Deborah Levy - US grants

DESCRIPTION (provided by applicant): Recent findings suggest that a significant proportion of the genetic variance in complex psychiatric disorders can be explained by a collection of individually rare, highly penetrant genetic variants. Each of these copy number variants (CNVs) may be a risk factor for disease, and many are non-recurrent and sporadic. Optimally, the identification of specific mutations would result in personalized treatment interventions tailored to the underlying biology of the mutation. 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. The carriers of this mutation are strong candidates to benefit from glycine augmentation of their psychotropic drug regimens. One aim of this R21 application is to carry out a proof-of-principle double-blind placebo-controlled glycin augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function. We also propose to carry out targeted neurobiological follow-up of mutation carriers and non-carriers in the same family in order to characterize the brain structural, functional and neurochemical properties of this mutation. These studies will probe glycine homeostasis using proton magnetic resonance spectroscopy, assess the relationship between brain and plasma glycine levels following an acute oral dose of glycine, and examine brain pathways (magnocellular) implicated in dysregulation of NMDA-mediated neurotransmission. The same procedures (except for the glycine loading scans) will be re-administered to carriers after six weeks of open label glycine augmentation. 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, for the first time, 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.

DESCRIPTION (provided by applicant): 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.

Project Summary/Abstract Disturbances in thinking are a fundamental component of the impairments in cognition associated with serious mental illnesses. The fact that compromised cognitive function transcends formal diagnostic categories makes these disturbances especially relevant to the RDoC domain of cognition. The thought disorder phenotype is of special interest, not only because of its non-specific association with serious mental illness, but also because of its exceptionally high recurrence among clinically unaffected first-degree relatives of probands. Although thought disorder per se is non-specific for any single diagnostic syndrome, certain thought disorder profiles are preferentially associated with specific disorders (e.g., schizophrenia and bipolar disorder). In this application, we propose to examine whether distinct qualitative and quantitative features of thought disorder are associated with each illness and also selectively aggregate among clinically unaffected first-degree relatives with odds ratios and effect sizes that would support their utility in genetic studies. Preliminary data support the convergent and discriminant validity of different thought disorder phenotypes in bipolar and schizophrenia probands and their respective first-degree relatives. Further, recurrence of these thought disorder phenotypes in clinically unaffected relatives is much higher than either clinical disorder among family members. Having thought disorder phenotypes for two disorders subsumed under the category of serious mental illness would be extremely useful in genetic studies, because it would allow probands and relatives to be combined independent of specific diagnosis. Moreover, the combination of the two thought disorder phenotypes is a more powerful discriminator of relatives of probands with serious mental illness than either is alone. The sample will be comprised primarily of probands with a diagnosis of bipolar disorder with psychotic features, their first- degree biological relatives and nonpsychiatric controls. A large dataset on probands with a diagnosis of schizophrenia and their first-degree relatives already exists and will be pooled with the newly collected data. The results will significantly enhance the identification of non-penetrant gene carriers among clinically unaffected relatives of probands with serious mental illnesses (SMI) and set the stage for using the composite SMI TD phenotype as a cognitive biomarker in future genetic studies.