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

Christine E Marx


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.



Good info from the Discussion:


Pregnenolone administration in this study results in approximately fourfold elevations in serum pregnenolone to physiologically relevant nanomolar levels. Preclinical data support the possibility that elevations of pregnenolone levels to this extent could have significant beneficial effects. For example, pregnenolone enhances learning and memory in rodent models at even lower concentrations than the nanomolar serum concentrations achieved in the current investigation (Flood et al, 1992). As pregnenolone is lipophilic and readily crosses the blood–brain barrier, it is likely that brain concentrations of pregnenolone in humans are also elevated following pregnenolone administration, as suggested by animal studies (Wang et al, 1997). Furthermore, we have demonstrated earlier that serum pregnenolone levels are closely correlated with hippocampal pregnenolone levels in rats (Marx et al, 2006a), and that CSF pregnenolone levels in humans are correlated with temporal cortex pregnenolone levels within the same subject cohort (Naylor et al, 2008). Serum pregnenolone (and possibly other neurosteroids) may thus serve as a proxy or surrogate marker for brain pregnenolone levels, potentially providing data that may be relevant to the prediction of clinical response.


Metabolism to pregnenolone sulfate: Our data demonstrate that pregnenolone administration triples serum levels of its sulfated derivative, pregnenolone sulfate. Pregnenolone sulfate levels attained in serum following pregnenolone administration are very consistent with doses required to achieve its positive effects on learning and memory in rodent models (Akwa et al, 2001; Flood et al, 1992, 1995; Mathis et al, 1996; Meziane et al, 1996). Furthermore, recent evidence suggests that pregnenolone sulfate may positively modulate NMDA receptors at concentrations in the nanomolar range at binding sites distinct from a number of known NMDA receptor targets (Johansson et al, 2008). Pregnenolone sulfate in the nanomolar range also enhances long-term potentiation (Sliwinski et al, 2004) and influences GABA release (Mtchedlishvili and Kapur, 2003) in rodents. In addition to these actions, pregnenolone sulfate may increase neurogenesis in rodent hippocampus (Mayo et al, 2005). In this study, patients with lower serum pregnenolone sulfate levels at baseline demonstrated greater cognitive improvements as assessed by the MCCB. It is therefore possible that a subset of patients with schizophrenia may demonstrate relative pregnenolone sulfate deficits (as well as lower baseline pregnenolone and allopregnanolone levels) that are potentially restored to optimal levels with pregnenolone administration. Pregnenolone metabolism to pregnenolone sulfate could thus result in a number of additional mechanistic contributions for this neurosteroid and its effects on cognitive and negative symptoms, including the amelioration of hypothesized NMDA receptor hypofunction.

Metabolism to the GABAergic neurosteroid allopregnanolone: Pregnenolone administration results in fivefold elevations in serum allopregnanolone levels in this pilot investigation, and it is possible that pregnenolone metabolism to this downstream GABAergic neurosteroid metabolite may play a role in its therapeutic efficacy. Supporting this possibility, increases in allopregnanolone predicted cognitive improvement as assessed by BACS composite scores. Given compelling evidence for a GABAergic deficit in patients with schizophrenia (Benes and Berretta, 2001; Benes et al, 2007; Guidotti et al, 2005; Lewis et al, 2003, 2004, 2005) and the fact that allopregnanolone potentiates GABAA receptor responses to a greater degree than benzodiazepines or barbiturates (Majewska et al, 1986; Morrow et al, 1987, 1990), it is possible that pregnenolone metabolism to the GABAergic neurosteroid allopregnanolone may contribute to its mechanism(s) of action.

Allopregnanolone elevations resulting from treatment with pregnenolone may also play a role in other physiological processes related to schizophrenia, as this GABAergic neurosteroid enhances neurogenesis (Wang et al, 2005) and shows multiple pronounced neuroprotective properties (Djebaili et al, 2005; Griffin et al, 2004; Lockhart et al, 2002; Mellon et al, 2008; Sayeed et al, 2006; Xilouri and Papazafiri, 2006). In addition, it enhances myelination (Ghoumari et al, 2003) and possesses anticonvulsant actions (Kokate et al, 1994, 1996). Furthermore, allopregnanolone shows multiple anti-inflammatory effects (He et al, 2004; VanLandingham et al, 2007) and decreases apoptosis (Charalampopoulos et al, 2004, 2006; Xilouri and Papazafiri, 2006), actions that may be relevant to schizophrenia (Dickerson et al, 2007; Glantz et al, 2006; Jarskog et al, 2005; Knight et al, 2007; Lencz et al, 2007). Finally, allopregnanolone levels are decreased in postmortem brain tissue from patients with Alzheimer's disease (Marx et al, 2006e), and hence the restoration of allopregnanolone levels by precursor loading with pregnenolone may be a logical approach for a number of disorders in which the disruption of cognition is a salient characteristic.

Metabolism to progesterone intermediary: Abundant evidence demonstrates that progesterone plays an important role in a number of brain functions in addition to its well-characterized non-central nervous system effects. Progesterone is present in both male and female human brain in nanomolar concentrations (Lacroix et al, 1987; Lanthier and Patwardhan, 1986; Weill-Engerer et al, 2002). Progesterone administration results in pronounced neuroprotective effects in rodent models of traumatic brain injury (Djebaili et al, 2004, 2005; He et al, 2004; Jones et al, 2005; Robertson et al, 2006; Roof et al, 1997), and also positively impacts myelination processes (Azcoitia et al, 2003; Ghoumari et al, 2003; Ibanez et al, 2003; Koenig et al, 1995; Schumacher et al, 2000) and dendritic outgrowth during development (Sakamoto et al, 2001). Extending these rodent investigations, a recent randomized controlled clinical trial reported that intravenous progesterone for 3 days reduced 30-day mortality rates by over 50% in acute moderate-to-severe traumatic brain injury (Wright et al, 2007), strongly supporting a neuroprotective role for this neurosteroid. This pivotal study has been described as the first successful clinical trial of a pharmacological agent for traumatic brain injury in 40 years, with no adverse events attributable to the intervention (Stein, 2008; Wright et al, 2007). Furthermore, these promising clinical findings have recently been replicated, and also extended to demonstrate enduring therapeutic progesterone effects 6 months following traumatic brain injury (Xiao et al, 2008).

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Possible metabolism to DHEAS: DHEAS levels are significantly increased following pregnenolone administration, but the magnitude of this effect is relatively modest (approximately 16%). Given less pronounced increases in serum DHEAS levels following treatment with pregnenolone as well as the small sample size of the current pilot study, this result will require replication in a larger cohort of subjects. Nonetheless, an earlier investigation determined that DHEA administration significantly attenuated negative symptoms in patients with schizophrenia and resulted in concomitant elevations of its sulfated derivative, DHEAS (Strous et al, 2003). It is therefore possible that pregnenolone metabolism to DHEAS may be relevant to its therapeutic mechanism(s) of action.

http://www.nature.com/npp/journal/v3...pp200926a.html