A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
Açar sözlər
Mücərrəd
Təsvir
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.
Tarixlər
| Son Doğrulandı: | 04/30/2020 |
| İlk təqdim: | 04/12/2018 |
| Təxmini qeydiyyat təqdim edildi: | 04/12/2018 |
| İlk Göndərmə: | 04/22/2018 |
| Son Yeniləmə Göndərildi: | 05/12/2020 |
| Son Yeniləmə Göndərildi: | 05/13/2020 |
| Həqiqi Təhsilin Başlama Tarixi: | 08/31/2018 |
| Təxmini İlkin Tamamlanma Tarixi: | 02/28/2022 |
| Təxmini İşin Tamamlanma Tarixi: | 02/28/2023 |
Vəziyyət və ya xəstəlik
Müdaxilə / müalicə
Drug: Pregnenolone
Drug: Placebo
Faza
Qol Qrupları
| Qol | Müdaxilə / müalicə |
|---|---|
| Experimental: Pregnenlone (phase 1 and 2) Participants will receive pregnenolone at phase 1 (baseline-WK 7) and 2 (WK 8-16). The titration schedule is as follows: at baseline a 50 mg (BID, 7 days). WK 1=150 mg (BID, 7 days); WK 2=250 mg (BID, 14 days) and WK 4=250 mg (BID, 14 days) (BID, 14 days). At phase 2 (WK 8) to maintain the double blind of rerandomization, treatment in all conditions recommence at a dosage frequency similar to phase 1. At WK 8=250 mg (BID, 7 days); at WK 9=250 mg (BID, 7 days); WK 10=250 mg (BID, 14 days) and WK 12=250 mg (BID, 14 days) . During the participants' final WK (16), they will be instructed to titrate down the treatment according to the following schedule: 150 mg (BID, 4 days) and 50 mg (BID, 4 days), discontinue. | |
| Placebo Comparator: Placebo rerandom to placebo Participants will receive placebo at phase 1 (baseline-WK 7) & treatment response assessed (MADRS score reduced <50% at WK8). Nonresponders are rerandomized to receive either treatment at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1= placebo (7 days); at WK 2=placebo (14 days) and WK 4=placebo (14 days). Placebo nonresponders rerandomized to placebo: At WK 8=placebo (7 days);WK 9=placebo (7 days);WK 10=placebo (14 days) and WK 12=placebo (14 days). During the participants' final WK (16), they will be instructed to titrate down (done in order to maintain the double blind) the treatment according to the following schedule: placebo (4 days) and placebo (4 days), discontinue. | |
| Experimental: Placebo rerandom to pregnenolone Participants will receive placebo at phase 1 (baseline-WK 7) & treatment response assessed (MADRS score reduced <50% at WK8). Nonresponders are rerandomized to receive either treatment at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1=placebo (7 days); WK 2=placebo (14 days) & WK 4=placebo (14 days). Placebo nonresponders who are rerandomized to pregnenolone: At WK 8=250 mg (7 days);WK 9=250 mg (7 days);WK 10=250 mg (14 days) & WK 12=250 mg (14 days). During the participants' final WK (16), they will be instructed to titrate down the treatment according to the following schedule: 150 mg (4 days) and 50 mg (4 days), discontinue. | |
| Placebo Comparator: Placebo responsive cont placebo Participants will placebo throughout phase 1 (baseline- WK 7) & treatment response assessed (MADRS score reduced <50% at WK8). Responders continue to receive placebo at phase 2 (WK8-16).The titration schedule is as follows (dosage throughout is BID): at baseline placebo (7 days). At WK 1=placebo (7 days); WK 2=placebo (14 days) & WK 4=placebo (14 days). Placebo responders remain on placebo: At WK 8, placebo (7 days); WK 9=placebo (7 days); WK 10=placebo (14 days) & WK 12=placebo (14 days). During the participants' final WK (16), they will be instructed to titrate down (done in order to maintain the double blind) the treatment according to the following schedule: placebo= 4 days) and placebo=4 days, discontinue. |
Uyğunluq Kriteriyaları
| Təhsil üçün uyğun yaşlar | 40 Years Üçün 40 Years |
| Təhsilə Uyğun Cinslər | Female |
| Sağlam Könüllüləri qəbul edir | Bəli |
| Kriteriyalar | 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 |
Nəticə
İlkin nəticə tədbirləri
1. Montgomery-Asberg Depression Rating Scale (MADRS) [16 weeks]
İkincili Nəticə Tədbirləri
1. Hamilton Anxiety Rating Scale (HRSA) [16 Weeks]
2. Pittsburgh Sleep Quality Index (PSQI) [16 Weeks]
3. Menopause Specific Quality of Life (MEN-QOL) [16 weeks]
4. Greene Climacteric Scale (GCS) [16 weeks]
5. Rey Auditory Verbal Learning Test (RAVLT) [16 Weeks]
6. Trail Making Test (TMT) [16 Weeks]
Digər nəticə tədbirləri
1. Blood drawn [16 weeks]
2. Systematic Assessment for Treatment Emergent Events (SAFTEE) [16 weeks]
3. Cognitive and Physical Functioning Questionnaire (CPFQ) [16 weeks]
4. Columbia-Suicide Severity Rating Scale (C-SSRS) [16 weeks]
