Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

Study Overview
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Brief Summary
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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.

Detailed Description
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Multiple rare structural variants of relatively recent evolutionary origin are recognized as important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders (e.g., autism spectrum disorders, mental retardation, epilepsy) with odds ratios as high as 7-30 (Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et al. 2009). We have found a de novo structural rearrangement on chromosome 9p24.1 in two psychotic patients. One of the genes in this region is the gene encoding glycine decarboxylase (GLDC), which affects brain glycine metabolism. GLDC encodes the glycine decarboxylase or glycine cleavage system P-protein, which is involved in degradation of glycine in glia cells. Carriers of the GLDC triplication would be expected to have low levels of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia (Olney & Farber, 1995; Coyle, 2006; Javitt, 2007). There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function (see Tsai & Lin, 2010; Lin et al. 2011 for reviews). Although many studies have reported positive results in at least one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006; Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van Berckel et al. 1999). Factors likely to contribute to this variability include: mechanism of action of the agent, compliance, concurrent treatment with first- vs second generation antipsychotic drugs, baseline glycine blood levels, presence/absence of kynurenine pathway metabolic abnormalities (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). Genetic variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators of NMDA receptor function are also likely to have significant effects. Although glycine augmentation has shown variable efficacy in patients unselected for having a mutation that would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in this study would be expected to result in unusually low brain glycine levels, supporting its therapeutic potential as an augmentation strategy. Thus, it is important to evaluate the therapeutic efficacy of glycine augmentation in individuals in whom there is a high prior probability of therapeutic benefit and to characterize the neurobiology of this mutation in terms of brain metabolites, brain function, and the pharmacokinetics of glycine metabolism using well-established methods (Kaufman et al. 2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009; Ongur et al. 2008).

Official Title
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Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase

Conditions
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Schizo-affective Disorder, Bipolar Disorder

Intervention / Treatment
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* Drug: Glycine
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Triplication of glycine decarboxylase gene Exclusion Criteria: Normal glycine decarboxylase copy number

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: glycine<br>Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind | Drug: Glycine<br>* Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine<br>|
| Placebo Comparator: Placebo<br>placebo, TID dosing, 6 weeks Double-blind | Drug: placebo<br> <br> |
| Active Comparator: glycine, open-label<br>glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks | Drug: Glycine<br>* Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine | Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms are measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms. | baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period | 
| Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine | Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution; standard deviation of 10. Only overall composite score is entered. | At baseline, during glycine treatment, during placebo treatment and during open-label glycine | 
| Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine | Plasma glycine levels; normal range is 122-467 nM/mL | At baseline, during glycine treatment, during placebo treatment and during open-label glycine | 
| Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine | Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms. | baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period | 
| Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period | Clinical Global Impression (CGI) severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients. | CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per treatment period | 
| Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period | Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13). | at 2 weeks, 4 weeks, and 6 weeks within each treatment period | 
| Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period | Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of ratings for 7 symptoms of mania is measured on a scale from 0-4 and the sum of 4 symptoms of mania is measured on a scale from 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms. | baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period | 
| Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period | Hamilton Depression Scale measures severity of depression symptoms. The sum of ratings for 9 depression symptoms are measured on a scale from 0-2 with 0 meaning no symptoms and 2 meaning some level of severity of that specific symptom. The rating for 1 depression symptom is measured on a scale from 0-3 with 0 meaning no symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms are measured on a scale from 0-4 with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. | baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Glycine/CR Ratio | magnetic resonance spectroscopy: glycine/creatine ratio. Participants were assessed at 1) BASELINE PRE-GLYCINE TREATMENT: pre-glycine challenge drink, 60 minutes post challenge drink, 80 minutes post challenge drink, 100 minutes post challenge drink, and 120 minutes post challenge drink (0.4 g/kg up to max of 30 g); and 2) IN WEEK 6 OF OPEN-LABEL GLYCINE TREATMENT: pre-glycine dose, and 60 minutes, 80 minutes, 100 minutes and 120 minutes post daily dose of glycine. Measured in posterior occipital cortex | baseline (pre-challenge, 60, 80, 100, 120 minutes post-challenge), and week 6 of glycine (pre-dose and 60, 80, 100, 120 minutes post-dose | 
| Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT | magnetic resonance spectroscopy - glutamate metabolite level. Participants were assessed 1) pre-glycine treatment and in week 6 of open-label glycine treatment. Measured in posterior occipital cortex. | baseline and week 6 of glycine | 
| Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT | Magnetic resonance spectroscopy GABA/Cr. Participants were assessed 1) pre-glycine treatment (baseline) and 2) in week 6 of open-label glycine treatment measured in posterior occipital cortex. | Baseline and week 6 of glycine | 
| Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE | Auditory evoked potentials latency: P300 at fz, cz, and pz); N100 at fz and cz); P200 at fz and cz. Participants were assessed at baseline and in week of open-label glycine treatment. | Recordings at baseline and week 6 of glycine | 
| Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected. | functional magnetic resonance imaging | 6 weeks per treatment arm | 
| Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT | Auditory evoked potentials amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2 amplitude; mismatch negativity (MMN) at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment. | Recordings at baseline and week 6 of glycine | 
| Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT | Auditory evoked potentials gamma: G40 hz phase locking at fz and cz; G20 hz phase locking response at fz and cz G30 hz phase locking response at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment. | Recordings at baseline and week 6 of glycine | 
| Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT | Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment. | Recordings at baseline and week 6 of glycine | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glycine, Glycine decarboxylase, Psychosis, Mutation