The Candesartan Adjunctive Bipolar Depression Trial – CADET: A double-blind, randomised, placebo-controlled trial
Summary
Depression is the single major unmet need in bipolar disorder, such that people with the
disorder spend almost half their lives in the depressive phase. Bipolar disorder consequently
has higher suicide mortality rates than any other psychiatric disorder. Current therapies are far
more efficacious in bipolar mania than bipolar depression such that bipolar depression is
inadequately addressed by available psychotherapy and pharmacotherapy. Known key
biological factors that contribute to the pathophysiology of bipolar disorder may be targeted by a
drug known as candesartan, an angiotensin-II type 1 receptor (AT1R) antagonist. Candesartan
reduces stress reactivity, impacts the hypothalamic-pituitary-adrenal (HPA) axis, oxidative and
inflammatory stress and enhances neurogenesis. This trial targets a major unmet need, is
grounded in pathophysiology, builds on an established defined long-term strategy for the
discovery of novel agents, and importantly, is the first study of this agent in bipolar disorder. The
proven safety, tolerability, affordability, and accessibility of candesartan raise its attraction as a
potential agent. Candesartan is off-patent, cheap and easily accessible to participants following
the study. Cardioprotective agents such as candesartan have additional benefits in bipolar
disorder, as there is greater risk of cardiovascular events.
Eligibility
Eligible ages: 18 to 100
Inclusion criteria:
Provide the inclusion criteria: (E2.16.91)
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 ≥ 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 will be required to nominate a current treating physician,
X. Willing to consent to blood collection for safety monitoring.
Exclusion criteria:
I. A diagnosis of another psychotic disorder and/or current substance use disorder, assessed
using the SCID-5-RV;
II. Undergoing electroconvulsive therapy (ECT) or transcranial magnetic stimulus (TMS)
therapy within one month of randomisation in the study;
III. Known or suspected clinically unstable systemic medical disorder, including heart
disease especially congestive heart failure, cerebrovascular, liver or kidney disease including
renal artery stenosis;
IV. Participants on current use of any AT1R blockers or ACE inhibitors medications (such
as captopril, enalapril, losartan, irbesartan) will be ineligible, although previous use of these
(i.e., cessation at least two weeks prior to entrance in the study) will not preclude participation;
V. Systolic blood pressure less than 110mmHg at the baseline;
VI. Symptoms or measures of postural hypotension (reduction in systolic blood pressure
of 20mmHg or more after standing from sitting/lying for at least one minute),
VII. Safety blood results not cleared by a Principal Investigator or eGFR less than 30 at
the baseline;
VIII. Current pregnancy or breastfeeding for females;
IX. Current use of medications contraindicated with concurrent use of candesartan:
aliskiren, digoxin, spironolactone, diuretics, or daily use of non-steroidal anti-inflammatory drugs
(such as ibuprofen or celecoxib; PRN use will be accepted);
X. Intolerance or allergy to candesartan or any of the trial prepare
Participate
Additional information
Contact information
Mental Health Clinical Trials Unit | Mathison Centre for Mental Health Research & Education Department of Psychiatry, Cummings School of Medicine, University of Calgary CWPH Building 1st. Floor | 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6 Phone: (403) 210-6903 | Fax: (403) 210-9346
Principal investigator:
Thomas Raedler
Clinical trial:
Yes
REB-ID:
REB25-1841