We have identified a complex structural rearrangement at 9p24.1 that segregates with psychosis in one family. One gene in the rearranged region, glycine decarboxylase (GLDC), is involved in the degradation of glycine in glia cells and is triplicated in mutation carriers. Glycine is a co-agonist for the N-methyl-D-aspartate receptor (NMDAR). Carriers of the GLDC triplication would be expected to have low levels of brain glycine, resulting in NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. Based on the rationale that the carriers of this mutation were strong candidates to benefit from glycine augmentation of their psychotropic drug regimens, we completed a double-blind placebo-controlled clinical trial, followed by open-label glycine (six weeks/arm). In that study, clinically significant improvement occurred on glycine compared with placebo. Since the doses of glycine required for a therapeutic effect (~0.8 g/kg) are too high to be administered by capsule, glycine must be administered as a powder (~20 g TID) and mixed with food or liquid, making it a cumbersome compound to deliver on a chronic basis. Of the FDA approved compounds that may, like glycine, also normalize glycinergic tone in these individuals, D-cycloserine (DCS) is the optimal choice since it is not only a partial agonist at the glycine modulatory site, but also inhibits kynurenic acid. Both carriers have significantly elevated levels of kynurenic acid, which may be potentiating the effect of the accelerated degradation of glycine by the triplication.
One aim of this R21 application is t carry out a double-blind placebo-controlled DCS augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function during acute (eight weeks) and chronic (nine months) DCS augmentation. We also propose to carry out targeted neurobiological follow-up in order to characterize the brain structural, functional and neurochemical properties of this mutation during acute and chronic treatment with DCS. These studies will probe glycine and glutamate homeostasis using proton magnetic resonance spectroscopy and dysregulation of NMDA-mediated neurotransmission using evoked response potentials and recordings of responses from retinal ganglion cells. Since similar studies were carried out before and during glycine augmentation, the proposed study will provide complementary clinical and neurobiological data on the effects of two different NMDAR modulatory interventions in the same individuals. The results will significantly enhance our understanding of the neurobiology of rare CNVs associated with psychosis and their relevance to disease pathophysiology. More importantly, the results will continue our efforts to link pathophysiology and a medically actionable treatment intervention to underlying genetics, with potential benefit to other patients with neuropsychiatric disease who have mutations in either the same gene or in other genes/pathways that are impacted by the same or related aberrant biological processes.
Genetic factors contribute substantially to risk for schizophrenia, bipolar disorder, and a variety of neurodevelopmental disorders, such as autism, intellectual disability and epilepsy. Characterizing the neurobiological effects of specific mutations and tailoring clinical interventions that target them will link pathophysiology and medically actionable treatment interventions to the genetic basis of these disorders.