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Bipolar Disorders 2012: 14 (Suppl.

2): 121

2012 John Wiley and Sons A/S


Review Article

Balanced ecacy, safety, and tolerability recommendations for the clinical management of bipolar disorder
Malhi GS, Bargh DM, McIntyre R, Gitlin M, Frye MA, Bauer M, Berk M. Balanced ecacy, safety, and tolerability recommendations for the clinical management of bipolar disorder. Bipolar Disord 2012: 14 (Suppl. 2): 121. 2012 The Authors. Journal compilation 2012 John Wiley & Sons A S. Objective: To provide practical and clinically meaningful treatment recommendations that amalgamate clinical experience and research ndings for each phase of bipolar disorder. Methods: A comprehensive search of the literature was undertaken using electronic database search engines (Medline, PubMed, Cochrane reviews) using key words (e.g., bipolar depression, mania, treatment). All relevant randomised controlled trials were examined, along with review papers, meta-analyses, and book chapters known to the authors. In addition, the recommendations from accompanying papers in this supplement have been distilled and captured in the form of summary boxes. The ndings, in conjunction with the clinical experience of international researchers and clinicians who are practiced in treating mood disorders, formed the basis of the treatment recommendations within this paper. Results: Balancing clinical experience with evidence informed and lead to the development of practical clinical recommendations that emphasise the importance of safety and tolerability alongside ecacy in the clinical management of bipolar disorder. Conclusions: The current paper summarises the treatment recommendations relating to each phase of bipolar disorder while providing additional, evidence-based, practical insights. Medicationrelated side eects and monitoring strategies highlight the importance of safety and tolerability considerations, which, along with ecacy information, should be given equal merit.

Gin S Malhia,b, Danielle M Bargha,b, Roger McIntyrecf, Michael Gitling, Mark A Fryeh, Michael Baueri and Michael Berkjn
CADE 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, h Department of Psychiatry, Mayo Mood Clinic and Research Program, Mayo College of Medicine, Rochester MN, USA, iDepartment of Psychiatry and Psychotherapy, Carl Gustav Carus University t Dresden, Hospital, Technische Universita Dresden, Germany, jSchool of Medicine, Deakin University, Geelong, kOrygen Youth Health Research Centre, Centre for Youth Mental Health, l Department 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:

Malhi et al.

Bipolar disorder (BD) is an episodic mood disorder with a progressive course that, in many individuals, is characterised by manic or hypomanic episodes in conjunction with depressive episodes, inter-episodic subsyndromal symptoms of mania, and or depression (13). It is one of the leading causes of disability worldwide because of its psychosocial sequelae, longterm unemployment, medical comorbidity, and suicide (48). Further, by virtue of its recurrent nature, patients are symptomatic for approximately half of their lives, a nding that highlights the importance of eectively ameliorating manic hypomanic and depressive symptoms (1, 9). Epidemiological studies estimate lifetime prevalence rates of 0.61% for bipolar I disorder, 0.4 1.1% for bipolar II disorder, and 2.45.1% for subthreshold BD (3, 9, 10). Further, bipolar spectrum disorder that includes threshold and subthreshold cases is estimated at rates of 1.5 6.4% (3, 9), but gures vary depending on the denition employed to dene cases and the nature of the population examined. The typical trajectory of BD involves the onset of subthreshold nonspecic symptoms in adolescence or early adulthood, followed eventually by the emergence of threshold depressive and manic or hypomanic episodes (11), with the latter often leading to a further depressive phase of illness. The delay in onset of manic hypomanic symptoms and the high prevalence of comorbid psychiatric disorders contribute to the high rate of misdiagnosis and consequently the prescription of inappropriate or unnecessary medications that can potentially worsen symptoms and produce adverse eects (3, 12, 13). In recent years, the management of BD has diversied to encompass psychological, social, and lifestyle interventions. This widening of therapeutic strategies not only recognises the multifaceted nature of BD, but also reects a ceiling eect that has been reached with pharmacotherapy alone. Pharmacotherapy in clinical practice remains suboptimal, partly because the mechanisms of action of medications and pathogenesis of BD are unknown, but also because the current medications are not used appropriately. The expanding repertoire of pharmacological options with dierent side eect proles and mechanisms of action and ecacy means that the potential choice of medications and combinations of treatments is complex and often incompletely supported by evidence (14).

make over-arching recommendations for the eective management of major psychiatric disorders. Their adoption, however, is limited due in part to the fact that they are not representative of patients encountered in real world practice and because they are often impenetrable (15). To this end, guidelines that incorporate clinical experience alongside evidence and provide recommendations in regards to assessment, care, and treatment have been developed (15), and the advice in this supplement builds on this foundation and provides further evidence-based guidance for the management of BD. The emphasis remains on pharmacotherapy and, where possible, the authors have integrated clinical experience with the available evidence to ensure that ecacy, safety, and tolerability are given equal consideration. This is because clinical decisions must be governed by the outcomes of high-quality ecacy studies but at the same time incorporate knowledge relating to the tolerability and safety of treatment options (16).
Balancing efcacy, safety, and tolerability

Clinical practice guidelines attempt to synthesise the available pharmacotherapeutic evidence and

The pharmacological management of BD has two basic goals: (i) to eectively treat the acute phases of the illness (mania hypomania and bipolar depression) and (ii) to maintain the gains of acute treatment and prevent relapse (1719). The adequate treatment of BD is therefore tailored to target mania, bipolar depression, and more complex presentations of the illness, including comorbidity, which are often more dicult to treat; whereas maintenance treatment focuses on sustaining mood stability and providing prophylaxis. The current paper summarises the recommendations from each of the accompanying articles that follow, each of which addresses a component of BD treatment. In addition, it draws attention to the key message of balancing ecacy against safety and tolerability when managing BD, which is invariably a recurrent or chronic lifelong illness. It is important to remember that all medications have the potential to cause harm (14) (see Tables 1 and 2) and that it is useful to evaluate the benets and risks of specic treatments in the context of individual patient variables, values, and preferences. Therefore, a summary of the ecacy of pharmacological agents commonly used in each phase of BD (see Table 3), along with a review of the relative risks associated with various treatments (see Class-specic side eects), has been

Ecacy, safety, and tolerability recommendations in BD

Table 1. Adverse effects of atypical antipsychotics used in the treatment of bipolar disordera,b Clozapine Neurological Somnolence EPS Metabolic Weight gain Dyslipidemia Glucose dysregulation Other: Endocrine Prolactin Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Iloperidone Asenapine

++++ + ++++ ++ ++

+++ DD +++ ++ ++

++ DD ++ + + DD

+++ ++ + +

+ DDc

+ DDc

+ ++ +

++ +

EPS = extrapyramidal symptoms; DD = dose dependent; = insufcient data. a Copyright (2010) Informa Healthcare; adapted with permission from (114). b Number of plus symbols indicates comparative side effect severity. c Akathisia. Table 2. Adverse effects of lithium and anticonvulsants used in the treatment of bipolar disordera,b Lithium Carbamazepine Valproate Lamotrigine Neurological Somnolence 0 Cognitive ++ impairment EPS +e Metabolic Weight gain ++ Dyslipidemia 0 Other Thyroid ++ Renal +++g


++ ++c,d DDf + 0 0 +

++ ++ +e +++ 0 0 +

0 + 0 0 0 0 0

Diagnosis. The management of BD requires accurate diagnosis at the outset. Treatment is necessarily predicated on diagnosis and therefore determining the nature of the illnessboth dierentiating BD from other psychiatric diagnoses and sub-typing within the disorder itselfis critical. This assists diagnosis and formulation and the implementation of necessary measures. Evaluation. Once a diagnosis of BD has been established, careful and comprehensive assessment is essential. Ideally, assessment should include a medical examination to exclude a treatable reversible secondary cause (e.g., organicity) and evaluate for the presence of comorbid medical illnesses (20), as well as a structured clinical interview that evaluates the risk of suicide. Then a tailored treatment plan can be formulated in conjunction with corroborative information from medical records, family, and friends. It needs to be emphasised that assessment is an ongoing process, as the clinical picture is constantly evolving.

EPS = extrapyramidal symptoms; DD = dose dependent. a Copyright (2010) Informa Healthcare; adapted with permission from (114). b Number of plus symbols indicates comparative side effect severity. c Ataxia. d Diplopia and blurred vision. e Tremor. f Akathisia. g Only over the long-term course of medication.

included to assist clinicians in achieving this balance.

The clinical management of BD

Once a diagnosis of BD is made, a clinicians primary responsibility is to act, initiate assessment, and ensure appropriate management, ideally in the context of a sustained therapeutic alliance. Specically, this involves (i) careful assessment so as to provide (ii) individualised care and (iii) eective treatment (20) (see Fig. 1: ACT). While assessment and care are equally as important as treatment, this supplement focuses on the pharmacological management of BD and a detailed discussion of these aspects would be beyond its scope.

Though self-evident, it is important to note that care underpins both assessment and treatment, and is therefore a key ingredient for success in the longterm management of BD (see Fig. 1). An optimal outcome is most likely to be achieved within a collaborative therapeutic alliance (21) that enhances patient knowledge, promotes regular monitoring of symptoms, and emphasises the importance of treatment adherence (22).

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

Malhi et al.
Table 3. Strength of evidence for monotherapy and combination treatments for acute and long-term bipolar mania and depressiona Acute mania Acute depression Prophylaxis mania Prophylaxis depression

Agents Monotherapy Lithium Anticonvulsants Valproate divalproex Carbamazepine Oxcarbazepine Lamotrigine Topiramate Gabapentin Atypical antipsychotics Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Clozapine Combination therapy Mood stabiliser + atypical antipsychotic Lithium divalproex + Risperidone Olanzapine Quetiapine Aripiprazole Bupropion Oxcarbazepine Ziprasidone Carbamazepine + risperidone Lithium divalproex carbamazepine + clozapine Mood stabilisers + anticonvulsants Lithium + valproate divalproex Lithium + carbamazepine Lithium + lamotrigine Carbamazepine + valproate divalproex Divalproex + lamotrigine Atypical antipsychotics + antidepressants Risperidone quetiapine + SSRI Olanzapine + uoxetine Mood stabilisers + antidepressants Lithium divalproex + SSRI Lithium + tricyclic antidepressant Lithium + MAOI

I I I II II (132) IV (134) I I I I I IV (138)



II (133) II (135) II (137)

I II I I (142) II (144) II (145) III

III (139) V II II (144)

III II II (39) II (143) III II (146) III

III (139) II (140)b II (141) II (143) IV (147)

III II IV (148) III IV (148)



II (98) II (149)c II (150)d

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; = insufcient or negative evidence for efcacy. a Copyright (2005, 2006) Wiley; adapted with permission from (105, 116, respectively). b Efcacy based on secondary outcome results (time to symptomatic relapse) (140). c Efcacy 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). d Efcacy in this study was suggested by lower discontinuation due to depression in the divalproex + SSRI group, relative to placebo + SSRI (150).

then sustain remission and prevent relapse, so as to ultimately limit disability and maximise psychosocial functioning (20). Therefore, once an accurate diagnosis of BD has been established, the clinician has to determine an appropriate rst-line treatment

(23, 24). This choice has to be made on the basis of an array of factors unique to the individuals psychiatric history; specically, the pattern and severity of symptoms, the course of illness, past treatments and tolerability prole, family history

Ecacy, safety, and tolerability recommendations in BD

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

of treatment response, the presence of comorbid psychiatric disorders, and the level of functional recovery when euthymic (24, 25). In addition, because treatments that are successful in the short term tend to be continued in maintenance treatment, the long-term tolerability of pharmacological agents warrants particular consideration (26). In cases where treatment only produces either a partial response or no response, compliance with medication should be conrmed and drug dosage may need to be optimised (24, 25). If treatment non-response continues or adverse intolerable side eects emerge, switching to another rst-line treatment may be necessary (see relevant Boxes and Switching medication) (24, 25). Agents that may be aggravating the illness course will need to be evaluated with the precautionary principle in mind. Clinically, the acute and maintenance phases of treatment naturally form a continuum, but for the sake of clarity and to maintain consistency with research ndings, the recommendations have been partitioned according to acute and maintenance treatment. Mania (Box 1), bipolar depression (Box 2), and mixed states (Box 3) are the principal targets for acute treatment and recommendations based on ecacy, safety, and tolerability considerations have been provided for each of these phases. In maintenance treatment (Box 4), the goal is to prevent acute breakthrough episodes, promote psychosocial functioning, treat inter-episode sub-

syndromal symptoms, and potentially address the process of neuroprogression inherent in the illness (20, 27) and, as such, it is the most important phase of treatment. During all phases over the longitudinal course of BD illness, various additional factors and combinations of factors can complicate diagnosis and treatment. These aspects are best conceptualised within the framework of a stratied model in which successive layers of complexity facilitate a systematic evaluation of BD and guide eective treatment. A comprehensive summary of the various complexity considerations and corresponding treatment recommendations are succinctly captured in Box 5. In order to establish any factors that may complicate treatment and ensure that adequate acute treatment and prophylaxis is provided, in addition to collecting general medical and psychiatric information at the time of assessment, it is necessary to continue to support the alliance and engagement, provide psychosocial support and education, and monitor symptoms and medication-emergent side eects throughout the course of treatment (see Box 6.1 and Box 6.2).
Pharmacological treatment recommendations

The pharmacological treatment of BD is complicated and requires a sophisticated and structured approach. Typical presentations include

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Box 1. Acute mania treatment Key principles of pharmacotherapy Goal The primary goal is to treat the symptoms of mania and control any associated behavioural disturbance. Strength of evidence The evidence for rst-line treatment of acute mania is considerable. Monotherapy combination therapy There is strong evidence for monotherapy in this phase of bipolar disorder. Patients with psychotic symptoms or behavioural disturbance may benet from the short-term administration of benzodiazapines or an atypical antipsychotic. These should be discontinued after the resolution of acute symptoms in order to avoid long-term adverse side effects. Recommended pharmacotherapy Monotherapy Combination therapy Lithium Lithium or valproate + quetiapine Valproate Lithium or valproate + olanzapine Atypical antipsychotic

Box 2. 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 symptoms and 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 mood stabilizer. (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 efcacious in the treatment of acute depression, and consequently there is signicant contention regarding the most efcacious 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 with lithium and lamotrigine. Recommended pharmacotherapy Monotherapy Combination therapy De novo depression Quetiapine or olanzapine Lithium + lamotrigine Lamotrigine Mood stabilizer + antidepressant Breakthrough depression N A Lithium + lamotrigine Mood stabilizer + antidepressant N A = Not applicable because individual is already receiving treatment. a Adjunctive psychotherapy (intensive, adjunctive family-focused, cognitive behavioural, and interpersonal and social rhythm therapy have all been proven to be efcacious) should span all phases of the illness and commence alongside pharmacotherapy.

mania hypomania and depression, and various forms of mixed states and more complex manifestations (see Fig. 2). Each of these acute phases of BD necessitates specic consideration and management and must be tailored according to the context in which symptoms arise (see 2830). Acute treatment, if successful, ultimately evolves to continuation treatment in which the aim is to maintain remission and prevent relapse (usually into the same polarity as the index episode). Typically, maintenance treatment begins after three months of stability has been achieved with continuation

treatment. The aim of maintenance treatment is to prevent the recurrence of any episodes and ensure long term prophylaxis (see Fig. 3).
Polarity and prior pattern of illness

During continuation and maintenance treatment there is some evidence to suggest that the polarity of the index episode is likely to predict the nature of subsequent recurrences. In essence, the past pattern of illness predicts future episodes. Given this possibility, it has been suggested that

Ecacy, safety, and tolerability recommendations in BD

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 denitions of mixed states employed across trials and failure to study the efcacy of antimanic agents in this population independently of pure acute mania. Haloperidol, atypical antipsychotics, carbamazepine, and divalproex have been demonstrated to have equal efcacy in reducing manic symptoms for pure mania and individuals who meet DSM-IV-TR criteria for mixed states. There is no evidence of differential efcacy 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. Monotherapy combination 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 Lithium or divalproex + atypical antipsychotic

maintenance treatment should reect any bias towards either pole or a particular pattern of illness. For example, if lamotrigine has been successful in treating acute bipolar depression (Fig. 3) then this should be maintained, especially if the individual has experienced many more depressive episodes than manic episodes in the past. Similarly, if the past history of the individual is that of mixed episodes and the index episode is also a mixed episode (Fig. 3), then maintenance treatment may need to consider agents that are particularly eective in combating mixed episodes and future depressive episodes.

treatment of acute mania. Lithium, valproate, and a number of the atypical antipsychotics, along with combinations of these agents, can be used (22, 33 43). Adjunctive use is recommended for coterminous psychotic or behavioural symptoms in mania (15, 25), and benzodiazapines [e.g., lorazepam or clonazepam (44)] can be used short term to control behavioural disturbance but should be discontinued once symptoms start to allay (19). Second-line. In patients that do not respond to rst-line agents, second-line options such as haloperidol and carbamazepine may be ecacious (36, 45); however issues such as side eect proles, maintenance ecacy, and drug interactions make these less optimal choices (25).

Acute mania

Some characteristics of hypomania, such as elevated mood, increased energy, and heightened selfesteem, do not necessarily cause impairment and may in the short term improve functioning (31, 32). As the severity of manic symptoms increase however, from mild subsyndromal to threshold levels, so too do the levels of psychosocial dysfunction and risk (32), and therefore acute mania often requires emergency hospitalisation to administer treatment and ensure safety. Acute treatment should therefore aim to quickly treat the symptoms of mania and control any associated behavioural disturbance. Recommendations specic to the treatment of acute mania are summarised in Box 1.
Recommended treatment

Acute bipolar depression

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

Depression is the predominant mood state experienced throughout the course of BD, with evidence from longitudinal naturalistic studies revealing that patients spend up to half of their lives in this phase (1). Additionally, the depressive phase of the illness is related to the highest risk of morbidity and suicide (3, 6, 9, 32, 46, 47), with psychosocial disability increasing incrementally alongside symptom severity (1, 32). It is therefore noteworthy that there is a paucity of robust placebo-controlled studies that evaluate the treatment of depression and it is because of this that there is substantial disagreement in regards to the most ecacious and well-tolerated medications for this phase of the illness. Box 2 provides a summary of the key principles and treatment recommendations specic to bipolar depression.

Malhi et al.
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. Monotherapy combination 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 benets continue to be administered. Strength of evidence Lamotrigine, olanzapine, and quetiapine have established efcacy in preventing both mania and depression. Lamotrigine is more efcacious in preventing depression whereas olanzapine is more effective in preventing mania. Recommended pharmacotherapy Mania predominance Equal Depression predominance Monotherapy Lithium Quetiapine Lamotrigine Olanzapine   Combination therapya Lithium or valproate + lamotrigine Lithium or valproate + quetiapine Lithium or valproate + aripiprazole

Recommendations apply to all three clinical scenarios.

Recommended treatment

First-line. First-line monotherapy includes lamotrigine, lithium, valproate, quetiapine, or olanzapine (25, 33, 4852), though, in practice, lithium has a relatively slow onset of action and valproate has only modest ecacy. Combination treatment is more the norm in acute bipolar depression and recommended rst-line combinations of agents include lithium combined with lamotrigine or valproate (20, 53); or a mood stabiliser plus an antidepressant. Second-line. Second-line choices favour adjunctive therapies and medication combinations, such as adjunctive risperidone, lithium augmentation of antidepressants, olanzapine combined with uoxetine, and lithium combined with valproate or lamotrigine (15, 5456).
Mixed states

Mixed states refer to the presence of admixtures of concurrent depressive and manic symptoms within an individual. The DSM-IV denition for mixed states requires the co-existence of full syndromal mania and depression for a minimum of one week (57). Recently however, this categorical denition has been criticised as being insuciently narrow, leading researchers to call for a spectrum reconceptualisation of mixed states incorporating subthreshold mixed states, with a view to encapsulate the broader clinical picture of this common BD subtype (58, 59). This is expected to be reected in the DSM-V. Further compounding the variable denitions of mixed states in the literature and

diagnostic confusion surrounding this issue, studies tend to evaluate overall treatment eects, often reporting insucient power to distinguish between participants with pure mania hypomania or depression and those with mixed bipolar disorder expressions. As no evidence-based treatment specically for mixed-state populations is currently available, treatment recommendations are extrapolated from studies of acute mania where a sucient cohort of mixed mania participants allows for conclusions about treatment ecacy in this subpopulation. Research has established several negative longterm consequences of mixed states, that highlight the complexity and clinical salience of this presentation, including substance abuse, suicidality, poorer recovery, and fewer and shorter periods of symptom remission (6064). Further, mixed presentations usually precipitate a predominately depressive course of illness, which carries substantial morbidity and mortality concerns of its own (65). Given that mixed states have greater vulnerability to depressive episode recurrence as compared to manic episode recurrence, the utility of lithium and lamotrigine in mixed states is justied, despite limited ecacy evidence exclusively in mixed states populations.
Recommended treatment

Controlled trials of mixed mania are plagued with inconsistencies in the criteria employed to dene mixed states and are typically limited by a failure to study this population independently from pure mania. As such, treatment recommendations are necessarily general (see Box 3) as there

Ecacy, safety, and tolerability recommendations in BD

Box 5. Complex bipolar disorder (BD) recommendationsa Layer of complexity Core features Example Extreme and or severe changes in mood, energy, and biorhythms Bipolar II disorderb Management Assess mood, energy levels, affect, temperament, and biorhythms

Subsyndromal bipolar symptoms Mixed states Rapid cycling

Quetiapine (D) Lithium (D + P) Lamotriginec (D + P) Adjunctive psychoeducation Adjunctive levetiracetam (M) Adjunctive CBT Atypical antipsychotics Lithium or divalproex + atypical antipsychotic Lithium (D + M + P) Lamotrigine (D + M) Divalproex (P)


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. Quetiapine (D) Olanzapine (D) Olanzapine + uoxetine (D) Psychoeducation Valproate (monotherapy or combined with lithium) (D + M)



Substance abuse 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. Lithium (M + D + P) Divalproex (M + P) 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) If possible, medication should be ceased, particularly in the rst 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.

Context considerations

Youth BD Geriatric BD

Maternal BD

CBT = cognitive behavioral therapy; DBT = dialectical behavior therapy; M = mania efcacy; D = bipolar depression efcacy; P = prophylactic efcacy. a Given 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 this phase. c The evidence for lamotrigine is not as consistent as it has been for quetiapine.

is little evidence to support the superiority of any one atypical antipsychotic in this subpopulation, and therefore treatment selection needs to be individualized and determined on the basis of patient, illness, medication, and contextual factors (66). The rst step in the management of mixed states is to remove agents that may be associated with increased cycling and or the emergence of hypomania (67). Trial evidence in mixed states studies

indicate that haloperidol, atypical antipsychotics, carbamazepine, and divalproex monotherapy signicantly mitigate manic symptoms comparable to that seen in participants with pure mania (36, 45, 6870). In practice, the majority of individuals with mixed states begin treatment with combination therapy (63) even though the benets of combination therapy, as compared to monotherapy, have not been rigorously trialled.

Malhi et al.
Box 6.1. Repeated general safety monitoring for all patients with bipolar disorder Investigation Blood pressure and thyroid function Full blood count and liver function Blood glucose and lipids Prolactin Smoking and alcohol Baseline 3 months 12 months

* **

4 4 4

4 4


*Thyroid six-monthly for those who experience rapid-cycling episodes. **Also check four weeks after initiating treatment. ***More frequently if clinically indicated.

First-line. First line choices include an atypical antipsychotic [quetiapine (71), olanzapine (72), ziprasidone (7375), asenapine (76), aripiprazole (77)] or divalproex (70). Second-line. The predominantly depressive trajectory associated with mixed states suggests that an atypical antipsychotic combined with lithium may be warranted, although this is yet to be empirically validated.

Given the chronic nature of BD and the high rates of treatment discontinuation and relapse, maintenance and prophylactic treatment are crucial to eective long-term clinical management (26). Highlighting this point, a naturalistic eectiveness study of individuals admitted to the hospital for an acute manic or mixed bipolar episode revealed that although the majority of patients experienced syndromal remission within two years, less than half achieved functional recovery and 40% experienced either a depressive or hypomanic manic relapse (65). Additionally, a recent prospective, naturalistic EMBLEM study (63) of patients experiencing a mixed or manic episode during maintenance treatment revealed that over the twoyear follow-up, more than half of the sample experienced a relapse (57% and 53% in the mixed states and pure mania groups, respectively). Moreover, in real world settings (i.e., epidemiological samples), poor treatment adherence and medication discontinuation appears to limit prophylactic benet as reected in the high rates of subsyndromal BD (3, 9, 78). In the aforementioned naturalistic eectiveness study (65), initially all hospital inpatients were receiving at least one psychotropic medication, with the majority of patients receiving lithium or antipsychotics. Two years after hospi-

talisation however, 36% of patients were no longer using any medication, despite the high rates of relapse and residual functional impairment found in this population. Additionally, the number of individuals receiving combinations of three or more medications over time reduced by 41%, suggesting that in addition to possible lack of ecacy, intolerable side eects and treatment nonadherence may have contributed to medication discontinuation and syndromal recurrence (65). Therefore, the goal of maintenance treatment is to treat inter-episode subsyndromal symptoms, promote psychosocial functioning (20), and prevent relapse into new manic hypomanic and depressive mood states. In this regard, symptom remission alone is insucient and not a good arbiter of functional outcome. Psychotherapy is an important adjunct to pharmacological treatment in prophylaxis, with preliminary research indicating that psychosocial interventions can improve adherence to medication by modifying knowledge and beliefs relating to medication (79, 80). Additionally, factors associated with treatment non-adherence include perceived lack of information about treatment, the need to take medication daily, and medicationrelated side eects (22). Psychotherapy, delivered within the context of a collaborative clinician patient partnership, can therefore provide a platform for psychoeducation that promotes the recognition of early indicators of relapse and reinforces the importance of ongoing medication even after the resolution of symptoms. In doing so, psychotherapy can foster patient engagement, medication adherence, and ultimately sustain well-being (22). Adjunctive psychotherapy also produces benets above and beyond medication adherence, with trials (81) establishing that intensive psychotherapy (family focused therapy, cognitive behavioural, or interpersonal social rhythm therapy) as an add-on to ongoing pharmacotherapy produced signicantly higher recovery rates, as compared to a brief psychoeducational intervention, and reduced relapse risk (82). Currently, there is a gap in the literature regarding mania hypomania and depression prophylaxis, with available studies suering from methodological limitations such as inadequate sample sizes and failure to include a placebo control group (83). Therefore, where studies have provided equivocal ndings, recommendations have been derived from the cumulative experience of clinicians, academics, and key opinion leaders. In addition to thoughtful consideration of individual patient variables such as treatment and tolerability history, an examination of the pattern


Ecacy, safety, and tolerability recommendations in BD

Box 6.2. Medication-specic monitoring for agents commonly used in bipolar disorder treatment Investigation Liver function Renal function Thyroid-stimulating hormone Full blood count Menstrual changes Calcium Serum levels Weight Blood pressure Fasting lipid prole Fasting plasma glucose Lithium Serum levels should be checked ve days after initiating treatment and after each change in dose titration and three-monthly for stable patients. Baseline
44 4

4 4

3 months
4 4

6 months

12 months
44 4

* * *


4 44

4 4

** **

4 44 4

44 4 4 4

** **

44 4 4 4

Valproate Serum levels should be checked if clinically indicated. Those who are experiencing weight gain should have their weight monitored.

Carbamazepine If relevant, ensure effective contraception. Advise patients to seek immediate medical assistance and cease medication if dermatological reactions emerge.

Atypical antipsychotics For olanzapine, fasting plasma glucose should be tested one month after implementing treatment. Prolactin levels and ECG where clinically indicated.

*Only necessary in the rst three months of treatment. **Only necessary in the rst year of treatment.

of mood states so as to identify the predominant pole of illness (e.g., depression versus mania dominant) can assist choice of pharmacotherapy for the prevention of future episodes of illness, as polarity at onset is generally relatively stable throughout the longitudinal course of illness (see Fig. 3) (11, 65). Box 4 summarises the key treatment principles and recommended maintenance pharmacotherapy.
Recommended treatment

In maintenance therapy, predominant polarity is thought to inuence treatment choice (84). Lithium has proven ecacy in prolonging the time to a manic episode and to a lesser extent, depression. Where depressive episodes predominate however, lamotrigine is perhaps preferable, even though some ecacy data suggests it is able to prolong the time to intervention for a manic hypomanic episode (8588). Valproate is widely used as a maintenance treatment for BD, although the original randomised, placebo-controlled trial yielded a negative nding (whereby valproate was in the form of divalproex), and the BALANCE study showed that lithium was superior to valproate (89, 90). It is possible, however, that methodological aws in the original study may have obscured the existence of a treatment eect. Of the atypical antipsychotics, olanzapine and aripiprazole have anti-manic prophylactic properties, with aripiprazole in particular demonstrating ecacy as an adjunct to both lithium and valproate for the

prevention of manic relapse (9194). In addition, quetiapine as a solo agent (95), and combined with lithium or valproate, has proven ecacy in the prevention of both manic and depressive episodes (96, 97). While the benets of acute treatment with combined lithium and lamotrigine are well-established, a recent randomised, placebo-controlled study (98) identied the long-term advantages of add-on lamotrigine, beyond the eects of lithium alone. In this study, time to relapse or recurrence of a depressive episode was longer for those on lithium and lamotrigine, relative to those on lithium and placebo (10 months versus 3.5 months, respectively). Additionally, after 68 weeks, a higher proportion of participants remained in the lamotrigine group relative to the placebo group (n = 18 versus n = 14, respectively). In light of limited evidence-based maintenance treatments, clinicians are advised to use clinical guidelines in conjunction with professional judgement and tailor individualised treatment algorithms.
Complex presentations

The clinical management of BD needs to reect the inherent complexity of the illness (15). Treatment studies have extensive inclusion and exclusion criteria and, therefore, recommendations based on this data are limited in terms of generalizability. As such, most treatment guidelines tend to omit clinical recommendations in regards to management strategies and ecacious treatments


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Assessing suicide risk

Fig. 2. A schematic of the most common symptom patterns (labeled 1-4) observed in bipolar disorder. Acute treatment targets one of the four presentations, and after resolution of symptoms, leads into continuation treatment. The latter typically 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 during an episode of mania (131)]; 4 = depressive mixed state [characterized by the presence of manic hypomanic symptoms during a depressive episode (131)]; Rx = treatment.

BD is associated with an increased risk of suicide as compared to the general population and other psychiatric disorders. The rate of lifetime suicide attempts is between 26% and 34% (57) and is more likely with depressive (29%) and mixed (28%) onsets of BD (11), and coexisting substance misuse (40%). Ultimately, 1015% of individuals with BD complete suicide, and the risk of suicide in BD is greater in males, those with a history of suicide attempts, and those with comorbid substance misuse (6, 47). Therefore, patient safety and assessment of suicidality are critical (19, 102), particularly during maintenance treatment (102).
Treatment monitoring strategies

Treatment selection is naturally contingent upon the unique treatment and tolerability history of the individual; however, additional consideration

for complex presentations; for example: (i) treatment resistant BD, (ii) coterminous psychiatric disorders, in particular anxiety and substance misuse, (iii) special populations, namely BD presentations in children and adolescents, elderly populations, and pregnant women, and (iv) treatment requirements at dierent illness stages (99). In addition, again due to a lack of research, clinical guidelines rarely address the dierent patterns of symptom severity and duration observed in BD, for example, rapid cycling and subsyndromal bipolar symptoms. A detailed consideration of treatments pertaining to complex bipolar presentations is provided in an accompanying article (100). These are structured around a stratied model (see Box 5) that captures the complexity of BD as additional levels of factors that often occur in conjunction with the typical patterns of clinical symptoms. These associated factors often make diagnosis more dicult and complicate treatment. In the early stages of making a diagnosis of BD, clinicians may wish to consider these factors that contribute to its complexity (101) (see Box 5). Specically, this involves evaluation of the core clinical features, the individuals character, comorbid psychiatric disorders, concurrent clinical conditions, and nally, consideration of the context within which all of these are occurring. This stratied approach ensures that important associated factors that can inuence management strategy and limit treatment ecacy are given adequate consideration.

Fig. 3. Summary of the various possible presentations of bipolar disorder with corresponding likely long-term symptomatic polarity, which can facilitate the choosing of an appropriate pharmacological treatment option. Rx = treatment.


Ecacy, safety, and tolerability recommendations in BD should also be given to the pharmacological prole of specic agents. Among the available treatments, lithium distinguishes itself as one of the few agents with recognised antisuicidal properties (103, 104). Ideally, complete medical and baseline laboratory investigations should be performed prior to initiating treatment (105, 106). Recommended baseline assessments for individuals with BD (106109) include the following: a thorough medical history, screening in particular for cardiovascular disease, substance misuse, and metabolic disease; a measurement of waist and hip circumference and or body mass index; investigations of renal function (electrolytes, urea, creatine); nonfasting triglycerides; plasma and urine analysis including toxicology; and physical examination of breasts in women and testes in men. Additional investigations to exclude organic causes include EEG, MRI, or CT scan, chest X-ray, pregnancy test, ECG (if clinically indicated), and formal drug screening should be considered if indicated. The more routine and regular investigations are summarised in Box 6.1. In addition to general monitoring, some medication-specic assessments are also necessary in order to prevent potentially harmful side eects. Safety monitoring considerations for commonly used agents in BD have been distilled from a number of recent clinical guidelines (106109) (summarised in Box 6.2). Inconsistencies in advice have been resolved by adopting the most conservative option; however, it needs to be stressed that these recommendations are derived from incomplete and indirect data and are thus a guide rather than a directive.

on the basis of ecacy and short-term tolerability, but also the likely long-term consequences (26, 113). Clinically, this can be achieved by determining the balance of ecacy and tolerability for both the acute and maintenance phases of the illness and selecting agents with long-term prophylaxis in mind (26). For example, where signicant psychotic or behavioural disturbances are present antipsychotics can be used to control the acute symptoms, following which the medication should be tapered while remaining on a mood stabiliser such as lithium, though this may not be always possible as some BD patients may require longer term treatment with an atypical agent. In cases of monotherapy, treatment could be gradually switched to a safer and better tolerated medication in order to prevent future episodes (113).
Balancing efcacy and tolerability

Tables 1 and 2 compare the side eects of medications commonly used in the treatment of BD. The classication of side eects and safety concerns has been divided into discrete categories [adapted from Liauw and McIntyre (114)]. In addition, Table 3 provides an evaluation of the relative ecacy of monotherapy and combination treatments using the National Health Medical Research Council (NHMRC) Levels of Evidence criteria (115) as adapted from the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the clinical management of patients with BD (105, 116).
Class-specic side effects

Adverse effects of medication

As the range of pharmacological options for BD has increased, the importance of balancing treatment ecacy with tolerability and safety concerns has become increasingly evident (26, 110). Medication tolerability has signicant impact on the long-term management of BD because adverse side eects often precipitate treatment noncompliance, resulting in discontinuation estimates as high as 60% (22, 79, 111, 112). In addition, safety concerns associated with BD, primarily the high risk of suicide (57), necessitate that suitable pharmacological treatment is established early in the course of the illness. In practice, agents that eectively resolve the acute symptoms of BD are likely to be continued and therefore it is important that prescribing clinicians choose treatments not only

While some features associated with atypical antipsychotics, such as sedation and somnolence, may be desirable in the short-term management of acute mania or depression, emerging research cautions against the long-term use of particular atypicals because of potential adverse eects on general medical health (114). The following section outlines the tolerability proles of pharmacological agents recommended for the treatment of BD. Note, only side eects applicable to classes of medications are discussed and detail regarding individual agents can be found in recent reviews [i.e., (23) or (106)].

Lithium is typically slow to oer clinically significant symptom reduction, with an average delay in therapeutic eect of 23 weeks. It has a relatively narrow therapeutic index and severe toxicity can


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lead to permanent organ failure. Therefore, appropriate dosing and careful monitoring of serum levels are essential (107), and maintaining adequate hydration and awareness of potential drug interactions that can precipitate toxicity is also important (106). Some individuals on lithium might experience dose-dependent mild or moderate side eects, such as weight gain, cognitive dulling, polyuria, polydipsia, and gastrointestinal problems, whereas serious side eects from long-term treatment, such as renal problems and hypothyroidism, are relatively uncommon (1020% and 5 35%, respectively) (107). Lithium dosing should therefore take into consideration the stage and severity of illness and aim to achieve the lowest level that is eective and well-tolerated (106, 117, 118).

these still occur; additionally, they have signicant side eects, such as somnolence and weight gain (38). The latter is particularly important as it is both a tolerability issue and a general medical concern and contributes to the risk of metabolic syndrome (110). This is a serious limitation when considering long-term therapy with atypical antipsychotics. Overall, atypical antipsychotics are probably a safer and more tolerable alternative to conventional antipsychotics, however, since individual agents have quite varied side-eect proles (see Table 1) their use should be considered within the constraints of their unique attributes (114).


Dose-related side eects with valproate include weight gain, gastrointestinal problems, abnormal liver function tests, tremor, osteoporosis, and sedation (23, 119). Toxicity with valproate is rare because it has a wide therapeutic window, but overdose is dangerous and can lead to heart block and coma (119). More common side eects of valproate include weight gain, thrombocytopenia, menstrual irregularities, elevated liver transaminases, ataxia, and skin rash (23, 107). Its use in women of child-bearing potential should be avoided because of potential teratogenic eects (109). When administering carbamazepine, rare, but potentially fatal, side eects such as blood dyscrasias, hypersensitivity reactions, and cardiac conduction disturbances need to be borne in mind (119). Cognitive side eects such as diplopia, blurred vision, and nausea are more common but these are usually dose-dependent and short-lived (106). Lamotrigine is a relatively easy drug to administer but a signicant proportion of patients (10 14%) develop a benign rash when it is rst prescribed. In contrast, a serious rash is extremely rare but, when it occurs, can be life-threatening. Therefore, if a rash emerges treatment should be immediately discontinued. Further, it is worthwhile noting that the risk of a rash is increased when lamotrigine is combined with valproate (23).
Atypical antipsychotics

Individual antidepressants have their own set of adverse eects; however, classes of antidepressants have some shared side eects. Selective serotonin reuptake inhibitors (SSRIs) often cause anxiety, sexual dysfunction, and nausea whereas tricyclics are more likely to produce blurred vision, urinary retention, constipation, memory impairments, and tachycardia, especially at high doses (120). Monoamine oxidase inhibitors (MAOIs) are used less often but can cause a hypertensive crisis if taken in conjunction with a variety of foods (e.g., cheese), alcohol, and medications (120), and can be associated with serotonin syndrome when combined with other medications with serotonergic properties such as SSRIs, clomipramine, and meperidine. Antidepressants and risk of switching. Understandably, antidepressants are used widely in the treatment of bipolar depression even though their ecacy in the treatment of this phase of BD is unclear, with the largest and most rigorous trials, as well as recent meta-analyses, proving to be negative (121). Consequently, their use in BD is somewhat controversial in light of evidence that some antidepressants can induce switching to mania hypomania and worsen the course of bipolar illness, particularly in those with a rapid cycling pattern (122, 123). This is most likely with conventional antidepressants, such as tricyclics and MAOIs, and is also more common with dual-acting agents such as venlafaxine (and, presumably, duloxetine), as compared to SSRIs (122124). It is important to note, however, that antidepressants might exert a predominant risk when prescribed as monotherapy, and that in conjunction with a mood stabiliser or an antipsychotic the risk is less likely (121, 124) and, in

Compared to conventional antipsychotics, atypical agents are less likely to produce extrapyramidal symptoms (EPS), tardive dyskinesia, and elevated serum prolactin levels (110, 114), but


Ecacy, safety, and tolerability recommendations in BD the most recent meta-analysis, antidepressants were not associated with higher switch rates (121). Additionally, some bipolar II disorder patients may do well with antidepressant monotherapy (125).
Switching medication

The BALANCE study (90) justies to some extent the use of combinations of medications for maintenance, specically the prescription of lithium and valproate. In practice, atypical antipsychotics are often used in conjunction with lithium and anticonvulsants and, given the increasing variety available, switching from one agent to another is increasingly commonplace.

number of options that can be exercised: (i) overlap medications or not; (ii) taper or stop start abruptly either or both medications; (iii) have a washout period or not. In practice, it is common to introduce and withdraw medication gradually and endeavour to minimise any un-medicated period. New data suggests that taper periods may need to be far longer than initially thought, perhaps over three months, in order to match the neurobiological processes secondary to discontinuation (128). Therefore, in reality, there are three essential switching strategies that clinicians can employ once a medication is deemed to be ineective or cannot be tolerated because of adverse side eects. Figure 4 illustrates the various modes of switching medication and discusses briey their respective benets and drawbacks: (A). Concurrent switch: In this option, the medications overlap and changes in dose of both medications are implemented simultaneously. (B). Overlapping switch: In this option, the medications overlap but dose changes are only implemented in one medication at a time. The medication in situ is continued at full dose, while gradually commencing the new medication. Once the new medication has reached its optimal dose, then begin tapering the medication that is being substituted.

The majority of individuals with BD receive an atypical antipsychotic as part of their long-term management (111). Further, nearly half of those receiving atypical antipsychotics will be either partially or completely non-adherent, and many may not respond or may develop adverse events (111). In these instances, strategic switching of medication can help prevent medication discontinuation and limit nonessential switching, thereby improving treatment response (66). It is important to bear in mind, however, that early treatment response (within rst week) prognosticates remission (126, 127) and therefore both ensuring optimal treatment and simultaneously determining the need to switch are essential. The management strategy should therefore prioritise optimising the dose of the current medication prior to considering switching (114). If target symptoms persist after an adequate trial of the index agent or adverse side eects limit drug tolerability, switching may be considered (66, 114). Potential opportunities to implement switching include hospitalisation following a relapse or during periods of long-term stability in the context of tolerability concerns (66, 114). However, even in these circumstances, the decision to switch medication is not to be taken lightly and should entail careful deliberation of the following: (i) the patients beliefs about medication, treatment response, and adherence to therapy, (ii) illness symptomology and severity, (iii) medication eectiveness (ecacy, safety, and tolerability), and (iv) social factors (i.e., level of support from family and friends) (66).

Based on empirical observations, when switching medication in the management of BD, there are a

Fig. 4. Schematic representation of strategies for switching antipsychotic medication in bipolar disorder [Copyright (2010) Informa Healthcare; adapted with permission from (114)]. Options A and B oer the advantage that the individual is always medicated, however, there is an increased likelihood of interactions and side eects. Options B and C allow iatrogenic side eects to be identied more easily because only one medication is being modied at a time, though interactions cannot be ruled out with option B. Option C is the cleanest way of substituting one medication for another but takes much longer, especially if it also includes a washout period. This option also runs the risk of signicant worsening because there is a considerable period when medication is at a subtherapeutic dose.


Malhi et al.

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

evolving and incomplete evidence base and therefore should be used in conjunction with individual patient information and personal experience.

BD is a chronic and debilitating illness that requires early intervention and eective and targeted longterm management. The high incidence of subsyndromal symptoms and residual functional impairment, even with treatment (3, 129), suggests that barriers due to stigma, acceptance, availability of psychoeducation, tolerability, and ecacy may be responsible for the high rates of treatment nonadherence and subsequent relapse in this population (79, 111). A thorough assessment at the outset allows clinicians to appraise any risk factors for medication-related adverse eects or barriers to treatment adherence. In formulating a treatment plan, clinicians should ensure that treatments are aorded an adequate trial before adding another medication or switching to another rst or second line agent. The expanding repertoire of pharmacological options available for the treatment of BD, each with a unique therapeutic prole and potential side eects, means that at every decision-point, clinicians have to carefully identify the best treatment option that balances ecacy, safety, and tolerability (14). This is particularly important when considering combination strategies where the sum of total therapeutic benets of agents has to be balanced against the cumulative side eect burden (14). In addition, whenever selecting medication, long-term tolerability must be considered because in practice agents that prove to be eective in acute treatment tend to be continued long-term. Further, continuous monitoring throughout the course of illness within the context of a collaborative therapeutic partnership is essential as it facilitates ongoing assessment of the eectiveness and suitability of medical regimens in light of tolerability and safety factors. It needs to be stressed that pharmacotherapy cannot be seen in isolation of evidence-based psychosocial and lifestyle interventions (130). Finally, it is important to note that further research is still necessary, specically, high-quality trials of depression and maintenance medication are particularly lacking. Currently there are substantial gaps in our knowledge in regards to the optimal management of many aspects of BD and, while the recommendations in this supplement are intended to assist clinicians in providing safe and eective treatment, they are ultimately based on an

GSM has received grant or research support from NHMRC, NSW Health, AstraZeneca, Eli Lilly & Co., Organon, Pzer, Servier, and Wyeth; has been a speaker for AstraZeneca, Eli Lilly & Co., Janssen Cilag, Lundbeck, Pzer, 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, Pzer, Lundbeck, Forest, and Sepracor; has served on the advisory boards of AstraZeneca, Bristol-Myers Squibb, Janssen-Ortho, Eli Lilly & Co., Lundbeck, Pzer, Shire, and Merck; is a member of the speakers bureaus of Janssen-Ortho, AstraZeneca, Eli Lilly & Co., Lundbeck, Merck, Pzer, and Otsuka; and has undertaken CME activities for AstraZeneca, Bristol-Myers Squibb, Physicians Postgraduate Press, CME Outtters, Merck, Eli Lilly & Co., Pzer, Lundbeck, and Otsuka. MG is on the speakers bureau for Bristol-Myers Squibb, Eli Lilly & Co., and AstraZeneca. MAF has received grant support from Pzer, 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, Beyond Blue, Geelong Medical Research Foundation, Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline, Organon, Novartis, Mayne Pharma, and Servier; has been a speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline, Janssen Cilag, Lundbeck, Merck, Pzer, Sano 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 conicts of interest to report.

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