DOI: 10.1111/bdi.12609 ORIGINAL ARTICLE Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder Lakshmi N Yatham1 | Sidney H Kennedy2 | Sagar V Parikh3 | Ayal Schaffer2 | David J Bond4 | Benicio N Frey5 | Verinder Sharma6 | Benjamin I Goldstein2 | Soham Rej7 | Serge Beaulieu7 | Martin Alda8 | Glenda MacQueen9 | Roumen V Milev10 | Arun Ravindran2 | Claire O’Donovan8 | Diane McIntosh1 | Raymond W Lam1 | Gustavo Vazquez10 | Flavio Kapczinski5 | Roger S McIntyre2 | Jan Kozicky11 | Shigenobu Kanba12 | Beny Lafer13 | Trisha Suppes14 | Joseph R Calabrese15 | Eduard Vieta16 | Gin Malhi17 | Robert M Post18 | Michael Berk19 1Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada 2Department of Psychiatry, University of Toronto, Toronto, ON, Canada 3Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA 4Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA 5Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada 6Departments of Psychiatry and Obstetrics & Gynaecology, Western University, London, ON, Canada 7Department of Psychiatry, McGill University, Montreal, QC, Canada 8Department of Psychiatry, Dalhousie University, Halifax, NS, Canada 9Department of Psychiatry, University of Calgary, Calgary, AB, Canada 10Departments of Psychiatry and Psychology, Queen’s University, Kingston, ON, Canada 11School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada 12Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan 13Department of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil 14Bipolar and Depression Research Program, VA Palo Alto, Department of Psychiatry & Behavioral Sciences Stanford University, Stanford, CA, USA 15Department of Psychiatry, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA 16Bipolar Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain 17Department of Psychiatry, University of Sydney, Sydney, NSW, Australia 18Department of Psychiatry, George Washington University, Washington, DC, USA 19Deakin 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: [email protected] Bipolar Disorders. 2018;1–74. wileyonlinelibrary.com/journal/bdi © 2018 John Wiley & Sons A/S. | 1 Published by John Wiley & Sons Ltd 2 | YATHAM ET AL. The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously pub- lished treatment guidelines for bipolar disorder in 2005, along with international com- mentaries 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, includ- ing updates to diagnosis and management as well as new research into pharmacologi- cal and psychological treatments. These advances have been translated into clear and easy to use recommendations for first , second, and third- line treatments, with consid- eration 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 first and second- line treat- ments 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, paliperi- done, 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 ini- tiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recom- mendations 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 psy- chiatric and medical comorbidities such as substance use, anxiety, and metabolic disor- ders. 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 prac- titioners across the globe. 1 | INTRODUCTION of the range of interventions available for this complex and varied ill- ness, 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. | 3 (DSM- 5).5 With increased research into various treatments for BD, TABLE 2 Definitions for line of treatment ratings the evidence ratings have also been modified to increase rigor; for Line Evidence level instance, minimum sample sizes are now specified for randomized First Level 1 or level 2 evidence for efficacy plus controlled trials (RCTs) at each level of evidence (Table 1). clinical support for safety/tolerability and no As with previous editions of CANMAT guidelines, clinical support risk of treatment- emergent switcha for efficacy was an important consideration in arriving at the final Second Level 3 or higher evidence for efficacy plus treatment recommendations (Table 2). Major conflicting data are ad- clinical support for safety/tolerability and low dressed in blue text boxes (figures) to clarify the rationale for arriving risk of treatment- emergent switcha at a specific level of evidence for efficacy. Third Level 4 evidence or higher for efficacy plus In the current edition, an additional distinction is made between clinical support for safety/tolerability safety and tolerability, and a consensus rating is assigned to each Not recommended Level 1 evidence for lack of efficacy, or level 2 medication on these two measures when used in both the acute evidence for lack of efficacy plus expert opinion and maintenance phase. Further, a rating is also assigned to each a medication for its propensity to switch patients into mania or de- The text will specifically note when lack of clinical support for safety/ tolerability or risk of treatment-emergent switch has impacted pression (treatment-emergent switch). More information on these recommendations. ratings can be found in the respective treatment sections, as well 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 first and 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-