SummaryMast cells, which are granulocytes found in peripheral tissue, play a central role in inflammatory and immediate allergic reactions. b-Tryptase is a neutral serine protease and is the most abundant mediator stored in mast cell granules. The release of b-tryptase from the secretory granules is a characteristic feature of mast cell degranulation. While its biological function has not been fully clarified, mast cell b-tryptase has an important role in inflammation and serves as a marker of mast cell activation. b-Tryptase activates the protease activated receptor type 2. It is involved in airway homeostasis, vascular relaxation and contraction, gastrointestinal smooth muscle activity and intestinal transport, and coagulation. Serum mast cell b-tryptase concentration is increased in anaphylaxis and in other allergic conditions. It is increased in systemic mastocytosis and other haematological conditions. Serum b-tryptase measurements can be used to distinguish mast cell-dependent reactions from other systemic disturbances such as cardiogenic shock, which can present with similar clinical manifestations. Increased b-tryptase levels are highly suggestive of an immunologically mediated reaction but may also occur following direct mast cell activation. Patients with increased mast cell b-tryptase levels must be investigated for an allergic cause. However, patients without increased mast cell tryptase levels should be investigated if the clinical picture suggests severe anaphylaxis.

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.