Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders
Status:
Completed
Trial end date:
2017-05-31
Target enrollment:
Participant gender:
Summary
The purpose of this study is to assess the efficacy of oral glycine as an augmentation
strategy in two psychotic patients with a triplication (4 copies) of the gene glycine
decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical
trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg,
administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week
period of no treatment will occur between treatment arms. A 6-week period of open-label
glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow
the double-blind placebo-controlled clinical trial. Prior to the double-blind
placebo-controlled clinical trial and at the end of the open-label glycine trial, the
following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T),
steady-state visual evoked potentials, and EEG. 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. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a
glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder
(Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital
Pharmacy.
Because the results of the double-blind placebo-controlled and open-label glycine treatment
arms showed substantial clinical benefit to the participants, the study has been extended to
include six months of chronic open-label glycine in order to determine 1) whether the
clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are
lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this
extension will be provided by Letco Medical.
The investigators hypothesize that mutation carriers will have reduced endogenous brain
glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine
administration will increase brain glycine in the two carriers, but to a lesser extent than
in non-carrier family members and controls.
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 glycine, but not placebo, will improve positive, negative
and affective symptoms as well as neurocognitive function.
The investigators also hypothesize that open-label glycine 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.