Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

Marx, Christine E.; Lee, Jimmy; Subramaniam, Mythily; Rapisarda, Attilio; Bautista, Dianne; Chan, Edwin Sy; Kilts, Jason D.; Boyer, Robert; Wai, Eu Pui; Verma, Swapna; Sim, Kang; Hariram, Jayaraman; Jacob, Rajesh; Keefe, Richard S.E.; Chong, Siow Ann

doi:10.1007/s00213-014-3673-4

Cited by 57 publications

(53 citation statements)

References 93 publications

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“…Twenty-four randomized controlled trials were retrieved that met our inclusion criteria, investigating the efficacy of hormonal augmentation on total, positive, and negative symptoms in a total of 1149 patients (Kulkarni et al, 2001(Kulkarni et al, , 2008(Kulkarni et al, , 2010(Kulkarni et al, , 2011(Kulkarni et al, , 2014Akhondzadeh et al, 2003;Louzã et al, 2004;Nachshoni et al, 2005;Ritsner et al, 2006aRitsner et al, , 2006bRitsner et al, , 2014Strous et al, 2007;Ko et al, 2008;Marx et al, 2009Marx et al, , 2014Feifel et al, 2010;Ritsner, 2010;Pedersen et al, 2011;Usall et al, 2011;Ghafari et al, 2013;Lee et al, 2013;Modabbernia et al, 2013;Cacciotti-Saija et al, 2014;Gibson et al, 2014;Kianimehr et al, 2014) (Table 1). Multiple dosages reported within a single study are represented separately.…”

Section: Resultsmentioning

confidence: 99%

“…Twelve studies examined cognitive function in at least one domain as an outcome measure (Ritsner et al, 2006bStrous et al, 2007;Pedersen et al, 2011;Feifel et al, 2012;Cacciotti-Saija et al, 2014;Gibson et al, 2014;Huerta-Ramos et al, 2014;Kreinin et al, 2014;Kulkarni et al, 2014;Marx et al, 2014Marx et al, , 2009 (Table 2). In all instances, effects of hormonal augmentation on cognitive functioning were studied alongside effects on positive and negative symptomatology as described in the papers discussed above, but in three papers Fig.…”

Section: Cognitionmentioning

confidence: 99%

“…Four RCTs concerning the efficacy of pregnenolone were included (Marx et al, 2009(Marx et al, , 2014Ritsner et al, 2010Ritsner et al, , 2014, including a total of 222 patients (Table 1). The study by Ritsner et al (2010) provided only PANSS positive and negative scores.…”

Section: Pregnenolonementioning

confidence: 99%

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Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review

Heringa

Begemann

Goverde

et al. 2015

Schizophrenia Research

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Section: Resultsmentioning

confidence: 99%

Section: Cognitionmentioning

confidence: 99%

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Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review

Heringa

Begemann

Goverde

et al. 2015

Schizophrenia Research

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“…Thus future experiments to address the differences in whole-cell responses in dialyzed and perforated conditions upon preapplication of PS may reveal interesting results that may be relevant to neurosteroid physiology in the central nervous system. Interestingly, PS is also being evaluated for its efficacy for treating cognitive and behavioral impairments in mental disorders (see, for example, Marx et al, 2014;and Wong et al, 2015). Our data suggest that there is a need to better understand the pharmacologic basis of actions of PS and to assess the ability of newly discovered allosteric modulators of NMDAR to serve as intracellular cell state-dependent agents.…”

mentioning

confidence: 95%

Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-d-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu

Chopra¹,

Monaghan²,

Dravid³

2015

Mol Pharmacol

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Pregnenolone sulfate (PS), one of the most commonly occurring neurosteroids in the central nervous system, influences the function of several receptors. PS modulates N-methyl-D-aspartate receptors (NMDARs) and has been shown to have both positive and negative modulatory effects on NMDAR currents generally in a subtype-selective manner. We assessed the gating mechanism of PS modulation of GluN1/GluN2A receptors transiently expressed in human embryonic kidney 293 cells using wholecell and single-channel electrophysiology. Only a modest effect on the whole-cell responses was observed by PS in dialyzed (nonperforated) whole-cell recordings. Interestingly, in perforated conditions, PS was found to increase the whole-cell currents in the absence of nominal extracellular Ca Further kinetic modeling of the singlechannel data suggested that the positive and negative modulatory effects are mediated by different gating steps which may represent GluN2 and GluN1 subunit-selective conformational changes, respectively. Our studies provide a unique mechanism of modulation of NMDARs by an endogenous neurosteroid, which has implications for identifying state-dependent molecules.

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“…Evidence is accumulating that neurosteroids participate in emotional regulation (Sripada et al, 2013a,b, 2014) and are potential targets as therapeutics in mood and anxiety disorders (Pinna and Rasmusson, 2012; Brown et al, 2014; Marx et al, 2014; Pinna, 2014). Neurosteroids as a class of neuromodulators are fairly complex and regionally distributed within the brain (Morrow, 2007).…”

Section: Introductionmentioning

confidence: 99%

Brain and Serum Androsterone Is Elevated in Response to Stress in Rats with Mild Traumatic Brain Injury

et al. 2016

Self Cite

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Exposure to lateral fluid percussion (LFP) injury consistent with mild traumatic brain injury (mTBI) persistently attenuates acoustic startle responses (ASRs) in rats. Here, we examined whether the experience of head trauma affects stress reactivity. Male Sprague-Dawley rats were matched for ASRs and randomly assigned to receive mTBI through LFP or experience a sham surgery (SHAM). ASRs were measured post injury days (PIDs) 1, 3, 7, 14, 21, and 28. To assess neurosteroids, rats received a single 2.0 mA, 0.5 s foot shock on PID 34 (S34), PID 35 (S35), on both days (2S), or the experimental context (CON). Levels of the neurosteroids pregnenolone (PREG), allopregnanolone (ALLO), and androsterone (ANDRO) were determined for the prefrontal cortex, hippocampus, and cerebellum. For 2S rats, repeated blood samples were obtained at 15, 30, and 60 min post-stressor for determination of corticosterone (CORT) levels after stress or context on PID 34. Similar to earlier work, ASRs were severely attenuated in mTBI rats without remission for 28 days after injury. No differences were observed between mTBI and SHAM rats in basal CORT, peak CORT levels or its recovery. In serum and brain, ANDRO levels were the most stress-sensitive. Stress-induced ANDRO elevations were greater than those in mTBI rats. As a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, increased brain ANDRO levels are expected to be anxiolytic. The impact of brain ANDRO elevations in the aftermath of mTBI on coping warrants further elaboration.

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Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

Cited by 57 publications

References 93 publications

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review

Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-d-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu

Brain and Serum Androsterone Is Elevated in Response to Stress in Rats with Mild Traumatic Brain Injury

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