Pregnenolone for Depression

(SADIE-P Trial)

Overseen By Aleta Wiley

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Brigham and Women's Hospital

Must not be taking: Systemic hormone, corticosteroid

Disqualifiers: Other psychiatric illnesses, substance use, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

80 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to identify how enhanced allopregnanolone activity (via pregnenolone) affects behavior and neurobiology that may underlie perimenopausal depression.

Will I have to stop taking my current medications?

You can continue taking your current psychotropic medications (drugs that affect mood, perception, or behavior) if the dose is stable before and during the study. However, you cannot take systemic hormone therapy, systemic corticosteroids, or any medications that are contraindicated (not allowed) with pregnenolone.

What evidence supports the effectiveness of the drug pregnenolone for depression?

Research suggests that pregnenolone may help improve depressive symptoms in people with bipolar disorder and major depressive disorder, showing greater improvement compared to a placebo in some studies. It was also found to be safe and well-tolerated. ^{1 2 3 4 5}

Is pregnenolone safe for use in humans?

Pregnenolone has been generally well-tolerated in humans, with studies showing no significant effects on mood, memory, sleep quality, or well-being when taken at doses of 15 mg to 30 mg per day over four weeks. ^{2 6 7 8 9}

What makes the drug Pregnenolone unique for treating depression?

Pregnenolone is unique for treating depression because it is a hormone that may influence mood by affecting brain chemicals differently than traditional antidepressants, which typically target neurotransmitters like serotonin or norepinephrine. ^{10 11 12 13 14}

Research Team

Katherine Burdick, Ph.D

Principal Investigator

Brigham and Women's Hospital

Hadine Joffe, MD MSc

Principal Investigator

Brigham and Women's Hospital

Eligibility Criteria

This trial is for women aged 40 to 60 who are going through menopause and experiencing depression. They can be on stable psychotropic medications, must understand basic math, and agree to participate by signing a consent form.

Inclusion Criteria

I am a woman aged 40-60 going through menopause.

I am experiencing symptoms of depression.

My psychotropic medication dose has been stable and will remain so during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 250mg of pregnenolone or placebo twice per day for four weeks

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Pregnenolone

Trial Overview The study is testing the effects of pregnenolone, a substance that may influence mood changes during menopause, compared with a placebo (a treatment with no active drug).

Participant Groups

Group I: pregnenolone Experimental Treatment 1 Intervention

Participants will take 250mg of pregnenolone twice per day (daily total=500mg) for four weeks

Group II: placebo Placebo Group 1 Intervention

Participants will take placebo twice per day for four weeks

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Findings from Research

In a study of 11 patients with bipolar depression and 4 healthy controls, serum MAP2 levels were found to be higher in the depressed patients, suggesting a potential biomarker for mood disorders.

Pregnenolone treatment showed a positive correlation between changes in MAP2 levels and improvements in depressive symptoms, indicating that MAP2 may play a role in the antidepressant effects of pregnenolone, although the results were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone. Daftary, S., Yon, JM., Choi, EK., et al.[2022]

In a study of 64 adolescents with autism spectrum disorders, adding pregnenolone to risperidone treatment showed significant improvements in irritability, stereotypy, and hyperactivity, suggesting it may enhance the effectiveness of standard treatment.

The addition of pregnenolone did not increase the frequency or severity of adverse effects compared to placebo, indicating it is a safe adjunct therapy for managing symptoms of ASD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial? Ayatollahi, A., Bagheri, S., Ashraf-Ganjouei, A., et al.[2023]

In a 12-week pilot study involving 12 young adults with autism spectrum disorder, pregnenolone significantly reduced irritability, as measured by the Aberrant Behavior Checklist, with scores improving from 17.4 to 11.2 (p = 0.028).

Pregnenolone was well-tolerated with no severe side effects reported, and only mild adverse effects like tiredness and diarrhea were noted, indicating its safety for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Fung, LK., Libove, RA., Phillips, J., et al.[2021]

In a study of 70 participants with bipolar disorder or major depressive disorder and a history of substance abuse, pregnenolone showed a statistically significant reduction in depression symptoms compared to placebo after 8 weeks, indicating its potential efficacy in mood improvement.

Pregnenolone was found to be safe and well tolerated, but it did not demonstrate significant effects on cognitive function, suggesting that its benefits may be more focused on mood rather than cognitive deficits in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone for cognition and mood in dual diagnosis patients. Osuji, IJ., Vera-Bolaños, E., Carmody, TJ., et al.[2013]

In a study of 80 adults with bipolar disorder, pregnenolone (500 mg/day) as an add-on therapy for 12 weeks significantly improved depressive symptoms, with a remission rate of 61% compared to 37% in the placebo group.

Pregnenolone was well tolerated and led to significant changes in neurosteroid levels, suggesting it may be a safe and effective option for treating depression in bipolar disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Brown, ES., Park, J., Marx, CE., et al.[2021]

The study identified two metabolites, 7 alpha-hydroxy-PREG and 7 beta-hydroxy-PREG, produced in mouse brain microsomes, with different kinetic properties indicating distinct enzymatic pathways for their production.

Different cytochrome P450 (CYP) enzymes are involved in the hydroxylation of pregnenolone, with specific inhibitors revealing that 7 alpha-hydroxylation is primarily inhibited by certain compounds, while 7 beta-hydroxylation involves CYP 1A1 and other unidentified enzymes, providing insights for future research on these metabolic processes in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes. Doostzadeh, J., Morfin, R.[2019]

A new series of compounds derived from pregnenolone were synthesized and characterized, showing significant activity against EC109 cancer cells, indicating potential for cancer treatment.

The synthesis involved biotransformation using the fungus Mucor circinelloides, which highlights a novel method for creating these bioactive derivatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis of 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives and their cytotoxic activities. Shan, LH., Liu, HM., Huang, KX., et al.[2013]

Pregnenolone at a dose of 10 μM was found to be optimal for promoting the proliferation of neural stem cells (NSCs), significantly increasing the number of neurospheres compared to controls.

Lower doses of pregnenolone (5 and 10 μM) enhanced NSC differentiation into oligodendrocytes, while higher doses (15 μM) promoted differentiation into neurons, indicating that pregnenolone can regulate NSC fate depending on the concentration used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone enhances the proliferation of mouse neural stem cells and promotes oligodendrogenesis, together with Sox10, and neurogenesis, along with Notch1 and Pax6. Negintaji, K., Ghanbari, A., Frozanfar, M., et al.[2023]

In a study with 17 volunteers, pregnenolone was found to be well-tolerated but did not significantly affect mood, memory, or sleep quality over a 4-week period.

In a follow-up study with 11 participants, those pre-treated with pregnenolone experienced significantly less sedation from diazepam, suggesting that pregnenolone may counteract some effects of benzodiazepines, indicating a potential for enhancing arousal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Meieran, SE., Reus, VI., Webster, R., et al.[2019]

General practitioners and psychiatrists perceive the severity of depression and suicidal risk similarly in elderly (70 years) and younger (40 years) patients, indicating no age bias in their assessment.

However, there are significant differences in clinical practice: older patients are more likely to receive brain imaging and tetracyclic antidepressants, while younger patients are prescribed more non-antidepressant psychotropic medications, suggesting a need for better adherence to treatment guidelines for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Depression in older adults. What are the differences in clinical practice?] Le Bivic, G., Limosin, F., Lemogne, C., et al.[2023]

A study of 632 patients treated for depression revealed that while 91.2% of prescribed SSRIs and SNRIs were at adequate doses, only 40.2% of these treatments were considered adequate overall, indicating a significant gap in adherence to treatment guidelines.

The study found that 58.1% of patients discontinued their antidepressant treatment, primarily due to feeling cured (47.6%) or experiencing side effects (23.6%), highlighting the need for better patient education and support to improve treatment adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines and reality in practical use of and compliance to antidepressants in the treatment of depression: incidence survey in Lorraine and Champagne-Ardenne (France)]. Hérique, A., Kahn, JP.[2009]

The guidelines provide a comprehensive review of evidence-based practices for treating major depression, focusing on biological treatments such as medications and brain stimulation therapies, which are applicable to various age groups.

The literature was rigorously evaluated and categorized into levels of evidence and recommendation grades, ensuring that the guidelines are clinically relevant and scientifically grounded for physicians treating unipolar depressive disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. part 2: maintenance treatment of major depressive disorder-update 2015. Bauer, M., Severus, E., Köhler, S., et al.[2022]

This study aims to develop and test a community-based intervention to prevent depression in individuals with subthreshold symptoms, involving 64 participants who will be randomly assigned to either the intervention or usual care.

The intervention includes a revised manual and a 1-day workshop, with outcomes assessed 3 months later to evaluate the feasibility and acceptability of the approach, which is crucial given that existing treatments only reduce depression burden by 35%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing depression in the community by voluntary sector providers (PERSUADE): intervention development and protocol for a parallel randomised controlled feasibility trial. Kenning, C., Blakemore, A., Bower, P., et al.[2020]

Depression is increasingly recognized as a major public health issue, with its prevalence rising over the past 50 years, potentially due to better recognition and willingness to diagnose it.

Nursing can significantly contribute to the prevention of mild-to-moderate depression by enhancing the role of non-mental health nurses in primary care and influencing health policy at community and structural levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The contribution of nursing to public health practice in the prevention of depression. Wood, S.[2008]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents With Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial? [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

Pregnenolone for cognition and mood in dual diagnosis patients. [2013]

5. England pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Synthesis of 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives and their cytotoxic activities. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Pregnenolone enhances the proliferation of mouse neural stem cells and promotes oligodendrogenesis, together with Sox10, and neurogenesis, along with Notch1 and Pax6. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. [2019]

10. France pubmed.ncbi.nlm.nih.gov

[Depression in older adults. What are the differences in clinical practice?] [2023]

11. France pubmed.ncbi.nlm.nih.gov

[Guidelines and reality in practical use of and compliance to antidepressants in the treatment of depression: incidence survey in Lorraine and Champagne-Ardenne (France)]. [2009]

12. England pubmed.ncbi.nlm.nih.gov

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. part 2: maintenance treatment of major depressive disorder-update 2015. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Preventing depression in the community by voluntary sector providers (PERSUADE): intervention development and protocol for a parallel randomised controlled feasibility trial. [2020]

14. Australia pubmed.ncbi.nlm.nih.gov

The contribution of nursing to public health practice in the prevention of depression. [2008]