The Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder are now available in Bipolar Disorders.

CANMAT previously published treatment guidelines in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. These last 2 updates were published in collaboration with the ISBD. The 2018 guidelines are the first full guidelines to be published since 2005 and include updates to diagnosis and management, as well as new research into pharmacological and psychological treatments. These guidelines represent the significant advances that have been made in the diagnosis and treatment of bipolar disorders since 2005.

Lakshmi N. Yatham, MBBS, FRCPC, MRCPsych, from the Department of Psychiatry, University of British Columbia, Vancouver, Canada and colleagues have translated these advances into recommendations for first-, second-, and third-line therapies, 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.

The expert panel created hierarchical rankings for first- and second-line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder (BPI). First-line recommendations require level 1 or 2 evidence for efficacy plus clinical support for safety and tolerability and no risk for treatment-emergent switch. Second-line recommendations require level 3 or higher evidence for efficacy plus clinical support for safety and tolerability and low risk for treatment-emergent switch. As for a third-line recommendation, it requires level 4 evidence or higher for efficacy plus clinical support for safety and tolerability, but there is no requirement for risk for treatment-emergent switch. Treatments that receive a “not recommended” status have level 1 evidence for lack of efficacy, or level 2 evidence for lack of efficacy plus expert opinion.

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The hierarchical rankings of therapy are new to the 2018 guidelines. They were designed with the effect of treatment across all phases of illness taken into consideration. As bipolar disorder I (BDI) is a chronic illness characterized by recurrent mood episodes and subsyndromal mood symptoms, including both mania and depression, most patients will require maintenance therapy. Thus, the choice of a medication to treat an acute mood disorder should consider the efficacy in maintenance as well. The expert panel recommends trying treatments that have demonstrated efficacy across the spectrum of illness first.

Diagnosis and Staging

The new guidelines review the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), diagnostic criteria and note the spectrum of bipolar disorder subgroups, including BDI, which sits at 1 end of the spectrum, bipolar disorder II (BDII), which features hypomania rather than the mania characteristic of BDI, and cyclothymia, which is characterized by subthreshold presentation of hypomanic and depressive symptoms, which, although chronic, do not meet the diagnostic criteria for a major depressive episode or manic/hypomanic episode. The guidelines note that the DSM-5 has replaced the bipolar disorder not otherwise specified category found in the DMS-IV with 2 new categories: other specified bipolar and related disorder and unspecified bipolar and related disorder. The DMS-5 also includes substance/medication-induced bipolar and related disorder and bipolar and related disorder resulting from another medical condition.

The guidelines also provide recommendations on staging and screening and diagnosis of bipolar disorder. They note that the heterogeneity intrinsic to bipolar disorder has prevented the clinical use of staging systems and that the diagnosis of bipolar disorder is difficult, as it often presents as depression and is misdiagnosed as major depressive disorder. They list several features of depression that may increase suspicion of bipolarity, including earlier age of illness onset, highly recurrent depressive episodes, a family history of bipolar disorder, depression with psychotic features, psychomotor agitation, atypical depressive symptoms such as hypersomnia, hyperphagia, and leaden paralysis, postpartum depression and psychosis, past suicide attempts, and antidepressant-induced manic symptoms or rapid cycling.

Overall Management of BDI

The guidelines recommend a long-term, multidisciplinary approach to management; regular, ongoing monitoring of mood symptoms; strategies to reduce stigma (particularly self-stigma); psychosocial interventions for acute depressive episodes and as maintenance treatment to prevent relapse and restore quality of life to the individual and family; and psychoeducation for both patient and family. A large study demonstrated that a 6-week session Life Goals Program psychoeducational intervention was equivalent in relapse prevention to 20 sessions of individual cognitive behavioral therapy (CBT). However, the guidelines note that psychoeducation does not appear to be of significant benefit in either acute depressive or manic episodes. As for CBT itself, results in bipolar disorder have been mixed; however, a new “recovery-focused CBT” has shown promise, with evidence of reduction in relapse in the intervention group. Group CBT may increase time in remission in euthymic patients with bipolar disorder.

Family-focused therapy may be of value in reducing recurrence of new episodes of depression, but no evidence exists for its efficacy in mania, so no recommendation is made in these guidelines. Interpersonal and social rhythm therapy is recommended as an adjunctive third-line treatment for acute depression and for maintenance based on limited level 2 evidence. No evidence exists and no recommendation is made for interpersonal and social rhythm therapy in mania. Peer interventions receive a third-line treatment recommendation based on level 2 evidence as an adjunctive maintenance therapy. Functional remediation involves a 21-session group intervention over the course of 6 months and may have a substantial effect on functioning, in comparison with treatment as usual, whereas computer-based cognitive remediation may show positive effects on cognition, but not on functioning.

Pharmacologic Treatment of BDI

The guidelines suggest a review of general principles and an assessment of medication status for a patient presenting in a manic state, including an immediate assessment for risk for aggressive or violent behavior and risk to self or others. They also note that symptoms secondary to drugs of abuse, medications, other treatments, or a general medical or neurological condition, or other factors that could be perpetuating symptoms, including prescribed medications, must be ruled out before initiating pharmacotherapy.

The 2018 guidelines recommend lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination as first-line therapies for acute mania. In addition, they have advice on adding on or switching therapy with alternate first-line agents and second- or third-line agents. Combination therapy with lithium or divalproex and an atypical antipsychotic is recommended when a fast response is needed. Guidelines are provided for anxious distress, mixed features, psychotic features, and rapid cycling as well. Agents not recommended for the treatment of acute mania include eslicarbazepine/licarbazepine, gabapentin, omega-3 fatty acids, allopurinol, lamotrigine, topiramate, valnoctamide, or zonisamide.

The guidelines note that depressive symptoms are often more pervasive and debilitating to patients than manic states, and estimates are that depressive mood accounts for up to two-thirds of time spent feeling ill. They recommend aggressive treatment of subsyndromal depressive symptoms, as they are a major source of functional impairment. This phase confers a higher risk for suicide, and up to 70% of suicide deaths occur during the depressive phase of bipolar disorder. First-line options for BDI depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. As with treatment for acute mania, the guidelines also provide recommendations for add-on or switching therapy to alternate first-line agents, followed by recommendations for second- or third-line agents. Transcranial magnetic stimulation is recommended as third-line therapy for both mania and bipolar depression. Aripiprazole, which failed to demonstrate efficacy over placebo in 2 bipolar depression trials, is not recommended for the treatment of acute bipolar depression. Other agents not recommended include ziprasidone monotherapy or adjunctive therapy, lamotrigine in combination with folic acid, and mifepristone as adjunctive therapy.

Although the guidelines recommend continuing medication that has been effective for the acute phase for the maintenance phase of BDI, the panel notes there are some exceptions, such as antidepressants. Available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination therapy with lithium or divalproex should be considered first-line for those initiating or switching treatment during the maintenance phase.

Management of BDII and Special Populations

The new guidelines also address the management of BDII. First-line therapy for the acute management of hypomania includes quetiapine, lithium, and lamotrigine. Treatment should also include discontinuing agents that can worsen or prolong symptoms, such as antidepressants and stimulants. However, the guidelines note that hypomania is not well studied.

The guidelines recommend quetiapine as the only first-line treatment for acute management of BDII depression with level 1 evidence, and quetiapine has been found to be equally effective for both BDI and BDII depression. Lithium and lamotrigine are first-line options with level 2 evidence. Second- and third-line recommendations are provided as well.

The 2018 guidelines also provide advice on specific populations, such as women at various stages of the reproductive cycle, including pregnancy, the postpartum period, and menopause. Recommendations are made regarding children, adolescents, and older adults with bipolar disorder. They provide discussions on the effect of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. For both BDI and BDII, nonpharmacologic therapies such as transcranial magnetic stimulation and electroconvulsive therapy are discussed as well, as is ketamine, a therapy for which long-term evidence is still lacking.

Reference

Yatham LN. Kennedy SH, Parikh SV, et al. 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. Bipolar Disord. 2018;20:97-170.