The use of modern dopamine partial agonists in bipolar depression: is the evidence sound?

Bipolar depression is a leading cause of morbidity in patients with bipolar disorder (BD)¹ with at least half of bipolar patients who initially present with a depressive episode². Unfortunately, this condition is often resistant to conventional antidepressant agents approved for major (unipolar) depression. Treatment-resistant bipolar depression (TRBD) occurs in about 25% or more of patients with BD³. While several pharmacologic agents have been regularly approved in Europe and are currently available for treating bipolar mania^4–6, there are limited evidence-based treatment options that may be successfully prescribed to treat bipolar depression. To date, only a few treatments including quetiapine (monotherapy)⁷ (2013 in Europe, 2006 in the U.S.), lurasidone⁸ (as monotherapy or adjunctive with lithium or valproate) (2017 in Europe, 2013 in the U.S.), and olanzapine⁹ (when combined with fluoxetine) (2009 in Europe, 2003 in the U.S) and cariprazine (approved in 2019 in the U.S) are currently approved by the U.S. Food and Drug Administration (FDA) in this condition. Conventional antidepressants are commonly prescribed in the treatment of bipolar depression but they showed limited efficacy in clinical trials¹⁰ as they may enhance the risk of mood destabilization (switch to mania, hypomania, mixed state or rapid cycling) or suicide risk in specific patient populations when used on a long-term perspective^11,12. Unfortunately, the study design usually adopted to test the efficacy of psychopharmacological medications in the acute phase of BD is limited by the short duration (e.g. few weeks) of most available trials and in the maintenance treatment (e.g. the longer duration allowing to test whether the indicated medications may prevent relapse for both mania and depression but usually adopting an enrichment design). Moreover, there is only minimal evidence to support the use of combinations of drugs for maintenance treatment with only limited indications concerning the complexity of BD management of bipolar illness and how long to continue as well as which medications to prefer in the long-term period¹³.

To date, three partial agonist compounds have been approved for acute psychosis associated with schizophrenia by regulatory agencies: aripiprazole, brexpiprazole, and cariprazine. With the exception of lurasidone, modern dopamine receptor D3/D2 modulators demonstrated their efficacy in mania¹⁴ with most of the currently available compounds that are indicated for bipolar maintenance therapy¹⁵. However, novel encouraging data are now emerging regarding the use of partial dopamine agonists having different binding affinities for D2 and D3 dopamine receptors¹⁶ in the treatment of bipolar depression. These agents have been preliminarily used to treat depressed bipolar patients but the findings are quite controversial.

Concerning aripiprazole, it is approved as adjunctive therapy for unipolar depression but has never been approved for bipolar depression after 2 failed controlled trials by the FDA, a post-hoc analysis of pooled data showed that aripiprazole monotherapy may provide some improvements in core depressive symptoms in a sample of 133 bipolar patients (of which 62 on active aripiprazole) who were more severely depressed¹⁷. Similarly, based on a six-week prospective, nonrandomized, open-label study, depressive symptoms improved in bipolar patients treated with open-label aripiprazole¹⁸. Open adjunctive aripiprazole also appeared effective and well-tolerated in outpatients with TRBD. Moreover, 2 of 4 patients who initially responded to aripiprazole augmentation for TRBD achieved sustained remission for 36 months suggesting that aripiprazole augmentation may be useful to prevent the recurrence of subsequent depressive episodes¹⁹ although the usefulness of this medication seems to be limited by the emergence of side effects such as akathisia²⁰ and high discontinuation rate²¹. However, other evidence²² did not support the efficacy of aripiprazole for the treatment of acute bipolar depression and prevention of depressive relapse. In particular, according to Kemp and colleagues²³ the absence of early improvement after 3 weeks of treatment reliably predicted non-response/non-remission at the study endpoint with high sensitivity and negative predictive value. Similarly, a small pilot study²⁴ found no significant difference at any point of time after 6 weeks of treatment between inpatients with bipolar depression treated with citalopram (20–40 mg daily) who were randomly assigned in a 1:1 ratio to either aripiprazole (15 mg/day) or placebo. Thus, the effectiveness of aripiprazole in monotherapy or as an add-on to another mood stabilizer in bipolar depression needs to be further tested.

Regarding cariprazine, the study of Durgam and colleagues²⁵ investigated three cariprazine doses (0.75 mg/day; 1.5 mg/day and 3.0 mg/day) in treating bipolar depression and found a significant difference between cariprazine and placebo only for the 1.5 mg/day dose in terms of clinical response and remission. More recently, even some RCTs showed the efficacy of cariprazine in the treatment of bipolar depression. Earley et al.²⁶ showed that cariprazine at both 1.5 mg/day and 3.0 mg/d, was effective and well-tolerated in reducing depressive symptoms in adults with BD. Similarly, the same research group²⁷ showed that cariprazine was generally safe and well-tolerated in the treatment of bipolar depression in both modal dose (0.25–3 mg/d) and fixed-dose (1.5 and 3 mg/d) analyses.

To date, only one study²⁸ examined the effects of brexpiprazole on mood symptoms in 19 patients with bipolar depression over an 8-week period and found a significant difference in depressive symptom severity, with participants showing a reduction in depressive symptoms from baseline to both week 4 and week 8. While the stronger activity at the serotonin 5HT1A receptor might be associated with greater antidepressant properties with brexpiprazole than aripiprazole, further additional randomized controlled trials (RCTs) are required to test the effectiveness of brexpiprazole in the long-term period. Overall, with brexipiprazole, it remains unclear whether the antidepressant properties are due to the partial dopamine agonist or its action on serotonin and adrenergic receptors. Brexpiprazole was approved in the U.S. as adjunctive therapy for unipolar depression but has not been approved for bipolar depression. Overall, dopamine receptor partial agonists are generally well tolerated with a favorable safety profile²⁹.

Evidence suggested that dopamine may play an interesting role in major affective disorders in terms of mechanism of action^30–32 providing further evidence in support of the notion that partial dopamine agonists might be an interesting treatment option. In a preclinical study, the administration of imipramine was associated with a significant increase in D3 receptor gene expression after 21 days of treatment while amitriptyline and fluoxetine were similarly linked to an increase in D3 receptor binding when administered for 42 days³³. Depressed subjects also showed increased D2 receptor binding in the striatum based on functional imaging studies^34,35, suggesting that dopamine function may be reduced in these patients. Furthermore, dopaminergic enhancement may promote the action of antidepressants, particularly in patients complaining of a lack of energy and motivation^36,37. This effect may depend on a resensitization/potentiation of mesolimbic dopamine D2/D3 receptors postulated as the final common pathway of the long-term use of antidepressants^33,38. D3 auto-receptors, which are structurally similar to D2 receptors, are able to modulate the phasic dopaminergic activity and are highly expressed in brain regions involved in cognitive function, motivation, and reward-related behavior³⁹, providing evidence concerning the possible effect of this medication on neurocognition⁴⁰ and mood but mostly on different aspects of reward including the reduction of anhedonia^41–43. Hence, an exciting opportunity is the potential efficacy of dopamine receptor partial agonists for the treatment of addictive disorders, given the high rates of comorbidity with bipolar depression and the binding properties of these agents with neural regions involved in addiction⁴⁴.

However, we are only at the beginning of a fascinating journey but future clinical studies in human subjects are warranted to extend our knowledge about the real-world effectiveness of partial dopamine agonists in patients with bipolar depression. There are now three available antipsychotic drugs with partial agonist effects, but the possible development of further alternatives remains still an unmet need. In addition, controlled studies evaluating efficacy for prophylaxis of patients with BD are absolutely required in clinical practice.

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Declaration of funding

The authors confirm that the paper is not funded.

Declarations of financial/other relationships

Prof. H. Nasrallah was advisor and speaker for Otsuka and Abbvie, (the companies that manufacture the partial agonists included in this report). Prof. G. Serafini was speaker for Otsuka (one of the companies that manufacture the partial agonists included in this report). A reviewer on this article has disclosed that they have received manuscript or speaker fees from Astellas, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Takeda Pharmaceutical, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Dainippon Sumitomo Pharma, Eisai, Mochida Pharmaceutical, Meiji Seika Pharma and Shionogi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.