A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression

Abstract

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 ¼ 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 ¼ 73), a significant treatment by week interaction for the HRSD (F(5,288) ¼ 2.61, p ¼ 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 (w 2 (1) ¼ 3.99, p ¼ 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) ¼ À 0.43, p ¼ 0.036) and pregNANolone (r(22) ¼ À 0.48, p ¼ 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.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…A number of agents do not have sufficient data to warrant specific recommendations for BDII depression, including cranial electrotherapy stimulation (CES),479 dextromethorphan + quinidine,480 light therapy,481, 482, 483, 484, 485 lisdexamfetamine (adjunctive),300 olanzapine,486 pioglitazone,302 adjunctive pregnenolone,306 celecoxib,297 levetiracetam,487 adjunctive lisdexamfetamine,300 s‐adenosylmethionine,488, 489, 490 acetyl‐ l ‐carnitine + alpha‐lipoic acid,491 adjunctive modafinil,268 rTMS,275, 492, 493 and memantine 494…”

Clinical Potential of Neurosteroids for CNS Disorders

“…These differences have spurred interest in the development of new approaches tailored to the BPD setting. A recent randomized, double-blind, placebo-controlled clinical trial investigated the therapeutic value of oral pregnenolone therapy (500 mg/day) in alleviating symptoms of depressive episodes in 73 enrolled BPD patients, as scored on the Hamilton Rating Scale for Depression (HRSD) and Inventory of Depressive Symptomatology Self-Report (IDS-SR) along with other indices [115]. Additionally, baseline and post-treatment serum neurosteroid levels were obtained to monitor pregnenolone, AP, and pregnanolone.…”

Simultaneous Determination of Seven Neuroactive Steroids Associated with Depression in Rat Plasma and Brain by High Performance Liquid Chromatography?Tandem Mass Spectrometry

“…Pregnenolone is the precursor of progestogens, mineralocorticoids, glucocorticoids, androgens, and estrogens, and it has been shown to exert antidepressant effects. 38 These results suggest that the increased level of pregnenolone may be a compensatory response to the depression induced in rats by FST; there may also be some changes in the activity levels of enzymes such as 11β-hydroxylase, cytochrome P450 19, and 3β-hydroxysteroid dehydrogenase, which result in the observed reductions in the concentrations of cortisol, estradiol, and progesterone, respectively. These results have provided information relating to the mechanisms underlying depression and antidepressant effects.…”