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.

Pregnenolone is a neuroactive steroid that exhibits actions highly relevant to treating depression in people with HIV. The investigators' recent human data suggest that neuroactive steroids are decreased in people with HIV and depression. In addition, multiple groups have reported reductions in neuroactive steroids in people without HIV who have depression. A total of 120 people living with HIV on antiretroviral therapy with depression will be randomized to either pregnenolone or placebo (2 groups/90 participants receiving pregnenolone and 30 participants receiving placebo). Drug dosage will begin at 50 mg daily and incrementally increase to 500 mg daily within the first 4 weeks, with a stable 500 mg/day regimen for the final 4 weeks. Behavioral testing and blood draw will be performed at baseline, 2 weeks, 4 weeks, and 8 weeks, while magnetic resonance spectroscopy (MRS), and task-based functional magnetic resonance imaging (MRI) will be conducted at 2 weeks and 8 weeks.

The investigators hypothesize that pregnenolone will be well-tolerated in people with HIV and depression, and that this intervention may improve brain activity and reduce inflammation.

Inclusion Criteria:

• 18-85 years
• HIV-1 viral load <200 copies/mL on antiretroviral therapy (ART) at screening visit
• Center for Epidemiological Studies - Depression (CES-D) score ≥ 20

Exclusion Criteria:

• Contraindication to magnetic resonance imaging (MRI) or poor-quality baseline MRI preventing image analyses as determined by radiologist assessment
• Recent severe infections including opportunistic infections, active bacterial, mycobacterial, fungal, or certain viral infections
• Vulnerable populations (e.g., pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Use of cobicistat or ritonavir
• High risk for suicide (active suicidal ideation (SI) with plan/intent as assessed by using the Columbia Suicide Severity Rating (C-SSRS) or > 2 attempts in lifetime or any in the past 6 months) or expresses homicidal ideation necessitating clinical intervention or representing an imminent concern
• Any severe (life-threatening or unstable) medical condition as determined by clinician assessment
• Blood pressure, with the lowest reading taken after three repeat readings during screening visit, ≥ 160 mmHg systolic OR ≥ 95 mmHg diastolic or other life-threatening vital signs as determined by clinician assessment
• Clinically significant abnormalities in physical examination or ECG that would interfere with study participation
• Decompensated cirrhosis, active liver inflammation (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≥ 5 times the upper limit of normal) or unsuppressed viral hepatitis B or C infection
• Severe renal disease (estimated glomerular filtration rate ≤ 30 mL/min/1.73m2)
• Seizure disorder requiring antiepileptic treatment
• History of allergic reaction or side effects with prior pregnenolone use
• Currently using testosterone enanthate, testosterone cypionate, or estrogen containing preparations that significantly increase systemic estrogen levels, including but not limited to oral and transdermal forms of estrogen. All other forms of exogenous sex steroid hormones will be evaluated at the discretion of the PI and/or clinical delegates.
• Currently using systemic immunosuppressive agents, including corticosteroids, chemotherapy, or specific immunomodulating agents, such as monoclonal antibodies and TNF-inhibitors
• Excessive alcohol or other substances use that would interfere with classification of major depression disorder, study procedures and/or follow-up
• Current diagnosis of bipolar disorder
• Diagnosis of a psychotic disorder (current or lifetime)
• Diagnosis of schizophrenia (current or lifetime)
• <70% adherence to study drug prior to randomization
• Inability to swallow pills/capsules
• Not able to complete neuropsychological testing in English
• Concurrent participation in another interventional trial, except for lifestyle and device studies (For vaccination studies, individuals in the observation period are not exclusionary. Other interventions will be evaluated at the discretion of the PI and/or clinical delegates.)

This is a randomized, double-blind, placebo-controlled trial. All roles will be masked except the research pharmacist and statistician.