The Candesartan Adjunctive Bipolar Depression Trial - CADET: A double-blind, randomised, placebo-controlled trial

INTERVENTION: 16 weeks of adjunctive candesartan 16mg oral tablet, once a day. Treatment adherence will be assessed by tablet count of returned trial medication bottles. CONDITION: Bipolar depression; ; Bipolar depression Mental Health ‐ Depression PRIMARY OUTCOME: Change in severity of mood symptoms, measured using Montgomery‐Ã…sberg Depression Rating Scale (MADRS)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16 (primary endpoint). ] ; [Conducted at baseline and Week 16] INCLUSION CRITERIA: I. A DSM‐5 diagnosis of bipolar disorder I or II, determined using the SCID‐5‐RV; II. Currently experiencing a major depressive episode, determined using the SCID‐5‐RV III. Moderate to severe depression indexed by a MADRS score of greater than or equal to 20. If there is a delay of >7 days between screening and baseline assessments, or baseline assessment and medication commencement, the inclusion scale (MADRS) should be administered again to ensure the participant still meets eligibility criteria; IV. Aged 18 years and above; V. Have the capacity to consent to the study and to follow its instructions and procedures; VI. Participants will need to have been on stable pre‐existing pharmacological or psychotherapy regimens for two weeks prior to study entry; VII. Be using effective contraception if female, sexually active and of childbearing age, VIII. Be able to speak, read, write and understand the English language, IX. Participants w SECONDARY OUTCOME: Change in angiotensin II, and ACE activity, [Bloods collected from consenting participants at baseline Week 4 and Week 16] Change in Clinical Global Impression Scale for bipolar disorder (CGI‐BP) (Severity and improvement)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in functioning, measured by the Range of Impaired Functioning Tool (LIFE‐RIFT)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in functioning, measured by the Social and Occupational Functioning Scale (SOFAS), [Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in inflammatory markers (CRP), cytokines (TNFa, IL6, IL10, IL1)[Bloods collected from consenting participants at baseline Week 4 and Week 16] Change in kidney function measured by blood urea, electolytes and creatinine [Blood collected from all participants at Baseline, Week 4 and Week 16] Change in lithium blood levels[Bloods collected from all applicable participants taking lithium at Baseline and weeks 2,4 and 16] Change in markers of oxidative stress (thiobarbituric acid reactive substances – TBARS, nitric oxide, glutathione – GSH, and the activities of the antioxidant enzymes catalase – CAT, and glutathione peroxidase – GPX, superoxide dismutase – SOD)[Bloods collected from consenting participants at baseline Week 4 and Week 16] Change in microglial markers (quinolinic acid, kynurenine, kynurenic acid). [Bloods collected from consenting participants at baseline Week 4 and Week 16] Change in neurotrophic factors (BDNF)[Bloods collected from consenting participants at baseline Week 4 and Week 16] Change in Patient Global Impression Scale (PGI)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in quality of life, measured by Quality of life Enjoyment and Satisfaction Questionnaire – Short Form (Q‐LES‐Q‐SF)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in quality of life, measured by the Assessment of Quality of Life (AQoL‐4D) scale. [Conducted monthly ‐ Baseline (week 0) and Weeks, 4, 8, 12 and 16. ] Change in severity of anxiety symptoms, measured using Hamilton Anxiety Rating Scale (HAM‐A)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in severity of bipolar symptomatology, measured using Bipolar Disorder Rating Scale (BDRS)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in severity of mania symptomatology, measured using Young Mania Rating Scale (YMRS) [Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Change in severity of mood symptoms, measured using Montgomery‐Ã…sberg Depression Rating Scale Self‐report Version (MADRS‐S)[Conducted at all trial visits ‐ Baseline (week 0) and Weeks 2, 4, 8, 12 and 16. ] Changes in cognition as measured on pen and paper tasks (forward and backward digit span, trail making and symbol digit task)[Comparison between baseline and Week 16] Economic evaluation of adjunctive candesartan treatment compared to placebo, where $50,000 per quality adjusted life year (QALY) is the accepted benchmark for cost‐effectiveness. Measured using the Resource Use Questionnaire, Work Productivity and Activity Impairment Questionnaire: General Health (WPAI‐GH) and the Assessment of Quality of Life (AQoL‐4D).