Revisiting cariprazine for bipolar I disorder maintenance treatment

Abstract

We read with interest the study by McIntyre et al. “Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder”¹ concluding that cariprazine was not superior to placebo in relapse prevention. However, based on our clinical experience successfully utilizing cariprazine to treat acute depressive, manic, and mixed episodes of bipolar I disorder, we have also found cariprazine helpful in preventing recurrence for the vast majority of patients who have remained on cariprazine over the past decade, when the dosing regimen is individualized to meet their needs.² Unfortunately, this was not the case for this study protocol, which may have contributed to an incorrect conclusion.

As a partial dopamine agonist with eightfold greater affinity for D3 than D2 receptors, and higher D3 affinity than one's endogenous dopamine,³ cariprazine is a dynamic medication whereby finding the correct dose is critical to optimizing effects and minimizing side effects. Lower doses function as a dopamine agonist such that 1.5 mg daily can rapidly improve bipolar I depression within 2 weeks.³ In contrast, higher approved doses, such as 4.5 mg and 6 mg, which function as a dopamine antagonist, may be required for rapid control of mania and psychosis over several days.³ At times, patients who are stable on 1.5 mg cannot tolerate 3 mg due to akathisia. The 3 mg dose lies somewhere in between; it may be too dopamine blocking for some depressed patients yet insufficient for control of mania and psychosis. The unique pharmacodynamic features of cariprazine allow the prescriber to dial in the precise dose to meet patients' needs: lower doses for bipolar I depression; higher doses for bipolar mania and mixed episodes, potentially achieving full spectrum coverage as a relatively well-tolerated monotherapy.

Another unique aspect of cariprazine is the exceedingly long half-life of its active metabolites, and the protracted time to reach a steady state, which can surpass 12 weeks.³ Occasionally, dose reduction is appropriate for late-occurring side effects, such as insomnia. It can also take up to 12 weeks following discontinuation for total cariprazine metabolites to become undetectable, and even longer for poor 3A4 metabolizers or for those taking 3A4 inhibitors,³ such as cannabis (permitted in this study). This feature enables effective intermittent dosing schedules for those who either cannot tolerate daily dosing,³ prefer intermittent dosing, or face challenges with adherence. Unlike many other antipsychotics, we do not typically encounter withdrawal effects with cariprazine due to low binding affinities for acetylcholine and histamine.³ In our experience, bipolar I disorder patients who have taken cariprazine over several months may remain stable over several subsequent months following discontinuation due to long-lasting effects.

These pharmacodynamic and pharmacokinetic considerations raise many questions as to this study's design. Why force titrate bipolar I depressed patients to 3 mg instead of following FDA guidelines?³ During this phase, adverse events leading to discontinuation (67) may be attributable to this aggressive schedule. Conversely, why not allow bipolar I manic and mixed patients to take 4.5 mg or 6 mg as per FDA guidelines?³ During this phase, discontinuation rates due to lack of efficacy (35) may be attributable to subtherapeutic dosing. Failure to meet randomization criteria (143) may also reflect a lack of individualized dosing. More than half of open-label patients discontinued prior to double-blind randomization limiting the generalizability of the sample to those who do best on the 3 mg, which begs the next question: why lower them to 1.5 mg? A more effective design would have allowed dose titration tailored to index episode, with adjustments permitted during the double-blind phase to address early signs of relapse and/or tolerability, as was the design for oral⁴ and long-acting injectable aripiprazole⁵ bipolar I maintenance studies. Furthermore, why stop the study after only 39 weeks when cariprazine metabolites last longer than that of oral aripiprazole whose maintenance studies were 74 weeks?⁴ The Kaplan–Meier curves just begin to diverge at 36 weeks for both time to any relapse, and for time to manic relapse, which may reflect the higher doses of cariprazine required for mania compared with lower doses sufficient for depression in terms of pharmacodynamic effects.

Taken in real-world clinical context, this study could likewise conclude that loading 16 weeks of cariprazine 3 mg provides durable relapse prevention of depressive, manic, and mixed episodes in bipolar I disorder, comparable to dose reduction to 1.5 mg, 3 mg continuation, or discontinuation over an additional 39 weeks, “with all symptom and functional improvements maintained.”¹ Relapse rates were all below 20 percent,¹ lower than has been found in separate studies of long-term treatment with either oral⁴ or monthly injectable aripiprazole,⁵ which treat manic and mixed episodes but not depressive episodes in bipolar I disorder.

Both authors participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.