abilify lithium

DOI: 10.1111/bdi.12609 ORIGINAL ARTICLE Canadian Network for Mood and Anxiety Treatments (CANMAT) and

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International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder Lakshmi N Yatham1 | Sidney H Kennedy2 4 David J Bond 7 5 | Benicio N Frey 7 | Serge Beaulieu Soham Rej 10 | Sagar V Parikh3 | Ayal Schaffer2 6 | Verinder Sharma 8 2 | Benjamin I Goldstein 9 | Martin Alda | 2 | Glenda MacQueen 8 | | Diane McIntosh1 | Roumen V Milev | Arun Ravindran Raymond W Lam1 | Gustavo Vazquez10 | Flavio Kapczinski5 | Roger S McIntyre2 11 Jan Kozicky 12 | Shigenobu Kanba 15 Joseph R Calabrese | Claire O’Donovan | 13 14 | Beny Lafer 16 | Eduard Vieta | Trisha Suppes 17 | Gin Malhi 18 | Robert M Post | | | 19 Michael Berk 1 Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada 2 Department of Psychiatry, University of Toronto, Toronto, ON, Canada 3 Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA 4 Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA 5 Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada 6 Departments of Psychiatry and Obstetrics & Gynaecology, Western University, London, ON, Canada 7 Department of Psychiatry, McGill University, Montreal, QC, Canada 8 Department of Psychiatry, Dalhousie University, Halifax, NS, Canada 9 Department of Psychiatry, University of Calgary, Calgary, AB, Canada 10 Departments of Psychiatry and Psychology, Queen’s University, Kingston, ON, Canada 11 School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada 12 Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan 13 Department of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil 14 Bipolar and Depression Research Program, VA Palo Alto, Department of Psychiatry & Behavioral Sciences Stanford University, Stanford, CA, USA 15 Department of Psychiatry, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA 16 Bipolar Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain 17 Department of Psychiatry, University of Sydney, Sydney, NSW, Australia 18 Department of Psychiatry, George Washington University, Washington, DC, USA 19 Deakin Univeristy, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Vic., Australia Correspondence Lakshmi N Yatham, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Email: yatham@mail.ubc.ca Bipolar Disorders. 2018;20:97–170. wileyonlinelibrary.com/journal/bdi © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd | 97 98 | YATHAM et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first­, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-­emergent switch risk. New to these guidelines, hierarchical rankings were created for first­and second-­line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-­based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-­ line treatments for acute mania. First-­line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe. 1 | INTRODUCTION of the range of interventions available for this complex and varied illness, with the goal of providing clear, easy to use recommendations In the 20 years since the Canadian Network for Mood and Anxiety for clinicians to improve outcomes in their patients. Treatments (CANMAT) first published guidelines on the management Given that 13 years have elapsed since the publication of the last of BD (BD),1 there has been an explosion of research on treatment of full edition in 2005, the objective of these 2018 CANMAT and ISBD this illness. During this time period, CANMAT has strived to translate Bipolar Disorder Management Guidelines is to provide a compre- advances in research into international consensus on evidence-­based hensive, up-to-date review of research evidence on the treatment clinical management; first by publishing 2005 guidelines accompanied of various phases of BD, translated into clinical recommendations by expert commentaries, then by providing updates in 2007,2 20093 for evidence-­based management. Updated principles related to di- and 20134 in collaboration with the International Society for Bipolar agnosis and management are also included, in response to signif- Disorders (ISBD). The main objective of these publications was to syn- icant changes made in the 5th edition of the American Psychiatric thesize the wealth of evidence on the efficacy, safety, and tolerability Association Diagnostic and Statistical Manual for Mental Disorders | YATHAM et al. (DSM-­5).5 With increased research into various treatments for BD, TABLE 2 the evidence ratings have also been modified to increase rigor; for instance, minimum sample sizes are now specified for randomized controlled trials (RCTs) at each level of evidence (Table 1). Definitions for line of treatment ratings Line Evidence level First Level 1 or level 2 evidence for efficacy plus clinical support for safety/tolerability and no risk of treatment-­emergent switcha Second Level 3 or higher evidence for efficacy plus clinical support for safety/tolerability and low risk of treatment-­emergent switcha Third Level 4 evidence or higher for efficacy plus clinical support for safety/tolerability Not recommended Level 1 evidence for lack of efficacy, or level 2 evidence for lack of efficacy plus expert opinion As with previous editions of CANMAT guidelines, clinical support for efficacy was an important consideration in arriving at the final treatment recommendations (Table 2). Major conflicting data are addressed in blue text boxes (figures) to clarify the rationale for arriving at a specific level of evidence for efficacy. In the current edition, an additional distinction is made between safety and tolerability, and a consensus rating is assigned to each medication on these two measures when used in both the acute and maintenance phase. Further, a rating is also assigned to each medication for its propensity to switch patients into mania or depression (treatment-emergent switch). More information on these ratings can be found in the respective treatment sections, as well 99 a The text will specifically note when lack of clinical support for safety/ tolerability or risk of treatment-emergent switch has impacted recommendations. as in Section 8. The final grading of recommendations into first, second, or third- previous ongoing treatment was partially effective, and the addition of line considers levels of evidence for efficacy, clinical support based the new agent will provide benefits in either an additive or synergistic on experience, and consensus ratings of safety, tolerability, and risk manner. In contrast, agents specifically listed as adjunctive therapy may of treatment-­emergent switch. In addition, hierarchical rankings were have no evidence for efficacy as monotherapy, and/or may have safety created and are listed in the tables for first­and second line recom- concerns if prescribed as monotherapy (eg. antidepressants), and are mendations for acute mania, depression and maintenance treatment only recommended for use in combination with other evidence-­based in bipolar I disorder (BDI). This hierarchy was created by considering agents. the impact of each treatment across all phases of illness (Figure 1). As with previous editions, these guidelines also have a “not rec- The rationale for the hierarchical approach is that BD is a chronic ommended” category which includes treatments that have clearly lifetime condition with recurrent mood episodes and subsyndromal been shown to be ineffective in double-­blind RCTs. Further, we have mood symptoms, and most if not all patients will require maintenance included another category called “no specific recommendation/agents treatment. Since treatments that are prescribed for an acute mood ep- that require further study” to list treatments with insufficient evidence isode are usually continued into maintenance treatment, maintenance or clinical experience to make a recommendation, or where there is a efficacy should be considered when choosing acute-­phase treatments. reason to believe that negative trials failed because of methodologi- Treatments that have demonstrated efficacy across the spectrum cal problems-especially when the results are inconsistent with what is of the illness should thus be tried first before treatments that have expected based on the pharmacological properties of treatment and demonstrated efficacy for only selective phases of the disorder. As an clinical experience. Inclusion in this category means the efficacy of example, if two treatments are shown to be similarly effective in acute these agents is unknown at this time. mania, and if only one of these treatments has demonstrated efficacy As in previous editions, these guidelines are organized into eight for maintenance treatment, the treatment with evidence for mainte- sections (Table 3), including the Introduction. Foundations of man- nance would be placed higher in the hierarchical ranking. agement (Section 2) discusses the epidemiology of BD, screening Of note, when a treatment is listed as a monotherapy, that implies and diagnostic considerations, the importance of monitoring risk for that it may be used on its own or in combination with other ongoing suicide, the chronic disease management model and patient-­centred treatments, even if there are no specific studies demonstrating the ef- care (including shared decision making), as well the importance of ficacy of that combination. In this situation, the assumption is that the incorporating psychoeducation and other psychosocial treatment TABLE 1 Definitions for level of evidence ratings Level Evidence 1 Meta-­analysis with narrow confidence interval or replicated double-­blind (DB), randomized controlled trial (RCT) that includes a placebo or active control comparison (n ≥ 30 in each active treatment arm) 2 Meta-­analysis with wide confidence interval or one DB RCT with placebo or active control comparison condition (n ≥ 30 in each active treatment arm) 3 At least one DB RCT with placebo or active control comparison condition (n = 10-­29 in each active treatment arm) or health system administrative data 4 Uncontrolled trial, anecdotal reports, or expert opinion 100 | YATHAM et al. What are hierarchical rankings? Hierarchical rankings of treatment op ons are new to the 2018 Guidelines. They were created for first and second line treatment recommenda ons for acute mania, depression, and maintenance treatment of bipolar I disorder; and will further assist clinicians in making evidence based treatment decisions. These orders were created by considering the efficacy of each treatment across all phases, as well as acute and maintenance safety and tolerability and the risk for treatment emergent switch. Thus, for example if two treatments were shown to be similarly effec ve in acute mania, and if only one of these treatments has demonstrated efficacy for maintenance treatment, or had be€er safety or tolerability, that treatment would be placed higher in the hierarchical recommenda on. When making treatment decisions, we recommend that agents listed higher in the hierarchy be tried first, unless there are pa ent-specific reasons for choosing an agent lower in the order (such as pa ent preference, prior treatment non/response, or clinical features which favor treatments lower in the ranking). F I G U R E 1 Hierarchical rankings of treatment recommendations: How were they arrived at? [Colour figure can be viewed at wileyonlinelibrary.com] TABLE 3 Sections Section 1: Introduction Section 2: Foundations of management Section 3: Acute management of bipolar mania Section 4: Acute management of bipolar I depression Section 5: Maintenance therapy for bipolar I disorder applicable for practitioners from across the globe. As with previous publications, CANMAT will strive to publish regular updates to these guidelines, incorporating new knowledge useful for practising clinicians. As not all medications included in these guidelines will be available in all countries, including Canada, clinicians are advised to follow the recommendations of local regulatory bodies. Section 6: Bipolar II disorder Section 7: Specific populations Section 8: Safety and monitoring strategies into treatment. Additional information on presentation and hierarchical rankings of treatment options for acute mania (Section 3) and depression (Section 4) are reviewed, and include descriptions of clinical features that may help direct treatment choices. The importance of long-­term maintenance treatment and promotion of treatment adherence for mood stability, as well as hierarchical rankings of treatment options are discussed in Section 5. An expert review of the available evidence for treatments of bipolar II disorder (BDII) and recommendations based on those findings are presented in Section 6. The management issues related to specific populations, including women at various stages of the reproductive cycle, children and adolescents, older adults, and those with psychiatric or medical comorbidity are each discussed in Section 7. Finally, 2 | FOUNDATIONS OF MANAGEMENT 2.1 | Epidemiology 2.1.1 | Prevalence Bipolar disorder is a common and disabling mental illness with significant morbidity and mortality. The estimates of prevalence of BD vary. The World Mental Health Survey Initiative reported total lifetime (and 12-­month) prevalence estimates of 2.4% (1.5%) across BDI, BDII and subthreshold BD subtypes. While the prevalence rates for each subtype varied across the nine countries studied, subthreshold BD was the most common at 1.4% (0.8%), followed by BDI at 0.6% (0.4%) and BDII at 0.4% (0.3%).6 While Canada was not included in this study, similar results were reported from the Canadian Community Health Survey-­Mental Health, which found the lifetime prevalence of BDI was 0.87% and that of BDII was 0.67%.7 the principles of medical monitoring and an overview of safety and tolerability concerns for recommended treatments are provided in Section 8. 2.1.2 | Age of onset For convenience and to avoid confusion, these guidelines also Bipolar disorder frequently manifests in late adolescence and include a table of commonly used terms (with an explanation of the young adulthood, with an overall average age of onset of 25 years. intended meaning) that may have overlapping definitions or criteria in Statistical models suggest the presence of three age of onset sub- the literature (Table 4). groups within BDI and these can be categorized into a large early-­ These guidelines are intended for use by psychiatrists and primary onset group (mean ± standard deviation (SD) 17.24 ± 3.20 years), care providers who care for patients with BD throughout the lifespan, and smaller middle-­ o nset (23.93 ± 5.12 years) and late-­ o nset supporting them to provide evidence-­based assessment, treatment of (32.20 ± 11.96 years) groups, with the proportion of individu- acute symptoms, prevention of episode recurrence, and management of als falling into each category being 41.7%, 24.7% and 33.6% comorbidities. These guidelines are not meant to replace clinical judge- of the total sample, respectively. 8 However, the ages of onset ment or define standards of care. While designed with Canadian physi- tend to differ somewhat depending upon the origins of sam- cians in mind, input from experts from the ISBD makes these guidelines ples analysed. For instance, a recent study showed that the | YATHAM et al. TABLE 4 101 Clarifying overlapping terminology Term Use Mood stabilizer Use in the literature is inconsistent, and so this term will not be used in these guidelines Divalproex Encompasses valproate, valpromide, valproic acid and divalproex sodium Conventional antipsychotics Include first-­generation antipsychotics with high affinity for dopamine D2 receptors. Note these are referred to as dopamine receptor antagonists (D2) in the new neuroscience-­based nomenclature Atypical antipsychotics Comprise second-­generation antipsychotics with affinity for dopamine D2 and serotonin 5-­HT2 receptors as well as those that have partial agonist effects at D2/D3 receptors. Note these are referred to as dopamine and serotonin receptor antagonists (D2 and 5-­HT2A), dopamine 2 partial agonists and serotonin receptor antagonists, and dopamine 2/3 partial agonists in the new neuroscience-­based nomenclature Recurrence Re-­emerging episode(s) of mania or depression whether it be within the previous episode or a new episode. Note that, while the literature may use “relapse” and “recurrence”, respectively, inconsistencies in how they are applied and their irrelevance to treatment decisions mean we will use “recurrence” to refer to both Maintenance Prophylactic therapy after stabilization of acute manic or depressive episodes mean age of onset for a USA sample was 20 years, with ages a systematic review addressing cost of illness studies, with findings of onset of 14.5 ± 4.9 years (63%), 26.5 ± 7.6 years (28.5%), demonstrating that the worldwide annual costs per person with BD and 39.5 ± 12.5 years (8.5%) for early-­, middle-­ and late-­o nset range from US $1904 to $33 090; higher per person costs associated groups, respectively; while a European sample showed a later with BDI, delayed or misdiagnosis, frequent psychiatric interventions, mean age of onset of 29 years and a later onset in each of the use of atypical antipsychotics, treatment non-­adherence, poor prog- three categories, with 19 ± 2.7 years (24.8%), 27.2 ± 6.3 years nosis, relapse, and comorbidity.26 (50.7%), and 41.8 ± 10.7 years (24.5%) as the ages of onset for early, middle and late-­o nset groups, respectively. 9 Those with an earlier age of onset tend to have a longer delay to treatment, greater depressive symptom severity, and higher levels of comorbid anxiety and substance use. 10 While manic episodes can 2.2 | Diagnostic assessment 2.2.1 | DSM-­5 diagnostic criteria occur for the first time after the age of 50 years as a part of BDI, Bipolar disorder encompasses a spectrum of diagnostic subgroups the possibility of organic mania should be considered and inves- primarily divided according to the severity of mood elevation expe- tigated in these cases. 11 rienced during acute episodes5 On this spectrum, BDI is placed at one pole due to the presence of threshold manic episodes in which features include inflated self-­esteem, decreased need for sleep, pres- 2.1.3 | Burden of illness sured speech, racing thoughts, distractibility, psychomotor agitation, People living with BD experience substantial impairment, being symp- and risky behaviour that leads to significant functional impairment, and tomatic with syndromal or subsyndromal symptoms, particularly those may include psychotic features, and/or necessitate hospitalization. At of depression, for approximately half of their lives.12,13 Patients are the other end of the spectrum, cyclothymia is characterized by sub- unable to maintain proper work role function approximately 30% or threshold presentation of hypomanic and depressive symptoms that, more of the time. 14 Quality of life is reduced in both symptomatic and while chronic, do not meet diagnostic criteria for a major depressive non-­symptomatic patients when compared to healthy controls,15-17 episode or manic/hypomanic episode. BDII sits between the two con- and several domains of functioning have been identified by patients ditions with hypomanic episodes qualitatively like manic periods but, as being of particular importance- including physical, sleep, mood, although distinct and observable, are not of a sufficient duration or cognition, leisure, social, spirituality, finances, household, self-­esteem, severity to cause significant functional impairment, hospitalization, or independence, identity, work, and education.18 For both psychosocial psychosis. Individuals with BDII also experience threshold depressive functioning and quality of life, impairments are more pronounced in episodes. patients with depressive symptoms,19-21 in those with more previous episodes/longer duration of illness, 20,22 and in those with lower cognition.23 DSM-­5 has replaced the BD not otherwise specified (NOS) category in DSM-­IV with two new categories; other specified bipolar and related disorder and unspecified bipolar and related disorder. Also, Consistent with these observations, the Global Burden of Disease DSM-­5 includes substance/medication-­induced bipolar and related Study attributed 9.9 million years lost to disability (YLD) to BD, mak- disorder and bipolar and related disorder due to another medical th ing it the 16 leading cause of YLD worldwide. 24 The impact that BD condition. For more detailed discussion of diagnostic categories, the has on young people is even greater, with being the sixth leading reader is advised to consult DSM-­5 and recent Royal Australian and cause of disability-­adjusted life years among people aged 10-­24 years New Zealand College of Psychiatrists guidelines for treatment of mood worldwide.25 The burden of this disease was further emphasized in disorders.27 102 | YATHAM et al. episodes as well as decline in functioning and cognition.31 So far, the 2.2.2 | DSM-­5 specifiers for bipolar and related disorders heterogeneity intrinsic to BD has prevented the clinical use of stag- DSM-­5 also includes a range of specifiers that clinicians may use to ability of staging systems to guide prognosis and treatment is still to further clarify the specific course, severity, and features of BDs. While be determined. Overall, the model of staging has helped clinicians to a more detailed description can be found in the DSM-­5 manual, the appreciate the importance of early identification and treatment as well available specifiers and their use across the spectrum are listed in as illness trajectories in BD.33 ing systems.32 In addition, the field of staging is in its infancy and the Table 5. Many of these specifiers may also be used to guide treatment decisions for acute mania (Section 3) and depression (Section 4). Amongst these, the mixed features specifier, which has replaced 2.2.4 | Screening and diagnosis of bipolar disorder mixed episodes, warrants consideration because of the multiple and Due to frequent depressive onset, variable help seeking for hypomanic complex presentations of mixed states it can give rise to. Furthermore, or manic periods, temporal instability of symptoms, and high rates of the nascency of this terminology has meant that treatment data are as comorbidity; accurate the timely identification of BD can be difficult yet sparse. DSM-­5 has added mixed features as a specifier during an to achieve in many cases. Indeed, many individuals are not accurately episode of major depressive disorder (MDD) as well, which will prob- diagnosed until up to 10 years after the onset of symptoms, with one ably pose some pragmatic diagnostic challenges and management di- to four alternate diagnoses typically being given prior to correct rec- lemmas for clinicians. ognition and treatment34,35 This delay has important consequences, including inadequate initial treatment and worse prognosis in terms of episode recurrence and functional outcome.36,37 2.2.3 | Staging bipolar disorder The most frequent misdiagnosis is that of MDD, as patients The course of BD is heterogeneous but, on average, the risk of recur- are more likely to present for the treatment of depressive symp- rence increases with the number of previous episodes.28 In addition, toms and may not recall periods of hypomania or mania, or may data examining the effect of episodes on the course of illness shows not interpret them as being pathological. Recall and insight are that the number of previous episodes is associated with increased du- particularly impaired during periods of acute depression, with pro- ration and symptomatic severity of subsequent episodes. Moreover, nounced memory or concentration difficulties. There are several the number of episodes is associated with a decreased threshold for features of depression that may increase suspicion of bipolarity, developing further episodes and with an increased risk of dementia and prompt more careful investigation, including earlier age of ill- in the long term.28 The progressive course of illness in patients with ness onset, highly recurrent depressive episodes, a family history multiple episodes is called clinical progression and the biological basis of BD, depression with psychotic features, psychomotor agitation, of clinical progression is defined as neuroprogression. 28,29 atypical depressive symptoms such as hypersomnia, hyperphagia, The concepts of clinical progression and neuroprogression have and leaden paralysis, postpartum depression and psychosis, past provided the basis for the development of staging systems in BD.30 suicide attempts, and antidepressant-­induced manic symptoms or Overall, the staging models describe three broad clinical stages: (I) rapid cycling (Table 6) Given the recent change in DSM-­5 to allow individuals at increased risk for developing BD due to family history the possibility of depression symptoms with subthreshold simulta- as well as certain subsyndromal symptoms predictive of conversion neous hypomanic symptoms (mixed specifier), it is also important into full-­blown BD; (II) patients with fewer episodes and optimal func- to explore if an individual is experiencing mixed symptoms.38,39 tioning in the interepisodic periods, and (III) patients with recurrent Schizophrenia and other psychotic disorders are the second most TABLE 5 DSM-­5 specifiers for bipolar and related disorders Specifier Manic episode Depressive episode Anxious distress X X Mixed features X X Rapid cycling Illness course X Melancholic features X Atypical features X Psychotic features X X Catatonia X X Peripartum onset X X Seasonal pattern X Remission X X Current episode severity X X | YATHAM et al. common misdiagnosis, occurring as the initial diagnosis in as many as 30% of patients. 40 103 medical or neurological conditions, substance use, and medications must be considered in the differential diagnosis (Table 7). In addition to this under-­diagnosis, there are also concerns that BD may be over-­diagnosed in some circumstances.41 For instance, the symptoms of borderline personality disorder, substance use disorder 2.3 | Suicide risk (SUD) and attention deficit hyperactivity disorder (ADHD) overlap sig- It is important for clinicians to frequently monitor suicidal ideation nificantly those of hypomania/mania, and some reports suggest that and risk. Suicide is one of the leading causes of death in BD, with ap- patients with these conditions often get misdiagnosed with BD. These proximately 6%-­7% of identified patients with BD dying by suicide; conditions also are often comorbid with BD, which makes the diagno- thus, suicide risk is substantially higher in BD than in the general sis of this condition often challenging. 42 population (10.7 per 100 000 per year).46,47 The fatality of suicide Validated self-­report instruments, such as the Mood Disorders attempts is also higher in BD than in the general population.48,49 Questionnaire (MDQ), may be used as a screening tool to flag patients Worldwide, approximately 43% of patients with BD report suicidal for whom a more detailed assessment is needed. It is important to ideation, 21% a plan, and 16% a suicide attempt within the past note, that such tools have poor sensitivity and specificity, especially in year.6 Men are at a higher risk of death by suicide, with an estimated community or highly comorbid populations, and will thus have an ele- rate of 0.366 per 100 person years, compared to 0.217 for women.47 vated risk of also flagging those with borderline traits. 43 As such, tools As reviewed in the ISBD Task Force on Suicide in Bipolar such as the MDQ should be used only as an adjunct for screening clini- Disorder,50 a number of sociodemographic and clinical risk factors cal populations and not for diagnostic or treatment planning purposes. need to be considered in determining the level of suicide risk (Table 8). To improve the accuracy of diagnosis, it is important that clinicians Factors reported to be significantly associated with suicidal attempt strictly adhere to diagnostic criteria rather than relying on heuristics.44 include female sex, younger age of illness onset, depressive polarity It is important to complete a careful psychiatric history, including in of first illness episode, depressive polarity of current or more recent first-­degree relatives, with attention paid to any suspected periods of episode, comorbid anxiety disorder, comorbid SUD, comorbid cluster increased activity, irritability, or other change in behaviours. Collateral B/borderline personality disorder, first-­degree family history of sui- information from friends and family members should be included cide, and previous suicide attempts. Only male sex and first-­degree wherever possible. Ongoing monitoring of symptoms, such as mood family history of suicide have been significantly associated with sui- charting, can also help to detect bipolarity that may only become ap- cide deaths.50,51 The periods during and following hospital admission parent over time. Confirmation of the diagnosis can then be made further represent times of particularly high risk, with 14% of suicides more confidently when episodes are prospectively observed. occurring during an inpatient stay and another 26% within 6 weeks of discharge.47,52 A comprehensive assessment for suicide risk should occur during 2.2.5 | Comorbidities and mimics all clinical interactions. Risk stratification using assessment tools is not As described in Section 6, patients diagnosed with BD very commonly sufficiently accurate for prediction of suicide risk in clinical use; in- have one or more comorbid psychiatric diagnoses, with SUDs, im- stead, clinical assessment should focus on modifiable risk factors that pulse control disorders, anxiety disorders, and personality disorders could be targeted to reduce the risk.53 The ISBD has developed clinical (especially cluster B disorders) particularly common. 45 The presence tips and patient information sheets (translated into several languages) of comorbidity increases the complexity of the illness and can make that can be useful tools for clinicians, patients and families to develop an accurate diagnosis even more difficult. a comprehensive approach to suicide prevention (http://www.isbd. In addition to differentiating BD from other psychiatric diagnoses, alternative causes of mood symptoms, such as personality disorders, TABLE 6 org/Files/Admin/Knowledge-Center-Documents/Suicide-PreventionTip-Sheet.pdf). Features of depression that may increase suspicion of a bipolar vs unipolar illness Feature Suggestive of bipolarity Suggestive of unipolarity Symptomatology and mental state signs Hypersomnia and/or increased daytime napping Hyperphagia and/or increased weight Other “atypical” depressive symptoms such as leaden paralysis Psychomotor retardation Psychotic features and/or pathological guilt Lability of mood; irritability; psychomotor agitation; racing thoughts Initial insomnia/reduced sleep Appetite and/or weight loss Normal or increased activity levels Somatic complaints Course of illness Early onset of first depression (25 years) Long duration of current episode (>6 months) Family history Positive family history of bipolar disorder Negative family history of bipolar disorder Adapted from Mitchell et al.38 and Schaffer et al.39 104 | TABLE 7 YATHAM et al. Differential diagnosis of bipolar disorder Diagnosis Distinguishing features Major depressive disorder or persistent depressive disorder Manic or hypomanic episodes probed for and not present Bipolar or related disorder due to another medical condition Episodes are judged to be a consequence of a medical condition such as traumatic brain injury, brain tumours such as frontal lobe meningiomas, multiple sclerosis, stroke, Cushing’s disease or hyperthyroidism. Onset or exacerbation of mood coincides with that of the medical condition Substance-­or medication-­induced mood disorder Episodes are judged to be a consequence of a substance such as an illicit drug, or a medication (stimulants, steroids, l-­dopa or antidepressants) or toxin exposure. Episodes may be related to intoxication or withdrawal Cyclothymic disorder Hypomanic symptoms do not meet the full criteria for a hypomanic episode, and depressive symptoms do not meet the criteria for a major depressive episode Psychotic disorders (schizoaffective disorder, schizophrenia and delusional disorder) Periods of psychotic symptoms in the absence of prominent mood symptoms. Consider onset, accompanying symptoms, pervious course and family history Borderline personality disordera Instability of interpersonal relationships, self-­image and mood, with marked impulsivity and a central theme of intense abandonment fears. Early onset and long-­standing course. True euphoria and prolonged well-­functioning intervals are extremely rare Narcissistic personality disordera Grandiosity, need for admiration and lack of empathy of early onset. Grandiosity not associated with mood changes or functional impairments Antisocial personality disordera Early onset of disregard for, and violation of, the rights of others, which does not occur only in the context of a manic episode Adapted from Yatham et al. 20052 Can occur comorbidly with bipolar disorder. a The association between various treatments and suicide risk directly to the primary care provider with attention to continuity of has been reviewed by the ISBD Task Force and others, which care.58 Additional psychosocial treatments (described below) may also suggest that lithium 54 and, to a lesser extent, anticonvulsants may be selected to fit the specific needs and preferences of the patient. contribute to preventing suicide attempts and deaths; although more A strong therapeutic alliance is central to improve treatment adher- data are needed to determine their relative efficacies. There were lim- ence and outcomes.59,60 Providers should encourage individuals to ac- ited data on both antipsychotics and antidepressant agents.47 As the tively participate in treatment planning, using a shared decision-­making most common method of suicide in this population is self-­poisoning, approach.61,62 Whenever possible, family members or key friends should the potential benefits of various treatments should be considered be included as part of the care team. There is evidence that specialized, against their risk of toxicity and lethality. One small Canadian study team-­approach-­based interventions combining pharmacotherapy and indicated higher rates of lethal doses of antipsychotics (32%), opioids psychoeducation are more effective than standard community care.63 (29%), benzodiazepines (27%), carbamazepine (21%) and diphenhydr- Regular, ongoing monitoring of mood symptoms and other mea- amine (15%) compared to lithium (3%) in 34 self-­poisoning deaths.55 sures related to the patient’s own individual recovery, such as sleep, cognition, functioning, and quality of life is encouraged.18 For many 2.4 | Chronic disease management patients, daily recording of mood symptoms such as through a mood diary or National Institute of Mental Health (NIMH) Life Chart Due to the chronic, relapsing and remitting nature of BD, a long-­term, Method-­Self Rating Scale can help identify early warning signs of re- multidisciplinary approach to management is needed. The Chronic lapse, as well as outline relationships between mood and treatment or 56 Disease Management Model outlines several important principles to lifestyle factors such as diet, exercise, or stress.64 While many patients enhance long-­term care for these individuals and their families (Table 9). will agree with the value of completing a mood diary, and this strategy After basic clinical management, including attention to diagnosis, comor- has been shown to improve treatment, regular completion can be a bidity, and medical health has been established, patient health education burden.65 Online solutions such as mobile apps may improve adher- and pharmacotherapy should be the initial and foundational steps for ence,66 such as the Self-­Monitoring and Psychoeducation In Bipolar all patients. Ideally, the patient will be connected to a health care team Patients smartphone app (SIMPLE) which provides weekly and daily which includes at least one other health care professional (typically a mood tests, with reminders to take medication or see their doctor.67-69 nurse) in addition to the psychiatrist for psychoeducation, ongoing monitoring, psychosocial support, and referral to community resources.57 All patients should have access to a primary care provider to attend to 2.5 | Dealing with stigma mental and physical health needs. If the patient is stable and discharged Stigma is an important issue that will impact individuals with BD, as well to primary care, the mental health care system should provide support as their family members, potentially preventing individuals from seeking | YATHAM et al. T A B L E 8 Summary of main factors associated with suicide attempt and suicide deaths in bipolar disorder (BD) 105 can be perceived or experienced with interactions with others, including health care providers, or internalized (self-­stigma). Specific strategies to reduce stigma, particularly self-­stigma, by enhancing coping Increased likelihood of suicide attempts Increased likelihood of suicide deaths Sex Female Male Age Younger Older—higher lethality Older—higher ratio of deaths/attempts Race Minorities—youth only Marital status Single, divorced, single parents Age of onset Younger may also be useful for acute depressive episodes, as well as in main- First episode polarity Depression Mixed symptoms Mania—more violent attempts tenance treatment to prevent relapse and to restore quality of life Predominant polarity Depressive cognitive behavioural therapy (CBT), family-­focused therapy (FFT), in- Current episode polarity Depressive Mixed Depressive Mixed Manic with psychotic features Other episode characteristics Mixed features Greater number/ severity of episodes Rapid cycling Anxiety Atypical features Suicidal ideation Hopelessness Psychomotor agitation Substance use disorder Cigarette smoking Coffee intake Anxiety disorder Eating disorder Anxiety disorder Variable Psychiatric comorbidity skills through improvements in self-­esteem, empowerment, and help-­ seeking behaviour can improve outcomes in this population.71 2.6 | Psychosocial interventions While pharmacotherapy is essential and forms the foundation for the successful treatment of BD, adjunctive psychosocial interventions to the individual and family.72,73 No evidence exists, and hence there are no recommendations, for specific psychosocial interventions in acute mania. Positive evidence has been found for psychoeducation, terpersonal and social-­rhythm therapy (IPSRT), and peer support in the maintenance phase of BD and these interventions are included as recommended adjunctive treatment options. Additional studies are needed before conclusions can be drawn regarding other strategies such as family/caregiver interventions, dialectical behavioural therapy (DBT), mindfulness-­based cognitive therapy (MBCT), cognitive and functional remediation, and online interventions (Table 10). In general, provision of psychoeducation to all patients and family members is recommended for prevention of relapse, particularly at illness onset, with selection of any additional psychosocial therapies based on individual concerns/presentations or deficits. 2.6.1 | Psychoeducation Personality disorders Present—particularly borderline or cluster B Psychoeducation broadly includes provision of information about Physical comorbidity Obesity or high BMI the patient and family.74 Current psychoeducational models for BD First-­degree family history Mood disorders BD Suicide Mood disorders BD Suicide Prior suicide attempts Present Present Early life trauma Childhood abuse Early life stress Psychosocial precipitants Interpersonal problems Occupational problems Bereavement Social isolation Sexual dysfunction the nature of the illness, its treatments, and key coping strategies to teach skill development in detecting and managing prodromes of depression and mania, ongoing stress management, problem solving, how to diminish the effects of stigma and denial of the illness, and provide tips on enhancing medication adherence and developing healthy lifestyles (eg, minimizing the use of alcohol, tobacco, drugs, stimulants such as caffeine; getting regular exercise; and regulating sleep and wake times). A key goal is the creation of perPresent within 1 week of death Present Adapted from Schaffer et al.50 BMI, body mass index. sonalized coping strategies to prevent mood relapse. Psychoeducation may be delivered individually or in group settings. Empirical models of psychoeducation involve face-­to-­face interaction with a therapist, but new models are being tested that involve online tools, smartphone apps, and workbooks.75 Consistent with broader theories of learning, it is believed that psychoeducation is enhanced when it features active learning, with attention to monitoring the development of understanding, active skill development, and homework between sessions. Peer support and group learning are also or engaging in treatment or causing them to conceal their illness, reduc- postulated to add efficacy to psychoeducation. Regardless of the type ing social support, functioning and quality of life.70 Linked to stereotypi- of model and content included, priority should be given to maximize cal negative attitudes that mental illness is due to personal weaknesses the therapeutic alliance, convey empathy, and consistently monitor or decisions, or associated with violent or criminal behaviour, stigma symptoms.76 106 | YATHAM et al. TABLE 9 The chronic disease management model Self-­management support Empower and prepare patients to manage their health and health care Use effective self-­management support strategies that include assessment, goal setting, action planning, problem solving, and follow-­up Decision support Promote clinical care that is consistent with scientific evidence and patient preferences Embed evidence-­based guidelines into daily clinical practice and share this and other information with patients to encourage their participation Use proven provider education materials Community Encourage patients to participate in effective community programs Form partnerships with community organizations Delivery system design Provide clinical care and self-­management support that patients understand and that fits with their cultural background Ensure regular follow-­up by the care team, with defined tasks for different team members Provide clinical case management services for complex patients Clinical information systems Provide timely reminders for providers and patients Facilitate individual patient care planning Share information with patients and providers to coordinate care Health system Measure outcomes and use information to promote effective improvement strategies aimed at comprehensive system change Develop agreements that facilitate care coordination within and across organizations Adapted from Wagner.56 Two models of psychoeducation, both delivered in group for- additional booster sessions. Despite evidence of efficacy for CBT mat to individuals who are well (euthymic), have published manu- for MDD and psychosis, the results of CBT trials for BD have been als and have substantial research support. These programmes, the mixed. One large RCT supports it use for acute bipolar depression84 Barcelona BDs Program Goals Program 78 77 (21 sessions over 6 months) and the Life in a trial that compared the efficacy of up to 30 (mean 14) CBT (phase I is six weekly sessions), also have tools sessions against those of FFT, IPSRT, and a three-­session control to aid implementation with workbooks and handout materials, intervention, but it was not possible to identify whether the ben- and both are first-­line psychoeducational interventions based on efits came from changes in the medications prescribed or the psy- level 2 evidence for the prevention of relapse. Individual psycho- chosocial treatments. Efficacy of CBT in relapse prevention was education based on these manuals would probably be effective, observed in one RCT,85 but not in another larger RCT, at least in and when individual trials utilizing several different approaches patients who had multiple mood episodes.86 From meta-­analyses, to psychoeducation are combined in a meta-­a nalysis, individual effects on either depressive symptoms or on relapse remain uncer- psychoeducation of at least five sessions would still be a first-­ tain due to important methodological problems and study selection line intervention for relapse prevention, based on level 2 evi- factors.87-89 A promising new direction in CBT has been established dence. 75,79,80 One large study demonstrated that the six-­s ession by a pilot study of “recovery-­focused CBT” where 33 subjects re- Life Goals Program psychoeducational intervention was equiva- ceived the novel CBT intervention, with evidence of reduction of lent in relapse prevention to 20 sessions of individual CBT, at far relapse in the intervention group.90 Group CBT in euthymic pa- lower cost, 81 with probable shared mechanisms. 82 Furthermore, tients with BD is also a new direction and has shown to increase that study demonstrated that integration of best practices in med- time in remission.91 ication and psychotherapy simultaneously produced striking over- In MDD, CBT, interpersonal psychotherapy (IPT) and behavioural all improvement in course of illness. 83 Psychoeducation does not activation have been explored in multiple RCTs and in general dis- have any significant evidence of utility in either acute depressive play similar efficacies.92 Based on this and the findings of the study or manic episodes. by Miklowitz and colleagues in acute bipolar depression,84 CBT is still recommended as an adjunctive second-­line treatment for acute bipo- 2.6.2 | Cognitive behavioural therapy lar depression (level 2). The recommendation is also second-line for maintenance treatment (level 2) for patients with fewer episodes and CBT in BD is supported by several published manuals and typi- less severe form of illness. No evidence exists, and hence no recom- cally is given in 20 individual sessions over 6 months, often with mendation is made, for CBT in mania. | YATHAM et al. TABLE 10 107 Strength of evidence and recommendations for adjunctive psychological treatments for bipolar disordera Maintenance: Recommendation (Level of Evidence) Depression: Recommendation (Level of Evidence) Psychoeducation (PE) First-line (Level 2) Insufficient evidence Cognitive behavioural therapy (CBT) Second-line (Level 2) Second-line (Level 2) Family-­focused therapy (FFT) Second-line (Level 2) Second-line (Level 2) Interpersonal and social rhythm therapy (IPSRT) Third-line (Level 2) Third-line (Level 2) Peer support Third-line (Level 2) Insufficient evidence Cognitive and functional remediation Insufficient evidence Insufficient evidence Dialectical behavioural therapy (DBT) Insufficient evidence Insufficient evidence Family/caregiver interventions Insufficient evidence Insufficient evidence Mindfulness-­based cognitive therapy (MBCT) Insufficient evidence Insufficient evidence Online interventions Insufficient evidence Insufficient evidence a See text for specific definitions of type of therapy and number of sessions needed (“dose of psychosocial intervention”) corresponding to this recommendation and evidence. the intensity and number of sessions, changes in medication use, or 2.6.3 | Family-­focused therapy specific attributes of IPSRT. Two small studies failed to demonstrate FFT93 presumes that outcomes in BD may be enhanced with the sup- specific benefits of IPSRT compared to control conditions.99,100 Other port and cooperation of family or significant others, particularly in fam- open studies have shown some pre-­post benefits in very small sam- ilies characterized by high levels of expressed emotion. FFT focuses on ples.101-103 Again, since many psychosocial treatments for bipolar dis- communication styles between patients and their families or marital order share common core elements that may be psychoeducational, relationships, with the goal of improving relationship functioning, and it is possible that the relapse prevention aspects of psychoeducation is delivered to the family and patient in 21 sessions over 9 months. may also result from IPSRT interventions, mediated by the same ther- For acute bipolar depression in adults, an intensive FFT (up to 30 apeutic processes.104 94 Overall, IPSRT is recommended as an adjunctive third-­line treat- although this study was limited by the caveats identified for CBT and ment for acute depression and for maintenance, based on limited (ef- IPSRT. Given that the original creation of FFT targeted factors related fect size and small sample size) level 2 evidence in each phase. No to depression, it may have specific antidepressant activity, which is evidence exists, and hence no recommendation is made, for IPSRT for also suggested by reduced depression relapse in maintenance stud- mania. sessions; mean 14) out-­performed a three-­session control condition, ies. For relapse prevention, four significant RCTs of varying sizes have been conducted, delivered to a mixed audience of young adults and adolescents.95 In these studies, FFT demonstrated efficacy in reduc- 2.6.5 | Peer interventions ing recurrence of new episodes of depression, but not mania. Overall, Peer interventions, such as peer groups or one-­on-­one support, are FFT is recommended as adjunctive second-­line treatment for acute an important strategy believed to reduce self-­stigma and isolation in depression (level 2) and for maintenance (level 2). No evidence exists, BD, and to help improve engagement in treatment.105 Some caution and hence no recommendation is made, for FFT for mania. is needed when applying this strategy, however, as there may be risks if the peers delivering the intervention are not adequately trained or 2.6.4 | Interpersonal and social rhythm therapy supported, and if they promote a viewpoint that does not support treatment compliance or promotes substance use. IPSRT expands on the IPT focus on grief, interpersonal role tran- Reviews of peer interventions for persons with serious mental sition, role dispute, and interpersonal deficits by including regula- illnesses, usually incorporating a small but significant number of in- tion of social and sleep rhythms, specifically targeted to the bipolar dividuals with BD, have demonstrated modest evidence from RCTs population. It is typically delivered in 24 individual sessions over and other controlled studies suggesting that there are important im- 9 months. 96,97 provements in self-­efficacy and reduction in self-­stigma.106-109 The Few controlled trials of IPSRT have been conducted, with lim- largest peer intervention study involving BD allocated 153 individuals ited evidence of acute efficacy. The first, large trial98 showed no ef- to attend 21 weekly group psychoeducation events, with another 151 fect of IPSRT compared to a control condition but did show benefit assigned to attend 21 weekly group peer support events. The two pro- for reduction of relapse and improved occupational functioning. An grammes achieved similar outcomes in terms of time to relapse, and acute bipolar depression study84 showed intensive IPSRT (up to 30 increased knowledge about BD, although psychoeducation was more sessions; mean 14) out-­performed a three-­session control condition, acceptable to the subjects and worked more effectively at preventing but it is impossible to state whether the performance was related to relapse in a subset of people with fewer previous episodes.110 108 | YATHAM et al. A significant source of peer support is emerging from online resources, particularly through the websites of peer advocacy or- 2.6.7 | Cognitive and functional remediation ganizations such as the Depression and Bipolar Support Alliance Functional impairment as well as cognitive deficits are found in many (http://www.dbsalliance.org/site/PageServer?pagename=peer_ individuals with BD, not just during an acute episode but even be- landing), the Mood Disorders Association of Ontario (https://www. tween episodes, prompting the evaluation of various psychosocial mooddisorders.ca/), the research and advocacy group CREST.BD and biological strategies to address these problems. One intervention, (http://www.crestbd.ca/), (www.moodswings.net. functional remediation (FR), involves a 21-­session group intervention au/), and Revivre (http:/wwww.Revivre.org). YouTube is also emerg- over 6 months. In a large RCT, FR was shown to have a substantial im- ing as an important source of peer support, along with other social pact on functioning, in comparison to treatment as usual.117 Coupled media.111,112 with the results of other small studies involving other interventions, MoodSwings Overall, peer interventions receive a third-­line treatment recommendation (level 2) as an adjunctive maintenance therapy. these findings suggest that there is considerable hope in addressing cognitive and functional deficits in BD.118 Computer-­based cognitive remediation, though, may show positive effects on cognition but not 2.6.6 | Other psychosocial interventions Various other approaches have been tried in BD, with a variety of aims, modalities, and outcome targets. None of the other interven- on functioning.119 2.6.8 | Online and digital strategies tions have been specifically targeted for bipolar depression or for Modern trends to rely on the internet and apps, along with access mania. Some have been designed in part to reduce episode recur- problems in mental health, have led to the study of various online rence, but none have been successful in providing substantial evi- tools and mobile phone apps.120 Such strategies also build on strong dence of efficacy. Because CANMAT recommendations are for the traditions of self-­ monitoring and self-­ management developed for- treatment of acute depression and mania, and maintenance treat- mally in traditional psychoeducational interventions. In reviews, such ment to prevent them, we do not make specific recommendations internet and mobile health interventions have shown good adherence regarding these treatments. However, some of these approaches have to validated psychological health principles, good acceptability to pa- been helpful in ameliorating some important symptoms in individuals tients, ease of access, and ease of use. However, research is mostly with BD, (such as residual mood symptoms or anxiety) and so we will limited to pilot studies and the relatively few larger studies have not describe them briefly. shown unequivocal benefit.68,121 Although somewhat like FFT, family/caregiver interventions constitute a distinctly different psychosocial intervention in that the intervention is given to the family/caregiver, not the person with BD, and evidence exists that such interventions improve clinical outcomes in the patient.75,113 Clinical wisdom and common practice, however, support the importance of family or caregivers being included in at 3 | ACUTE MANAGEMENT OF BIPOLAR MANIA 3.1 | Presentations of mania least some sessions with the patient (particularly for psychoeduca- DSM-­55 made a change to “criterion A” for mania which now requires tion), both to reduce symptom burden on the individual with BD and a distinct period of abnormally and persistently elevated, expansive, to reduce burnout and emotional burden on the caregiver. Validated or irritable mood and abnormally and persistently increased activity or caregiver resources are available online, such as www.bipolarcaregiv- energy present most of the day, nearly every day for at least 1 week ers.org. 114 (or less time if hospitalization is necessary). In addition, a diagnosis of DBT, which includes distress tolerance training, has several small a “manic episode” requires at least three (or four if the mood is only studies showing its utility in the reduction of some depressive symp- irritable) of the following symptoms: inflated self-­esteem or grandios- toms and suicidality.75 ity, decreased need for sleep, more talkative than usual or pressure One RCT of MBCT involving 95 patients did not demonstrate any of speech, flight of ideas or subjective experience that thoughts are difference in relapse prevention compared to a treatment-­as-­usual racing, distractibility, increased goal-­directed activity or psychomotor group, but did reveal fewer anxiety and depressive symptoms in the agitation, or excessive involvement in activities with a high potential MBCT arm.115 Coupled with the findings of other smaller studies, this for painful consequences. The mood disturbance must lead to marked suggests that MBCT may have a role to play in anxiety reduction in impairment in functioning, require hospitalization, or be accompanied BD.75,116 by psychotic features. While not reviewed here, given that individuals with BD may have Unlike DSM-­IV, DSM-­5 allows a diagnosis of BDI in patients with histories of childhood abuse and comorbid personality disorders, and major depression whose mania emerges during treatment (eg, during experience various sequelae such as shame or conflict due to be- medication or electroconvulsive therapy [ECT]) and persists at a fully haviours experienced during acute bipolar episodes, all of these may syndromal level beyond the physiological effect of the treatment. rightly be a target for psychosocial intervention in a very individualized manner. DSM-­5 has eliminated the categorical “mixed episode” specifier, replacing it with the more dimensional “mixed features”. DSM-­5 also | YATHAM et al. 109 includes other specifiers that can accompany a manic episode: anx- In countries where inhaled loxapine is available, this could be consid- ious distress, rapid cycling, mood-­ congruent or mood-­ incongruent ered if there are no contraindications. psychotic features, catatonia, peripartum onset, and seasonal pattern If oral preparations are ineffective or if the agitation is severe (Table 5). The utility of several of these specifiers in selecting treat- and if the patient is refusing oral medications, or when oral ther- ment options for mania is discussed later in this section (see “Clinical apy cannot be safely or reliably administered, then IM formulations features that help direct treatment choice”). should be considered.124 Because of the strength of evidence for efficacy in alleviating agitation in this population, aripiprazole IM (level 2),125,126 lorazepam IM (level 2),125,127 loxapine inhaled (Level 3.2 | Management of agitation 1)128,129 and olanzapine IM (level 2)127,130-133 are recommended as Agitation is common in mania, and is particularly frequent in patients who have mixed features. 122 Defined in DSM-­5 as “excessive motor 5 the first-­line option. Sublingual asenapine (level 3),134 haloperidol IM (level 3),131,135,136 haloperidol IM + midazolam IM (level 3),131,137 hal- activity associated with a feeling of inner tension”, agitation can operidol IM + promethazine IM (level 3),131,137,138 risperidone ODT manifest as pacing or fidgeting in mild cases to uncooperative, threat- (level 3),136 and ziprasidone IM (level 3)131,137,139 are recommended ening, or aggressive behaviours in severe cases. Severe symptoms of as a second-­line treatment. Haloperidol per os (PO) (level 4),140,141 agitation require prompt attention in order to reduce distress, mitigate loxapine IM (level 4) (clinical opinion), quetiapine PO (level 4),141 potentially dangerous behaviour, and allow for an assessment and and risperidone PO (level 4)140 are included as third-­line options evaluation of underlying manic symptoms. 123 (Table 11). A key step in treating agitation is preventing it, or at least mitigating its severity, by rapidly treating the causative manic episode. When addressing agitation in patients with BDI, clinicians need to be aware 3.3 | Pharmacological treatment of manic episodes that akathisia may present as agitation and, therefore, this must be There are a range of strategies that have been investigated for use in excluded before implementing the general principles of management mania; including lithium, divalproex, other anticonvulsants, typical and of acute mania described in step 1 (see “Pharmacological treatment atypical antipsychotics, and other agents and therapies. These treat- of manic episodes”). Since agitation in this context is a manifestation ments have been evaluated using the criteria for strength of evidence of mania, it is assumed that effective interventions for treating mania for efficacy (Table 1) as well as safety and tolerability (Section 8). The that have rapid onset of efficacy would be effective in reducing agita- evidence for efficacy and the recommendations for treating acute tion. Therefore, if the patient is agreeable to taking oral medications, mania are summarized in Table 12. antimanic agents with rapid onset of efficacy should be considered first. As stated previously, the first­and second-­line agents are listed hierarchically taking into consideration not only their efficacy for acute When agitation persists despite administration of antimanic mania but also their efficacy in preventing mania or depression, treating treatments, additional rapidly acting pharmacotherapy may often be acute bipolar depression, safety/tolerability and the risk of treatment-­ needed. The evidence for specific efficacy of various agents in short-­ emergent switch. The implication of this hierarchical recommendation term treatment of agitation is summarized in Table 11. Some of these is that those listed higher up in the table should be considered first agents are either not available or rarely used in North America (eg, before moving on to the next on the list, unless other factors such midazolam and promethazine). We further note that the dose ranges as history of previous non-­response or patient’s preferences preclude in Table 11 are based on the doses studied in the trials, and would such strategy in a given patient. probably be appropriate in most situations. However, a comprehen- Monotherapy and combination therapy are listed separately sive evaluation of the agitated patient is necessary (ie, medical con- as first-­l ine treatments for acute mania in Table 12. This does not ditions, treatments, drugs, intoxication, etc.) to determine a safe and mean that all monotherapy agents should be tried first before adequate dose. considering combination therapy for acute mania. We suggest As can be seen from Table 11, the highest level of evidence avail- that the treating clinician make a decision as to whether to treat able in short-­term treatment of agitation for oral formulations of any a given patient with monotherapy or combination therapy. That agent is level 3, and level 2 for intramuscular (IM) or inhaled formula- decision is typically based on the rapidity of response needed tions. In this context, it is important to remember that the absence of (eg, combination treatments tend to work faster), whether the evidence does not constitute lack of efficacy. Indeed, clinical expe- patient had a previous history of partial response to monother- rience suggests that agitation in many patients with acute mania re- apy, severity of mania, tolerability concerns with combination sponds well to the oral medications. Thus, a loading dose of divalproex, therapy, and willingness of the patient to take combination ther- oral formulations of atypical antipsychotics, conventional antipsychot- apy. Once a decision is made whether to treat the patient with ics such as haloperidol or loxapine, and/or benzodiazepines such as monotherapy or combination therapy, then hierarchy related lorazepam may be appropriate. If a patient indicates willingness to take to monotherapy or combination therapy could be followed. We oral treatment but there is a suspicion that the patient might “cheek” also suggest that clinicians evaluate the efficacy and tolerabil- the medication, then either orally dispersing tablets (ODT), those that ity at the end of weeks 1 and 2 and modify treatment options rapidly melt, oral liquid, or oral inhalation forms should be considered. accordingly. 110 | TABLE 11 YATHAM et al. Level of evidence and recommendations for short-­term pharmacological management of agitationa Dose range of studiesb Level of recommendation Agent Formulation Level of evidence Single dose Max/24 h First-line Aripiprazole IM 2 9.75 mg 15 mg Lorazepam IM 2 2 mg IM Loxapine Inhaled 1 5 mg 10 mg Olanzapine IM 2 2.5 mg 10 mgc Asenapine Sublingual 3 10 mg Haloperidol IM 3 5 mg 15 mg Haloperidol + midazolam IM 3 2.5 mg (haloperidol) + 7.5 mg (midazolam) 5 mg (haloperidol) + 15mg (midazolam) Haloperidol + promethazine IMe 3 2.5 mg (haloperidol) + 25 mg (promethazine) 5 mg (haloperidol) + 50 mg (promethazine) Risperidone ODTe 3 2 mg 4 mg Ziprasidone IMe 3 2 mg 20 mg 15 mg Second-line Third-line d Haloperidol PO 4 5 mg Loxapine IM 4 N/A Quetiapine POd 4 Mean (SD) = 486.7 (317.2) mg/day Risperidone POe 4 2 mg a See text for recommendations about use of oral antipsychotics and divalproex. IM, intramuscular; ODT, orally disintegrating tablet; PO, per os. Doses are reported as per studies. c 26.3% received two or three 10 mg injections. d Assessed 2 h after the dose. e Doses are not specifically for bipolar disorder but included schizophrenia or other diagnoses. b 3.3.1 | Step 1: review general principles and assess medication status monitoring patients for a period of time after antidepressant discontinuation and obtain collateral information to confirm whether symptoms remain and antimanic treatment is necessary. Patients Examination of a patient presenting in a manic state should include should also be supported to discontinue stimulant use, including caf- an immediate assessment for risk of aggressive behaviour, violence feine and alcohol. Current and prior therapies should be assessed, and safety threat to others, suicide risk especially in those with mixed including appropriateness of medications, dosing, and trough serum features, degree of insight and the ability to adhere to treatment, levels (where indicated), as well as past response; and this should comorbidity (including substance use that may be aggravating or be used to direct subsequent therapeutic choices. Attention should contributing to clinical presentation), and availability of a psychoso- be paid to managing withdrawal symptoms that may occur in manic cial support network. A physical examination with laboratory inves- patients with histories of substance abuse. tigations (described in Section 8) should be conducted, but may be When the symptoms of mania have remitted, behavioural and ed- deferred for patients who are uncooperative. Results of the overall ucational strategies should be applied to promote ongoing medication assessment should be used to establish the most appropriate treat- adherence, reduce residual symptoms, help identify early signs of re- ment setting (eg, ambulatory or inpatient). lapse, and support functional recovery (see Section 2). Before initiating pharmacological treatment for a manic episode, it is imperative to rule out symptoms secondary to drugs of abuse, medications, other treatments, or a general medical or neurological condition (although, even in these cases, symptomatic treatment 3.3.2 | Step 2: initiate or optimize therapy and check adherence may be applied on a short-­term basis). Steps should be taken to rule It is recommended that, for all patients (including those who are un- out any other factors that may be perpetuating symptoms such as treated as well as those receiving a non-­first-­line treatment), therapy prescribed medication, illicit drug use/abuse or an endocrine dis- be initiated with one of the available first-­line monotherapy or com- order. Any patients presenting with mania who have been taking bination treatments. antidepressants should have these medications discontinued. If there is a previous diagnosis of BD, it is appropriate to immediately First-­line monotherapy commence antimanic agents. If this is the first emergence of manic Approximately 50% of patients will respond to monotherapy with symptoms, clinicians are advised to confirm the diagnosis of BD by significant improvement in manic symptoms within 3-­ 4 weeks.142 Hierarchical rankings of first­and second-­line treatments recommended for management of acute mania DVP, divalproex; ECT, electroconvulsive therapy; Li, lithium. , level 1 evidence; , level 2 evidence; , level 3 evidence; , level 4 evidence; , level 1 negative evidence; , level 2 negative evidence; , level 3 negative evidence; , level 4 negative evidence; n.d., no data; Limited impact on treatment selection; , minor impact on treatment selection; , moderate impact on treatment selection; , significant impact on treatment selection. a Although monotherapies are listed above combination therapies in the hierarchy, combination therapies may be indicated as the preferred choice in patients with previous history of partial response to monotherapy and in those with psychotic mania or in situations where rapid response is desirable. b Did not separate from placebo in those with index mania; no studies available in index depression. c No controlled trials; however, clinical experience suggests that it is a useful strategy. d Did not separate from placebo on core symptoms of depression. e Divalproex and carbamazepine should be used with caution in women of childbearing age. [Colour table can be viewed at wileyonlinelibrary.com] TABLE 12 YATHAM et al. | 111 112 | YATHAM et al. Lithium (level 1), quetiapine (level 1), divalproex (level 1), asenapine (level 1), aripiprazole (level 1), paliperidone (level 1 for doses >6 mg), risperidone (level 1), and cariprazine (level 1) are all recommended as 3.3.3 | Step 3: add on or switch therapy (alternate first-­line agents) first-­line treatment options. Overall, these agents show comparable If therapy with one or a combination of the first-­line agents (lithium, efficacy (Cohen’s d 0.32-­0.66; small to medium effect size).143 divalproex and/or an atypical antipsychotic) at optimal doses is inad- Although they have comparable efficacy for treating acute mania, equate or not tolerated, the next step is to switch to or add on an al- we recommend that the agents listed first in the text and placed higher ternate first-­line agent. An exception is that, despite level 1 evidence in Table 12 be tried first, in the order listed, unless there are patient-­ for monotherapy with paliperidone and ziprasidone, we do not specific reasons for choosing an agent lower down in the order (see recommend combination therapy with these agents due to lack of “Clinical features that help direct treatment choices”). For instance, evidence for additional efficacy (see “No specific recommendation/ lithium should be considered first for acute mania unless there are agents that require further study” below). Because there are multiple specific reasons not to, such as mixed features, comorbid substance first-­line agents with substantial efficacy data and relative safety and use or previous non-­response to lithium. tolerability, the use of second-­and third-­line agents is only recom- Carbamazepine, olanzapine, ziprasidone and haloperidol also have mended after unsuccessful trials of multiple first-­line strategies. level 1 evidence for efficacy but they are downgraded to second-­line options due to safety/tolerability risks with these agents. 3.3.4 | Step 4: add on or switch therapy (second-­line agents) First-­line combination therapy Combination therapy with the atypical antipsychotics quetiapine Second-line (level 1), aripiprazole (level 2), risperidone (level 1), or asenapine (level In patients who are inadequately responsive to first-­ line agents, 2) and lithium or divalproex is also recommended as first-­line treat- second-­line choices include monotherapy with olanzapine (level 1), ment options with greater efficacy than monotherapy with lithium carbamazepine (level 1), ziprasidone (level 1), and haloperidol (level or divalproex alone, especially in those with higher index severity.144 1)143 or combination therapy with olanzapine plus lithium or dival- In general, combination therapy is preferred to mood stabilizer proex (level 1). While each of these strategies has strong support for monotherapy because clinical trials suggest that on average about their efficacy, as indicated above, safety and tolerability concerns 142,145,146 relegate them to second-­line options. Although widely used in clini- There is also some evidence to suggest the benefit of combination cal practice, the combination of lithium and divalproex is also recom- therapy compared to atypical antipsychotic monotherapy, although mended as a second-­line choice, as evidence supporting its efficacy is there are fewer trials. Specifically, lithium plus quetiapine showed su- limited to uncontrolled trials (level 3).148-151 20% more patients will respond to combination therapy. periority to quetiapine alone.147 While there is also level 1 evidence ECT is also recommended as a second-­line option (level 3)152 and, for olanzapine combination therapy over olanzapine monotherapy, although the number of controlled trials is limited, there is evidence to this is downgraded to second-line due to tolerability/safety concerns suggest that up to 80% of patients will show marked clinical improve- with olanzapine. ments.153 Brief pulse therapy with two or three treatments per week The decision to treat with one or a combination of available first-­ has been used. Bifrontal electrode placement is preferred over bitem- line agents should be informed by current and prior medication use, poral as it is associated with faster treatment response and fewer cog- with treatment previously shown to be successful in managing symp- nitive side effects.154-156 toms preferred. Safety and tolerability factors for each medication and When all first-­line agents have failed, the hierarchy should be ap- clinical features predictive of better response (see “Clinical features plied to second-­line agents as well. Hence, olanzapine, which is high- that help direct treatment choices”) should also be considered. In gen- est in the hierarchy amongst second-­line agents, should be first choice eral, combination therapy is associated with more adverse events than before moving down the list in Table 12. monotherapy. Whenever possible, options should be discussed with the patient and/or their caregiver and their preferences considered prior to treatment selection. If symptoms are not controlled using monotherapy or combination 3.3.5 | Step 5: add on or switch therapy (third-­line agents) therapy with first-­line agents, dosing should be optimized, issues of Third-line non-­adherence identified and addressed, and consideration given to Agents recommended as third-­line options for treatment of acute mania possible substance use (Section 4) prior to adding or switching ther- include monotherapy with chlorpromazine (level 2),157 monotherapy apies (Step 3). Given that almost all antimanic agents separated from with clonazepam (level 2),158 monotherapy or adjunctive therapy with placebo within 1 week, some therapeutic response is expected with clozapine (level 4),159-162 and monotherapy with tamoxifen (level 2).143 antimanic agents within 1-­2 weeks. If no response is observed within Tamoxifen is downgraded because of the risk of uterine cancer and the 2 weeks with therapeutic doses of antimanic agents, and other con- lack of clinical experience despite evidence for efficacy. Combination tributing factors for non-­response are excluded, then switch or add-­on treatments with carbamazepine or oxcarbazepine (level 3),163 haloperi- strategies should be considered. dol (level 2),144,164 or tamoxifen (level 2)165 plus lithium or divalproex are | YATHAM et al. TABLE 13 Additional agents evaluated for use in acute mania Studies of olanzapine (level 2 negative) 174 Third-line negative) 173 113 or risperidone (level 3 plus carbamazepine have been negative, although this is Agent Level of evidence Carbamazepine/oxcarbazepine + Li/DVP Level 3 Chlorpromazine Level 2 tions are unpredictable and effective doses have not been established, Clonazepam Level 2 we are unable to provide a specific recommendation. Clozapine Level 4 Nutraceuticals such as branched chain amino acids (level 3),175 Haloperidol + Li/DVP Level 2 folic acid (level 2),176 and l-­tryptophan (level 3),177 as well as other rTMS Level 3 experimental agents such as medroxyprogesterone (level 3),178,179 me- Tamoxifen Level 2 mantine (level 4),180 mexiletine (level 4),181 levetiracetam (level 4)182 Tamoxifen + Li/DVP Level 2 and phenytoin (level 3),183 have all shown indications of efficacy when Level 1 negative used adjunctively with other antimanic agents, as have glasses that Not recommended Allopurinol probably due to enzyme-­inducing effects of carbamazepine. While this may be overcome by dosing adjustments, because such interac- Eslicarbazepine/licarbazepine Level 2 negative Gabapentin Level 2 negative Lamotrigine Level 1 negative Omega-­3 fatty acids Level 1 negative Topiramate Level 1 negative Valnoctamide Level 2 negative Zonisamide Level 2 negative DVP, divalproex; Li, lithium; rTMS, repetitive transcranial magnetic stimulation. block blue light (level 3).184 Larger controlled trials are needed, however, before a recommendation for their use in mania can be made. While an initial small RCT did not show anti-­manic efficacy for verapamil,185 there is some evidence that it may work as an adjunctive therapy (level 4)186 or as monotherapy in women (level 4).187 Larger studies are needed before a conclusion can be made. 3.3.8 | Clinical features that help direct treatment choices Clinical features, including DSM-­5 specifiers, may assist in making treatment choices between first­and second-­line treatment options. also included as third-line. Repetitive transcranial magnetic stimulation In general, lithium is preferred over divalproex for individuals who (rTMS) in the right prefrontal cortex at 110% motor threshold (level display classical euphoric grandiose mania (elated mood in the ab- 3)166 can also be considered in combination with pharmacotherapy. sence of depressive symptoms), few prior episodes of illness, a mania-­ The third-­line agents should only be used if a patient has not re- depression-­euthymia course,188-190 and/or those with a family history sponded to adequate trials with all first­and second-­line agents alone of BD, especially with a family history of lithium response. Divalproex and in combination. Given that the evidence is very limited for third-­ is equally effective in those with classical and dysphoric mania. line agents, it was not possible to list them in any hierarchical order Further, divalproex is recommended for those with multiple prior and they are thus listed alphabetically (Table 13). episodes, predominant irritable or dysphoric mood and/or comorbid substance abuse or those with a history of head trauma.188,191-195 Because of its teratogenic potential, however, caution should be ex- 3.3.6 | Agents not recommended for the treatment of acute mania ercised when prescribing divalproex to women of childbearing age. Patients with specific factors such as a history of head trauma, comor- Antimanic efficacy has not been demonstrated for allopurinol (level 1 167 negative), 168 eslicarbazepine/licarbazepine (level 2 negative), gabap- entin (Level 2 negative), lamotrigine (level 1 negative),143 omega-­3 fatty 169 acids (level 1 negative), 143 topiramate (level 1 negative), valnoctamide (level 2 negative),170,171 or zonisamide (level 2 negative)172 (Table 13). bid anxiety and substance abuse, schizoaffective presentations with mood-­incongruent delusions, or negative history of bipolar illness in first-­degree relatives may respond to carbamazepine.196 Combination therapy with lithium or divalproex and an atypical antipsychotic is recommended when a response is needed faster, in patients judged at risk, who have had a previous history of partial acute 3.3.7 | No specific recommendation/agents that require further study or prophylactic response to monotherapy or in those with more severe Trials with paliperidone (level 2 negative) and ziprasidone (level 2 neg- Anxious distress ative) adjunctive therapy to lithium or divalproex showed lack of ef- Symptoms of anxiety frequently co-­occur during a manic episode, and ficacy.144 This is surprising given that all other atypical antipsychotic are a predictor of poor outcome; including greater severity of manic agents that showed efficacy in monotherapy have also been shown to symptoms,197 a longer time to remission,197,198 and more reported offer additional benefit when combined with lithium or divalproex. It is side effects of medication.198 There have been no studies specifically likely that methodological problems have contributed to failure in these examining the efficacy of any agents in reducing symptoms of anxiety studies; hence, further studies are needed before specific recommen- during a manic episode, although these symptoms do tend to improve dations can be made about the use of these combinations for mania. concurrently with mood disturbance. Post hoc analyses suggest that manic episodes.145 | 114 YATHAM et al. divalproex, quetiapine, and olanzapine may have specific anxiolytic double mood stabilizer therapy in a single RCT,221 although methodo- benefits199 and carbamazepine may be useful as well.196 logical weaknesses probably limited interpretability of the findings. Mixed features Seasonal pattern Depressive symptoms co-­ occur alongside mania in 10%-­ 30% of While some individual patients may show a seasonal pattern, Canadian 200,201 cases, with studies suggesting mixed features are indicative of data are mixed as to whether episodes of mania or depression in BD a more severe and disabling course, as well as a higher rate of sui- follow a consistent seasonal variation.222 There is no evidence for the 201,202 cide. Evidence supports the preferential use of atypical antip- sychotics and divalproex in these cases, with combination therapy 195,203 frequently required. superiority of any agent in patients with an observed seasonal pattern of manic episodes. Atypical antipsychotics such as asenapine, aripiprazole, olanzapine and ziprasidone have been shown to be equally effective in treating manic symptoms in those with classical mania as well as in mixed mania or in manic patients with mixed features.196,204,205 4 | ACUTE MANAGEMENT OF BIPOLAR DEPRESSION Psychotic features (mood congruent or incongruent) 4.1 | Presentations of bipolar depression At least half of manic episodes are characterized by the presence of psychosis,206 and theories suggest that it is a nonspecific feature which improves alongside underlying manic symptoms.207 While the prognosis for patients experiencing mood-­congruent psychotic features may not differ from those with an absence of psychotic symptoms, limited evidence does suggest that those with mood-­incongruent features have a more severe illness with poorer long-­term prognosis.207-212 There is no evidence of superiority of any first-­ line monotherapy treatment in comparison to other monotherapy options in treating patients with psychotic features. Similarly, there is no evidence that any first-­line combination therapy of lithium or divalproex plus an atypical antipsychotic is more effective than other first-­line combination 174,193,213,214 therapy. However, clinical experience suggests that the combination of lithium or divalproex plus an atypical antipsychotic is more appropriate for manic patients with mood-­incongruent psychotic features (ie, other than grandiose delusions). Similarly, in patients where the diagnostic possibility of schizoaffective disorder with manic symptoms is considered, either use of an atypical antipsychotic or combination of an atypical antipsychotic with a mood stabilizer is more appropriate. Rapid cycling The DSM-­ 5 criteria for bipolar depression are unchanged from DSM-­IV. Depression is characterized by a minimum of 2 weeks of depressed mood and/or anhedonia and at least four other symptoms that include changes in sleep, appetite/weight, energy, psychomotor activity, concentration, thought content (guilt and worthlessness), and suicidal intent. For many patients with BD, the depressive polarity is often more pervasive and more debilitating than manic states, with estimates that depressed mood accounts for up to two-­thirds of the time spent unwell, even with treatment.12,223,224 Subsyndromal depressive symptoms, which persist despite treatment, are particularly common and a major source of functional impairment in these patients.225-229 They should be treated aggressively. DSM-­5 includes several specifiers that may accompany depressive episodes: anxious distress, mixed features, rapid cycling, melancholic features, atypical features, mood-­ congruent or mood-­ incongruent psychotic features, peripartum onset, and seasonal pattern (Table 5). The utility of several of these specifiers in selecting treatment options for depression is discussed later in this section (see “Clinical features that help direct treatment choices”). 4.2 | Diagnostic and treatment challenges Rapid cycling, or a course of illness that includes four or more mood episodes a year, affects up to one-­third of patients with BDI.215-218 Hypothyroidism, antidepressant use and substance abuse are often 4.2.1 | Misdiagnosis and delayed diagnosis associated with rapid cycling; thus assessing thyroid function and dis- Patients with depression occurring in the context of BD are fre- continuation of antidepressants, stimulants, and other psychotropic quently misdiagnosed as having MDD, since the presence of mania agents that are contributors to cycling are imperative. Consideration or hypomania (particularly mild or moderate episodes which do not should be given to gradually withdrawing substances in order to pre- require hospitalization) may be challenging to establish retrospec- vent withdrawal, but this needs to be balanced against the severity of tively. This is especially true in the absence of a comprehensive mood cycling and the need for rapid mood stabilization. As there is diagnostic interview or collateral information, as patients may often no evidence for the superiority of any first-­line treatment in address- lack basic knowledge of what hypomania/mania is, and/or have lim- ing acute manic symptoms in patients with a rapid cycling course,219 ited insight into these symptoms; and thus may not disclose this appropriate pharmacotherapy should be selected primarily based on information unless specifically asked. Alternatively, patients who effectiveness in the maintenance phase, if known (see Section 5). It is will ultimately present with hypomanic or manic episodes may only likely that combinations of mood-­stabilizing drugs may be more often have experienced episodes of depression. Thus, clinicians must be necessary than monotherapies when rapid cycling is present,220 but vigilant for a diagnosis of BD, and routinely ask for symptoms of triple mood stabilizer therapy has not demonstrated superiority to a previous manic/hypomanic episode in every patient presenting | YATHAM et al. 115 with a major depressive episode. A diagnosis of MDD should be further exacerbate cognitive difficulties238 (see Section 8). Although made only after excluding the possibility of BD. evidence for their efficacy is limited, cognitive enhancement therapies In addition to overt manic/hypomanic symptoms, there are nu- can be considered experimental in this population.72,239,240 merous features that increase the likelihood of a diagnosis of BD in depressed individuals. These include earlier age of illness onset (before 25 years), brief, highly recurrent depressive episodes, a family history of BD, depression with psychotic features, atypical 4.3 | Psychological interventions for acute bipolar I depression features such as reverse vegetative symptoms of hypersomnia and While pharmacotherapy is essential and forms the foundation for hyperphagia, leaden paralysis, psychomotor agitation, postpartum successful treatment of BD, adjunctive psychosocial interventions depression or psychosis, and antidepressant-­ induced irritability, may also be useful for acute depressive episodes. As described in manic symptoms or rapid cycling38,39 (Table 6). Section 2, there are no first-­line psychosocial treatment options for Individuals with depression who are at high risk for BD, par- acute bipolar depression. Selecting between second-­line options ticularly those with a strong family history of BD, should be such as CBT (level 2) and FFT (level 2), as well as the third-­line op- closely monitored for emergence of manic or mixed symptoms. tion IPSRT (level 3), should be based on individual strengths and Consideration should also be given to applying the BD depression needs. treatment recommendations amongst those at very high risk, rather than risk potential iatrogenic effects of antidepressant monotherapy, although this recommendation is based on clinical experience as there is a lack of sufficient research addressing this issue. As 4.4 | Pharmacological treatment for acute bipolar depression discussed in Section 2, there are also several useful psychosocial Lithium, anticonvulsants, atypical antipsychotics, and other agents interventions, such as individual and family psychoeducation and such as antidepressants have all been investigated for efficacy in man- FFT, that have been shown to have some benefit in this population. aging bipolar depression. These treatments have been evaluated using the criteria for strength of evidence for efficacy (Table 1) as well as 4.2.2 | Suicide risk safety and tolerability (Section 8). Recommendations are summarized in Table 14. Principles related to management of suicidal ideation and risk (see Section 2 and47) are of utmost importance during depressive episodes, as >70% of suicide deaths and suicide attempts in patients with BD occur during this phase.230,231 Depressive episodes with 4.4.1 | Step 1: review general principles and assess medication status mixed features are a particularly dangerous period associated Examination of a patient presenting in a depressed state should in- with even higher short-­term risks of suicide attempts or death.232 clude an assessment of the nature and severity of depression and Overall, it is imperative for clinicians to review risk factors (Table 9) associated symptoms, risk of suicide/self-­harm behaviour, ability and determine an appropriate treatment setting to address any to adhere to a treatment plan, availability of a psychosocial sup- safety issues. All patients at risk should be encouraged to develop port network, and functional impairment. Laboratory investigations and share a written safety plan listing coping strategies and sources (described in Section 8) should also be completed. Results of the of support which may be applied during times of crisis. As described overall assessment should be used to establish the most appropriate in Section 2, the most common method of suicide in this population treatment setting (eg, ambulatory or inpatient), with consideration is self-­poisoning, and so potential benefits of various treatments given to management of safety risks. Before initiating pharmacolog- should be considered against their risk of toxicity and lethality. One ical treatment for a depressive episode, it is imperative to rule out study found that there were fewer deaths due to lethal lithium lev- symptoms secondary to alcohol/drug use, medications, other treat- els compared to carbamazepine, and that opioids and benzodiaz- ments, or a general medical condition. Patients should be supported epines were the most common medication classes ingested at lethal to discontinue stimulant use and limit nicotine, caffeine, drug, and levels—noteworthy given the lack of efficacy of these agents in the alcohol use. Course of illness and treatments used in current and disorder.55 prior episodes should be assessed, including past response to and tolerability of specific medications and doses, and used to direct 4.2.3 | Cognitive and functional impairment subsequent therapeutic choices. Consideration should be given to Part of the impact of acute and subsyndromal depressive symptoms coincide with a depressive relapse. restarting medications if their recent discontinuation appeared to on functional impairment is thought to be mediated through cogni- Psychoeducation and other psychosocial strategies should also tive performance, which is both subjectively and objectively impaired be offered alongside pharmacological treatment to promote ongoing in bipolar depression and linked to poor psychosocial function.233-236 medication adherence, reduce residual symptoms and suicidal be- Because of the important link between cognition and functioning,237 attention should be paid to avoiding treatments that may haviour, help identify early signs of relapse, and support functional recovery (see Section 2). Hierarchical rankings of first­and second-­line treatments recommended for management of acute bipolar I depression adj, adjunctive; DVP, divalproex; ECT, electroconvulsive therapv; Li, lithium, SSRIs, selective serotonin reuptake inhibitors. , level 1 evidence; , level 2 evidence; , level 3 evidence; , level 4 evidence; , level 1 negative evidence; , level 2 negative evidence; , level 3 negative evidence; , level 4 negative evidence; n.d., no data; , limited impact on treatment selection; , minor impact on treatment selection; , moderate impact on treatment selection; , significant impact on treatment selection. a Trend for superiority on the primary efficacy measure, hence the lower rating. b Effective in those with an index episode of depression. c Negative data from the trial are probably due to methodological issues; rating based on expert opinion. d Divalproex and carbamazepine should be used with caution in women of child bearing age. [Colour table can be viewed at wileyonlinelibrary.com] TABLE 14 116 | YATHAM et al. | YATHAM et al. 117 Why are lithium and lamotrigine recommended as first-line agents for bipolar depression? Reconciling conflicng data Lithium In the only large double blind placebo controlled trial conducted to date, lithium was not more effecve than placebo for treang acute bipolar depression(254). So, how does one jusfy recommending lithium as a first-line agent? The mean serum lithium levels in this study was only 0.61 mEq/L and this may account for la…
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