Pregnenolone for Depression in HIV
(SOOTHE Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
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
Prior Safety Data
Approved in 2 Jurisdictions
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.12345
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.13678
Is the drug pregnenolone a promising treatment for depression in people with HIV?
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.
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Trial 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 (Neuroactive Steroid)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: PregnenoloneExperimental Treatment1 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: PlaceboExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Massachusetts General HospitalBoston, MA
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Who Is Running the Clinical Trial?
Massachusetts General HospitalLead Sponsor
Institute for Medical Research, Inc.Industry Sponsor
National Institute of Mental Health (NIMH)Collaborator
References
Pregnenolone for cognition and mood in dual diagnosis patients. [2013]Mood and substance-use disorders are both associated with cognitive deficits. Patients with mood and substance-use disorders have poorer cognition than patients with only a mood disorder. Pregnenolone may have beneficial effects on mood and cognition. In a proof-of-concept investigation, 70 participants with bipolar disorder or recurrent major depressive disorder and history of substance abuse/dependence (abstinent for > or =14days prior to enrollment) were randomly assigned to receive pregnenolone (titrated to 100mg/day) or placebo for 8weeks. Participants were assessed using the Mini International Neuropsychiatric Interview, Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT-B), and Stroop Test. Mood was assessed bi-weekly, while cognition was evaluated at baseline, and weeks 4 and 8. Groups were compared using a random regression analysis that used all of the available data. The pregnenolone group showed trends toward greater improvement, relative to placebo, on the HRSD and YMRS. A post hoc analysis of completers found a statistically significant reduction in HRSD scores with pregnenolone as compared to placebo. Pregnenolone appeared to be safe and well tolerated. Findings suggest that pregnenolone use may be associated with some improvement in manic and depressive symptoms, but not cognition in depressed patients with a history of substance use. Larger trials examining the impact of pregnenolone on mood in more narrowly defined populations may be warranted.
Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone. [2022]Pregnenolone, and related neurosteroids, may have antidepressant properties. Preclinical research proposes that microtubule associated protein 2 (MAP2) binding may be a mechanism for antidepressant properties of pregnenolone. Thus, MAP2 might be a novel target for antidepressant therapy. This clinical study is the first to examine serum MAP2 levels in people with bipolar depression and controls, and whether pregnenolone treatment is associated with a change in MAP2 levels.
Effects of cytochrome P450 inhibitors and of steroid hormones on the formation of 7-hydroxylated metabolites of pregnenolone in mouse brain microsomes. [2019]Hydroxylations of pregnenolone (PREG) at the 7 alpha- and 7 beta-positions have been reported in numerous murine tissues and organs and responsible cytochrome P450 (CYP) species await identification. Using thin layer chromatography and gas chromatography-mass spectrometry, we report identification of 7 alpha-hydroxy-PREG and 7 beta-hydroxy-PREG metabolites produced in mouse brain microsome digests and kinetic studies of their production with apparent KM values of 0.5 +/- 0.1 microM and 5.1 +/- 0.6 microM for 7 alpha- and 7 beta-hydroxylation respectively. Investigation of CYP inhibitors and of steroid hormone effects on both 7 alpha- and 7 beta-hydroxylations of PREG showed that: (i) different CYP were involved in 7 alpha- and 7 beta-hydroxylation of PREG because solely 7 alpha-hydroxylation was extensively inhibited by metyrapone, alpha-naphthoflavone, ketoconazole and 3 beta-hydroxysteroids, (ii) CYP 1A2, 2D6, 2B1 and 2B11 were not responsible for 7 alpha- and 7 beta-hydroxylation of PREG because respective specific inhibitors furafylline, quinidine and chloramphenicol triggered no inhibition, (iii) CYP 1A1 was responsible for only part of the 7 beta-hydroxylation of PREG because use of alpha-naphthoflavone, which inhibits specifically CYP 1A1, did not suppress entirely 7 beta-hydroxylation, while ketoconazole, metyrapone and antipyrine, which do not inhibit CYP 1A1, decreased part of the 7 beta-hydroxylation, (iv) 7 alpha-hydroxylation of PREG may be shared with other 3 beta-hydroxysteroids such as isoandrosterone and 5-androstene-3 beta,17 beta-diol which were strong inhibitors, but not with dehydroepiandrosterone which was a non-competitive inhibitor as weak as 3-oxosteroids, and (v) 7 beta-hydroxylation of PREG was not markedly changed by other steroids. Taken together, these findings will be of use for identification of the CYP species responsible for 7 alpha- and 7 beta-hydroxylation of PREG and for studies of their activities in brain.
A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. [2021]Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ(2)(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=-0.43, p=0.036) and pregNANolone (r(22)=-0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.
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]We compared the effectiveness of a biweekly regimen of 150 mg nandrolone with placebo in HIV-infected men with mild to moderate weight loss and contrasted its effects against a Food and Drug Administration-approved regimen of recombinant human (rh)GH.
Pregnenolone enhances the proliferation of mouse neural stem cells and promotes oligodendrogenesis, together with Sox10, and neurogenesis, along with Notch1 and Pax6. [2023]Pregnenolone is a precursor of various steroid hormones involved in osteoblast proliferation, microtubules polymerization and cell survival protection. Previous reports focused on the effects of pregnenolone metabolites on stem cell proliferation and differentiation; however, the effects of pregnenolone itself has not been well explored. The present study aimed to investigate the role of pregnenolone on NSC proliferation and to determine the doses required for NSC differentiation as well as the various genes involved in its mechanism of action.
Synthesis of 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives and their cytotoxic activities. [2013]A series of novel 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives were synthesized and characterized by NMR, HRMS. The pregnenolone (1) was first biotransformed by Mucor circinelloides var lusitanicus to 3beta, 7alpha, 11alpha-trihydroxy-pregn-5-en-20-one (3), then 3 was treated with various benzaldehydes to produce 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives. These derivatives showed remarkable activity against EC109 cells. The absolute configuration of 3 was also confirmed by signal-crystal X-ray analysis.
Pregnenolone sulfate: from steroid metabolite to TRP channel ligand. [2021]Pregnenolone sulfate is a steroid metabolite with a plethora of actions and functions. As a neurosteroid, pregnenolone sulfate modulates a variety of ion channels, transporters, and enzymes. Interestingly, as a sulfated steroid, pregnenolone sulfate is not the final- or waste-product of pregnenolone being sulfated via a phase II metabolism reaction and renally excreted, as one would presume from the pharmacology textbook knowledge. Pregnenolone sulfate is also the source and thereby the starting point for subsequent steroid synthesis pathways. Most recently, pregnenolone sulfate has been functionally "upgraded" from modulator of ion channels to an activating ion channel ligand. This review will focus on molecular aspects of the neurosteroid, pregnenolone sulfate, its metabolism, concentrations in serum and tissues and last not least will summarize the functional data.
Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. [2019]Pregnenolone is the major steroid precursor in humans. It is also a "neurosteroid" and possesses intrinsic behavioral and brain effects in animals, affecting the GABA(A) and other receptors. In two preliminary studies, we sought to characterize its tolerability and psychotropic effects in humans. In Study 1, 17 normal volunteers received pregnenolone and placebo for 4 weeks each (15 mg PO per day x2 weeks followed by 30 mg PO per day x2 weeks, vs. placebo x4 weeks) in a within-subject, double-blind, cross-over design, with a 4 week drug-free washout period separating the two arms. Subjects' behavioral responses were assessed at the beginning and end of the 4-week pregnenolone arm and the 4-week placebo arm. Pregnenolone was generally well-tolerated but, by itself, had no significant effects on mood, memory, self-rated sleep quality or subjective well-being. In Study 2, 11 subjects from Study 1 received a single dose of diazepam (0.2 mg/kg PO) immediately following completion of Study 1 in order to assess, in a between groups design, the impact of 4-weeks' pre-treatment with pregnenolone (N=5) vs. placebo (N=6) on the acute sedative, amnestic and anxiolytic effects of this benzodiazepine. Pregnenolone-pretreated subjects showed significantly less sedation following diazepam (p