Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine

Detailed Summary

The purpose of this study is to assess the efficacy of d-cycloserine (DCS) as an augmentation strategy in two psychotic patients with a triplication (4 copies) of the glycine decarboxylase (GLDC) gene. Subjects will first undergo an eight-week open-label arm of treatment with DCS (50 mg/d) followed by six 6-week double-blind placebo-controlled exposures to DCS or placebo. The length of each double-blind arm is limited to six weeks to minimize the length of symptom exacerbation experienced by the subjects when they are receiving placebo. The randomization scheme will allow two consecutive exposures to DCS, but will not allow two consecutive exposures to placebo, again to minimize the length of any symptom exacerbation. At the end of the open-label DCS trial, the following procedures will be carried out: structural MRI (3T), proton 1H MRS (4T), fMRI (3T), steady-state auditory evoked potentials, and electroretinogram recordings. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a DCS will be assessed. Baseline data on all of these measures were previously obtained as part of a different study registered in clinical trials.gov - NCT01720316). Positive, negative, and affective symptoms and neurocognitive function as well as plasma levels of large neutral and large and small neutral and excitatory amino acids and psychotropic drug levels will be assessed periodically. Pharmaceutical grade DCS) or placebo will be compounded and dispensed by the McLean Hospital Pharmacy. The investigators hypothesize that mutation carriers will have reduced endogenous brain glycine and GABA levels and increased brain glutamate and glutamine levels. DCS administration will increase brain glycine in the two carriers compared to baseline and treatment with glycine (0.8g/kg). The investigators hypothesize reduced activation of magnocellular pathways and abnormal ERPs modulated by NMDA in mutation carriers compared with non-carrier family members and controls. . The investigators hypothesize that DCS, but not placebo, will improve positive, negative and affective symptoms as well as neurocognitive function. The investigators also hypothesize that DCS will improve clinical and cognitive functioning, will partially normalize decreased baseline glycine and GABA and increased glutamate and glutamine, and will partially normalize magnocellular pathway activation and abnormal evoked potentials.

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