Effects of Estradiol on Depression and Psychosis in Perimenopausal Women

Inclusion Criteria:

* Provision of signed and dated informed consent form
* Stated willingness to comply with all study procedures, lifestyle considerations, and availability for the duration of the study
* 44-55 years old unmedicated perimenopausal women who have ≥ 2 skipped menstrual cycles, amenorrhea ≥ 60 days, corresponding to the late menopause transition (Stages of Reproductive Aging Workshop (STRAW stage -1).
* Anhedonia or psychosis symptoms that began during the period of menstrual irregularity.
* Clinician's Global Impression Scale-Severity score (CGI-S) \> 3 to confirm a clinically impaired sample.
* Anhedonia severity inclusion criteria and stratification: All participants will have Snaith-Hamilton Pleasure Scale (SHAPS) scores \> 20 consistent with the NIMH Fast-Fail Trial for Mood and Anxiety Disorders, corresponding to clinically impairing anhedonia.
* Psychosis severity inclusion criteria and stratification: Participants will be stratified according to scores on the psychotic subscale of the Brief Psychiatric Rating Scale (BPRS)
* Willingness to adhere to the estradiol regimen

Exclusion Criteria:

* Pregnancy; allergies to any active or inactive ingredients in the Climara® patch or Prometrium®.
* BMI \< 18 or \> 35 kg/m\^2
* A history of chronic menstrual cycle irregularity, meaning \> 1 year without menses
* MR contraindications: Metal in the body, dental work other than fillings or gold, tattoos, metal injury, any other implant unless they are 100% plastic.
* PET contradictions: participation in \>1 research study in the past 12 months that included ionizing radiation exceeding 3 rem to the whole body (e.g., PET, CT). Standard of care imaging is not exclusionary.
* The use of psychotropics or hormonal preparations.
* History of psychiatric illness during the 2 years before the onset of perimenopause.
* History of chronic, recurrent mood or psychotic disorders (i.e., more than one non-reproductive-related mood episode prior to the perimenopausal index episode).
* A history of mood episodes requiring hospitalization.
* Current mania;
* Depressive episode(s) within 2 years of enrollment not associated with the transition to menopause;
* A history of suicide attempts within the last year or current active suicidal ideation with intent and plan.
* Neurological conditions (e.g., history of seizure or TBI)
* Brain stimulation treatment in the past six months.
* Endometriosis;
* First degree relative with premenopausal breast cancer or breast cancer presenting in both breasts or multiple family members (greater than three relatives) with postmenopausal breast cancer.
* Current medication use (i.e., current psychotropics, current anti-hypertensives, current statins, current hormonal preparations, or frequent use of anti-inflammatory agents (\> 10 times/month)). Women will be allowed to enroll who take medications without known mood effects (e.g. stable thyroid hormone replacement and occasional (\< 5 times/month) use of Ambien)\*;
* Pregnant, breastfeeding or trying to conceive;
* Last menstrual period more than 12 months prior to enrollment;
* History of undiagnosed vaginal bleeding;
* Undiagnosed enlargement of the ovaries;
* Polycystic ovary syndrome;
* History of breast or ovarian cancer;
* First degree relative with ovarian cancer;
* Abnormal finding in a provider breast exam and/or mammogram;
* Known carrier of BRCA1 or 2 mutation;
* Porphyria;
* Malignant melanoma;
* Hodgkin's disease;
* Recurrent migraine headaches that are preceded by aura;
* Gallbladder or pancreatic disease\*\*;
* Heart or kidney disease\*\*;
* Liver disease;
* cerebrovascular disease (stroke);
* First degree relative with history of heart attack or stroke;
* Current nicotine use;
* Self-reported claustrophobia
* Peanut allergy

  * all reported prescription medications will be reviewed and cleared by a study physician prior to a participant's enrollment;

    * participants will be given the opportunity to describe these conditions in the online screening survey. Reported conditions that are acute in nature and/or benign will be reviewed by a study physician and exclusions will be decided case-by-case. All chronic conditions will be exclusionary. For those where it is deemed that an exclusion does not apply, primary analyses will not be affected, but exploratory analyses will be conducted excluding these individuals