Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence

  title={Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence},
  author={C. E. Marx and Daniel W. Bradford and Robert M. Hamer and Jennifer C. Naylor and Trina B. Allen and J. A. Lieberman and Jennifer L. Strauss and Jason D. Kilts},

Pregnenolone Rescues Schizophrenia-Like Behavior in Dopamine Transporter Knockout Mice

Pregnenolone holds promise as a therapeutic candidate in schizophrenia after being found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition deficits in DAT KO mice in a dose-dependent manner.

Neurosteroids and potential therapeutics: Focus on pregnenolone

  • M. Vallée
  • Biology
    The Journal of Steroid Biochemistry and Molecular Biology
  • 2016

Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress

Progesterone and its metabolites as therapeutic targets in psychiatric disorders

Both preclinical and clinical studies show that certain treatments may normalize the levels of PROG, suggesting that the amelioration of psychiatric symptoms may occur due to upregulation of PROG metabolites, giving support to new possibilities of treatment for patients with psychiatric symptoms.

Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

The results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses and can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.



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

Pregnenolone may be a promising therapeutic agent for negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics and merits further investigation for cognitive symptoms in schizophrenia.

Glutamate as a therapeutic target in psychiatric disorders

  • D. Javitt
  • Psychology, Biology
    Molecular Psychiatry
  • 2004
Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders, and other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD.

Steroid structure and pharmacological properties determine the anti‐amnesic effects of pregnenolone sulphate in the passive avoidance task in rats

Enantioselectivity was demonstrated by the ability of natural PREGS to be an order of magnitude more effective than its synthetic enantiomer in reversing scopolamine‐induced amnesia, identifying a novel neuropharmacological site for the modulation of memory processes by neuroactive steroids.

Neuroactive steroids, mood stabilizers, and neuroplasticity: alterations following lithium and changes in Bcl-2 knockout mice.

Many neuroactive steroids (NS) demonstrate neurotrophic and neuroprotective actions, including protection against apoptosis via Bcl-2 protein, which may be relevant to mechanisms contributing to lithium therapeutic efficacy and neuroprotection.

Nanomolar Concentrations of Pregnenolone Sulfate Enhance Striatal Dopamine Overflow in Vivo

It is demonstrated that exogenous PS, at nanomolar concentrations, is able to increase DA overflow in the striatum through an NMDA receptor-mediated pathway.

In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis

  • G. Pinna
  • Biology, Psychology
    Behavioural pharmacology
  • 2010
Preclinical studies show that in socially isolated mice, rather than selective serotonin reuptake inhibitor mechanisms, allopregnanolone biosynthesis in glutamatergic corticolimbic neurons offers a nontraditional target for fluoxetine to decrease signs of aggression, normalize fear responses, and decrease anxiety-like behavior.

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

  • M. Millan
  • Psychology, Biology
  • 2005
Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia, and drugs that increase activity at GlycineB sites may be of use as adjuncts to other classes of antipsychotic agent.