The CANMAT and ISBD Guidelines for the Treatment of Bipolar Disorder: Summary and a 2023 Update of Evidence

A thorough assessment including risk of violence, self-harm, insight, and the ability to adhere to treatment, and comorbidity should be conducted to establish the most appropriate treatment setting. Physical examination and laboratory investigations can be deferred for uncooperative patients. Antidepressants in a patient presenting with acute mania should be discontinued. Patients should also be supported to discontinue substances such as stimulants (including caffeine) and alcohol. Past response to and tolerability of medications used in current and prior episodes should be assessed and used to direct subsequent therapeutic choices.

Both monotherapy and the combination of a mood stabilizer and an atypical antipsychotic are appropriate first-line treatments for acute mania. Specific medications include lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine as first-line monotherapy options and a combination of quetiapine, aripiprazole, risperidone, or asenapine with lithium or divalproex as first-line combination therapy options.

As previously stated in the introduction, the first- and second-line recommendations are listed hierarchically on the basis of the efficacy of each agent in treating acute mania as well as treating bipolar depression, relapse prevention, safety and tolerability, and risk of treatment-emergent affective switch. The 2018 CANMAT/ISBD guideline recommends that treatments listed higher up in Box 1 need to be considered first, unless other factors such as history of previous nonresponse or patient’s preferences dictate otherwise.

If symptoms are not controlled with first-line agents, dosing should be optimized. In case of no improvement in symptoms within the first 2 weeks of receiving therapeutic doses, factors such as possible nonadherence and ongoing substance use should be considered before adding or switching medications.

If treatment with one or a combination of first-line agents at optimal doses is inadequate or intolerable, the next step is to switch to or add on an alternate first-line treatment.

When all first-line options have failed, second-line choices—including monotherapy with olanzapine, carbamazepine, ziprasidone, and haloperidol; combination therapy with olanzapine plus lithium or divalproex or with lithium plus divalproex; or electroconvulsive therapy (ECT)—should be considered.

Third-line options for treatment of acute mania are outlined in Box 1. These agents should only be used if there has been no response to adequate trials with all first- and second-line agents alone and in combination.

A recent meta-analysis (21) showed that augmentation therapy with antipsychotics and mood stabilizers is more effective than monotherapy (Level 1) in treating manic symptoms without any significant difference in tolerability at weeks 3 and 6.

A thorough assessment of the nature and severity of depression and associated symptoms, risk of self-harm, ability to adhere to a treatment plan, availability of a psychosocial support network, and functional impairment should be conducted to establish the most appropriate treatment setting. Laboratory investigations should also be completed. Patients should be supported to discontinue substance use. Past response to and tolerability of medications used in current and prior episodes should be assessed and used to direct subsequent therapeutic choices.

Patients presenting with acute bipolar depression should be initiated on one of the first-line treatments. Quetiapine, lithium, lamotrigine, and lurasidone are recommended as first-line monotherapy options; lurasidone and lamotrigine are also recommended as first-line adjunctive treatments.

The first- and second-line recommendations are listed hierarchically. The 2018 CANMAT/ISBD guideline recommends that treatments listed higher up in Box 2 need to be considered first, unless other factors such as history of previous nonresponse or patient’s preferences dictate otherwise.

In case of a lack of response to the first trial, the next step is to switch to or add on an alternate first-line treatment. In principle, a switch is preferred over an add-on to limit the degree of polypharmacy unless there was a partial response.

In case of inadequate response to first-line options, monotherapy with divalproex or adjunctive antidepressants (selective serotonin reuptake inhibitors [SSRIs] or bupropion) can be considered as a second-line option. The ISBD Antidepressant Task Force (22) recommends that antidepressants should be avoided or used cautiously in patients with a history of antidepressant-induced mania, current or predominant mixed features, or recent rapid cycling.

It is important to inform patients (and families, if appropriate) of the risk of treatment-emergent affective switch and advise that antidepressants should be discontinued should early warning signs of mania emerge. Antidepressants should not be used as monotherapy for the treatment of bipolar I depression.

Finally, ECT is also a second-line treatment, particularly for patients with treatment-refractory bipolar depression and those with severe depression with imminent risk of suicide, catatonia, or psychotic depression or when a rapid response is important for medical stabilization.

Third-line options for treatment of acute bipolar depression are outlined in Box 2. These agents should be considered only after multiple first- and second-line options have been trialed first.

Three RCTs (23–25) have shown the superior efficacy of cariprazine compared with placebo in the treatment of bipolar I depression. The most common treatment-emergent side effects were akathisia, nausea, fatigue, and sedation. Cariprazine was recommended as a second-line treatment option in the 2018 CANMAT/ISBD guidelines because of less clinical experience; it has been upgraded to a first-line option, given the data and clinical experience since then.

Lumateperone is a novel antipsychotic acting on various serotonin and dopamine receptors. It is a potent 5-HT_2a antagonist, dopamine D₂ receptor presynaptic partial agonist, and postsynaptic antagonist; a D₁ receptor–dependent indirect modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (or, AMPA) and N-methyl-d-aspartate (or, NMDA) currents; and a serotonin reuptake inhibitor (26). A recently published RCT (Level 2) has shown greater efficacy of lumateperone (at 42 mg) in bipolar I and bipolar II depression compared with placebo (27). In this study (27), lumateperone monotherapy (N=188) was associated with significant improvement in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) compared with placebo (N=189). In the second study (28), patients with bipolar depression who had inadequate response to lithium or valproate showed significantly greater improvements in MADRS score with adjunctive lumateperone (N=177) (Level 2) compared with adjunctive placebo (N=176). The common adverse events of lumateperone include nausea and somnolence, with an advantage of low incidence of extrapyramidal symptoms and an increase in prolactin (27, 28).

In general, it is recommended that medications that have been effective in the acute phase be continued during the maintenance phase (except for long-term use of antidepressants, which is generally not recommended in treating bipolar disorder). For patients who are not receiving or responding to pharmacological treatment, a detailed history of clinical course, response to previous trials, and family history should be collected. Other factors to consider would include comorbidity, the predominant mood polarity, and the polarity of the most recent mood episode.

As with treatment for acute mania and depression, the 2018 CANMAT/ISBD guideline recommends that treatment choices for maintenance treatment of bipolar disorder should follow the hierarchy listed in Box 3, unless patient preference or clinical factors such as previous response, tolerability, or predominant polarity warrant other options. In addition, if a patient has been treated for an acute mood episode and responded to a first-line maintenance treatment, the recommendation is to continue that treatment for maintenance even if lower down in the hierarchy. At times, it may be necessary to lower the dose to some degree during maintenance treatment if there are tolerability concerns, as treatment adherence may be a challenge if doses are not adjusted.

There is evidence that the risk of recurrence is lowered when an antipsychotic is combined with lithium or divalproex. When a combination of an atypical antipsychotic with lithium or divalproex was used to treat acute mania, continuing the atypical antipsychotic for the first 6 months after response reduced the risk of relapse (29), but the benefits beyond 6 months remain uncertain.

Lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole (oral or once-monthly injection) monotherapies are recommended as first-line maintenance treatments. Combination therapies recommended as first-line include quetiapine or aripiprazole combined with lithium or divalproex.

For patients who experience a relapse or remain symptomatic while on a first-line maintenance treatment, the next step is to optimize the dose and address potential issues with adherence before moving to step 3.

If treatment with the first-line agent (or combination of agents) at optimal doses proves to be inadequate or intolerable, the next step is to switch to or add on an alternate first-line agent.

After unsuccessful trials of multiple first-line options, second-line choices—including olanzapine, long-acting injectable risperidone monotherapy or adjunctive therapy, carbamazepine, paliperidone, adjunctive ziprasidone, and adjunctive lurasidone—should be considered.

Third-line options for maintenance treatment of bipolar disorder are outlined in Box 3.

When combination therapy of an atypical antipsychotic with lithium or divalproex was used to treat acute mania, CANMAT/ISBD 2018 guidelines recommended continuing the atypical antipsychotic for the first 6 months and then re-evaluating, as the benefits of maintenance combination therapy beyond 6 months remains uncertain (29). However, a recently published meta-analysis (30) showed that combination of atypical antipsychotics and mood stabilizers is associated with lower rates for recurrence of any mood episode and all-cause discontinuation at 1, 2, 3, 9, and 12 months when compared with placebo and mood stabilizers (Level 1).

Although, for some patients, hypomania may be associated with only minimal functional impairment or even brief periods of above-normal functioning, others may experience rather prolonged, relatively severe, or irritable or mixed hypomania that can be impairing. Most standard antimanic agents have not been studied in hypomania. However, clinical experience suggests that all antimanic medications can also be effective for the treatment of hypomania. Therefore, if hypomania is frequent, severe, or impairing, clinicians should consider classic mood-stabilizing medications, such as lithium or divalproex, and/or atypical antipsychotics.

First-, second-, and third-line treatment options for bipolar II depression are listed in Box 4. Quetiapine is the only recommended first-line treatment for bipolar II depression. Second-line options include lithium, ideally at a serum level of 0.8–1.2 mEq/L, and the antidepressants sertraline and venlafaxine, mainly for patients with pure (nonmixed) depression. Lamotrigine is also recommended as a second-line agent. ECT is considered as a second-line option, especially for patients with treatment-refractory bipolar II depression and those who require rapid response.

As mentioned earlier, a recent RCT (Level 2) showed the efficacy of 42 mg lumateperone in the treatment of bipolar I and bipolar II depression (27). Given that the data for bipolar II depression was based on a small number of patients and, furthermore, that there is only limited clinical experience with lumateperone in this population, we recommend it as a second-line option for the treatment of acute bipolar II depression.

Maintenance treatment is important to prevent relapse and restore functioning and quality of life. Selection of an agent for maintenance should be informed by acute-phase treatment. First-, second-, and third-line treatment options are listed in Box 4.

Quetiapine, lithium, and lamotrigine monotherapies are first-line options, whereas venlafaxine and fluoxetine are considered second-line options.

Between one-third and two-thirds of individuals with bipolar disorder experience their first mood episode during childhood or adolescence. Despite developmental differences in the way symptoms manifest themselves, the diagnosis of bipolar disorder in children and adolescents should be made on the basis of the same criteria used in adults (31). It is important for clinicians to distinguish between discrete periods of elevated or irritable mood that are characteristic of manic or hypomanic episodes and chronic irritability with episodic behavioral outbursts that can be seen in other conditions such as emerging personality disorders, substance use disorder, and ADHD. When defined according to DSM-5 criteria, the course of bipolar disorder in youths tends to be characterized by high rates of symptomatic recovery but also high rates of recurrence (32).

Readers should consult the 2018 guideline document for more detailed information about the rationale for recommended treatment options.

In 2005, about 25% of the patients with bipolar disorder in the United States were over 60 years old (34), and by 2030, over half of all patients with bipolar disorder are expected to be older than 60 years of age (35). The lifetime prevalence of late-life bipolar disorder is between 1% and 2% in the general population. About 90%–95% of older adults with bipolar disorder experience their first mood episode before age 50, whereas there is a minority who will have a later onset (36, 37). Late onset is often related to neurological or physical comorbidity (38) and might indicate poor prognosis (39).

Manic symptoms tend to be less prominent in this population, but depressive and cognitive symptoms are more often observed (40). Cognitive impairment is a major concern, with over 30% showing significant deficits across all cognitive domains, even during euthymia (41, 42).

Psychiatric comorbidity is less prevalent than in younger patients, with anxiety and substance use disorder being the most common (37). In addition, older adults with bipolar disorder have an average of three to four comorbid medical conditions (43) that contribute to a life expectancy reduction of 10–15 years with bipolar disorder, compared with nonpsychiatric populations (44). Assessment of an older adult with bipolar disorder should include a thorough physical and neurological examination, as well as clinical laboratory tests. Neuroimaging should also be considered particularly if there are focal neurological signs and symptoms; if there is an abrupt, late onset; or if the presentation is different from previous episodes.

A complete medical history as well as assessment of body mass index and laboratory investigations should be performed prior to initiating pharmacological treatment for bipolar disorder or as soon as the patient is cooperative. Baseline laboratory investigations include complete blood count, fasting glucose, fasting lipid profile, electrolytes, and calcium; liver enzymes; serum bilirubin; prothrombin time and partial thromboplastin time; urinalysis; urine toxicology for substance use; serum creatinine and estimated glomerular filtration rate; thyroid‐stimulating hormone; electrocardiogram (for patients over 40 years of age or if otherwise indicated); pregnancy test; and serum prolactin. In individuals of childbearing potential, pregnancy should be ruled out, and consultation should be provided regarding the possibility of lamotrigine and carbamazepine affecting the efficacy of oral contraceptives. For patients who are on lithium, thyroid and renal function as well as plasma calcium should be assessed at baseline, after 6 months, and at least annually thereafter. In patients who are on divalproex, menstrual history (to assess for polycystic ovary syndrome), hematology profile, and liver function tests should be obtained at 3- to 6-month intervals during the first year and yearly thereafter. Health Canada warns “Valproate products (valproic acid, divalproex sodium) should not be used in female children, in female adolescents, in women of childbearing potential and pregnant women unless alternative treatments are ineffective or not tolerated because of its high teratogenic potential and risk of developmental disorders in infants exposed in utero to valproate” (45). Patients initiated on lamotrigine or carbamazepine should receive education regarding the risks of skin rashes and the potential for Stevens-Johnson syndrome and toxic epidermal necrolysis. In addition, those who are on carbamazepine should have serum sodium levels measured at least annually because of the risk of hyponatremia. Patients on atypical antipsychotics should have their body weight monitored monthly in the first 3 months and every 3 months thereafter. In addition, blood pressure, fasting glucose, and lipid profile should be assessed at 3 months and yearly thereafter. Regular monitoring for extrapyramidal symptoms is also recommended.

Lithium, divalproex, and carbamazepine serum levels need to be monitored regularly. Measurement of serum levels should be done at the trough point, which is 12 hours after the last dose. Two consecutive serum levels in the therapeutic range should be established after the initiation of lithium and divalproex, and then measurement should be repeated at least every 3–6 months. Carbamazepine levels may be monitored every 6–12 months and as clinically indicated. Target serum level for lithium is 0.8–1.2 mEq/L (0.4–0.8 mEq/L in older adults) in the acute phase and 0.6–1 mEq/L during maintenance. Serum levels should be checked at least 5 days after the most recent dose titration. The target serum level for divalproex is 350–700 mM/L (50–100 μg/mL) and should be checked at least 3–5 days after the most recent dose titration.