Cyclical Neuroactive Steroid Changes, Arousal, and Proximal Suicide Risk: An Experimental Approach

Suicide is the second leading cause of death among women of reproductive age, and female suicide attempts occur most frequently around menses (perimenstrually), when estradiol (E2) and progesterone (P4) fall rapidly. A recent prospective study demonstrated that suicidal ideation (SI) and attempts peak perimenstrually in natural cycles, and that this perimenstrual worsening of SI can be prevented by administering stabilizing doses of E2+P4 (relative to placebo). Therefore, while E2+P4 withdrawal is a viable model of proximal suicide risk in females with SI, mechanisms are unclear. GABAergic neuroactive steroid metabolites of ovarian hormones (e.g., allopregnanolone), exert potent sedative and antidepressant effects; we hypothesize that acute perimenstrual withdrawal from these hormone metabolites may increase suicide risk by increasing hyperarousal and hopelessness. The long-term objectives of this research are to (1) use the menstrual cycle as a model to probe the proximal mechanisms of suicide, and (2) develop long-term treatments that eliminate hormonal contributions to suicide. The objective of the current work is to use a crossover placebo-controlled trial of E2+P4 stabilization (vs. natural E2+P4 withdrawal under placebo) in the perimenstrual weeks to probe behavioral (hopelessness, hyperarousal) and molecular/genetic (neuroactive steroid levels, mRNA expression for enzymes critical for synthesizing neuroactive steroids) mediators of perimenstrual suicide risk. Design: In this mechanistic trial, 90 female outpatients with past-month SI will complete two counterbalanced conditions: (1) two weeks of placebo during natural perimenstrual E2+P4 withdrawal, and (2) two weeks of perimenstrual E2+P4 stabilization (.1mg/day transdermal estradiol + 200mg/day oral micronized progesterone) to prevent withdrawal. Five labs per condition will capture changes in gas chromatography mass spectrometry (GC-MS) quantified neuroactive steroids, messenger ribonucleic acid (mRNA) expression for enzymes critical for synthesizing neuroactive steroids, and physiological arousal. Our app (BiAffect) will collect ecological momentary assessments (EMA; 4x/day) of behavioral constructs and SI, and will passively track arousal via movement and typing speed instability. Specific Aims. Aim 1 is to evaluate hyperarousal and hopelessness as interacting mechanisms by which perimenstrual E2+P4 withdrawal (vs. experimental E2+P4 stabilization) increases proximal suicide risk. Aim 2 is to evaluate neuroactive steroid withdrawal as a mechanism by which perimenstrual E2+P4 withdrawal (vs. stabilization) increases proximal suicide risk. If appropriate, a multilevel path model will test a path in which E2+P4 withdrawal (vs. stabilization) causes neuroactive steroid withdrawal, which increases in hopelessness and hyperarousal, which in turn increases proximal suicide risk. Relevance. By conducting a mechanistic experiment to probe the mediators of a known cause of proximal suicide risk, the proposed research responds to public calls from the National Institute of Mental Health (NIMH)-sponsored Suicide Research Prioritization Agenda to identify modifiable causes of proximal suicide risk.

Inclusion criteria

• Ability to adhere to medication regimen
• Speaks English
• Assigned female at birth with intact ovaries
• Premenopausal
• Normal menstrual cycles between 25-35 days
• Under current care of an outpatient mental health provider with visits occurring at least once every 3 months.
• At least 1 year postpartum.
• Willing to use a barrier method of birth control during the study.
• Normal weight (BMI between 18-29)
• Must report at least some recent suicidal ideation (in the past month) at the time of recruitment.
• Must be categorized as having acceptably low imminent risk for suicidal crisis/attempt by a licensed clinical psychologist utilizing evidence-based clinical and research guidelines for imminent suicide risk management.

Exclusion criteria

• Must not be pregnant, breastfeeding, or trying to become pregnant.
• Must not be taking any form of exogenous hormones or hormonal intrauterine device, and must have ended previous use of hormonal preparations at least one month prior to the study.
• Must not have a personal history of any chronic medical condition, including but not limited to metabolic or autoimmune disease, epilepsy, endometriosis, cancer, diabetes, cardiovascular, gastrointestinal, hepatic, renal, or pulmonary disease, and no personal or first degree family history of thromboembolic events.
• Any current cigarette smoking is exclusionary.
• Must not report a history of clinical diagnosis or treatment for postpartum depression or premenstrual dysphoric disorder (Note: Premenstrual Dysphoric - - - Disorder diagnosis must have been made based on prospective daily ratings).
• Must not report any history of manic episode, any history of psychotic symptoms, or current substance use disorder.