Comment by Diane McIntosh, BSc Pharmacy, MD, FRCPC – Vancouver, British Columbia
Among the many clinical challenges in the management of bipolar I disorder, the need for effective treatments that maintain symptomatic remission and promote long-term adherence is paramount. Depending on the study population and the methodology employed, up to 60% of patients diagnosed with bipolar disorder do not adhere to treatment recommendations (Colom et al. Bipolar Disord 2005;7(suppl 5):24-31). A recent study reported that patients with bipolar disorder missed doses a mean of three days in the preceding week (Levin et al. J Nerv Ment Dis 2017;205:182-187). Treatment nonadherence is a major risk factor for relapse, readmission to hospital and suicidality (Rascati et al. Psychiatr Serv 2011;62:1032-1040) and is associated with higher rates of work absenteeism and disability (Bagalman et al. J Occup Environ Med 2010;52:478-485).
To address the need for treatment efficacy and adherence, several consensus guidelines now recommend the use of injectable antipsychotic agents as the initial treatment for acute episodes of mania, and as maintenance therapy for bipolar disorder (reviewed in Hammett & Youssef. Ann Clin Psychiatry 2017;29:266-282). In the updated Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of bipolar disorder, the only atypical antipsychotic agents recommended for the first-line treatment of agitation are aripiprazole long-acting injectable (LAI) and olanzapine LAI (Yatham et al. Bipolar Disord 2018;20:97-170). Risperidone LAI and ziprasidone LAI are recommended as second-line agents.
LAIs may be particularly useful during the maintenance phase of bipolar treatment. The CANMAT 2018 guidelines recommend aripiprazole LAI as a first-line option for maintenance treatment, while risperidone LAI, either as monotherapy or as an adjunct treatment, is a second-line option.
The use of LAIs in bipolar I disorder has been shown to be associated with improved patient outcomes. A Finnish national cohort study (n=18,018, mean follow-up 7.2 years) of patients with bipolar disorder reported that the use of antipsychotic agents or mood stabilizers was associated with the lowest risk of rehospitalization (Lahteenvuo et al. JAMA Psychiatry 2018;75:347-355). LAIs were associated with a lower risk of psychiatric rehospitalization (hazard ratio 0.70) and all-cause hospitalization (HR 0.70) compared with oral antipsychotics.
Aripiprazole LAI (Abilify Maintena) administered once-monthly was approved by Health Canada in November 2017 (July 2017 in the U.S.) as monotherapy for the maintenance treatment of bipolar I disorder in adult patients.
Approval of aripiprazole LAI for bipolar I disorder was based on the results of a randomized, double-blind, placebo-controlled one-year withdrawal study conducted in seven countries, including Canada and the U.S. (Calabrese et al. J Clin Psychiatry 2017;78:324-331). For the initial treatment phases, patients were switched to and stabilized on oral aripiprazole (4–6 weeks and 2–8 weeks, respectively; target dose 15-30 mg/day). Stabilized patients were then initiated on intramuscular aripiprazole 400 mg q4weeks for weeks 12–28. Patients who were stable on aripiprazole LAI for >8 consecutive weeks were randomized to aripiprazole LAI or placebo for the long-term maintenance phase. Stability was defined as Young Mania Rating Scale (YMRS) score < 12, Montgomery-Asberg Depression Rating Scale (MADRS) total score < 12, outpatient status, and no active suicidality. The primary outcome measure was the time from randomization to recurrence of any mood episode. The enriched design, which analysed outcomes in patients who had previously demonstrated a response to the study drug, was consistent with the methodology used in other trials of maintenance therapies (Yatham et al. Bipolar Disord 2013;15:1-44).
A total of 266 patients entered the double-blind withdrawal phase and were randomized to aripiprazole LAI or placebo. The completion rate was 48.1% in the aripiprazole arm compared to 28.6% in the placebo arm. The time to recurrence of any mood episode was significantly delayed with aripiprazole LAI versus placebo (HR 0.45; 95% CI, 0.30-0.68, p<0.0001), which corresponded to a 55% lower risk of recurrence. The proportion of patients with recurrence was also significantly lower with aripiprazole LAI versus placebo (26.5% vs. 51.1%). Treatment differences were observed both for manic episodes and mixed episodes. There were no significant between-group differences for recurrence of depressive episodes. The median time to all-cause discontinuation was 345 days with aripiprazole LAI compared to 170 days with placebo (p=0.0026). The most common reasons for discontinuation were a recurrence of any mood episode with or without adverse events (aripiprazole LAI 12.0% and 14.3%; placebo 24.8% and 26.3%). During the randomized double-blind phase, the most common adverse events with aripiprazole LAI and placebo were weight gain (23.5% vs. 18.0%), and akathisia (21.2% vs. 12.8%). There were no clinically meaningful changes in serum prolactin levels with aripiprazole LAI. The proportion of patients with adverse events leading to treatment discontinuation was 17.4% in the aripiprazole LAI arm and 25.6% in the placebo arm.
A subsequent analysis of the same study reported a significant delay in time to hospitalization for any mood episode for aripiprazole LAI compared to placebo (p=0.0002) (Calabrese et al. J Affect Disord 2017;227:649-656). Clinical gains achieved during the stabilization phase in mania symptom severity and overall function, as assessed by YMRS and the Functioning Assessment Short Test (FAST), were maintained with aripiprazole LAI during the maintenance phase, but worsened with placebo. MADRS scores were low at the start of the trial and did not differ between groups for the duration of the study. A noteworthy observation was that aripiprazole LAI was not associated with a worsening of depressive episodes, which is in contrast to the worsening of depression in bipolar I patients reported with typical antipsychotics (Ahlfors et al. Acta Psychiatr Scand 1981;64:226-237 ; White et al. Int Clin Psychopharmacol 1993;8:119-122).
These results support the finding that LAI antipsychotics are as effective as oral antipsychotics in the treatment of bipolar I disorder (Kishi et al. Int J Neuropsychopharmacol 2016;19:pii:pyw038). A recent review of 11 studies (n=1418) found that patients with bipolar I disorder have a generally positive view of antipsychotic treatment, most notably if treatment is associated with a longer duration of clinical stability (Sajatovic et al. Neuropsychiatr Dis Treat 2017;13:2285-2296). The conclusion of the pivotal trial was that LAI antipsychotics, by addressing the challenge of treatment adherence, have the potential to improve long-term outcomes in patients with bipolar I disorder (Calabrese 2017).
Dr. Diane McIntosh: I began offering LAIs to my patients who have bipolar disorder a few years ago. Initially, I thought only of my patients who struggled with compliance, but as my experience grew and I began to see the benefits first hand, I started to offer them to patients I would never have considered might accept an LAI. I now think about LAIs for those who have had repeated episodes, very serious episodes, and those with residual symptoms not fully managed with oral treatments. I have been surprised by how willing so many of my patients have been to consider an LAI, even if they are still taking other oral agents.
I see two really clear benefits: I feel strongly that my patients experience a mood benefit that is superior to what is seen with oral agents; and an LAI gives me an opportunity to intervene if they are getting ill due to non-compliance with other treatments. I know for certain LAIs have prevented the need for hospitalization for many of my patients because when a patient or their family becomes aware of symptom exacerbation, the LAI gave me the time to intervene and prevent a relapse.