A Neurosteroid Intervention for Menopausal and Perimenopausal Depression

Despite the introduction of new antidepressants, major depressive disorder (MDD) remains
challenging to treat. Antidepressant effectiveness trials conducted suggest depression
remission rates of only 15%-35%. Therefore, new antidepressants with mechanisms that move
beyond norepinephrine and serotonin targets are greatly needed. Importantly, comorbid
symptoms including anxiety, cognitive complaints and somatic symptoms often co-occur with
depression and further impact functioning and quality of life.

The lifetime prevalence of MDD in women at > 20%, is approximately twice of that of men, with
increased risk during the menopausal transition (perimenopause and early postmenopause). Hot
flashes and other menopausal symptoms, such as cognitive symptoms and sleep dysregulation,
affect up to 80% of women after perimenopause onset. Two large NIH-funded prospective
epidemiological studies demonstrated an increased risk of onset of MDD during perimenopause
(mMDD), with hormonal variability serving as a biomarker of risk of MDD. Short-term studies
have demonstrated an augmentation benefit of estrogen and serotonin reuptake inhibitors can
be used to target both mMDD and hot flashes. However, limited data from controlled trials
suggest modest benefit for mMDD with standard antidepressants. Furthermore, due to safety
concerns, many women prefer options other than estrogen replacement. Therefore, new and more
effective treatments are needed for mMDD. Despite the fact that midlife women are the most
frequent consumers of complementary and alternative therapies, trials of these approaches for
mMDD are lacking. Pregnenolone is a naturally occurring neurosteroid made from cholesterol in
the adrenal glands and brain, sold as an over-the-counter supplement, and the use of which at
this time is common, unregulated and unstudied in women around the menopausal transition.
Pregnenolone is a precursor of hormones known to fluctuate during the menopausal transition,
and may decrease this hormonal variability known to increase the risk of MDD.

Preclinical research suggests that pregnenolone has antidepressant and neuroprotective
effects, and improves cognition. Lower cerebrospinal fluid levels of pregnenolone are
reported in people with bipolar disorder (BPD) or major depressive disorder (MDD) than
controls. The investigators conducted two pilot studies of pregnenolone in depressed
patients. The first study included patients with bipolar as well as unipolar depression (i.e.
MDD). Pregnenolone (100 mg/d) was superior to placebo in improving depressive symptom
severity. The second study found that 500 mg/d of pregnenolone was superior to placebo for
bipolar depression. Baseline anxiety, fatigue, anhedonia and physical symptoms predicted a
favorable depressive symptom response to pregnenolone compared to placebo. Improvement in
cognition (e.g. declarative and working memory) was also observed in women given
pregnenolone. Additionally, in women, changes in depressive symptoms showed strong inverse
correlations with changes in pregnenolone (r=-0.83), and other neurosteroid levels.
Furthermore, in both studies women responded better to pregnenolone relative to placebo for
depression than men. Therefore, pregnenolone appears to have sex-specific antidepressant
effects, or at least demonstrates a substantial sex difference in response. Women over age 40
showed a more robust response than younger women. Pregnenolone was very well tolerated in
both studies. Based on these data, a larger, longer and more definitive trial of pregnenolone
is now proposed. Unlike the prior pilot studies, this trial will be larger and focus on
unipolar rather than bipolar depression, and will be limited to women with mMDD.

Given the widespread availability of pregnenolone, as well as promising preclinical and
clinical data, and the extensive use of integrative treatments among midlife women, the
investigators propose to examine its efficacy as an antidepressant in mMDD. Pregnenolone has
the potential to provide women with an efficacious and appealing treatment option. To achieve
this objective, a randomized, placebo-controlled trial of pregnenolone is proposed in 144
women with mMDD. A novel clinical trial design that enhances power to detect between-group
differences and that allows for a longer observation period (16 weeks) will be used.
Depressive symptoms, anxiety, quality of life, cognition and vasomotor symptoms (e.g. hot
flashes) will be assessed. Blood levels of pregnenolone, and other neurosteroids (e.g.
allopregnanolone, progesterone) will be obtained, and safety and tolerability data collected.
A multiple PI team with extensive experience in mood disorders clinical trials, women's
mental health and neurosteroids will conduct the study.

Inclusion Criteria:

The participants must meet the following criteria:

- Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years
of the last menstrual period if not surgically postmenopausal), including:

- Women who have experienced changes in menstrual cycle frequency or duration, and/or
physical symptoms indicative of menopausal transition, as determined by clinician

- Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20
mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making
irregular/absent periods difficult to assess as related to the menopausal transition).

- Women with significant menopause-related physical symptoms, indicated by any of the
following criteria:

- Greene Climacteric Scale total scores > 20

- Greene Climacteric Scale sub-score for vasomotor symptoms >3

- 5 or more bothersome hot flashes per week (self-reported)

- Women meeting DSM-5 criteria for current major depressive disorder (assessed by the
SCID)

- Baseline HRSD score of ≥ 18

- Subject agrees to abstain from disallowed medications for the duration of the trial

Exclusion Criteria:

The participants must not meet any of the following criteria:

- Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual
impairment, incarcerated)

- Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding

- Psychiatric disorder other than MDD that is acute and the primary focus of symptom
burden or treatment.

- History of bipolar disorder or psychotic disorder

- Current substance use disorder

- Positive baseline urine drug screen of an illicit substance with the exception of a
medication used with a prescription such as an opioid pain medication

- Current eating disorder

- Treatment resistant depression (failure of 2 adequate antidepressant trials or
electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials
are defined as within the US FDA approved dosage for the medication and used for at
least 6 weeks, with failure described by the patient as <50% improvement based on her
subjective experience). )

- High risk for suicidal acts including active suicidal ideation with plan and intent or
> 2 suicide attempts in lifetime or any attempt in the past 6 months

- Women who have used psychoactive or centrally acting medications within 2 weeks prior
to study screening

- Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy,
hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic,
regular, stable-dose benzodiazepines and hypnotics such as zolpiderm, Sonata
(Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom
(Doxylamine succinate) or diphenhydramine allowed), and antidepressants within 2 weeks
of the baseline visit and randomization.

- Use of natural menopause and depression supplements, phytoestrogens, soy-based
medications, steroids within 2 weeks of baseline visit and randomization.

- Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy,
hormonal contraceptives (hormonal IUDs allowed), natural menopause supplements,
episodic sleep medications (chronic, regular, stable-dose benzodiazepines allowed),
antidepressants, phytoestrogens, soy-based medications, steroids within 4 weeks of
randomization

- Use of any disallowed medications (specified in the Excluded Concomitant Medication
section below)

- Women who have received a gonadal hormonal intervention within 1 month prior to study
entry (stable thyroid medications are allowed).

- Not using a medically approved method of birth control, if sexually active and not 12
or more months since last menstrual period (IUDs, condoms, abstinence are acceptable
forms of contraception in this study; due to the possible interactions with the study
medication, oral contraceptive pills will be prohibited)

- Uncontrolled hypertension (>160/95mmHg)

- Active Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis,
pulmonary embolism or blood clotting disorder

- Any severe, life threatening or unstable medical condition that, based on
clinician-judgment, would make participation in the study unsafe or inappropriate

- Personal or first- degree family history of known hormone sensitive tumors

- History of allergic reaction or side effects with prior pregnenolone use

- Clinically significant laboratory, physical examination

- Concurrent enrollment in another clinical trial

Exclusion of Concomitant Medications:

- Selective estrogen-receptor modulators (SERMs)

- Hormone replacement therapy

- Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone

- Natural menopause or antidepressant supplements

- Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and
hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR
sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine
allowed)

- Antidepressants used at indicated, therapeutic, FDA-approved doses (Note:
sub-therapeutic dosages of antidepressants used for other indications will be
permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin).

- Phytoestrogens

- Soy-based medications or supplements