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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how pregnenolone, a hormone, might enhance brain function, reduce inflammation, and alleviate depression in people living with HIV. Participants will receive either pregnenolone or a placebo while continuing their regular depression medications. The trial includes brain scans and behavior assessments to evaluate the treatment's effects. It suits individuals with HIV who are on antiretroviral therapy, have a stable viral load, and experience depression. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that pregnenolone is likely to be safe for humans?

Research has shown that pregnenolone might be safe for people with HIV and depression. Early results suggest that pregnenolone causes few serious side effects. Participants in past studies found it well-tolerated and reported few negative effects. Pregnenolone, a hormone that affects the brain, is often lower in people with HIV and depression, suggesting it could be a safe treatment option. However, further research is needed to confirm these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression in HIV?

Pregnenolone is unique because it targets depression in individuals with HIV by potentially influencing neurosteroid levels in the brain, a different approach compared to standard antidepressants like SSRIs or SNRIs that mainly focus on serotonin or norepinephrine pathways. Researchers are excited about pregnenolone because it is a naturally occurring steroid hormone that may offer a novel mechanism of action, potentially leading to improved mood regulation and cognitive function. Additionally, its multi-step dosing schedule could provide flexibility in treatment and help manage side effects more effectively than some current options.

What evidence suggests that pregnenolone might be an effective treatment for depression in HIV?

Research has shown that pregnenolone, a natural body chemical, might help reduce depression symptoms. Studies have found that people with HIV and depression often have lower levels of these chemicals. Pregnenolone, which participants in this trial may receive, is believed to improve mood by enhancing brain function and reducing inflammation. Early results suggest it can lift mood in mental health conditions due to its role in brain chemistry. Although more research is needed, these early signs are promising for treating depression in people with HIV. ^{1 2 3 6 7}

Who Is on the Research Team?

Shibani Mukerji, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05570812?cond=HIV&locn=%22brigham+and+women%27s%22+OR+%22Massachusetts+General+Hospital%22+OR+%22Beth+Israel+Deaconess%22+OR+%22Fenway+Health%22+OR+%22Fenway+Institute%22+OR+%22Children%27s+Hospital+Boston%22+OR+%22Ragon+Institute%22+OR+%22Dana+Farber%22&aggFilters=status%3Anot+rec

Neuroactive Steroid to Treat Depressed Mood: A Trial for ... This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people with HIV who have ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05570812

Neuroactive Steroid to Treat Depressed Mood: A Trial for ... The investigators' recent human data suggest that neuroactive steroids are decreased in people with HIV and depression.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8136979/

Low Neuroactive Steroids Identifies a Biological Subtype of ... This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores.

4. massgeneral.trialstoday.org massgeneral.trialstoday.org/trial/NCT05570812

Mass General - Division of Clinical Research This study will determine the effects of pregnenolone on brain function, inflammation and depressive symptoms in people with HIV who have ...

5. reporter.nih.gov reporter.nih.gov/project-details/10914089

In Vivo Targeting of Neuroactive Steroid and Immune ... Neuroactive steroids can improve depressive symptoms in psychiatric conditions and are effective in chronic pain. In human studies, the effect was mediated ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7109513/

Pregnane steroidogenesis is altered by HIV-1 Tat and morphine Data demonstrate that steroidogenesis is altered by HIV-1 Tat or ... HIV-1 Tat increases brain pregnenolone and progesterone's 5α-reduced metabolites.

7. rally.massgeneralbrigham.org rally.massgeneralbrigham.org/study/mghsoothe

Are you living with HIV and depression? One of these hormones, called pregnenolone, may be lower in people with depression and HIV. ... pregnenolone are safe to take without causing too many side ...