p < 0.05 are included in thetable. Complete list of variables included in the models was as follows:demographics (age category, gender, race, state, number of physicians inthe ZIP codes), proxy measurements of severity (duration of disease, priorhospitalization), Medicaid eligibility groups (foster care, TemporaryAssistance to Needy Families), comorbidity (substance abuse disorder,attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety,adjustment disorder, psychotic disorder, prior mania), comedications (stimu-lant, sedative, hypnotic, anticholinergic, psychotherapy, SGA, mood stabilizer).

SGA, second-generation antipsychotic.

Table 6. Association between Instrumentsand Treatment Cohorts

Treatment groups Comparison groups F statistics R2


SGA monotherapy 149 0.28


mood stabilizermonotherapy

150 0.40


SGA-mood stabilizerpolytherapy

285 0.27

SGA, second-generation antipsychotic.

558 BHOWMIK ET AL.

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, one-

time 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 an-

tidepressant 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% ofchildren 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 mono-

therapy, or between antidepressant polytherapy and SGAmood

stabilizer combination. Overall, the study findings support the

current guidelines that antidepressant monotherapy should be al-

ways 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

medication adherence among Medicaid enrolled children and ado-

lescents 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 pre-

scribing 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 de-

pressive 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 random-

ized 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: Long-

itudinal 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 re-

source 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 Psy-

chiatry 166:164172, 2009.

Fumagalli F, Frasca A, Racagni G, Riva MA: Dynamic regulation of

glutamatergic postsynaptic activity in rat prefrontal cortex by re-

peated 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, Bir-

maher B, Nusrat N, Ryan ND, Vitiello B, Tillman R, Lavori P: A

randomized controlled trial of risperidone, lithium, or divalproex


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 over-

interpretation? 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 differen-

tially 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: Antidepressant-

induced 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/FacultyAndStaff/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.

Macmillan CM, Withney JE, KorndORfer SR, Tilley CA, Mrakotsky

C, GonzalezHeydrich JM: Comparative clinical responses to ris-

peridone 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 ado-

lescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry

36:138157, 1997.

Mendlewicz J, Youdim MB: Antidepressant potentiation of 5-hydro-

xytryptophan 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 compar-

ison of imipramine and paroxetine in the treatment of bipolar de-

pression. Am J Psychiatry 158:906912, 2001.

Pavuluri MN, Henry DB, Findling RL, Parnes S, Carbray JA, Mo-

hammed 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 in-

hibitors 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 in-

struments. Econometrica 65:557586, 1997.

Stensland MD, Schultz JF, Frytak JR: Diagnosis of unipolar depres-

sion 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, Del-

Bello 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 estima-

tion: 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, Bey-

mer 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 Sar-

dinian 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

560 BHOWMIK ET AL.

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, Con-

nolly 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.

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: [email protected]


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