Review Article

Treatment options for acute depression inbipolar disorder

Introduction

Major depressive episodes (MDE) represent themost debilitating dimension of the illness for mostpatients with bipolar disorder, where difficulties tofind the appropriate treatment strategy are usuallyencountered. While mania has been the focus of

research in the past, several longitudinal reports inthe last decade consistently emphasize depres-sion being the hallmark of bipolar disorder,demonstrating that depressive symptoms and epi-sodes dominate the long-term course of the illness(1–3). As a consequence, bipolar depressionengenders substantial morbidity and psychosocial

Bauer M, Ritter P, Grunze H, Pfennig A. Treatment options for acutedepression in bipolar disorder.Bipolar Disord 2012: 14 (Suppl. 2): 37–50. ª 2012 The Authors.Journal compilation ª 2012 John Wiley & Sons A ⁄S.

Objective: The burden of depression represents the most debilitatingdimension for the majority of patients with bipolar disorder anddominates the long-term course of the illness. The purpose of thismanuscript is to review the evidence base of the available treatmentoptions for bipolar depression within two frequent clinical scenarios.

Methods: The evidence is largely based on a systematic literaturesearch and appraisal that was part of the development of the GermanGuideline for Bipolar Disorders. All relevant randomized controlledtrials were critically evaluated.

Results: Overall, the number of suitably controlled studies for thetreatment of bipolar depression is relatively low. There are two commonscenarios. Scenario A, if a patient with bipolar depression is currently notbeing treated with a mood-stabilizing agent (de novo depression, first orsubsequent episode), then quetiapine or olanzapine are options, oralternatively, carbamazepine and lamotrigine can be considered.Antidepressants are an option for short-term use, but whether they arebest administered as monotherapy or in combination with mood-stabilizing agents is still controversial. In practice, most clinicians useantidepressants in combination with an antimanic agent. Scenario B, if apatient is already being treated optimally with a mood-stabilizing agent(good adherence and appropriate dose) such as lithium, lamotrigine is anoption. There is no evidence for additional benefit from antidepressantswhere a patient is already being treated with a mood stabilizer; however,in practice an antidepressant is often trialled. Efficient psychotherapy isan important part of the treatment regimen and should span all phases ofthe illness.

Conclusions: Treatment decisions in bipolar depression involve a rangeof different pharmacological and non-pharmacological options.Monitoring potential unwanted effects and the appropriateness oftreatment can help to effectively balance benefits and risks in individualsituations. However, the quality of the assessment and reporting of risksin clinical trials need to be improved to better inform treatmentdecisions.

Michael Bauera, Philipp Rittera,Heinz Grunzeb and Andrea Pfenniga

aDepartment of Psychiatry and Psychotherapy, Carl

Gustav Carus University Hospital, Technische

Universitat Dresden, Dresden, Germany, bInstitute

of Neuroscience, Newcastle University, Newcastle

upon Tyne, UK

doi: 10.1111/j.1399-5618.2012.00991.x

Key words: anticonvulsants – atypical

antipsychotics – bipolar disorder – depression –

lithium – pharmacotherapy – psychotherapy

Received 8 August 2011, revised and accepted for

publication 22 October 2011

Corresponding author:

Michael Bauer, M.D., Ph.D.

Department of Psychiatry and Psychotherapy

Carl Gustav Carus University Hospital

Technische Universitat Dresden

Fetscherstraße 74

01307 Dresden, Germany

Fax: +49 (0)351 458 4324

E-mail: michael.bauer@uniklinikum-dresden.de

Bipolar Disorders 2012: 14 (Suppl. 2): 37–50 ª 2012 John Wiley and Sons A/S

BIPOLAR DISORDERS

37

impairment. A substantial amount of morbidityearly in the course is related to the depressivepolarity of the illness. The age of onset of bipolardisorder usually falls between 15 and 24 years (1,2), although there is often a 5- to 10-year intervaluntil first treatment is obtained (3). Currently, littleis known about the early clinical stages of theillness and descriptions of the onset and earlycourse are largely based on patient recall. Numer-ous studies have confirmed that approximately40% of individuals with bipolar disorder areinitially misdiagnosed with unipolar depression(4), as often, an initial depressive presentationdelays the initiation of specific �bipolar� treatment(5, 6).

Definition and goals of treatment

In the DSM-IV-TR, the occurrence of a MDE inthe course of bipolar disorder is defined withidentical criteria for major depression as in unipo-lar depressive disorders. Despite some likely dif-ferences in symptom profiles and severitymeasures, a cross-sectional clear categorical dis-tinction between the bipolar and unipolar depres-sive episode is currently not possible (7).The main goal of treating acute depression in

bipolar disorder is to achieve (full) remission sinceresidual and subsyndromal depressive symptomspredict negative outcome and are associated withan increased risk of relapse. An additional goal oftreatment is to avoid suicidal acts. Recent datasuggests that approximately 35% of bipolar disor-der patients will have a lifetime suicide attempt (8)and the prevalence of suicide has been estimated at4–19% (9), with the majority of suicides occurringduring the depressed or mixed affective phase ofthe illness. Among the best known risk factors forsuicide are family history of suicide, early onset ofaffective symptoms, young age, a history of priorsuicide attempts, and comorbidity of anxiety andsubstance abuse disorders (10).

General aspects of treatment and its selection

Given the recent increase in evidence-based treat-ment options for bipolar depression, both phar-macological and non-pharmacological, clinicianshave a wider range of choices in developing anoptimized individual care plan. In contrast tomania, there is no accepted standard treatmentfor acute bipolar depression, although guidelinesmay prioritize one intervention over another (11,12). In clinical practice, the main cornerstone oftreatment is usually adequate psychopharmacol-ogy. Depending on patient needs and availability

of services, this should be complemented by aspecific psychological intervention and, in selectedpatients, non-pharmacological biological therapiesmay be considered.Independent of which intervention is chosen,

responsible psychiatric management should be ini-tiated and continued throughout treatment. Thisincludes determining the overall treatment plan,establishing and maintaining a therapeutic alliance,and monitoring and reassessing the psychiatricstatus of the patient. In the treatment of bipolardisorder, it is crucial that clinicians: (i) monitor therisk of suicide; (ii) continually re-assess the adequacyof the diagnosis; (iii) monitor the patient�s treatmentresponse, side effects, andgeneralmedical condition;and (iv) educate patients and families as to theimportance of adherence to treatment.In addition to conducting a full mental health

assessment, the initial evaluation of a patientshould also include a physical examination andscreening for: concurrent psychiatric and somaticdisorders, alcohol and illicit drug abuse, any non-psychiatric medications, and psychosocial stressfactors, all of which can contribute to the depres-sive syndrome or interfere with treatment. Addi-tional laboratory testing should also be conductedas indicated to rule out additional medical condi-tions that may be contributing to symptoms.After this initial evaluation, additional aspects of

treatment should be taken into consideration as thebasis of an informed and individual treatmentchoice. These include: the clinical characteristicsboth of the acute episode and the long-term courseof illness; patient-, drug-, and doctor-related vari-ables; and finally, judgment of risks versus benefitsof treatment strategies. In regards to the lattertreatment consideration, please refer to Malhi et al.(13) within this supplement for a review of theefficacy of various pharmacological agents com-monly used in the treatment of bipolar disorder, inconjunction with the side effects that are commonlyencountered.The clinical picture of an acute episode of

bipolar depression can be quite heterogeneous(e.g., melancholic, atypical, suicidal, or psychoticfeatures). The most important treatment modifiersare the presence of psychotic features and suicidalideation. The importance of recognizing suicidalityin particular, cannot be emphasized enough giventhe outstanding excess mortality from suicide inuntreated bipolar disorder patients (14). In some,suicidal ideation may warrant inpatient treatmentin a secure environment. Furthermore, if long-termtreatment is indicated, either due to frequency orseverity of episodes, previous suicidality andsuicide attempts are important features to consider.

Bauer et al.

38

Consideration of the predominant polarity of theillness is a rather new concept in the optimization oflong-term treatment (15) that may already impactacute treatment decisions. As an example, adepressed bipolar I disorder patient who has expe-rienced numerous severe manic episodes, but justone prior episode of depression, might benefit morefrom an agent that predominantly prevents maniaand has lower antidepressant potency (e.g., olanza-pine), with an adjunctive selective serotonin reup-take inhibitor (SSRI) in the short term. In contrast,the initiation of lamotrigine might be indicated incases with a predominant depressive polarity.

The impact of patient-, drug-, and physician-related

variables on treatment choice

Clinical experience suggests that factors unique tothe patient, drug, and physician also requirecareful consideration when devising a treatmentplan. Patient-related factors that influence treat-ment decisions are:

• Previous experience with the effectiveness oftreatments: previous response to a givenmedication has some predictive value forfuture treatment trials.

• A family history of bipolar depression and itstreatment.

• Age and gender (for tolerability and safety ofmedication, adherence to treatment, andsuitability and content of psychotherapies).

• Personality traits (e.g., neuroticism or othermaladaptive personality styles) and beliefsthat might complicate depression or directlyimpact on adherence to treatment.

• Psychiatric comorbidity, especially anxiety dis-orders, substance abuse, and eating disorders.

• Somatic comorbidity (e.g., metabolic, endo-crine, cardiovascular, or renal comorbiditiesor risk factors, and somatic co-medication).Necessary laboratory tests should also beperformed to rule out any of the abovecomorbidities [see also (16)].

• The potential for abuse of and addiction todrugs, and the risk of discontinuation, re-bound episodes, and suicidality (especially inthe case of lithium).

The choice of treatment is also subject to someadditional external factors, such as the degree ofsupport from relatives and friends, costs of treat-ment, and availability of formulations. Finally, thephysician also plays an important role in treatmentsuccess. Not only is adherence directly related to awell-functioning therapeutic alliance, the physi-cian�s knowledge about the illness and familiarity

with treatment options will also influence thepatient�s attitude toward treatment. Some generalrules that any treating physician should bear inmind include:

• When choosing medications in bipolar depres-sion, it is important to consider utility andlong-term tolerability in maintenance treat-ment since these factors will impact treatmentadherence and long-term success.

• Frequent monitoring and assessment is sug-gested for patients experiencing a moderate orsevere depressive episode, in order to deter-mine the adequacy of treatment, pending thatthis is supported by the infrastructure of thehealth care system.

• The effectiveness of the chosen interventionshould be assessed after four weeks, and if it isjudged to be ineffective, then the strategyshould be reviewed and adjusted.

• In cases of non-response to a medication forwhich therapeutic serum concentrations havebeen established, these need to be determinedto verify adequate dosage and monitor com-pliance.

Clinical scenarios

Three principal circumstances (A-C) exist in whicha patient with bipolar depression presents in theclinical setting:

A: New depressive episode in the absence of prophylactic(maintenance) treatment with a mood stabilizer (de novobipolar depression)

The treatment of a depressive episode is complicatedby the potential risk of a rapid switch tomania or theinduction and acceleration of rapid cycling that canbe caused by the use of antidepressant drugs(particularly tricyclics), and therefore it is generallyrecommended to co-administer an antidepressantdrug with a medication that possesses �antimanic�properties. Unique to bipolar disorder, the decisionto use antidepressants in the acute and continuationphase of treatment must outweigh the risk ofinducing mania or rapid cycling. In patients with acurrent or past history of rapid cycling, it seems wiseto strictly avoid antidepressants and to provideoptimized or additional (second or third) mood-stabilizing treatment.

B: Breakthrough episode

A patient previously in remission suffers a newdepressive episode whilst receiving ongoing moodstabilization treatment. The main reasons for a

Treatment options for acute bipolar depression

39

recurrence (new episode) are inadequate efficacy ofthe medication, insufficient dosing, poor compli-ance by the patient, or negative drug-drug interac-tions between the mood stabilizer and otherrecently administered medications. Patients suffer-ing a breakthrough depressive episode duringprophylactic treatment with a mood stabilizermay benefit from treatment optimization (e.g.,increase of dose or serum blood level of lithium oranticonvulsant; addition of thyroid hormone ifthyroid function is low). However, most patientsmay require an additional, second medication (e.g.,antidepressant or a second mood stabilizer).

C: Treatment-resistant episode

A depressed patient suffers from resistance totherapy [defined as having not responded ade-quately to at least two sufficient antidepressant trialsfor at least six weeks with or without augmentation(17), or lithium for at least eight weeks despite aserum level of at least 0.8 mmol ⁄ l (18)]. This thirdscenario ismore complex and is dealtwith separatelyin another paper within this supplement (19).Compared to the treatment of unipolar depres-

sion, the treatment of bipolar depression has beenclearly understudied, with a much lower number ofplacebo and comparator-controlled randomizeddouble-blind trials. (18–20). In this review articlethe evidence is evaluated in relation to the first twoscenarios in patients with an established bipolar Ior II disorder who present during an episode ofdepression and are currently not on a mood-stabilizing agent (i.e., have never received one or ithas been discontinued) (Scenario A); or are cur-rently on maintenance treatment (Scenario B), withone of the classic mood-stabilizing agents (lithiumor anticonvulsants: valproate, carbamazepine, orlamotrigine) [B(i)], or an atypical antipsychoticwith mood-stabilizing properties [B(ii)]. On thebasis of the quality of extant literature, coupledwith professional clinical experience, suggestionsare provided regarding the most suitable choice oftreatment for both clinical situations.

Current evidence for efficacy of treatment strategies

Methodological aspects

The evidence presented here is largely based on asystematic literature search and appraisal that waspart of the development of the German Guidelineon Diagnosis and Treatment of Bipolar Disorders(expected online publication in 2012). For thispurpose, the search strategy of the publishedNational Institute for Health and Clinical Excel-

lence (NICE) Guideline for management of bipolardisorders from 2006 (21) was adapted and used. Allincluded and excluded clinical trials mentioned inthe NICE Guidelines were reviewed for eligibilityand only studies fulfilling strict methodologicalcriteria (see below) were included. For the updatedsearch from 2005 on, the adapted search strategyof NICE was used in MedLine, Embase, PsycInfo,CINAHL, Ovid, and Cochrane Central. Titles andabstracts were scanned for relevance, and full-textarticles were retrieved in cases of uncertainty inorder to maximize sensitivity. The reference lists ofretrieved systematic reviews were checked, and allfull-text articles were assessed for eligibility. Onlyrelevant clinical studies were included; abstracts,pooled analyses, editorials, reviews, case-reports,observational studies, and unpublished reportswere excluded. Meta-analyses were only consideredin the cases that all referenced studies were alsoincluded into the guideline. In addition, meta-analyses that contained unpublished data withoutinappropriate selection were used.Participants in the studies had to be adults aged

18 years and older with a diagnosis of bipolardisorder. Studies including patients with otherdiagnoses were considered if no more than 10%of the population had other diagnoses (i.e., unipo-lar depression, schizoaffective disorder, or cyclo-thymia); or in the cases that baseline data ofrelevant clinical variables and results were pre-sented for the bipolar subgroup separately.A checklist for clinical studies was developed

consisting of 19 main items adapted from theextended CONSORT 2001 statement (22, 23).Before assessing the individual studies, items ofessential methodological and clinical relevancewere defined. Essential methodological informa-tion included randomization and allocation con-cealment, blinding, and details on the statisticalanalyses used (e.g., intent-to-treat). Clinically rel-evant items included information on the partici-pants (inclusion and exclusion criteria, details onthe validation of diagnosis, and baseline demo-graphic and clinical characteristics), the interven-tion, and the outcomes. Participants in each arm ofthe included studies had to be comparable atbaseline regarding age, sex, severity of illnesshistory, and severity of psychopathology. In caseswhere one or more of these characteristics was notreported and sample size was below 50 per group,results of the treatment arms were not compared,and instead, the pre ⁄post test results were used.The same was true in cases where comparabilitybetween arms was not reported. Statistical adjust-ments for sociodemographic variables that werenot evenly distributed were regarded as valid.

Bauer et al.

40

Following the appraisal of individual studies, anadapted Grades of Recommendation, Assessment,Development, and Evaluation (GRADE) appraisalwas applied to each clinical question (24). Detailson the literature search and appraisal are outlinedelsewhere (25, 26). In contrast to convention, wedissected out individual comparisons from studieswith more than two arms, so that two differentaspects of the same trial could be reported indifferent sections.As outlined in the Introduction, the choice of

treatment for a given patient with bipolardepression in clinical practice is governed by amultitude of factors. While clinical trials provideevidence for the efficacy of a certain interventionin a specific population, they cannot necessarilydetermine which intervention will be optimal fora given patient in a specific situation. They can,however, inform the choice of intervention and inparticular dissuade clinicians from choosinginterventions that have been shown to be inef-fective.

Clinical Scenario A: the bipolar-depressed patient is

currently not on a mood-stabilizing agent (de novo

depression)

Generally speaking, there is a choice between theuse of an antidepressant, a classic mood-stabilizingagent, or an atypical antipsychotic. As statedabove, the choice of treatment should be madewhile keeping the long-term goals of mood stabi-lization and the prevention of new episodes andsuicidal acts in mind.

Antidepressants

Five randomized, controlled studies that haveevaluated the use of antidepressants in bipolardepression fulfilled the necessary quality criteria.Two of these compared an antidepressant toplacebo (see Table 1).Cohn et al. (27) compared imipramine, fluoxe-

tine, and placebo in a six-week study of patientswith bipolar I or II disorder. Both medicationssignificantly improved depressive symptoms asmeasured with the Hamilton Depression RatingScale (HAM-D) when compared to placebo. Thedifference in HAM-D improvement was not sig-nificant between treatments; however, responserates, defined as ‡ 50 improvement in HAM-Dscore over baseline, were significantly higher inpatients receiving fluoxetine (86%) than thosereceiving imipramine (57%) and placebo (38%).The number needed-to-treat (NNT) was calculatedto be three with fluoxetine and six with imipramine

for one additional response. Regarding side effects,insomnia and nervousness were more common inthe fluoxetine-treated group, while dry mouth wassignificantly more frequent in the imipraminegroup. Discontinuation was more frequent in theplacebo group (66%) compared to imipramine(53%) and fluoxetine (43%).Within the EMBOLDEN II study (37) paroxe-

tine was compared to placebo. After eight weeksthere was no significant difference in responsebetween the two groups (55% versus 53%, NNT= 46). Side effects (dry mouth, headache, andnausea) were nonsignificantly more frequent in theparoxetine group. There was also no increase inrates of switch into mania or hypomania. Of note,the daily dose of 20 mg is below the dose typicallyused in clinical practice.Himmelhoch et al. (28) compared the irreversible

monoamine oxidase (MAO) inhibitor tranylcypro-mine with the trycyclic antidepressant imipramine.Patients with a diagnosis of bipolar I or II disorderand currently in a state of anergic depression wereincluded in a six-week trial. Treatment with tran-ylcypromine was superior with regard to improve-ment in HAM-D score as well as response rate.Neither rates of switch nor side effects werepublished.In an eight-week trial comparing the MAO

inhibitor moclobemide and the trycyclic antide-pressant imipramine (29), no significant differenceswere found between the two treatment arms.Numerically, imipramine was found to be superiorin reducing depressive symptoms as measured bythe HAM-D, but it was also associated withsignificantly more anticholinergic side effects, andnonsignificantly higher switch rates (11% forimipramine versus 4% for moclobemide). Approx-imately half of all patients in the study continuedtheir prior mood-stabilizing agent; however, out-comes of those with and without a mood stabilizerwere not published.In a 12-week open-label trial, Amsterdam and

Shults (30) compared venlafaxine with lithium in apopulation of depressed patients with bipolar IIdisorder. Venlafaxine produced a greater reductionof depressive symptoms determined by the HAM-D. The rates of response (58% versus 20%) andremission (44% versus 8%) were significantlyhigher in the venlafaxine-treated group than inthe lithium-treated group. Switch rates were gen-erally very low and the difference was not signif-icant (5% for venlafaxine versus 0% for lithium).While patients in the venlafaxine group sufferedmore frequently from constipation, dry mouth, andsexual dysfunction, lithium was associated withpolyuria, polydipsia, and tremor.

Treatment options for acute bipolar depression

41

Tab

le1.

Ove

rvie

wof

incl

uded

stud

ies

for

Sce

nario

sA

and

B

Stu

dy

Desig

nD

ura

tio

nS

tud

yarm

s

Cohn

et

al.

1989

(27)

Ran

DB

6w

ksFLU

OX

20–8

0m

g⁄d

ay

(n=

30)

IMI

75–3

00

mg

⁄day

(n=

30)

PLA

(n=

29)

Him

melh

och

et

al.

1991

(28)

Ran

DB

6w

ksTra

nyl

cyp

rom

ine

20–6

0m

g⁄d

ay

(n=

26)

IMI

150–3

00

mg

⁄day

(n=

21)

–

Silv

ers

tone

2001

(29)

Ran

DB

8w

ksM

oclo

bem

ide

450–7

50

mg

⁄day

(n=

81)

IMI

150–2

50

mg

⁄day

(n=

75)

–

Am

sterd

am

and

Shults

2008

(30)

Ran

NB

12

wks

Venla

faxi

ne

initi

ally

37.5

mg

⁄day,

incre

ase

to75

mg

⁄day

infir

stw

eek,

step

wis

ein

cre

ase

of

37.5

or

75

mg

⁄week,

titra

tion

tom

axi

mum

375

mg

⁄day

inw

eek

4(d

ose

could

be

red

uced

toa

min

imum

of

37.5

mg

⁄day)

(n=

43)

LIT

H:

initi

ally

600

mg

⁄day

for

1w

eek,

eve

ntu

ally

incre

ase

to900

mg

⁄day

inse

cond

week,

then

eve

ntu

ally

furt

her

incre

ase

sup

tole

velof

0.5

–1.5

mm

ol⁄

Lin

week

4(n

=40)

–

Sachs

et

al.

2007

(31)

Ran

DB

6+

20

wks

LIT

Hor

VA

L,

or

LIT

Hand

VA

L,

or

CA

RB

or

am

ood

-sta

bili

zing

aty

pic

alantip

sychotic

(tota

lN

=179)

+P

AR

OX

(n=

93)

or

+B

UP

R(n

=86)

LIT

Hor

VA

L,

or

LIT

Hand

VA

L,

or

CA

RB

or

am

ood

-sta

bili

zing

aty

pic

al

antip

sychotic

+P

LA

(n=

187)

–

Leve

rich

et

al.

2006

(32)

Ran

(with

the

exc

ep

tion

of

28

patie

nts

)D

B

10

wks

(+up

to52

wks

)

MS

(LIT

Hor

antie

pile

ptic

)or

am

ood

-st

ab

ilizi

ng

aty

pic

alantip

sychotic

+B

UP

R100–4

50

mg

⁄day

(n=

51)

MS

(LIT

Hor

antie

pile

ptic

)or

am

ood

-st

ab

ilizi

ng

aty

pic

alantip

sychotic

+S

ER

T50–2

00

mg

⁄day

(n=

58)

MS

(LIT

Hor

antie

pile

ptic

)or

am

ood

-sta

bili

zing

aty

pic

al

antip

sychotic

+ve

nla

faxi

ne

75–3

75

mg

⁄day

(n=

65)

Young

et

al.

2000

(33)

Ran

DB

6w

ksLIT

Hor

VA

L+

PA

RO

X(a

vg.

dose

36

mg

⁄day)

(n=

11)

LIT

Hor

VA

L+

VA

Lor

LIT

H(n

=16)

–

Bocchett

aet

al.

1993

(34)

Ran

DB

4w

ksLIT

H+

AM

IT50–7

5m

g⁄d

ay

(n=

15)

LIT

H+

L-s

ulp

irid

e50–7

5m

g⁄d

ay

(n=

15)

–

Tohen

et

al.

2003

(35)

Ran

DB

8w

ksO

LA

N+

FLU

OX

:6

+25

mg

⁄day,

6+

50

mg

⁄day,

or

12

+50

mg

⁄day

(n=

82)

OLA

N5–2

0m

g⁄d

ay

(n=

351)

PLA

(n=

355)

Bro

wn

et

al.

2006

(36)

Ran

DB

7w

ksO

LA

N+

FLU

OX

:6

+25

mg

⁄day,

12

+25

mg

⁄day,

6+

50

mg

⁄day,

or

12

+50

mg

⁄day

(n=

205)

LTG

200

mg

⁄day

or

150

mg

⁄day

(n=

205)

–

McE

lroy

et

al.

2010

(37)

Ran

DB

8w

ksP

AR

OX

20

mg

⁄day

(n=

122)

QU

ET

600

mg

⁄day

(n=

247)

QU

ET

300

mg

⁄day

(n=

245)

PLA

(n=

126)

Bauer

et

al.

1999

(38)

and

Pilh

ats

ch

et

al.

2010

(39)

Ran

DB

6w

ksLIT

H+

PA

RO

X:

initi

ally

20

mg

⁄day,

eve

ntu

ally

incre

ase

up

to40

mg

⁄day

LIT

H+

AM

IT:

initi

ally

75

mg

⁄day,

eve

ntu

ally

incre

ase

up

to150

mg

⁄day

–

Sup

pes

et

al.

2008

(40)

Ran

Rate

r-b

lind

ed

16

wks

LIT

H450

mg

⁄day

for

1w

eek,

incre

ase

to900

mg

⁄day

for

1w

eek,

then

eve

ntu

ally

incre

ase

(min

.0.8

tom

ax.

1.2

mE

q⁄L

)(n

=49)

LTG

:25

mg

⁄day

for

2w

eeks

,50

mg

⁄day

for

the

next

2w

eeks

,75

mg

⁄day

for

anoth

er

week,

100

mg

⁄day

for

anoth

er

week,

150

mg

⁄day

for

anoth

er

week,

and

200

mg

⁄day

inw

eek

8,

then

eve

ntu

ally

incre

ase

(max.

dose

400

mg

⁄day)

(n=

41)

–

Bauer et al.

42

Tab

le1.

(Con

tinue

d)

Stu

dy

Desig

nD

ura

tio

nS

tud

yarm

s

van

der

Loos

et

al.

2009

(41)

Ran

DB

8w

ksLIT

H+

PLA

LIT

H:

seru

mle

vel0.6

–1.0

mm

ol⁄

L(n

=60)

LIT

H+

LTG

:25

mg

⁄day

for

2w

eeks

,50

mg

⁄day

for

the

next

2w

eeks

,100

mg

⁄day

for

the

next

2w

eeks

,200

mg

⁄day

for

weeks

7and

8(n

=64)

–

Young

et

al.

2010

(42)

Ran

DB

8w

ksLIT

H:

initi

ally

600

mg

⁄day,

day

4–8

incre

ase

up

to900

mg

⁄day,

then

600–1

800

mg

⁄day;

seru

mle

vel0.6

–1.2

mE

q⁄L

(n=

136)

QU

ET

300

mg

⁄day:

initi

ally

50

mg

⁄day,

incre

ase

to300

mg

⁄day

on

day

4(n

=265)

QU

ET

600

mg

⁄day:

initi

ally

50

mg

⁄day,

incre

ase

to600

mg

⁄day

on

day

8(n

=268)

PLA

(n=

133)

Zhang

et

al.

2007

(43)

Ran

DB

12

wks

CA

RB

-IR

:in

itially

300

mg

⁄day,

eve

ntu

ally

incre

ase

up

to800

mg

⁄day

(n=

49;

47

inanaly

sis)

CA

RB

+FE

WP

CA

RB

:in

itially

300

mg

⁄day,

eve

ntu

ally

incre

ase

up

to800

mg

⁄day

(n=

50;

46

inanaly

sis)

PLA

(n=

25;

23

inanaly

sis)

Cala

bre

seet

al.

1999

(44)

Ran

DB

7w

ksLTG

50

mg

⁄day:

initi

ally

25

mg

⁄day;

from

week

2:

50

mg

⁄day

(n=

66)

LTG

200

mg

⁄day:

initi

ally

25

mg

⁄day;

from

week

2:

50

mg

⁄day;

from

week

3:

100

mg

⁄day;

from

week

4:

200

mg

⁄day

(n=

63)

PLA

(n=

66)

Cala

bre

seet

al.

2005

(45)

Ran

DB

8w

ksQ

UE

T300

mg

⁄day

(n=

172)

QU

ET

600

mg

⁄day

(n=

170)

PLA

(n=

169)

Thase

et

al.

2006

(46)

Ran

DB

8w

ksQ

UE

T300

mg

⁄day

(n=

172)

QU

ET

600

mg

⁄day

(n=

169)

PLA

(n=

168)

Sup

pes

et

al.

2010

(47)

Ran

DB

8w

ksQ

UE

T-X

R:

initi

ally

50

mg

⁄day;

day

2:

100

mg

⁄day;

day

3:

200

mg

⁄day;

300

mg

⁄day

from

day

4(n

=140)

PLA

(n=

140)

–

Thase

et

al.

2008

(48)

(CN

138-0

96)

Ran

DB

8w

ksA

RIP

:in

itially

10

mg

⁄day,

then

flexi

ble

dosi

ng

from

5to

30

mg

⁄day

(ste

pw

ise

+5

mg

⁄day

once

aw

eek)

(n=

186)

PLA

(n=

88)

Thase

et

al.

2008

(48)

(CN

138-1

46)

Ran

DB

8w

ksA

RIP

:in

itially

10

mg

⁄day,

then

flexi

ble

dosi

ng

from

5to

30

mg

⁄day

(ste

pw

ise

+5

mg

⁄day

once

aw

eek)

(n=

187)

PLA

(n=

88)

Mik

low

itzet

al.

2007

(49)

Ran

NB

12

mth

sP

art

lyw

ithp

harm

acoth

era

py

+in

tensi

vep

sychoth

era

py

[FFT

(n=

26),

CB

T(n

=75),

or

IPS

RT

(n=

62)]

Part

lyw

ithp

harm

acoth

era

py

+b

rief

psy

choed

ucatio

n(n

=130)

Cia

pp

are

lliet

al.

2001

(50)

Non-r

an

NB

Until

last

EC

TE

CT

twic

ea

week

(n=

23)

(bip

ola

rd

ep

ress

ion)

Not

rele

vant

Nahas

et

al.

2003

(51)

Ran

SB

(patie

nt)

plu

sra

ter-

blin

d

2w

ksrT

MS

left

pre

fronta

lly2

wks

on

each

work

ing

day

(n=

11)

Sham

left

pre

fronta

lly2

wks

on

each

work

ing

day

(n=

12)

Nie

renb

erg

et

al.

2008

(52)

DB

for

10

weeks

,th

en

NB

24

mth

sV

NS

+TA

U(n

=25)

Georg

eet

al.

2005

(53)

VN

S+

TA

U:

DB

for

10

weeks

,th

en

NB

TA

U:

ob

serv

atio

nal

stud

y

12

mth

sV

NS

+TA

U(n

=20)

Treatment options for acute bipolar depression

43

Classic mood stabilizers

Four studies evaluating the efficacy of monother-apy with a classic mood-stabilizing agent fulfilledthe inclusion criteria. Three of these studies com-pared a mood stabilizer to placebo (see Table 1).In the EMBOLDEN I study (42) lithium (n =

136) was compared to placebo (n = 133) indepressed patients with bipolar I or II disorder.After eight weeks of treatment, lithium was notsignificantly more effective than placebo in reduc-ing depression severity as determined by theMontgomery–Asberg Depression Rating Scale(MADRS) (NNT= 15 for response with lithium).The low average serum concentration of lithium(0.61 mmol ⁄ l), however, may have contributed tothe failure of lithium to separate from placebo inthis study, as only 64% of all patients attainedsufficient serum lithium concentration (‡ 0.6mmol ⁄ l).Furthermore, it should be taken into account

that bipolar II disorder seems to be less responsiveto lithium as compared to the typical bipolar Idisorder presentation in which recurrent, recogniz-able episodes of mania and depression are sepa-rated by discernible periods of remission (58). Theissue of lithium dosage (59) and specificity (60) iscritical.In a 12-week study, Zhang et al. (43) compared

carbamazepine (n = 49) to placebo (n = 25) in thetreatment of bipolar depression. Carbamazepinewas significantly more effective in terms of reduc-ing depression severity and producing response[determined by the HAM-D and Clinical GlobalImpressions (CGI) scale, NNT = 2].Two studies evaluated the antidepressant qual-

ities of lamotrigine in bipolar disorder. Calabreseet al. (44) conducted a seven-week trial comparinglamotrigine at low dose (50 mg ⁄day), lamotrigineat high dose (200 mg ⁄day), and placebo. Theresults were ambiguous. While the high-doselamotrigine group showed a significant improve-ment in the MADRS and CGI scales for Improve-ment (CGI-I) and Severity (CGI-S) scores, therewas no significant difference in HAM-D scores(NNT = 13 in the low-dose and 8 in the high-dosegroup for response HAM-D reduction ‡ 50%;NNT = 6 and 4, respectively, for response in theMADRS). Differences in discontinuation rateshardly differed, however, six out of seven switchesinto mania ⁄hypomania ⁄mixed episodes occurredin the lamotrigine group (with lamotrigine dosed ator below 50 mg ⁄day and in the first three weeks).Although the evidence from this trial is somewhatinconclusive, a later meta-analysis including indi-vidual patient data from four unpublished studies

Tab

le1.

(Con

tinue

d)

Stu

dy

Desig

nD

ura

tio

nS

tud

yarm

s

Kra

uss

et

al.

1992

(54)

Rate

r-b

lind

3w

ksLTher:

1w

kP

LA

–LTher

(300

lux)

and

2ad

diti

onalw

ksLTher

(2500

lux)

(n=

6)

Sm

era

ldiet

al.

1999

(55)

Ran

DB

for

pharm

acoth

era

py

9d

ays

(follo

w-u

p6

mth

s)

Slp

Dep

+P

LA

:3

cyc

les

of

Slp

Dep

(Day

1,

3,

5)

(n=

20)

Slp

Dep

+P

IND

(2.5

mg

3tim

es

⁄day)

3cyc

les

of

sleep

dep

riva

tion

(Day

1,

3,

5)

(n=

20)

Bened

ett

iet

al.

1999

(56)

Non-r

an

NB

6d

ays

(follo

w-u

p3

mth

s)

Slp

Dep

(n=

20)

LIT

H+

Slp

Dep

:3

succeed

ing

cyc

les

with

36

hrs

aw

ake

(Days

1–6

)(n

=20)

Bened

ett

iet

al.

1997

(57)

Ran

NB

4w

ksFLU

OX

(20

mg

⁄day)

+S

lpD

ep

(3cyc

les

on

Day

6,

8,

10)

(n=

5)

FLU

OX

20

mg

⁄day

(n=

5)

Ran

=ra

nd

om

ized

;D

B=

doub

le-b

lind

;N

B=

non-b

lind

ed

;N

on-r

an

=non-r

and

om

ized

;S

B=

sing

le-b

lind

ed

;FLU

OX

=flu

oxe

tine;

IMI

=im

ipra

min

e;

PLA

=p

laceb

o;

LIT

H=

lithiu

m;

VA

L=

valp

roate

;C

AR

B=

carb

am

aze

pin

e;P

AR

OX

=p

aro

xetin

e;B

UP

R=

bup

rop

ion;M

S=

mood

stab

ilize

r;S

ER

T=

sert

ralin

e;A

MIT

=am

itrip

tylin

e;O

LA

N=

ola

nza

pin

e;LTG

=la

motr

igin

e;Q

UE

T=

quetia

pin

e;IR

=im

med

iate

-rele

ase

;X

R=

ext

end

ed

-rele

ase

;A

RIP

=arip

ipra

zole

;FE

WP

=Fre

eand

Easy

Wand

ere

rP

lus;

FFT

=fa

mily

-focuse

dth

era

py;

CB

T=

cog

niti

veb

ehavi

ora

lthera

py;

IPS

RT

=in

terp

ers

onaland

socia

lrh

ythm

thera

py;

EC

T=

ele

ctr

oconvu

lsiv

eth

era

py;

rTM

S=

rep

etit

ive

transc

rania

lm

ag

netic

stim

ula

tion;

VN

S=

vag

us

nerv

est

imula

tion;

TA

U=

treatm

ent-

as-

usu

al;

LTher

=lig

ht

thera

py;

Slp

Dep

=sl

eep

dep

riva

tion;

PIN

D=

pin

dolo

l.

Bauer et al.

44

demonstrated efficacy of the higher lamotriginedose in the treatment of bipolar depression (61).The overall pooled effect was modest, although theadvantage over placebo was greater in moreseverely depressed participants. However, it shouldbe mentioned that four of the five placebo-controlled trials included in this latter meta-anal-ysis (with a total of 1,072 participants) comparinglamotrigine with placebo did not show significantresults on the primary outcome measure. There-fore, some uncertainty of the efficacy of lamotri-gine in bipolar depression remains.A study by Suppes et al. 2008 (40) compared

lamotrigine to lithium over a period of 16 weeks.Patients in both treatment arms improved in termsof depressive symptomatology. While lithiumtreatment was associated with higher rates ofadverse effects, there were no significant differencesin efficacy between the two groups.No studies fulfilled our quality criteria assessing

the effectiveness of valproate in the treatment ofbipolar depression, although a few have beenpublished [e.g., (62) and (63)].

Atypical antipsychotics

A total of eight studies evaluating the efficacy ofatypical antipsychotics fulfilled our inclusion crite-ria. In all cases: placebo was one of the comparatorconditions; five studies included depressed patientswith bipolar I or II disorder, with two exceptions(35, 48); and all studies employed large samples(see Table 1). Five studies evaluating quetiapinewere included.Two eight-week studies (BOLDER I and II) with

almost identical designs compared quetiapinemonotherapy in doses of 300 mg and 600 mg toplacebo. Quetiapine was significantly superior toplacebo in both trials with regard to response(MADRS reduction ‡ 50%, NNT = 5 for bothdoses) and remission (MADRS £ 12, NNT = 5 forboth doses) (64). There was no significant differ-ence in switch rates between groups. An explor-ative subgroup analyses of BOLDER I revealedthat quetiapine was mainly effective in bipolar Idisorder patients. A pooled analysis of both studiesdemonstrated antidepressant efficacy in both diag-nostic groups, with the greater benefit in bipolar Idisorder patients, regardless of dosage (65). Fur-ther post-hoc analyses revealed significantimprovements in quality of life and sleep qualityindexes (66). Discontinuation rates for quetiapine300 g ⁄day, placebo, and quetiapine 600 g ⁄day werehigh at 33%, 41%, and 46%, respectively, inBOLDER I; and 41%, 35%, and 47%, respec-tively, in BOLDER II.

Two further studies, EMBOLDEN I and II,compared the efficacy of quetiapine (dosed at 300mg ⁄day or 600 mg ⁄day) to lithium or placebo inEMBOLDEN I (42), and to paroxetine or placeboin EMBOLDEN II (37). Within EMBOLDEN I,significant improvement inMADRS scoreswas seenfor patients with bipolar I disorder. The 600mg ⁄dayquetiapine group showed significantly better reso-lution of depressive symptoms compared to thelithium group (though this needs to be judged withcaution due to the aforementioned low lithiumconcentrations). The NNT were calculated to be 8and 7 (for 300 mg ⁄day and 600 mg ⁄day, respec-tively) for an additional response; for remission theNNT was 7 for both groups. Discontinuation rateswere higher in the quetiapine groups, but switchrates did not differ. In EMBOLDEN II, both 300mg ⁄day and 600 mg ⁄day of quetiapine were supe-rior to placebo and paroxetine for patients withbipolar I or II disorder. The NNT were comparableto EMBOLDEN I. The most frequently mentionedadverse effects compared to placebo were sedation,dry mouth, and dizziness. Quetiapine caused weightincrease more frequently, but fewer switches into(hypo)mania compared to placebo or paroxetine.In an eight-week trial of quetiapine extended

release (300 mg ⁄day) by Suppes et al. (47), theaforementioned results were confirmed for bothbipolar I and II disorder patients. Quetiapineproved to be significantly superior to placebo inreducing depressive symptoms as measured by theMADRS (NNT were 4 and 7, respectively, forresponse and remission). Switch rates were lowercompared to placebo, but adverse effects includedsedation and dry mouth, leading to higher discon-tinuation rates.Two identically designed eight-week studies by

Thase et al. (48), (CN138-096 and CN138-146)evaluated the efficacy of aripiprazole (n = 274)compared to placebo (n = 275) in the treatment ofbipolar depression. Despite adequate dosing, therewas no significant difference in MADRS changecompared to placebo (NNT for response andremission were high at 24 and 42, respectively inthe first study and even higher in the second). Themost frequent side effects were akathisia, insomnia,nausea, restlessness, tiredness, and dry mouth.One study that compared olanzapine to placebo

fulfilled the inclusion criteria (35). After eightweeks, patients in the olanzapine group had asignificantly greater reduction in MADRS scoresand higher rates of response compared to placebo(39% versus 30%, respectively; NNT for responseand remission were 12 and 13, respectively). Therewas also a significant improvement in quality of lifemeasures. The validity of the results is somewhat

Treatment options for acute bipolar depression

45

questionable however, because of the high attritionrates (53%with olanzapine and 62%with placebo).For the combination of olanzapine and fluoxe-

tine (OFC), two studies were included that com-pared OFC with olanzapine monotherapy (35),(mentioned above) and lamotrigine (36) in patientswith bipolar I disorder (see Table 1). The use ofOFC was superior to olanzapine monotherapy interms ofMADRS score reduction after eight weeks.Discontinuation rates were lower in the combina-tion group (36%) compared to monotherapy witheither olanzapine (53%) or placebo (62%) (35).In a seven-week trial by Brown et al. (36), OFC

proved superior to lamotrigine in terms ofMADRS and CGI reduction and quality of lifemeasures. Response and remission rates werenumerically superior but the difference remainednonsignificant. While lamotrigine treatment wasassociated with significantly more frequent suicidalor self-injurious behaviours, OFC caused signifi-cant elevations in weight, serum cholesterol, andtriglycerides. Switch rates were approximatelyequal in both studies (6% versus 4%, respectively),and did not significantly differ from placebo.

Clinical Scenario B: the bipolar-depressed patient is

currently being treated (breakthrough depression)

B(i): with a classic mood-stabilizing agent

In the case of breakthrough depression, it isadvisable to first determine serum concentrations,where appropriate, to evaluate adherence, and toconsider a dose increase if the patient has beenreceiving an insufficient dose.Among the studies included, six investigated the

addition of a second substance to an ongoing treat-ment with a classic mood stabilizer (see Table 1).In the study by Sachs et al. (31) depressed

bipolar I or II disorder patients receiving ongoingtreatment (e.g., lithium, valproate, carbamazepine,or atypical antipsychotics) were treated addition-ally with either bupropion (n = 86), paroxetine(n = 93), or placebo (n = 187). Since fewer than10% were receiving an atypical antipsychotic, thestudy results were considered to be reasonablyapplicable to the above mentioned scenario.Remission rates at the primary endpoint of eightweeks were 23% with the addition of an antide-pressant and 27% with placebo. Differencesbetween groups for response and remission werenot significant. There was no difference in adverseeffects or switch rates.Similar results emerged from a study by Leverich

and colleagues (32). The addition of bupropion,venlafaxine, or sertraline to a mood-stabilizing

agent produced no significant difference in terms ofdepression improvement between groups. How-ever, since there was no placebo arm, no general-izable conclusions can be drawn as to whetheradding an antidepressant to mood-stabilizing treat-ment is of benefit. This is important because it is acommon scenario in clinical practice. Of note,venlafaxine was associated with significantly ele-vated switch rates (31%) compared to bupropion(14%) and sertraline (16%).Three further studies comparing the addition of

paroxetine versus a second mood stabilizer, (ami-triptyline versus L-sulpiride, and paroxetine versusamitriptyline) were similarly inconclusive (33, 34,38).Van der Loos et al. (41) examined the addition

of lamotrigine to ongoing lithium treatment. Sixty-four patients were randomized to lithium pluslamotrigine and sixty continued lithium monother-apy. After eight weeks, the addition of lamotriginewas significantly more effective in reducingMADRS scores compared to placebo. Responserates with lamotrigine were also superior comparedto placebo (52% versus 32%, respectively).Numerically, there were higher switch and discon-tinuation rates in the lamotrigine group, but thedifferences were not statistically significant.

B(ii): with an atypical antipsychotic

Although atypical antipsychotics are increasinglyprescribed for maintenance therapy, no studymeeting the inclusion criteria was detected.Although controlled-trials are lacking, guidelinesand expert clinical experience recommend thatcurrent treatment with an atypical antipsychoticought to be optimized by increasing dosage, and ifthis is insufficient checking serum concentrationsand adherence where appropriate (12).See Box 1 for a summary of pharmacological

treatment recommendations for Scenarios A and B.

Psychotherapy and non-pharmacological, biological

treatment options for Scenarios A and B

Bipolar disorder patients usually only seek psy-chotherapeutic treatment when depressed, butefficient psychotherapy should span all phases ofthe illness.Only one study assessing change in acute

depressive symptomatology could be included(see Table 1). In this randomized, non-blindedstudy, Miklowitz et al. (49) compared intensivepsychotherapy (family-focused n = 26, cognitivebehavioural n = 75, or interpersonal and socialrhythm therapy n = 62) to brief psychoeducation

Bauer et al.

46

(n = 130) (both in addition to the currentpsychopharmacological treatment) over 12 monthsin depressed bipolar I and II disorder patients.Patients who received intensive psychotherapy inaddition to their ongoing pharmacological treat-ment showed significantly higher recovery ratesthan controls (64% versus 52%, respectively).Clinical experience suggests that electroconvul-

sive treatment (ECT) is a useful option for thetreatment of severe bipolar depression, although nostudy with sufficient methodological quality wasavailable. In contrast, one randomized clinical studywith blinding of both bipolar-depressed patientsand raters (51), that compared two weeks of left-prefrontal repetitive transcranial magnetic stimula-tion (rTMS) (n = 11) to a sham condition (i.e.,active placebo) (n = 12) (in addition to a givenpharmacological treatment) (see Table 1), found nosignificant difference in symptom reduction. How-ever, indirect evidence from treatment trials inunipolar-depressed patients suggests that left-dor-solateral-prefrontal rTMS might be a viable optionin bipolar depression.Uncontrolled study data fromvagus nerve stimulation (VNS) in addition totreatment-as-usual in bipolar depressed patients(52, 53) resulted in modest response rates of

20–40%. Regarding light therapy and sleep depri-vation, only short-term studies were identified. Onerater-blinded studywas publishedwith six bipolar IIdisorder depressed patients with a seasonal type thatwere treated with light therapy at 2500 lux (54).After one week of light therapy, a pre ⁄postanalysis revealed improvements in depression.Lastly, sleep deprivation in combination withpsychopharmacological treatment has been as-sessed in several studies (Table 1), with resultsdemonstrating short-term efficacy and no indica-tion of elevated risk of switching [adjunctivepindolol (55), fluoxetine (57), and lithium (56)].

Balancing benefits and risks

While the quality of evidence to evaluate theefficacy of treatment options has increased withinrecent years, the same is not equally true for theevaluation of risks. In most clinical trials there isno (or only a secondary) hypothesis regardingrisks, and both the assessment and reporting ofthese are often insufficient to suitably capture rareevents (25). Additionally, registries are (if availableat all) often voluntary, and therefore incomplete. Itshould also be noted that relatively little data exist

Box 1. Acute bipolar depression treatment

Key principles of pharmacotherapy

Goal

• The main objective of treatment is to achieve the complete remission of depression so that there are no subsyndromal symptomsand there is full functional recovery.

• Two common clinical presentations provide the context for the pharmacotherapy of bipolar depression:(i) New depressive episode (de novo bipolar depression) in the absence of prophylactic maintenance treatment with a moodstabilizer.(ii) Breakthrough episode: occurs in the context of ongoing mood stabilizing maintenance treatment.

Strength of evidencea

De novo bipolar depression:• Overall, there is limited evidence as to which agents are efficacious in the treatment of acute depression, and consequently there is

significant contention regarding the most efficacious and well-tolerated treatments.• Quetiapine monotherapy is supported by strong evidence; one placebo-controlled, randomized trial supports olanzapine.• Both lamotrigine and carbamazepine appear to be of use in bipolar depression, but the lengthy duration of drug initiation with

lamotrigine may make it somewhat less practical in some instances.• Antidepressants may be of some utility in the short term.Breakthrough depression:• Lamotrigine should be considered an option for patients suffering a breakthrough episode on ongoing lithium treatment.• There is no evidence to support the use of antidepressants in general or any agent in particular in patients already receiving a

mood-stabilizing agent, however clinical experience suggests this may be a second-line option in the absence of treatment withlithium and lamotrigine.

Recommended pharmacotherapy

Monotherapy Combination therapy

De novo depression Quetiapine or olanzapineLamotrigine

Lithium + lamotrigineMood stabilizer + antidepressant

Breakthrough depression N ⁄ A Lithium + lamotrigineMood stabilizer + antidepressant

N ⁄ A = Not applicable because individual is already receiving treatment.aAdjunctive psychotherapy (intensive, adjunctive family-focused, cognitive behavioural, and interpersonal and social rhythm therapyhave all been proven to be efficacious) should span all phases of the illness and commence alongside pharmacotherapy.

Treatment options for acute bipolar depression

47

on potential long-term sequelae (e.g., metabolicrisks) for many of the newer treatment options.As a consequence, balancing benefits and risks

often remains a question of juggling modestevidence, clinical experience, the needs and wishesof the patient, and the individual situation in whichthe treatment decision has to be made. Asdescribed in the Introduction, bipolar disorderpatients spend the majority of their illness sufferingfrom depression, with suicide, the most seriousconsequence, most commonly occurring in thisphase of the illness. Decisions about the treatmentof bipolar depression can be based on a range ofdifferent pharmacological and non-pharmacologi-cal options. Frequent monitoring of potentialunwanted side effects and the appropriateness oftreatment can help to effectively balance benefitsand risks in individual situations. Nevertheless, thequality of the assessment and reporting of risks inclinical trials must improve in order to betterinform our clinical decisions.

Summary

The evidence reviewed in this paper is largely basedon a systematic literature search and appraisal thatwas part of the development of the GermanGuideline for Bipolar Disorders. Overall, theevidence from treatment trials in bipolar depres-sion is relatively sparse compared to the number ofcontrolled trials in the treatment of unipolardepression, and as such, the choice of treatmentis governed by a multitude of factors. While clinicaltrials provide evidence on the efficacy of a certainintervention in a specific population, they cannotnecessarily determine which intervention will beoptimal for a given patient in a specific situation.They can, however, provide information on thechoice of interventions and, in particular, preventclinicians from choosing interventions that havebeen shown to be ineffective.Two principal scenarios exist in which a patient

with bipolar depression presents in the clinicalsetting. If a patient is currently not treated with amood-stabilizing agent (Scenario A), quetiapine oralternatively olanzapine are options among theatypical antipsychotics, and lamotrigine or carba-mazepine can be considered from among theanticonvulsants. Antidepressants are an optionfor short-term use, but their best usage (as mono-therapy or in combination with mood-stabilizingagents) remains controversial. If a patient isalready being treated with a mood-stabilizing agentfor prophylaxis (Scenario B), after a dose adjust-ment and adherence check, then add-on lamotri-gine is an option in breakthrough episodes of

lithium-treated patients. There is little evidence foradditional effects of antidepressants if the patient isalready receiving a mood stabilizer, but in practicethis is often trialled. Efficacious psychotherapy ispart of the treatment regimen and should spanphases of the disorder.Decisions on the treatment of bipolar depression

can be based on a range of different pharmacolog-ical and non-pharmacological options. Frequentmonitoring of potential unwanted side effects andof the appropriateness of treatment can help toeffectively balance benefits and risks in the indi-vidual situations. The quality of the assessmentand reporting of risks, however, needs to beincreased to better inform doctors� decisions.

Acknowledgements

The authors thank Professor Gin Malhi and Ms. DanielleBargh for their valuable advice and their input to earlier draftsof this paper.

Disclosures

MB has received grant ⁄ research support from the StanleyMedical Research Institute, NARSAD, and the EuropeanCommission (FP7); and is a consultant for AstraZeneca, EliLilly & Co., Servier, Lundbeck, Bristol-Myers Squibb, andOtsuka. HG has received grant ⁄ research support fromMRC ⁄NIHR UK; has been a consultant and a member of thespeakers bureaus of AstraZeneca, Bristol-Myers Squibb,Otsuka, Gedeon-Richter, Lundbeck, Eli Lilly & Co., MerckSharp & Dohme, Merck, Roche, Desitin, UBS, and Sepracor.AP received a stipend ⁄ research support from GlaxoSmithKlineand research support from AstraZeneca; and has receivedspeaker honoraria fromAstraZeneca and Eli Lilly &Co. PR hasno conflicts of interest to report.

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