An International, Double-Blind, Randomized, Placebo-Controlled Clinical Trial of Adjunctive Trimetazidine to Treat People with Bipolar Depression (the TIDE Trial) Protocol

Bipolar disorder is dominated by the depressive phase, and its treatment represents the greatest unmet need in mood disorders. Converging evidence indicates that bipolar depression is characterized by reduced mitochondrial function compared to the euthymic phase, with the severity of depressive symptoms correlated with the extent of mitochondrial dysfunction. Trimetazidine, a medication for angina pectoris, improves efficiency of mitochondrial energy generation and reduces oxidative stress and inflammation - addressing the three core biological features of bipolar depression. Thus, the Trimetazidine In bipolar DEpression (TIDE) trial repurposes trimetazidine to test its efficacy in treating bipolar depression. The TIDE trial is a randomized, placebo-controlled, double-blinded, with a total recruitment target of 260 participants with bipolar disorder. Eligible participants will complete four visits and receive add-on trimetazidine or placebo across 8 weeks. Allocation to treatment arms will be randomized in a 1:1 ratio using permuted block randomization. An independent statistician will generate and retain the random allocation list. The trial biostatistician and clinicians, participants, their carers and physicians will be blinded to group allocations (i.e., a double-blind design). The effectiveness analysis will assess group differences (i.e., trimetazidine vs. placebo) in the primary outcome measure, the Montgomery Åsberg Depression Rating Scale total score, over the entire study period. The analysis will follow modified intention-to-treat principles and use a Generalized Estimating Equations (GEE) approach. Secondary outcomes include interviews and self-reports measuring global symptomology, anxiety symptoms, quality of life, day-to-day functioning, cognition, overall impairment, fatigue, cost effectiveness, and safety and tolerability data. Bipolar disorder is characterized by dysregulated energy metabolism, and trimetazidine is the first mitochondrial regulator identified as a potential drug to treat bipolar depression. Considering its established safety profile and novel target mechanism, a positive trial outcome may complement or even replace other options and offer an alternative for treating bipolar depression. If successful, its clinical impact could be global, improving health outcomes for hundreds of millions of people living with bipolar disorder. ANZCTR ACTRN12622000474752, registered 25th March 2023.