Pregnenolone for Depression in HIV

(SOOTHE Trial)

Overseen By Hemi Park, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must be taking: Antidepressants

Must not be taking: Cobicistat, Ritonavir, Immunosuppressants, others

Disqualifiers: Severe infections, Bipolar, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people with HIV who have depression. Participants in this study will receive a pill of either pregnenolone or placebo, and can stay on their current antidepression medications. Brain imaging and behavioral assessments will be performed during the study.

Do I have to stop taking my current medications for the trial?

You can stay on your current antidepression medications during the trial. The protocol does not specify about other medications, but certain medications like cobicistat, ritonavir, testosterone enanthate, testosterone cypionate, and some immunosuppressive agents are not allowed.

What data supports the idea that Pregnenolone for Depression in HIV is an effective treatment?

The available research shows that pregnenolone may help improve mood in people with depression. In one study, people with bipolar disorder who took pregnenolone had a higher rate of depression remission compared to those who took a placebo. Specifically, 61% of those taking pregnenolone showed improvement, compared to 37% in the placebo group. Although this study focused on bipolar depression, it suggests that pregnenolone could have positive effects on mood, which might be relevant for depression in HIV. However, more research specifically on HIV patients is needed to confirm its effectiveness for this group. ^{1 2 3 4 5}

What safety data exists for pregnenolone treatment?

The study titled 'Pregnenolone for cognition and mood in dual diagnosis patients' provides some safety data. In this study, 70 participants with bipolar disorder or recurrent major depressive disorder and a history of substance abuse were treated with pregnenolone. The treatment was titrated to 100mg/day over 8 weeks. The study found that pregnenolone appeared to be safe and well tolerated, with some improvement in manic and depressive symptoms. However, larger trials are needed to further evaluate its safety and efficacy. ^{1 3 6 7 8}

Is the drug pregnenolone a promising treatment for depression in people with HIV?

Pregnenolone shows potential as a treatment for depression. Studies suggest it may help improve mood and reduce depressive symptoms, especially in people with bipolar disorder. It appears to be safe and well-tolerated, making it a promising option for further research in treating depression. ^{1 2 3 4 9}

Research Team

Shibani Mukerji, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults aged 18-70 with HIV who are on antiretroviral therapy and have depression (CES-D score ≥ 20). They must not be pregnant, severely cognitively impaired, or using certain medications like cobicistat. People with recent severe infections, liver inflammation, severe renal disease, high blood pressure, or a history of bipolar disorder or schizophrenia cannot join.

Inclusion Criteria

Center for Epidemiological Studies - Depression (CES-D) score ≥ 20

I am between 18 and 85 years old.

My HIV-1 viral load is under 200 copies/mL while on ART.

Exclusion Criteria

I am currently taking cobicistat or ritonavir.

My kidney function is severely reduced.

I cannot swallow pills or capsules.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pregnenolone or placebo with dosage adjustments over 8 weeks

8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pregnenolone

Trial Overview The study tests if pregnenolone can improve brain function and reduce depressive symptoms in people with HIV. Participants will receive either pregnenolone or a placebo pill while continuing their current antidepressants. Brain scans and behavioral assessments will monitor changes.

Participant Groups

Group I: Pregnenolone Experimental Treatment 1 Intervention

Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks

Group II: Placebo Experimental Treatment 1 Intervention

Participants will be on the following dosage schedule: 50 mg daily for 2 weeks, THEN 100 mg daily for 1 week, THEN 250 mg daily for 1 week, THEN 500 mg daily for 4 weeks

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Institute for Medical Research, Inc.

Industry Sponsor

Trials

2

Recruited

260+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Findings from Research

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 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]

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]

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]

In a 12-week trial involving HIV-infected men with mild to moderate weight loss, nandrolone (150 mg biweekly) significantly increased lean body mass compared to placebo, showing an increase of +1.6 kg versus +0.4 kg for placebo.

Nandrolone's effectiveness in improving lean body mass was comparable to that of recombinant human growth hormone (rhGH), which had a greater increase of +2.5 kg, but rhGH was associated with more adverse effects and treatment discontinuations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, placebo-controlled trial of nandrolone decanoate in human immunodeficiency virus-infected men with mild to moderate weight loss with recombinant human growth hormone as active reference treatment. Storer, TW., Woodhouse, LJ., Sattler, F., et al.[2018]

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]

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 sulfate is a unique neurosteroid that not only modulates ion channels but also acts as an activating ligand for these channels, indicating its significant role in neurophysiology.

Unlike typical metabolites, pregnenolone sulfate is not just a waste product; it serves as a precursor for further steroid synthesis, highlighting its importance in steroid metabolism and function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnenolone sulfate: from steroid metabolite to TRP channel ligand. Harteneck, C.[2021]

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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. England pubmed.ncbi.nlm.nih.gov

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

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

A randomized, placebo-controlled trial of nandrolone decanoate in human immunodeficiency virus-infected men with mild to moderate weight loss with recombinant human growth hormone as active reference treatment. [2018]

6. 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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Pregnenolone sulfate: from steroid metabolite to TRP channel ligand. [2021]

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

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