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

Funding

Government body,National Health and Medical Research Council (NHMRC)

Scientific enquiries

Prof Michael Berk

Brief Summary

There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. Increasing attention to biomarker-indicated targets is likely to be a promising avenue for new drug discovery. Candesartan, an AT1R agonist, may target key biological factors in the pathophysiology of major depressive disorder. Candesartan reduces stress reactivity, impacts the HPA axis, oxidative and inflammatory stress and enhances n .... There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. Increasing attention to biomarker-indicated targets is likely to be a promising avenue for new drug discovery. Candesartan, an AT1R agonist, may target key biological factors in the pathophysiology of major depressive disorder. Candesartan reduces stress reactivity, impacts the HPA axis, oxidative and inflammatory stress and enhances neurogenesis; all documented pathological markers of major depressive disorder. The CADET-UD study will test the efficacy of candesartan 16 mg/day as an adjunctive treatment for major depression. CADET-UD is a multi-site, double-blind, randomised, placebo-controlled 16-week trial of candesartan as an add-on to treatment as usual. We plan to recruit 240 participants aged 18 years and above with moderate to severe major depressive disorder.
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Key Inclusion Criteria

I. A DSM-5 diagnosis of current major depressive disorder determined by the SCID-5-RV II. Moderate to severe depression indexed by a MADRS score of greater than or equal to 20. If there is a delay of greater than 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; III. Aged 18 years and above; IV. Have the capacity to consent to t .... I. A DSM-5 diagnosis of current major depressive disorder determined by the SCID-5-RV II. Moderate to severe depression indexed by a MADRS score of greater than or equal to 20. If there is a delay of greater than 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; III. Aged 18 years and above; IV. Have the capacity to consent to the study and to follow its instructions and procedures; V. Participants will need to have been on stable pre-existing pharmacological or psychotherapy regimens for two weeks prior to study entry; VI. Be using effective contraception if female, sexually active and of childbearing age, VII. Be able to speak, read, write and understand the English language, VIII. Participants will be required to nominate a current treating physician, IX. Willing to consent to blood collection for safety monitoring.
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Key Exclusion Criteria

I. A diagnosis of bipolar disorder and/or 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; 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 .... I. A diagnosis of bipolar disorder and/or 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; 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 one month prior to entrance in the study) will not preclude participation; V. Systolic blood pressure less than 110 mmHg 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. Current pregnancy or breastfeeding for females; VIII. Current use of medications contraindicated with concurrent use of candesartan: aliskiren, digoxin, potassium supplements (note: small amounts of potassium less than or equal to 4mg found in multivitamins will be accepted), spironolactone, diuretics, or daily use of non-steroidal anti-inflammatory drugs (such as ibuprofen or celecoxib; PRN use will be accepted); IX. Intolerance or allergy to candesartan or any of the trial preparations; X. Current enrolment in another psychiatric intervention study; XI. Participants on lithium will be accepted on the study but will require additional monitoring of lithium levels; XII. Participants with current suicidal ideation with a specific plan, defined as a score of 5 or 6 on the MADRS item 10.
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