The
neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents.
Pregnenolone sulfate also positively modulates
NMDA receptors and could thus ameliorate hypothesized
NMDA receptor hypofunction in
schizophrenia. Furthermore,
clozapine increases
pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive
pregnenolone for cognitive and negative symptoms in patients with
schizophrenia or
schizoaffective disorder receiving stable doses of second-generation
antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to
pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group).
Pregnenolone was well tolerated. Patients receiving
pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to
pregnenolone compared with placebo. However, serum
pregnenolone increases predicted BACS composite scores at 8 weeks in the
pregnenolone group (r(s)=0.81, p=0.022). Increases in
allopregnanolone, a GABAergic
pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline
pregnenolone (r(s)=-0.76, p=0.037),
pregnenolone sulfate (r(s)=-0.83, p=0.015), and
allopregnanolone levels (r(s)=-0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for
neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (r(s)=0.74, p<0.0001).
Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for
cognitive symptoms in
schizophrenia.