Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

Abstract

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 (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −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 (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

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

“…The several-fold increases in pregnenolone and allopregnanolone levels posttreatment are consistent with findings in a previous study that administered pregnenolone (500 mg/day) for 8 weeks to patients with schizophrenia (Marx et al, 2009). In addition, pregNANolone levels also increased several-fold posttreatment.…”

“…More recent work has suggested that pregnenolone and its metabolites modulate functional connectivity in the human amygdala (Sripada et al, 2014) and enhance activation of neurocircuits pertinent to mood and emotions (Sripada et al, 2013). Clinical trials suggest that pregnenolone and its derivatives, such as allopregnanolone, have potential in treating schizophrenia (Marx et al, 2009;Ritsner et al, 2010;Zorumski et al, 2013b). However, the sample sizes in these studies have been small.…”

“…The combination of pregnenolone (30 mg/day) with DHEA was more effective than placebo for positive symptoms and cognition in patients with schizophrenia (Ritsner et al, 2010). Another report in patients with schizophrenia suggested that pregnenolone (500 mg/day) reduced negative symptoms (eg, anhedonia, alogia, affective blunting) of the illness (Marx et al, 2009). A small study that included both unipolar and bipolar depressed patients suggested improvement in depressive symptoms with pregnenolone (100 mg/day) as compared with placebo (Osuji et al, 2010).…”

“…Both preclinical and human data suggest that pregnenolone may be a promising treatment for bipolar depression (Carta et al, 2012;Marx et al, 2009;Ritsner et al, 2010). Pregnenolone is an endogenous neurosteroid (Baulieu, 1998) that is a precursor to numerous other downstream steroids, including cortisol, allopregnanolone, dehydroepiandrosterone (DHEA), and progesterone.…”

Classification issues in women’s mental health: clinical utility and etiological mechanisms

“…In a broader sense, a better explication of hormonal effects on neural circuits may not only reveal mechanisms of risk for women but can inform our understanding of the relevant disorders more generally. As one example, activation of the prefrontal cortex during a working memory task is dependent on gonadal steroid stimulation, providing a potential approach to one of the fundamental deficits in schizophrenia (Berman et al 1997;Marx et al 2009). …”