A New Intervention to Improve Function in Veterans With Anxiety and Depression

Background: Anxiety and depression disorders can be very debilitating and result in substantial disability. These disorders are extremely common, occurring at rates that exceed other common medical illnesses such as hypertension, diabetes or asthma. Further, anxiety and depression disorders often co-occur (more the rule than the exception) and having one diagnosis substantially increases the risk for having the other. The clinical benefits of an intervention that ameliorates both anxiety and depression-related disability and clinical symptoms could be critically important, as odds of Veteran suicide completion significantly increase when depression co-occurs with anxiety disorders. Extensive preclinical and clinical data (from the investigators' group and others) support a novel neurosteroid intervention (pregnenolone/PREG) as a promising new treatment for anxiety and depression disorders. Furthermore, extensive evidence in rodent models and clinical biomarker candidate studies suggests substantial analgesic, anxiolytic, sleep and anti-inflammatory actions. PREG also significantly reduced low back pain in a randomized controlled trial of 94 OEF/OIF/OND-era Veterans compared to placebo, and allopregnanolone (ALLO) levels are inversely correlated with several commonly co-occurring symptoms, including sleep disturbance and pain disorders. Restoration of ALLO levels via a precursor loading strategy with PREG could thus ameliorate ALLO deficits and alleviate multiple functionally impairing and health-related symptoms. Additionally, PREG has been very well-tolerated in multiple clinical trials and exhibits a very favorable side effect profile - potentially supporting a superior safety and side effect profile advantage compared to existing pharmacological interventions. The investigators thus propose to conduct a 10-week double-blind, randomized, placebo-controlled trial of PREG versus placebo in Veterans with anxiety and depression.

Methods: The primary goal of this proposed project is to conduct a 10-week adaptive, randomized, double-blind, placebo-controlled trial to evaluate flexibly dosed pregnenolone to improve functional impairment and disability associated with anxiety and depression. Following a 2-week placebo-only lead-in period, 84 subjects will be enrolled and randomly assigned to receive PREG or placebo for 8 weeks (flexible dosing strategy). The investigators hypothesize that treatment with PREG will significantly reduce functional impairment and disability associated with anxiety and depression symptoms. Secondary outcomes include diagnostic improvements in anxiety and depression, pain symptoms and sleep quality. The investigators hypothesize that PREG will improve symptoms of anxiety and depression, pain and sleep quality. Finally, the investigators will quantify serum neurosteroid levels at baseline and post-treatment by highly sensitive and specific mass spectrometry-based techniques to determine if PREG and downstream neurosteroid metabolites such as ALLO are predictors of functional/therapeutic response. The investigators will also examine proinflammatory markers. The investigators hypothesize that changes in PREG and other neurosteroids (as well as proinflammatory markers) will predict improvements in mental health and functional outcomes.

Conclusion: Results from the proposed trial could provide rigorous scientific rationale for future pivotal Phase 3 trials to test PREG for the treatment of anxiety and depression disorders (improving functional outcomes and mitigation of pain and sleep disturbance). PREG has been very well-tolerated in multiple Veteran cohorts and could thus be a safe, inexpensive and efficacious new intervention to improve function and multiple behavioral symptoms.

Inclusion criteria

• Veterans enrolled for care at the Durham VAHCS
• Veterans who score a minimum score of 20 or higher (moderate symptoms) on the PHQ-ADS (Kroenke et al 2017)
• Oral pregnenolone could reduce the effectiveness of oral contraceptives, thus women will be required to use a medically and study-approved contraceptive or otherwise not be of child-bearing potential. Birth control methods must be non-hormonal
• No anticipated need to alter psychiatric medications for duration of study involvement
• Ability to participate fully in the informed consent process

Exclusion criteria

• History of allergy to PREG
• Medical disorders that may preclude safe administration of PREG or exacerbate mental or physical health symptoms
• PTSD diagnosis, as per the PCL-5, scores of 38 or higher
• Current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern

• Prior attempts or suicidal ideation that does not require clinical intervention or represent an imminent concern is permitted
• Serious unstable medical illness, such as history of cerebrovascular accident, prostate, uterine or breast cancer, others (at the discretion of the PI and medical oversight team)
• Standard pharmacological interventions for mental health disorders will not be exclusionary; however, there may be no changes in psychotropic medications for mental or physical health conditions 4 weeks prior to study randomization
• Benzodiazepine or opioid use
• Current diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than mild TBI (assessed at screening)
• Initiation or change in psychotherapy within 3 months of randomization (i.e., psychotherapy must be stable for 3 months prior to study start
• Due to lack of safety data in pregnant and breast-feeding women, female participants who are pregnant or breast-feeding will be excluded
• As indicated by the DSM-5, moderate or severe Substance Use Disorders (excluding caffeine and tobacco) within 1 month of study entry