CLEAR Trials (1-4)

Please start here for epidemiologic background: Suicide & the Cycle.

Goal: Broadly, the goal of this series of crossover trials is to clarify the role of perimenstrual hormone (estradiol and progesterone) withdrawal/depletion on perimenstrual-onset exacerbation of suicidality and affective symptoms.

Samples: Naturally-cycling psychiatric outpatients (on stable meds or therapy), recruited for transdiagnostic suicidal ideation in the past month.

Experimental Designs: Crossover RCTs giving estradiol, progesterone, or both (versus a placebo) in the two weeks surrounding expected menses onset (LH+7-21) with the goal of reducing the severity of hormone withdrawal/depletion.

FAQs

CLEAR-1 Trial (K99MH-109667)

<aside> 1️⃣ The CLEAR-1 Trial Manuscript

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• Primary Trial Outcome Paper: Eisenlohr-Moul, T. A., Bowers, S. M., Prinstein, M. J., Schmalenberger, K. M.*, Walsh, E. C., Young, S. L., ... & Girdler, S. S. (2022). Effects of acute estradiol and progesterone on perimenstrual exacerbation of suicidal ideation and related symptoms: a crossover randomized controlled trial. Translational Psychiatry, 12(1), 528.
  • Takeaway: In a sample of naturally-cycling patients recruited for past-month SI, giving perimenstrual E2 and P4 (days LH+7-21) reduced perimenstrual worsening of suicidal ideation, depression, hopelessness, and perceived burdensomeness observed under placebo. No effects on irritability or mood swings.
• Secondary Biomarker Paper: Barone, J. C., Wenzel, E., Alluri, V.*, Moriarity, D., Pinna, G., Walsh, E., Morrow, A. L., Rubinow, D., & Eisenlohr-Moul, T. A. (in press). Effects of estrogen and progesterone on neuroactive steroids and cytokines in patients with suicidality. Psychoneuroendocrinology.

CLEAR-2 Trial (R00MH-109667)

<aside> 2️⃣ The CLEAR-2 Trial Manuscript

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• In Preprint/Under Review;
  • Eisenlohr-Moul, T. & Girdler, S.G. (under review). Independent effects of acute estradiol or progesterone on perimenstrual changes in suicidal ideation, affective symptoms, and 3α-reduced neuroactive steroids: A crossover randomized controlled trial.
• Takeaway: In a sample of naturally-cycling patients recruited for past-month SI, we did a new three-period crossover trial. Relative to PBO, giving E2 alone (on days LH+7-21) reduced perimenstrual worsening of suicidal ideation, depression, hopelessness, and perceived burdensomeness observed under placebo. Giving P4 alone worsened SI but did not significantly impact any other outcomes.

CLEAR-3 Trial (RF1MH-180243)

<aside> 🚧 Data Collection Ongoing

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• Purpose: a new two-period crossover trial with the same design as CLEAR-1 (but with a larger sample and more measures) to conduct a comprehensive test of our (thus far unsupported) hypothesis that withdrawal from progesterone metabolites and related processes underlie the benefit of acute perimenstrual E2+P4 administration (vs PBO) seen in the CLEAR-1 Trial (K99MH-109667).