balanced eﬃcacy, safety, and tolerability

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Review Article

Balanced efficacy, safety, and tolerabilityrecommendations for the clinical managementof bipolar disorder

Malhi GS, Bargh DM, McIntyre R, Gitlin M, Frye MA, Bauer M,Berk M. Balanced efficacy, safety, and tolerability recommendations forthe clinical management of bipolar disorder.Bipolar Disord 2012: 14 (Suppl. 2): 121. 2012 The Authors.Journal compilation 2012 John Wiley & Sons AS.

Objective: To provide practical and clinically meaningful treatment

recommendations that amalgamate clinical experience and researchfindings for each phase of bipolar disorder.

Methods: A comprehensive search of the literature was undertakenusing electronic database search engines (Medline, PubMed, Cochranereviews) using key words (e.g., bipolar depression, mania, treatment). Allrelevant randomised controlled trials were examined, along with reviewpapers, meta-analyses, and book chapters known to the authors. Inaddition, the recommendations from accompanying papers in thissupplement have been distilled and captured in the form of summaryboxes. The findings, in conjunction with the clinical experience ofinternational researchers and clinicians who are practiced in treatingmood disorders, formed the basis of the treatment recommendationswithin this paper.

Results: Balancing clinical experience with evidence informed and leadto the development of practical clinical recommendations that emphasisethe importance of safety and tolerability alongside efficacy in the clinicalmanagement of bipolar disorder.

Conclusions: The current paper summarises the treatmentrecommendations relating to each phase of bipolar disorder whileproviding additional, evidence-based, practical insights. Medication-related side effects and monitoring strategies highlight the importance ofsafety and tolerability considerations, which, along with efficacyinformation, should be given equal merit.

Gin S Malhia,b, Danielle M Bargha,b,Roger McIntyrecf, Michael Gitling,Mark A Fryeh, Michael Baueri andMichael Berkjn

aCADE Clinic, Department of Psychiatry, Royal

North Shore Hospital, bDiscipline of Psychiatry,

Sydney Medical School, The University of Sydney,Sydney, New South Wales, Australia, cDepartment

of Psychiatry, dDepartment of Pharmacology,

University of Toronto, eMood Disorders

Psychopharmacology Unit, University Health

Network, fInstitute of Medical Science, University of

Toronto, Toronto, ON, Canada, gDepartment of

Psychiatry, Geffen School of Medicine, University of

California at Los Angeles, Los Angeles, CA,hDepartment of Psychiatry, Mayo Mood Clinic and

Research Program, Mayo College of Medicine,

Rochester MN, USA, iDepartment of Psychiatry and

Psychotherapy, Carl Gustav Carus University

Hospital, Technische Universitat Dresden,

Dresden, Germany,

j

School of Medicine, DeakinUniversity, Geelong, kOrygen Youth Health

Research Centre, Centre for Youth Mental Health,lDepartment of Psychiatry, University of Melbourne,

Parkville, mBarwon Health and the Geelong Clinic,

Swanston Centre, Geelong, nThe Mental Health

Research Institute of Victoria, Parkville, VIC,

Australia

doi: 10.1111/j.1399-5618.2012.00989.x

Key words: acute treatment bipolar disorder

evidence-based review guidelines

maintenance treatment treatment

Received 28 September 2011, revised and

accepted for publication 12 December 2011

Corresponding author:

Professor Gin S. Malhi

Department of Psychiatry

University of Sydney

CADE Clinic

Level 5, Building 36

Royal North Shore Hospital

St. Leonards, NSW 2065, Australia

Fax: +61 2 9926-7730

E-mail: [email protected]

Bipolar Disorders 2012: 14 (Suppl. 2): 121 2012 John Wiley and Sons A/S

BIPOLAR DISORDERS

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Introduction

Bipolar disorder (BD) is an episodic mood disorderwithaprogressivecoursethat,inmanyindividuals,ischaracterised by manic or hypomanic episodes inconjunction with depressive episodes, inter-episodic

subsyndromal symptoms of mania, andor depres-sion (13). It is one of the leading causes of disabilityworldwidebecauseofitspsychosocialsequelae,long-term unemployment, medical comorbidity, andsuicide (48). Further, by virtue of its recurrentnature, patients are symptomatic for approximatelyhalf of their lives, a finding that highlights theimportance of effectively ameliorating manichypo-manic and depressive symptoms (1, 9).

Epidemiological studies estimate lifetime preva-lence rates of 0.61% for bipolar I disorder, 0.41.1% for bipolar II disorder, and 2.45.1% forsubthreshold BD (3, 9, 10). Further, bipolarspectrum disorder that includes threshold andsubthreshold cases is estimated at rates of 1.56.4% (3, 9), but figures vary depending on thedefinition employed to define cases and the natureof the population examined.

The typical trajectory of BD involves the onset ofsubthreshold nonspecific symptoms in adolescenceor early adulthood, followed eventually by theemergence of threshold depressive and manic orhypomanicepisodes(11),withthelatteroftenleadingto a further depressive phase of illness. The delay inonset of manichypomanic symptoms and the high

prevalence of comorbid psychiatric disorders con-tribute to the high rate of misdiagnosis and conse-quently the prescription of inappropriate orunnecessary medicationsthatcan potentially worsensymptoms and produce adverse effects (3, 12, 13).

In recent years, the management of BD has diver-sifiedto encompasspsychological, social, and lifestyleinterventions. This widening of therapeutic strategiesnotonlyrecognisesthemultifacetednatureofBD,butalso reflects a ceiling effect that has been reached withpharmacotherapyalone.Pharmacotherapyinclinicalpractice remains suboptimal, partly because the

mechanisms of action of medications and pathogen-esis of BD are unknown, but also because the currentmedications are not used appropriately. The expand-ingrepertoire of pharmacological options withdiffer-ent side effect profiles and mechanisms of action andefficacy means that the potential choice of medica-tionsand combinations of treatments is complex andoften incompletely supported by evidence (14).

Guidelines

Clinical practice guidelines attempt to synthesisethe available pharmacotherapeutic evidence and

make over-arching recommendations for theeffective management of major psychiatric dis-orders. Their adoption, however, is limited duein part to the fact that they are not represen-

tative of patients encountered in real worldpractice and because they are often impenetrable(15). To this end, guidelines that incorporateclinical experience alongside evidence and pro-vide recommendations in regards to assessment,care, and treatment have been developed (15),and the advice in this supplement builds on thisfoundation and provides further evidence-basedguidance for the management of BD. Theemphasis remains on pharmacotherapy and,where possible, the authors have integratedclinical experience with the available evidenceto ensure that efficacy, safety, and tolerabilityare given equal consideration. This is becauseclinical decisions must be governed by theoutcomes of high-quality efficacy studies but atthe same time incorporate knowledge relating tothe tolerability and safety of treatment options(16).

Balancing efficacy, safety, and tolerability

The pharmacological management of BD has twobasic goals: (i) to effectively treat the acute phasesof the illness (maniahypomania and bipolar

depression) and (ii) to maintain the gains of acutetreatment and prevent relapse (1719). The ade-quate treatment of BD is therefore tailored totarget mania, bipolar depression, and more com-plex presentations of the illness, including com-orbidity, which are often more difficult to treat;whereas maintenance treatment focuses on sus-taining mood stability and providing prophylaxis.The current paper summarises the recommenda-tions from each of the accompanying articles thatfollow, each of which addresses a component ofBD treatment. In addition, it draws attention to

the key message of balancing efficacy againstsafety and tolerability when managing BD, whichis invariably a recurrent or chronic lifelong illness.It is important to remember that all medicationshave the potential to cause harm (14) (seeTables 1 and 2) and that it is useful to evaluatethe benefits and risks of specific treatments in thecontext of individual patient variables, values, andpreferences. Therefore, a summary of the efficacyof pharmacological agents commonly used in eachphase of BD (see Table 3), along with a review ofthe relative risks associated with various treat-ments (see Class-specific side effects), has been

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included to assist clinicians in achieving thisbalance.

The clinical management of BD

Once a diagnosis of BD is made, a cliniciansprimary responsibility is to act, initiate assess-ment, and ensure appropriate management, ide-ally in the context of a sustained therapeuticalliance. Specifically, this involves (i) carefulassessment so as to provide (ii) individualisedcare and (iii) effective treatment (20) (see Fig. 1:ACT). While assessment and care are equally asimportant as treatment, this supplement focuseson the pharmacological management of BD anda detailed discussion of these aspects would be

beyond its scope.

Assessment

Diagnosis. The management of BD requires accu-

rate diagnosis at the outset. Treatment is necessarilypredicated on diagnosis and therefore determiningthe nature of the illnessboth differentiating BDfrom other psychiatric diagnoses and sub-typingwithin the disorder itselfis critical. This assistsdiagnosis and formulation and the implementationof necessary measures.

Evaluation. Once a diagnosis of BD has been estab-lished, careful and comprehensive assessment isessential. Ideally, assessment should include a med-ical examination to exclude a treatablereversible

secondary cause (e.g., organicity) and evaluate forthe presence of comorbid medical illnesses (20), aswell as a structured clinical interview that evaluatestheriskof suicide. Then a tailored treatmentplancanbe formulated in conjunction with corroborativeinformation from medical records, family, andfriends. It needs to be emphasised that assessment isan ongoing process, as the clinical picture isconstantly evolving.

Care

Though self-evident, it is important to note that

careunderpins both assessment and treatment, andis therefore a key ingredient for success in the long-term management of BD (see Fig. 1). An optimaloutcome is most likely to be achieved withina collaborative therapeutic alliance (21) thatenhances patient knowledge, promotes regularmonitoring of symptoms, and emphasises theimportance of treatment adherence (22).

Treatment

The goal of treatment in BD is to quell the acutesymptoms of the illness as quickly as possible and

Table 1. Adverse effects of atypical antipsychotics used in the treatment of bipolar disordera,b

Clozapine Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Iloperidone Asenapine

Neurological

Somnolence ++++ +++ ++ +++ + + + ++

EPS + DD DD DDc DDc

MetabolicWeight gain ++++ +++ ++ ++ ++ +

Dyslipidemia ++ ++ + +

Glucose dysregulation ++ ++ + + +

Other: Endocrine

Prolactin DD

EPS = extrapyramidal symptoms; DD = dose dependent; = insufficient data.aCopyright (2010) Informa Healthcare; adapted with permission from (114).bNumber of plus symbols indicates comparative side effect severity.cAkathisia.

Table 2. Adverse effects of lithium and anticonvulsants used in the

treatment of bipolar disordera,b

Lithium Carbamazepine Valproate Lamotrigine

Neurological

Somnolence 0 ++ ++ 0

Cognitive

impairment

++ ++c,d ++ +

EPS +e DDf +e 0

Metabolic

Weight gain ++ + +++ 0

Dyslipidemia 0 0 0 0

Other

Thyroid ++ 0 0 0

Renal +++g + + 0

EPS = extrapyramidal symptoms; DD = dose dependent.aCopyright (2010) Informa Healthcare; adapted with permission

from (114).bNumber of plus symbols indicates comparative side effect

severity.cAtaxia.dDiplopia and blurred vision.eTremor.fAkathisia.gOnly over the long-term course of medication.

Efficacy, safety, and tolerability recommendations in BD

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then sustain remission and prevent relapse, so as toultimately limit disability and maximise psychoso-cial functioning (20). Therefore, once an accuratediagnosis of BD has been established, the clinician

has to determine an appropriate first-line treatment

(23, 24). This choice has to be made on the basis ofan array of factors unique to the individualspsychiatric history; specifically, the pattern andseverity of symptoms, the course of illness, past

treatments and tolerability profile, family history

Table 3. Strength of evidence for monotherapy and combination treatments for acute and long-term bipolar mania and depressiona

Agents

Acute

mania

Acute

depression

Prophylaxis

mania

Prophylaxis

depression

Monotherapy

Lithium I I I

AnticonvulsantsValproatedivalproex I I (50) II

Carbamazepine I II II

Oxcarbazepine II IV

Lamotrigine II (132) I II II (133)

Topiramate IV (134) IV

Gabapentin IV

Atypical antipsychotics

Olanzapine I II II II (135)

Risperidone I III II (136)

Quetiapine I II III II (137)

Ziprasidone I

Aripiprazole I II

Clozapine IV (138) III IV

Combination therapy

Mood stabiliser + atypical antipsychoticLithiumdivalproex +

Risperidone I III (139) III III (139)

Olanzapine II II II (140)b

Quetiapine I V II (39) II (141)

Aripiprazole I (142) II (143) II (143)

Bupropion II

Oxcarbazepine II (144) II (144) III

Ziprasidone II (145) II (146)

Carbamazepine + risperidone III

Lithiumdivalproex

carbamazepine + clozapine

III IV (147)

Mood stabilisers + anticonvulsants

Lithium + valproate divalproex III II II

Lithium + carbamazepine II III II

Lithium + lamotrigine IV (148) II (56) II (98)Carbamazepine + valproate divalproex III III

Divalproex + lamotrigine IV (148) III

Atypical antipsychotics + antidepressants

Risperidonequetiapine + SSRI III

Olanzapine + fluoxetine II (55) II (149)c

Mood stabilisers + antidepressants

Lithiumdivalproex + SSRI II III II (150)d

Lithium + tricyclic antidepressant II

Lithium + MAOI II

National Health and Medical Research Council (NHMRC) levels of evidence (115): (I) systematic review of all relevant randomized

controlled trials (RCT); (II) one or more properly designed RCT; (III) well-designed prospective trial (non-RCT), comparative studies with

concurrent controls and allocation not randomized, case-controlled, or interrupted time series with a control group; (IV) case series,

either post-test or pre-test post-test; (V) expert opinion. SSRI = selective serotonin reuptake inhibitor; MAOI = monoamine oxidase

inhibitor; = insufficient or negative evidence for efficacy.aCopyright (2005, 2006) Wiley; adapted with permission from (105, 116, respectively).bEfficacy based on secondary outcome results (time to symptomatic relapse) (140).cEfficacy based on patients who entered this randomised, open-label phase of the study in non-remission (whereas, there was no

change from baseline in those who experienced remission prior to entering this phase of the study) (149).dEfficacy in this study was suggested by lower discontinuation due to depression in the divalproex + SSRI group, relative to placebo +

SSRI (150).

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of treatment response, the presence of comorbidpsychiatric disorders, and the level of functionalrecovery when euthymic (24, 25). In addition,because treatments that are successful in the shortterm tend to be continued in maintenance treat-ment, the long-term tolerability of pharmacologi-

cal agents warrants particular consideration (26).In cases where treatment only produces either apartial response or no response, compliance withmedication should be confirmed and drug dosagemay need to be optimised (24, 25). If treatmentnon-response continues or adverse intolerable sideeffects emerge, switching to another first-linetreatment may be necessary (see relevant Boxesand Switching medication) (24, 25). Agents thatmay be aggravating the illness course will need tobe evaluated with the precautionary principle inmind.

Clinically, the acute and maintenance phases oftreatment naturally form a continuum, but for thesake of clarity and to maintain consistency withresearch findings, the recommendations have beenpartitioned according to acute and maintenancetreatment. Mania (Box 1), bipolar depression(Box 2), and mixed states (Box 3) are the principaltargets for acute treatment and recommendationsbased on efficacy, safety, and tolerability consider-ations have been provided for each of these phases.

In maintenance treatment (Box 4), the goal is toprevent acute breakthrough episodes, promotepsychosocial functioning, treat inter-episode sub-

syndromal symptoms, and potentially address theprocess of neuroprogression inherent in the illness(20, 27) and, as such, it is the most important phaseof treatment.

During all phases over the longitudinal course ofBD illness, various additional factors and combi-

nations of factors can complicate diagnosis andtreatment. These aspects are best conceptualisedwithin the framework of a stratified model in whichsuccessive layers of complexity facilitate a system-atic evaluation of BD and guide effective treat-ment. A comprehensive summary of the variouscomplexity considerations and correspondingtreatment recommendations are succinctlycaptured in Box 5.

In order to establish any factors that maycomplicate treatment and ensure that adequateacute treatment and prophylaxis is provided, in

addition to collecting general medical and psychi-atric information at the time of assessment, it isnecessary to continue to support the alliance andengagement, provide psychosocial support andeducation, and monitor symptoms and medica-tion-emergent side effects throughout the course oftreatment (see Box 6.1 and Box 6.2).

Pharmacological treatment recommendations

The pharmacological treatment of BD iscomplicated and requires a sophisticated andstructured approach. Typical presentations include

Fig. 1. Overview of the clinical management of bipolar disorder [Copyright (2009) Wiley; adapted with permission from (20)].Rx = treatment.


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maintenance treatment should reflect any biastowards either pole or a particular pattern ofillness. For example, if lamotrigine has beensuccessful in treating acute bipolar depression(Fig. 3) then this should be maintained, especiallyif the individual has experienced many moredepressive episodes than manic episodes in thepast. Similarly, if the past history of the individualis that of mixed episodes and the index episode isalso a mixed episode (Fig. 3), then maintenancetreatment may need to consider agents that areparticularly effective in combating mixed episodes

and future depressive episodes.

Efficacy

Acute mania

Some characteristics of hypomania, such as ele-vated mood, increased energy, and heightened self-esteem, do not necessarily cause impairment andmay in the short term improve functioning (31, 32).As the severity of manic symptoms increase how-ever, from mild subsyndromal to threshold levels,so too do the levels of psychosocial dysfunction

and risk (32), and therefore acute mania oftenrequires emergency hospitalisation to administertreatment and ensure safety. Acute treatmentshould therefore aim to quickly treat the symptomsof mania and control any associated behaviouraldisturbance. Recommendations specific to thetreatment of acute mania are summarised in Box 1.

Recommended treatment

First-line. Recently published reviews based on asubstantial evidence-base (15, 19, 25) support theuse of a number of monotherapy strategies for the

treatment of acute mania. Lithium, valproate, anda number of the atypical antipsychotics, along withcombinations of these agents, can be used (22, 3343). Adjunctive use is recommended for cotermi-nous psychotic or behavioural symptoms in mania(15, 25), and benzodiazapines [e.g., lorazepam orclonazepam (44)] can be used short term to controlbehavioural disturbance but should be discontin-ued once symptoms start to allay (19).

Second-line. In patients that do not respond tofirst-line agents, second-line options such as halo-

peridol and carbamazepine may be efficacious (36,45); however issues such as side effect profiles,maintenance efficacy, and drug interactions makethese less optimal choices (25).

Acute bipolar depression

Depression is the predominant mood state expe-rienced throughout the course of BD, withevidence from longitudinal naturalistic studiesrevealing that patients spend up to half of theirlives in this phase (1). Additionally, the depres-

sive phase of the illness is related to the highestrisk of morbidity and suicide (3, 6, 9, 32, 46, 47),with psychosocial disability increasing incremen-tally alongside symptom severity (1, 32). It istherefore noteworthy that there is a paucity ofrobust placebo-controlled studies that evaluatethe treatment of depression and it is because ofthis that there is substantial disagreement inregards to the most efficacious and well-toleratedmedications for this phase of the illness. Box 2provides a summary of the key principles andtreatment recommendations specific to bipolardepression.

Box 3. Mixed states treatment

Key principles of pharmacotherapy

Goal

The primary goal is to ameliorate concurrent depressive and manic symptoms.

Strength of evidence

There are many studies that have evaluated atypical antipsychotics, but studies of mixed states are severely limited in their

interpretability due to variable definitions of mixed states employed across trials and failure to study the efficacy of

antimanic agents in this population independently of pureacute mania.

Haloperidol, atypical antipsychotics, carbamazepine, and divalproex have been demonstrated to have equal efficacy in

reducing manic symptoms for pure mania and individuals who meet DSM-IV-TR criteria for mixed states.

There is no evidence of differential efficacy for atypical antipsychotics in mixed states, thus treatment selection should be

predicated on individual tolerability and safety factors with long-term prophylaxis in mind.

The predominantly depressive course of bipolar disorder suggests that lithium and lamotrigine may have a role in mixed states.

Monotherapycombination therapy

Most individuals will require combination therapy, although combination treatments have not yet been robustly investigated in

mixed states.

Recommended pharmacotherapy

Monotherapy Combination therapy

Atypical antipsychotic Lithiumordivalproex + atypical antipsychotic


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First-line. First-line monotherapy includes lamo-trigine, lithium, valproate, quetiapine, or olanza-pine (25, 33, 4852), though, in practice, lithiumhas a relatively slow onset of action and valproatehas only modest efficacy. Combination treatment ismore the norm in acute bipolar depression andrecommended first-line combinations of agentsinclude lithium combined with lamotrigine orvalproate (20, 53); or a mood stabiliser plus anantidepressant.

Second-line. Second-line choices favour adjunctivetherapies and medication combinations, such asadjunctive risperidone, lithium augmentation ofantidepressants, olanzapine combined with fluoxe-tine, and lithium combined with valproate orlamotrigine (15, 5456).

Mixed states

Mixed states refer to the presence of admixtures of

concurrent depressive and manic symptoms withinan individual. The DSM-IV definition for mixedstates requires the co-existence of full syndromalmania and depression for a minimum of one week(57). Recently however, this categorical definitionhas been criticised as being insufficiently narrow,leading researchers to call for a spectrum recon-ceptualisation of mixed states incorporating sub-threshold mixed states, with a view to encapsulatethe broader clinical picture of this common BDsubtype(58, 59). This is expected to be reflected inthe DSM-V. Further compounding the variable

definitions of mixed states in the literature and

diagnostic confusion surrounding this issue, studiestend to evaluate overall treatment effects, oftenreporting insufficient power to distinguish betweenparticipants with pure maniahypomania ordepression and those with mixed bipolar disorderexpressions. As no evidence-based treatment spe-cifically for mixed-state populations is currentlyavailable, treatment recommendations are extrap-olated from studies of acute mania where asufficient cohort of mixed mania participantsallows for conclusions about treatment efficacy inthis subpopulation.

Research has established several negative long-term consequences of mixed states, that highlightthe complexity and clinical salience of this presen-tation, including substance abuse, suicidality,poorer recovery, and fewer and shorter periods ofsymptom remission (6064). Further, mixed pre-sentations usually precipitate a predominatelydepressive course of illness, which carries substan-tial morbidity and mortality concerns of its own(65). Given that mixed states have greater vulner-ability to depressive episode recurrence as com-

pared to manic episode recurrence, the utility oflithium and lamotrigine in mixed states is justified,despite limited efficacy evidence exclusively inmixed states populations.


Controlled trials of mixed mania are plagued withinconsistencies in the criteria employed to definemixed states and are typically limited by a failureto study this population independently frompure mania. As such, treatment recommenda-

tions are necessarily general (see Box 3) as there

Box 4. Maintenance treatment

Key principles of pharmacotherapy

Goal

Maintenance is the predominant treatment phase in which the core goal is to prevent future mood episodes.

Given the recurrent nature of bipolar disorder and the high rates of relapse, reductions in the number, intensity, and length of

mood episodes and elimination of subsyndromal symptoms between episodes, are perhaps more realistic markers of the

effectiveness of maintenance treatment in clinical practice.

Monotherapycombination therapy

Monotherapy is the ideal but is seldom achieved and may not be as effective as combination therapy. If adjunctive therapy is

utilised, clinicians should be conscious of the side effect burden of multiple medications and continuously review medical

regimens to ensure only those which provide additional benefits continue to be administered.

Strength of evidence

Lamotrigine, olanzapine, and quetiapine have established efficacy in preventing both mania and depression. Lamotrigine is

more efficacious in preventing depression whereas olanzapine is more effective in preventing mania.

Recommended pharmacotherapy

Mania predominance Equal Depression predominance

Monotherapy Lithium

Olanzapine

Quetiapine Lamotrigine

Combination therapya Lithiumorvalproate + lamotrigine

Lithiumorvalproate + quetiapine

Lithiumorvalproate + aripiprazole

aRecommendations apply to all three clinical scenarios.

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is little evidence to support the superiority of anyone atypical antipsychotic in this subpopulation,and therefore treatment selection needs to be indi-vidualized and determined on the basis of patient,illness, medication, and contextual factors (66).

The first step in the management of mixed statesis to remove agents that may be associated withincreased cycling andor the emergence of hypo-

mania (67). Trial evidence in mixed states studies

indicate that haloperidol, atypical antipsychotics,carbamazepine, and divalproex monotherapy sig-nificantly mitigate manic symptoms comparable tothat seen in participants with pure mania (36, 45,6870). In practice, the majority of individuals withmixed states begin treatment with combinationtherapy (63) even though the benefits of combina-tion therapy, as compared to monotherapy, have

not been rigorously trialled.

Box 5. Complex bipolar disorder (BD) recommendationsa

Layer of complexity Example Management

Core features Extreme and or severe changes

in mood, energy, and biorhythms

Assess mood, energy levels, affect, temperament, and biorhythms

Bipolar II disorderb Quetiapine (D)

Lithium (D + P)

Lamotriginec (D + P)

Adjunctive psychoeducation

Subsyndromal bipolar symptoms Adjunctive levetiracetam (M)

Adjunctive CBT

Mixed states Atypical antipsychotics

Lithiumordivalproex + atypical antipsychotic

Rapid cycling Lithium (D + M + P)

Lamotrigine (D + M)

Divalproex (P)

Character Cyclothymia; personality traits

or disorder

A thorough evaluation of personality psychological factors is

essential; lithium, anticonvulsants, and neuroleptics should be

prescribed as indicated, but concurrent psychological

treatment (e.g., DBT) is critical.

Comorbidity Anxiety

Quetiapine (D) Olanzapine (D)

Olanzapine + fluoxetine (D)

Substance abuse Psychoeducation

Valproate (monotherapy or combined with lithium) (D + M)

Concurrent physical

illnesses

Physical illness and

medications

A thorough physical assessment and on-going safety monitoring

to rule out concurrent medical comorbidities is critical;

in particular, hypertension, metabolic syndrome, cardiovascular

disease, and diabetes.

Context considerations Youth BD Lithium (M + D + P)

Divalproex (M + P)

Geriatric BD Elderly BD patients have lower tolerability to medications used to

treat BD and, as such, are at heightened risk for adverse effects,

medication interactions, physical illnesses, and mortality. Lower

dosages of the following medications are therefore recommended: Lithium (M + P)

Paroxetine + lithium (D)

Lamotrigine (D + P)

Maternal BD If possible, medication should be ceased, particularly in the first

trimester of pregnancy. If medication is inescapable, monotherapy

should be used at the lowest possible therapeutic concentration,

alongside continuous monitoring. If possible, medication should

be replaced with psychosocial interventions.

CBT = cognitive behavioral therapy; DBT = dialectical behavior therapy; M = mania efficacy; D = bipolar depression efficacy;

P = prophylactic efficacy.aGiven the multiplicity of possible BD presentations and the evolving but limited research to date, treatment recommendations are

necessarily broad and have been drawn from incomplete data of variable strength. Therefore, recommendations should not be used in

isolation as a directive, but rather as a brief summary of the key points communicated in the preceding sections.b

Bipolar II disorder comprises mainly depressive episodes and, therefore, treatment recommendations apply predominantly to thisphase.cThe evidence for lamotrigine is not as consistent as it has been for quetiapine.


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First-line. First line choices include an atypicalantipsychotic [quetiapine (71), olanzapine (72),

ziprasidone (7375), asenapine (76), aripiprazole(77)] or divalproex (70).

Second-line. The predominantly depressive trajec-tory associated with mixed states suggests that anatypical antipsychotic combined with lithium maybe warranted, although this is yet to be empiricallyvalidated.

Maintenance

Given the chronic nature of BD and the high ratesof treatment discontinuation and relapse, mainte-nance and prophylactic treatment are crucial toeffective long-term clinical management (26). High-lighting this point, a naturalistic effectiveness studyof individuals admitted to the hospital for an acutemanic or mixed bipolar episode revealed thatalthough the majority of patients experiencedsyndromal remission within two years, less thanhalf achieved functional recovery and 40% expe-rienced either a depressive or hypomanicmanicrelapse (65). Additionally, a recent prospective,naturalistic EMBLEM study (63) of patientsexperiencing a mixed or manic episode during

maintenance treatment revealed that over the two-year follow-up, more than half of the sampleexperienced a relapse (57% and 53% in the mixedstates and pure mania groups, respectively). More-over, in real world settings (i.e., epidemiologicalsamples), poor treatment adherence and medica-tion discontinuation appears to limit prophylacticbenefit as reflected in the high rates of subsyndro-mal BD (3, 9, 78). In the aforementioned natural-istic effectiveness study (65), initially all hospitalinpatients were receiving at least one psychotropicmedication, with the majority of patients receivinglithium or antipsychotics. Two years after hospi-

talisation however, 36% of patients were no longerusing any medication, despite the high rates ofrelapse and residual functional impairment foundin this population. Additionally, the number ofindividuals receiving combinations of three ormore medications over time reduced by 41%,

suggesting that in addition to possible lack ofefficacy, intolerable side effects and treatmentnonadherence may have contributed to medicationdiscontinuation and syndromal recurrence (65).

Therefore, the goal of maintenance treatment isto treat inter-episode subsyndromal symptoms,promote psychosocial functioning (20), and pre-vent relapse into new manichypomanic anddepressive mood states. In this regard, symptomremission alone is insufficient and not a goodarbiter of functional outcome.

Psychotherapy is an important adjunct to phar-

macological treatment in prophylaxis, with pre-liminary research indicating that psychosocialinterventions can improve adherence to medicationby modifying knowledge and beliefs relating tomedication (79, 80). Additionally, factors associ-ated with treatment non-adherence include per-ceived lack of information about treatment, theneed to take medication daily, and medication-related side effects (22). Psychotherapy, deliveredwithin the context of a collaborative clinicianpatient partnership, can therefore provide aplatform for psychoeducation that promotes therecognition of early indicators of relapse andreinforces the importance of ongoing medicationeven after the resolution of symptoms. In doing so,psychotherapy can foster patient engagement,medication adherence, and ultimately sustainwell-being (22). Adjunctive psychotherapy alsoproduces benefits above and beyond medicationadherence, with trials (81) establishing that inten-sive psychotherapy (family focused therapy, cog-nitive behavioural, or interpersonal social rhythmtherapy) as an add-on to ongoing pharmacother-apy produced significantly higher recovery rates, ascompared to a brief psychoeducational interven-

tion, and reduced relapse risk (82).Currently, there is a gap in the literature

regarding maniahypomania and depression pro-phylaxis, with available studies suffering frommethodological limitations such as inadequatesample sizes and failure to include a placebocontrol group (83). Therefore, where studies haveprovided equivocal findings, recommendationshave been derived from the cumulative experienceof clinicians, academics, and key opinion leaders.

In addition to thoughtful consideration of indi-vidual patient variables such as treatment and

tolerability history, an examination of the pattern

Box 6.1. Repeated general safety monitoring for all patients with bipolar

disorder

Investigation Baseline 3 months 12 months

Blood pressure and

thyroid function

4* 4

Full blood count andliver function

4

** 4

Blood glucose and lipids 4 4 4

Prolactin 4 4***

Smoking and alcohol 4 4

*Thyroid six-monthly for those who experience rapid-cycling

episodes.

**Also check four weeks after initiating treatment.

***More frequently if clinically indicated.

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for complex presentations; for example: (i) treat-ment resistant BD, (ii) coterminous psychiatricdisorders, in particular anxiety and substancemisuse, (iii) special populations, namely BD pre-sentations in children and adolescents, elderlypopulations, and pregnant women, and (iv) treat-ment requirements at different illness stages (99). Inaddition, again due to a lack of research, clinicalguidelines rarely address the different patterns ofsymptom severity and duration observed in BD,for example, rapid cycling and subsyndromalbipolar symptoms.

A detailed consideration of treatments pertain-ing to complex bipolar presentations is provided inan accompanying article (100). These are struc-tured around a stratified model (see Box 5) thatcaptures the complexity of BD as additional levelsof factors that often occur in conjunction with thetypical patterns of clinical symptoms. These asso-

ciated factors often make diagnosis more difficultand complicate treatment. In the early stages ofmaking a diagnosis of BD, clinicians may wish toconsider these factors that contribute to its com-plexity (101) (see Box 5). Specifically, this involvesevaluation of the core clinical features, the indi-viduals character, comorbid psychiatric disorders,concurrent clinical conditions, and finally, consid-eration of the context within which all of these areoccurring. This stratified approach ensures thatimportant associated factors that can influencemanagement strategy and limit treatment efficacy

are given adequate consideration.

Safety

Assessing suicide risk

BD is associated with an increased risk of suicideas compared to the general population and otherpsychiatric disorders. The rate of lifetime suicide

attempts is between 26% and 34% (57) and ismore likely with depressive (29%) and mixed(28%) onsets of BD (11), and coexisting sub-stance misuse (40%). Ultimately, 1015% ofindividuals with BD complete suicide, and therisk of suicide in BD is greater in males, thosewith a history of suicide attempts, and those withcomorbid substance misuse (6, 47). Therefore,patient safety and assessment of suicidality arecritical (19, 102), particularly during maintenancetreatment (102).

Treatment monitoring strategies

Treatment selection is naturally contingent uponthe unique treatment and tolerability history of theindividual; however, additional consideration

Fig. 2. A schematic of the most common symptom patterns(labeled 1-4) observed in bipolar disorder. Acute treatmenttargets one of the four presentations, and after resolution ofsymptoms, leads into continuation treatment. The latter typi-cally lasts three months and if there is no relapse during this

time then maintenance treatment has commenced. 1 = mania(57); 2 = bipolar depression (57); 3 = manic mixed state[characterized by the presence of depressive symptoms duringan episode of mania (131)]; 4 = depressive mixed state [char-acterized by the presence of manic hypomanic symptomsduring a depressive episode (131)]; Rx = treatment.

Fig. 3. Summary of the various possible presentations ofbipolar disorder with corresponding likely long-term symp-tomatic polarity, which can facilitate the choosing of anappropriate pharmacological treatment option. Rx = treat-

ment.

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should also be given to the pharmacological profileof specific agents. Among the available treatments,lithium distinguishes itself as one of the few agentswith recognised antisuicidal properties (103, 104).

Ideally, complete medical and baseline labora-tory investigations should be performed prior to

initiating treatment (105, 106). Recommendedbaseline assessments for individuals with BD(106109) include the following: a thorough med-ical history, screening in particular for cardiovas-cular disease, substance misuse, and metabolicdisease; a measurement of waist and hip circum-ference andor body mass index; investigations ofrenal function (electrolytes, urea, creatine); non-fasting triglycerides; plasma and urine analysisincluding toxicology; and physical examination ofbreasts in women and testes in men. Additionalinvestigations to exclude organic causes include

EEG, MRI, or CT scan, chest X-ray, pregnancytest, ECG (if clinically indicated), and formal drugscreening should be considered if indicated. Themore routine and regular investigations aresummarised in Box 6.1.

In addition to general monitoring, some medi-cation-specific assessments are also necessary inorder to prevent potentially harmful side effects.Safety monitoring considerations for commonlyused agents in BD have been distilled from anumber of recent clinical guidelines (106109)(summarised in Box 6.2). Inconsistencies in advicehave been resolved by adopting the most conser-vative option; however, it needs to be stressed thatthese recommendations are derived from incom-plete and indirect data and are thus a guide ratherthan a directive.

Tolerability

Adverse effects of medication

As the range of pharmacological options for BDhas increased, the importance of balancing treat-ment efficacy with tolerability and safety concerns

has become increasingly evident (26, 110). Medi-cation tolerability has significant impact on thelong-term management of BD because adverse sideeffects often precipitate treatment noncompliance,resulting in discontinuation estimates as high as60% (22, 79, 111, 112). In addition, safety concernsassociated with BD, primarily the high risk ofsuicide (57), necessitate that suitable pharmaco-logical treatment is established early in the courseof the illness. In practice, agents that effectivelyresolve the acute symptoms of BD are likely to becontinued and therefore it is important thatprescribing clinicians choose treatments not only

on the basis of efficacy and short-term tolerability,but also the likely long-term consequences (26,113). Clinically, this can be achieved by determin-ing the balance of efficacy and tolerability for boththe acute and maintenance phases of the illness andselecting agents with long-term prophylaxis in

mind (26). For example, where significant psy-chotic or behavioural disturbances are presentantipsychotics can be used to control the acutesymptoms, following which the medication shouldbe tapered while remaining on a mood stabilisersuch as lithium, though this may not be alwayspossible as some BD patients may require longerterm treatment with an atypical agent. In cases ofmonotherapy, treatment could be graduallyswitched to a safer and better tolerated medicationin order to prevent future episodes (113).

Balancing efficacy and tolerability

Tables 1 and 2 compare the side effects of medi-cations commonly used in the treatment of BD.The classification of side effects and safety con-cerns has been divided into discrete categories[adapted from Liauw and McIntyre (114)]. Inaddition, Table 3 provides an evaluation of therelative efficacy of monotherapy and combinationtreatments using the National Health MedicalResearch Council (NHMRC) Levels of Evidencecriteria (115) as adapted from the CanadianNetwork for Mood and Anxiety Treatments(CANMAT) guidelines for the clinical manage-ment of patients with BD (105, 116).

Class-specific side effects

While some features associated with atypical anti-psychotics, such as sedation and somnolence, maybe desirable in the short-term management of acutemania or depression, emerging research cautionsagainst the long-term use of particular atypicalsbecause of potential adverse effects on generalmedical health (114). The following section out-

lines the tolerability profiles of pharmacologicalagents recommended for the treatment of BD.Note, only side effects applicable to classes ofmedications are discussed and detail regardingindividual agents can be found in recent reviews[i.e., (23) or (106)].

Lithium

Lithium is typically slow to offer clinically signif-icant symptom reduction, with an average delay intherapeutic effect of 23 weeks. It has a relatively

narrow therapeutic index and severe toxicity can


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lead to permanent organ failure. Therefore, appro-priate dosing and careful monitoring of serumlevels are essential (107), and maintaining adequatehydration and awareness of potential drug inter-actions that can precipitate toxicity is also impor-tant (106). Some individuals on lithium might

experience dose-dependent mild or moderate sideeffects, such as weight gain, cognitive dulling,polyuria, polydipsia, and gastrointestinal prob-lems, whereas serious side effects from long-termtreatment, such as renal problems and hypothy-roidism, are relatively uncommon (1020% and 535%, respectively) (107). Lithium dosing shouldtherefore take into consideration the stage andseverity of illness and aim to achieve the lowestlevel that is effective and well-tolerated (106, 117,118).

Anticonvulsants

Dose-related side effects with valproate includeweight gain, gastrointestinal problems, abnormalliver function tests, tremor, osteoporosis, and seda-tion (23, 119). Toxicity with valproate is rarebecause it has a wide therapeutic window, butoverdose is dangerous and can lead to heart blockand coma (119). More common side effects ofvalproate include weight gain, thrombocytopenia,menstrual irregularities, elevated liver transaminas-es, ataxia, and skin rash (23, 107). Its use in womenof child-bearing potential should be avoided be-cause of potential teratogenic effects (109).

When administering carbamazepine, rare, butpotentially fatal, side effects such as blooddyscrasias, hypersensitivity reactions, and cardiacconduction disturbances need to be borne inmind (119). Cognitive side effects such as diplo-pia, blurred vision, and nausea are more com-mon but these are usually dose-dependent andshort-lived (106).

Lamotrigine is a relatively easy drug to admin-ister but a significant proportion of patients (1014%) develop a benign rash when it is first

prescribed. In contrast, a serious rash is extremelyrare but, when it occurs, can be life-threatening.Therefore, if a rash emerges treatment should beimmediately discontinued. Further, it is worth-while noting that the risk of a rash is increasedwhen lamotrigine is combined with valproate (23).

Atypical antipsychotics

Compared to conventional antipsychotics, atypi-cal agents are less likely to produce extrapyra-midal symptoms (EPS), tardive dyskinesia, and

elevated serum prolactin levels (110, 114), but

these still occur; additionally, they have signifi-cant side effects, such as somnolence and weightgain (38). The latter is particularly important asit is both a tolerability issue and a generalmedical concern and contributes to the risk ofmetabolic syndrome (110). This is a serious

limitation when considering long-term therapywith atypical antipsychotics. Overall, atypicalantipsychotics are probably a safer and moretolerable alternative to conventional antipsychot-ics, however, since individual agents have quitevaried side-effect profiles (see Table 1) their useshould be considered within the constraints oftheir unique attributes (114).

Antidepressants

Individual antidepressants have their own set ofadverse effects; however, classes of antidepres-sants have some shared side effects. Selectiveserotonin reuptake inhibitors (SSRIs) often causeanxiety, sexual dysfunction, and nausea whereastricyclics are more likely to produce blurredvision, urinary retention, constipation, memoryimpairments, and tachycardia, especially at highdoses (120). Monoamine oxidase inhibitors (MA-OIs) are used less often but can cause ahypertensive crisis if taken in conjunction witha variety of foods (e.g., cheese), alcohol, andmedications (120), and can be associated with

serotonin syndrome when combined with othermedications with serotonergic properties such asSSRIs, clomipramine, and meperidine.

Antidepressants and risk of switching. Understand-ably, antidepressants are used widely in thetreatment of bipolar depression even thoughtheir efficacy in the treatment of this phase ofBD is unclear, with the largest and most rigoroustrials, as well as recent meta-analyses, proving tobe negative (121). Consequently, their use in BDis somewhat controversial in light of evidence

that some antidepressants can induce switchingto maniahypomania and worsen the course ofbipolar illness, particularly in those with a rapidcycling pattern (122, 123). This is most likelywith conventional antidepressants, such as tricyc-lics and MAOIs, and is also more common withdual-acting agents such as venlafaxine (and,presumably, duloxetine), as compared to SSRIs(122124). It is important to note, however, thatantidepressants might exert a predominant riskwhen prescribed as monotherapy, and that inconjunction with a mood stabiliser or an anti-psychotic the risk is less likely (121, 124) and, in

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the most recent meta-analysis, antidepressantswere not associated with higher switch rates(121). Additionally, some bipolar II disorderpatients may do well with antidepressant mono-therapy (125).

Switching medication

The BALANCE study (90) justifies to some extentthe use of combinations of medications for main-tenance, specifically the prescription of lithium andvalproate. In practice, atypical antipsychotics areoften used in conjunction with lithium and anti-convulsants and, given the increasing varietyavailable, switching from one agent to another isincreasingly commonplace.

Rationale

The majority of individuals with BD receive anatypical antipsychotic as part of their long-termmanagement (111). Further, nearly half of thosereceiving atypical antipsychotics will be either par-tiallyorcompletelynon-adherent,andmanymaynotrespondormaydevelopadverseevents(111).Intheseinstances, strategic switching of medication can helpprevent medication discontinuation and limit non-essential switching, thereby improving treatmentresponse (66). It is important to bear in mind,however, that early treatment response (within firstweek) prognosticates remission (126, 127) and there-fore both ensuring optimal treatment and simulta-neously determining the need to switch are essential.The management strategyshould thereforeprioritiseoptimisingthedoseofthecurrentmedicationpriortoconsidering switching (114). If target symptomspersist after an adequate trial of the index agent oradverse side effects limit drug tolerability, switchingmay be considered (66, 114). Potential opportunitiesto implement switching include hospitalisation fol-lowing a relapse or during periods of long-termstability in the context of tolerability concerns (66,114). However, even in these circumstances, the

decisiontoswitchmedicationisnottobetakenlightlyand should entail careful deliberation of the follow-ing: (i) the patients beliefs about medication, treat-ment response, and adherence to therapy, (ii) illnesssymptomology and severity, (iii) medication effec-tiveness (efficacy, safety, and tolerability), and (iv)social factors (i.e., level of support from family andfriends) (66).

Strategies

Based on empirical observations, when switching

medication in the management of BD, there are a

number of options that can be exercised: (i) overlapmedications or not; (ii) taper or stopstart abruptlyeither or both medications; (iii) have a washoutperiod or not. In practice, it is common to introduceand withdraw medication gradually and endeavourto minimise any un-medicated period. New data

suggests that taper periods may need to be far longerthan initially thought, perhaps over three months, inorder to match the neurobiological processes sec-ondary to discontinuation (128). Therefore, in real-ity, there are three essential switching strategies thatclinicians canemploy once a medication is deemed tobe ineffective or cannot be tolerated because ofadverse side effects. Figure 4 illustrates the variousmodes of switching medication and discusses brieflytheir respective benefits and drawbacks:

(A). Concurrent switch: In this option, the medi-cations overlap and changes in dose of bothmedications are implemented simulta-neously.

(B). Overlapping switch: In this option, the med-ications overlap but dose changes are onlyimplemented in one medication at a time.The medication in situ is continued at fulldose, while gradually commencing the newmedication. Once the new medication hasreached its optimal dose, then begin taperingthe medication that is being substituted.

Fig. 4. Schematic representation of strategies for switchingantipsychotic medication in bipolar disorder [Copyright (2010)Informa Healthcare; adapted with permission from (114)].Options A and B offer the advantage that the individual isalways medicated, however, there is an increased likelihood ofinteractions and side effects. Options B and C allow iatrogenicside effects to be identified more easily because only onemedication is being modified at a time, though interactionscannot be ruled out with option B. Option C is the cleanest wayof substituting one medication for another but takes muchlonger, especially if it also includes a washout period. Thisoption also runs the risk of significant worsening because thereis a considerable period when medication is at a subtherapeutic

dose.


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(C). Sequential switch: Taper the medication insitu and once this has been fully withdrawn,gradually introduce and titrate the newmedication to optimal dosage.

Summary

BD is a chronic and debilitating illness that requiresearly intervention and effective and targeted long-term management. The high incidence of sub-syndromal symptoms and residual functionalimpairment, even with treatment (3, 129), suggeststhat barriers due to stigma, acceptance, availabilityof psychoeducation, tolerability, and efficacy may beresponsible for the high rates of treatment non-adherence and subsequent relapse in this population(79, 111).

A thorough assessment at the outset allows

clinicians to appraise any risk factors for medica-tion-related adverse effects or barriers to treatmentadherence. In formulating a treatment plan, clini-cians should ensure that treatments are afforded anadequate trial before adding another medication orswitching to another first or second line agent. Theexpanding repertoire of pharmacological optionsavailable for the treatment of BD, each with aunique therapeutic profile and potential sideeffects, means that at every decision-point, clini-cians have to carefully identify the best treatmentoption that balances efficacy, safety, and tolerabil-ity (14). This is particularly important whenconsidering combination strategies where the sumof total therapeutic benefits of agents has to bebalanced against the cumulative side effect burden(14). In addition, whenever selecting medication,long-term tolerability must be considered becausein practice agents that prove to be effective in acutetreatment tend to be continued long-term. Further,continuous monitoring throughout the course ofillness within the context of a collaborative ther-apeutic partnership is essential as it facilitates on-going assessment of the effectiveness and suitabilityof medical regimens in light of tolerability and

safety factors. It needs to be stressed thatpharmacotherapy cannot be seen in isolation ofevidence-based psychosocial and lifestyle interven-tions (130).

Finally, it is important to note that furtherresearch is still necessary, specifically, high-qualitytrials of depression and maintenance medicationare particularly lacking. Currently there are sub-stantial gaps in our knowledge in regards to theoptimal management of many aspects of BD and,while the recommendations in this supplement areintended to assist clinicians in providing safe and

effective treatment, they are ultimately based on an

evolving and incomplete evidence base and there-fore should be used in conjunction with individualpatient information and personal experience.

Disclosures

GSM has received grant or research support from NHMRC,NSW Health, AstraZeneca, Eli Lilly & Co., Organon, Pfizer,

Servier, and Wyeth; has been a speaker for AstraZeneca, Eli

Lilly & Co., Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier,

and Wyeth; and has been a consultant for AstraZeneca, Eli

Lilly & Co., Janssen Cilag, Lundbeck, and Servier. RM has

received research support or grants from the Stanley Medical

Research Institute, the National Alliance for Research on

Schizophrenia and Depression (NARSAD), the National

Institutes of Mental Health (NIMH), Eli Lilly & Co.,

Janssen-Ortho, Shire, AstraZeneca, Pfizer, Lundbeck, Forest,

and Sepracor; has served on the advisory boards of AstraZen-

eca, Bristol-Myers Squibb, Janssen-Ortho, Eli Lilly & Co.,

Lundbeck, Pfizer, Shire, and Merck; is a member of the

speakers bureaus of Janssen-Ortho, AstraZeneca, Eli Lilly &

Co., Lundbeck, Merck, Pfizer, and Otsuka; and has undertakenCME activities for AstraZeneca, Bristol-Myers Squibb, Physi-

ciansPostgraduate Press, CME Outfitters, Merck, Eli Lilly &

Co., Pfizer, Lundbeck, and Otsuka. MG is on the speakers

bureau for Bristol-Myers Squibb, Eli Lilly & Co., and

AstraZeneca. MAF has received grant support from Pfizer,

NARSAD, NIMH, the National Institute of Alcohol Abuse

and Alcoholism (NIAAA), and the Mayo Foundation. M.

Bauer has received grant research support from the Stanley

Medical Research Institute, NARSAD, and the European

Commission (FP7); and is a consultant for AstraZeneca, Eli

Lilly & Co., Servier, Lundbeck, Bristol-Myers Squibb, and

Otsuka. M. Berk has received grant research support from the

National Institute of Health (NIH), the Simons Autism

Foundation, the Cancer Council of Victoria, the Stanley

Medical Research Foundation, MBF, NHMRC, BeyondBlue, Geelong Medical Research Foundation, Bristol-Myers

Squibb, Eli Lilly & Co., GlaxoSmithKline, Organon, Novartis,

Mayne Pharma, and Servier; has been a speaker for AstraZen-

eca, Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline,

Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo,

Servier, Solvayand, and Wyeth; and has served as a consultant

for AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co.,

GlaxoSmithKline, Janssen Cilag, Lundbeck, and Servier.

DMB has no conflicts of interest to report.

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