A Pilot, Open-Label Study of Pregnenolone in the Treatment of Irritability in Autism Spectrum Disorder

Background:  

One proposed model of autism suggests that the condition is a result of an altered ratio of excitation/inhibition in key neural systems. As GABAergic systems are the most important inhibitory neural pathways, modulators of GABA_A receptors may correct the imbalance between excitation and inhibition in the brain. Pregnenolone is the precursor of GABAergic neurosteroids such as pregnenolone sulfate and allopregnanolone. We hypothesize that individuals with autism spectrum disorder (ASD) receiving pregnenolone will show reduction in disruptive behaviors as measured by standard rating scale for irritability. 

Objectives:  

(1) To conduct a pilot, open-label, 12-week trial to assess the effectiveness of pregnenolone in reducing irritability in adults with ASD. (2) To examine the safety and tolerability of pregnenolone in adults with ASD.

Methods:  

This was a 12-week, prospective open-label study of pregnenolone in adults with ASD. Pregnenolone was initiated at a dose of 50 mg twice daily in weeks 1 and 2, then 100 mg twice daily in weeks 3 and 4, then 150 mg twice daily in weeks 5 and 6, then 200 mg twice daily in weeks 7 and 8, then 250 mg twice daily from weeks 9 to 12. If subjects could not tolerate a specific dose, s/he would be maintained at the highest tolerated dose.  This initial phase was followed by a 4-week washout period to allow a better appreciation of the benefits observed while subjects were taking pregnenolone, by monitoring the effect of tapering and discontinuation of the medication. Primary outcome measure included the irritability subscale of the aberrant behavior checklist (ABC-I). Secondary measures included the other subscales of ABC, Social Responsiveness Scale (SRS), Sensory Profile Questionnaire (SPQ), and Vineland Adaptive Behavior Scale (VABS). In addition, vital signs and Dosage Record and Treatment Emergent Symptom Scale (DOTES) were monitored for adverse events. Paired, 2-tailed student t-tests were performed to compare outcome measures between baseline and 12 weeks. 

Results:  

Ten men and two women with ASD (mean age 22.5 ± 5.8 years; range 18.1-35.5 years; 9 Caucasians and 4 Asians) met the study criteria for inclusion in this open-label study. Pregnenolone yielded a statistically significant improvement in the primary measure, ABC-I [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028, df = 11, t = 2.5)]. Secondary measures were not statistically significant with the exception of ABC-lethargy  (p = 0.046) and total SPQ score (p = 0.009). During the 12-week treatment period, two participants dropped out of the study. No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness (n = 1), diarrhea (n = 1) and depressive affect (n =1) that could be related to pregnenolone were reported. 

Conclusions:  

Pregnenolone was modestly effective and well tolerated with participants with ASD in this pilot study. Further randomized controlled trials are warranted.