REPURPOSING CANDESARTAN, THE ANTIHYPERTENSIVE DRUG, FOR TREATMENT OF BIPOLAR DISORDER

Abstract Background The depressive phase of bipolar disorder lasts longer than the manic phase and poses the highest risk due to its negative impact on quality of life and mental health, and peak in suicide attempts. Unfortunately, current therapies for bipolar disorder are far more efficacious in mania than depression, suggesting an urgent need for new and improved therapies for bipolar depression. The literature suggests the chronic presence of low-grade peripheral and central inflammation is a key pathophysiology of depression. In particular, Angiotensin II Type I receptor (AT1R) of the renin-angiotensin system appears to play a critical role in activating the relevant stress, oxidative stress and inflammatory pathways (see Vian et al., 2017, for review). In support of this, cutting-edge genomic studies (e.g. Kidnapillai et al., 2020), findings from animal models of bipolar disorder (e.g. Luo et al., 2020), independent large-scale epidemiological studies (e.g. Johansen et al., 2012) and a meta-analysis (Brownstein et al., 2018) have collectively nominated agents that reduce AT1R activity as a potential novel therapy for depression. Thus, our team designed clinical trials using candesartan, a common anti-hypertensive medication and AT1R blocker, to target this major unmet need in depression. Aims & Objectives The clinical trials aim to investigate the efficacy of adjunctive candesartan versus placebo for the treatment of major depression in unipolar and bipolar disorder. To achieve this aim, two separate trials are run in parallel for participants with either bipolar disorder or major depressive disorder. The two streams are: The Candesartan Adjunctive Bipolar Depression Trial (CADET-BD) and The Candesartan Adjunctive Major Depression Trial (CADET-UD). These trials are the first study of this agent in bipolar and major depressive disorder and will provide important proof-of-principle of the role of the angiotensin system in mood regulation. The primary outcome will measure if candesartan is superior to placebo in reducing depressive symptoms. The secondary outcomes will measure weather candesartan is superior to placebo in reducing anxiety symptoms, inflammatory biomarkers, and improving quality of life, social and work function and cognition. Method Funded by National Health and Medical Research Council (NHMRC) and Medical Research Future Fund (MRFF), the CADET trials are both 16-week multi-site double-blind randomized placebo-controlled trials and will aim to recruit 240 participants each (i.e. bipolar depression and unipolar depression). The trials are being conducted at five sites in Australia and each site is equipped with a team of Research Assistants and Principal Investigators to assess participants for inclusion (e.g. moderate to severe depression indexed by a depression rating scale score of 20 or higher), exclusion (e.g. a diagnosis of another psychotic disorder assessed using the SCID-5-RV) and withdrawal criteria, and conduct participant interviews. The participant will first attend the screen visit, followed by six visits within the 16 weeks, either in-person or via telehealth. The participants will complete different sets of tasks at each visit (Figure 1). Results, Discussion & Conclusion The trials are double-blinded and currently recruiting participants. The results, discussion and conclusion will be available once the recruitment is complete. References Brownstein, D.J., Salagre, E., Kö hler, C., Stubbs, B., Vian, J., Pereira, C., Chavarria, V., Karmakar, C., Turner, A., Quevedo, J. and Carvalho, A.F., 2018. Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials. Australian &New Zealand Journal of Psychiatry, 52(1), pp.24-38. Kidnapillai, S., Bortolasci, C.C., Udawela, M., Panizzutti, B., Spolding, B., Connor, T., Sanigorski, A., Dean, O.M., Crowley, T., Jamain, S. and Gray, L., 2020. The use of a gene expression signature and connectivity map to repurpose drugs for bipolar disorder. The World Journal of Biological Psychiatry, 21(10), pp.775- 783. Luo, H., Wu, P.F., Cao, Y., Jin, M., Shen, T.T., Wang, J., Huang, J.G., Han, Q.Q., He, J.G., Deng, S.L. and Ni, L., 2020. Angiotensin-converting enzyme inhibitor rapidly ameliorates depressive-type behaviors via bradykinin-dependent activation of mammalian target of rapamycin complex 1. Biological Psychiatry, 88 (5), pp.415-425. Johansen, A., Holmen, J., Stewart, R. and Bjerkeset, O., 2012. Anxiety and depression symptoms in arterial hypertension: the influence of antihypertensive treatment. The HUNT study, Norway. European journal of epidemiology, 27, pp.63-72. Vian, J., Pereira, C., Chavarria, V., Kö hler, C., Stubbs, B., Quevedo, J., Kim, S.W., Carvalho, A.F., Berk, M. and Fernandes, B.S., 2017. The renin– angiotensin system: a possible new target for depression. BMC medicine, 15, pp.1-13.