Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

• Sponsor: Mclean Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01720316
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 2
• Location: 1
• Arms: 3
• Actual Duration (Months): 53.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Schizo-affective Disorder; Bipolar Disorder	Drug: Glycine; Drug: placebo	Phase 2

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase
• Actual Study Start Date: Dec 10, 2012
• Actual Primary Completion Date: May 31, 2017
• Actual Study Completion Date: May 31, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 [baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period]

   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.

2. Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine [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.

3. Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine [At baseline, during glycine treatment, during placebo treatment and during open-label glycine]

   Plasma glycine levels; normal range is 122-467 nM/mL

4. 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 [baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period]

   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.

5. Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period [CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per 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.

6. Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period [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).

7. Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period [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.

8. Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period [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.

Secondary Outcome Measures

1. Brain Glycine/CR Ratio [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]

   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

2. Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT [baseline and week 6 of glycine]

   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.

3. Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT [Baseline and week 6 of glycine]

   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.

4. Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE [Recordings at baseline and week 6 of 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.

5. Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected. [6 weeks per treatment arm]

   functional magnetic resonance imaging

6. Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT [Recordings at baseline and week 6 of glycine]

   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.

7. 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 [Recordings at baseline and week 6 of glycine]

   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.

8. Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT [Recordings at baseline and week 6 of glycine]

   Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Triplication of glycine decarboxylase gene

Exclusion Criteria:

• Normal glycine decarboxylase copy number

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	McLean Hospital	Belmont	Massachusetts	United States	02478

Sponsors and Collaborators

• Mclean Hospital
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Deborah L Levy, PhD, Mclean Hospital

Study Documents (Full-Text)

• Informed Consent Form - Nov 11, 2012
• Statistical Analysis Plan - Oct 17, 2012
• Study Protocol - Oct 2, 2012

More Information

Publications

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• Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):365-84. Epub 2006 Jun 14. Review.
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• Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry. 1999 Feb 15;45(4):512-4.
• Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT. D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry. 1996 Dec;153(12):1628-30.
• Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciūte D, Tate SK, Caboclo LO, Sander JW, Clayton L, Linney KN, Shianna KV, Gumbs CE, Smith J, Cronin KD, Maia JM, Doherty CP, Pandolfo M, Leppert D, Middleton LT, Gibson RA, Johnson MR, Matthews PM, Hosford D, Kälviäinen R, Eriksson K, Kantanen AM, Dorn T, Hansen J, Krämer G, Steinhoff BJ, Wieser HG, Zumsteg D, Ortega M, Wood NW, Huxley-Jones J, Mikati M, Gallentine WB, Husain AM, Buckley PG, Stallings RL, Podgoreanu MV, Delanty N, Sisodiya SM, Goldstein DB. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010 May 14;86(5):707-18. doi: 10.1016/j.ajhg.2010.03.018. Epub 2010 Apr 15.
• Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. 2004 Jan 15;55(2):165-71.
• Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D. Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry. 1996 Nov;169(5):610-7.
• Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry. 1999 Jan;56(1):29-36.
• Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, Lindenmayer JP, Suckow R, Zukin SR. Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2001 Dec;4(4):385-91. doi: 10.1017/S1461145701002590.
• Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69-108. Review.
• Jensen JE, Licata SC, Ongür D, Friedman SD, Prescot AP, Henry ME, Renshaw PF. Quantification of J-resolved proton spectra in two-dimensions with LCModel using GAMMA-simulated basis sets at 4 Tesla. NMR Biomed. 2009 Aug;22(7):762-9. doi: 10.1002/nbm.1390.
• Kaufman MJ, Prescot AP, Ongur D, Evins AE, Barros TL, Medeiros CL, Covell J, Wang L, Fava M, Renshaw PF. Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study. Psychiatry Res. 2009 Aug 30;173(2):143-9. doi: 10.1016/j.pscychresns.2009.03.004. Epub 2009 Jun 24.
• Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai GE. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry. 2008 Jan 1;63(1):9-12. Epub 2007 Jul 20.
• Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav. 2012 Feb;100(4):665-77. doi: 10.1016/j.pbb.2011.03.023. Epub 2011 Apr 1. Review.
• Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, Sebat J. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron. 2011 Dec 22;72(6):951-63. doi: 10.1016/j.neuron.2011.11.007.
• Martínez A, Hillyard SA, Dias EC, Hagler DJ Jr, Butler PD, Guilfoyle DN, Jalbrzikowski M, Silipo G, Javitt DC. Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging. J Neurosci. 2008 Jul 23;28(30):7492-500. doi: 10.1523/JNEUROSCI.1852-08.2008. Erratum in: J Neurosci. 2008 Sep;28(37):9319.
• McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009 Nov;41(11):1223-7. doi: 10.1038/ng.474. Epub 2009 Oct 25.
• Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995 Dec;52(12):998-1007.
• Öngür D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, Renshaw PF. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry. 2008 Oct 15;64(8):718-726. doi: 10.1016/j.biopsych.2008.05.014. Epub 2008 Jul 7.
• Prescot AP, de B Frederick B, Wang L, Brown J, Jensen JE, Kaufman MJ, Renshaw PF. In vivo detection of brain glycine with echo-time-averaged (1)H magnetic resonance spectroscopy at 4.0 T. Magn Reson Med. 2006 Mar;55(3):681-6.
• Sebat J, Levy DL, McCarthy SE. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 2009 Dec;25(12):528-35. doi: 10.1016/j.tig.2009.10.004. Epub 2009 Oct 31. Review.
• Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004 Mar 1;55(5):452-6.
• Tsai G, Yang P, Chung LC, Lange N, Coyle JT. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998 Dec 1;44(11):1081-9.
• Tsai GE, Lin PY. Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des. 2010;16(5):522-37. Review.
• Tsai GE, Yang P, Chang YC, Chong MY. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2006 Feb 1;59(3):230-4. Epub 2005 Sep 9.
• Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. 1999 Nov;156(11):1822-5.
• van Berckel BN, Evenblij CN, van Loon BJ, Maas MF, van der Geld MA, Wynne HJ, van Ree JM, Kahn RS. D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. Neuropsychopharmacology. 1999 Aug;21(2):203-10.
• Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ; Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008 Feb 14;358(7):667-75. doi: 10.1056/NEJMoa075974. Epub 2008 Jan 9.
• Wonodi I, Schwarcz R. Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia. Schizophr Bull. 2010 Mar;36(2):211-8. doi: 10.1093/schbul/sbq002. Epub 2010 Feb 10. Review.

• Responsible Party: Deborah L. Levy, Associate Professor, Mclean Hospital
• ClinicalTrials.gov Identifier: NCT01720316
• Other Study ID Numbers: 2012p001597; R21MH097470-01A1
• First Posted: Nov 2, 2012
• Last Update Posted: Sep 19, 2017
• Last Verified: Sep 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Deborah L. Levy, Associate Professor, Mclean Hospital: Glycine; Glycine decarboxylase; Psychosis; Mutation
• Additional relevant MeSH terms: Disease; Bipolar Disorder; Mood Disorders; Psychotic Disorders; Glycine

Study Results

Participant Flow

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then the participant received open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then the participant received open-label glycine for 6 weeks.
Period Title: Double-Blind Glycine Placebo Crossover
STARTED	1	1
COMPLETED	1	1
NOT COMPLETED	0	0
Period Title: Double-Blind Glycine Placebo Crossover
STARTED	1	1
COMPLETED	1	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine	Total
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.	Total of all reporting groups
Overall Participants	1	1	2
Age (years) [Mean (Full Range) ]
age	59	32	45.5
Sex: Female, Male (Count of Participants)
Female	1 100%	0 0%	1 50%
Male	0 0%	1 100%	1 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	1 100%	1 100%	2 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	1 100%	1 100%	2 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	1 100%	1 100%	2 100%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.
Measure Participants	1	1
Positive symptoms at baseline	13	19
Positive symptoms at 2 weeks intervention 1	12	20
Positive symptoms at 4 weeks intervention 1	9	19
Positive symptoms at 6 weeks intervention 1	8	13
Positive symptoms, end of washout1	7	13
Positive symptoms at 2 weeks intervention 2	12	12
Positive symptoms at 4 weeks intervention 2	11	10
Positive symptoms at 6 weeks intervention 2	14	11
Positive symptoms, end of washout2	14	11
Positive symptoms at 2 weeks open label	9	8
Positive symptoms at 4 weeks open label	9	7
Positive symptoms at 6 weeks open label	7	8
Positive symptoms, end of washout3	7	8

2. Primary Outcome

Title	Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine
Description	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.
Time Frame	At baseline, during glycine treatment, during placebo treatment and during open-label glycine

Outcome Measure Data

Analysis Population Description

Data provided for each participant separately.

Arm/Group Title	Baseline	Composite Score on Glycine, Double-blind	Composite Score on Placebo	Composite Score on Glycine, Open-label
Arm/Group Description	Composite Score at Baseline	Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind Glycine: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine	placebo, TID dosing, 6 weeks Double-blind placebo	glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Glycine: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
Measure Participants	2	2	2	2
Participant 1	45	52	52	49
Participant 2	48	52	55	46

3. Primary Outcome

Title	Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine
Description	Plasma glycine levels; normal range is 122-467 nM/mL
Time Frame	At baseline, during glycine treatment, during placebo treatment and during open-label glycine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine Then Placebo	Placebo Then Glycine
Arm/Group Description	Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind Glycine: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine	placebo, TID dosing, 6 weeks Double-blind placebo
Measure Participants	1	1
Baseline	216	271
Glycine double-blind	410	761
Placebo	194	347
Glycine open-label	516	634

4. Primary Outcome

Title	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
Description	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.
Time Frame	baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.
Measure Participants	1	1
BPRS at baseline	39	46
BPRS at 2 weeks intervention 1	38	38
BPRS at 4 weeks intervention 1	32	39
BPRS at 6 weeks intervention 1	21	28
BPRS, end of washout1	22	34
BPRS at 2 weeks intervention 2	37	32
BPRS at 4 weeks intervention 2	31	20
BPRS at 6 weeks intervention 2	37	23
BPRS, end of washout2	32	24
BPRS at 2 weeks open label	23	20
BPRS at 4 weeks open label	22	18
BPRS at 6 weeks open label	21	19
BPRS, end of washout3	19	23

5. Primary Outcome

Title	Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Description	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.
Time Frame	CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.
Measure Participants	1	1
CGI severity score at baseline	4	4
CGI severity score at 2 weeks intervention 1	4	4
CGI severity score at 4 weeks intervention 1	3	4
CGI severity score at 6 weeks intervention 1	2	4
CGI severity score, end of washout1	2	4
CGI severity score at 2 weeks intervention 2	4	4
CGI severity score at 4 weeks intervention 2	4	4
CGI severity score at 6 weeks intervention 2	4	3
CGI severity score, end of washout2	4	3
CGI severity score at 2 weeks open label	3	3
CGI severity score at 4 weeks open label	3	3
CGI severity score at 6 weeks open label	2	2
CGI severity score, end of washout3	2	2

6. Primary Outcome

Title	Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Description	Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13).
Time Frame	at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.
Measure Participants	1	1
CGI therapeutic effect at 2 weeks intervention 1	13	5
CGI therapeutic effect at 4 weeks intervention 1	5	5
CGI therapeutic effect at 6 weeks intervention 1	5	5
CGI therapeutic effect, end of washout1	5	5
CGI therapeutic effect at 2 weeks intervention 2	13	13
CGI therapeutic effect at 4 weeks intervention 2	13	5
CGI therapeutic effect at 6 weeks intervention 2	13	5
CGI therapeutic effect, end of washout2	13	5
CGI therapeutic effect at 2 weeks open label	5	1
CGI therapeutic effect at 4 weeks open label	5	1
CGI therapeutic effect at 6 weeks open label	1	1
CGI therapeutic effect, end of washout3	1	1

7. Primary Outcome

Title	Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Description	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.
Time Frame	baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.
Measure Participants	1	1
Manic symptoms at baseline	4	7
Manic symptoms at 2 weeks intervention 1	1	7
Manic symptoms at 4 weeks intervention 1	0	6
Manic symptoms at 6 weeks intervention 1	0	0
Manic symptoms, end of washout1	0	0
Manic symptoms at 2 weeks intervention 2	17	0
Manic symptoms at 4 weeks intervention 2	0	0
Manic symptoms at 6 weeks intervention 2	2	0
Manic symptoms, end of washout2	2	0
Manic symptoms at 2 weeks open label	1	0
Manic symptoms at 4 weeks open label	0	0
Manic symptoms at 6 weeks open label	0	0
Manic symptoms, end of washout3	0	0

8. Primary Outcome

Title	Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Description	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.
Time Frame	baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glycine, Then Placebo	Placebo, Then Glycine
Arm/Group Description	One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.	One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.
Measure Participants	1	1
Depression symptoms at baseline	18	12
Depression symptoms at 2 weeks intervention 1	17	5
Depression symptoms at 4 weeks intervention 1	11	5
Depression symptoms at 6 weeks intervention 1	3	0
Depression symptoms, end of washout1	1	3
Depression symptoms at 2 weeks intervention 2	19	3
Depression symptoms at 4 weeks intervention 2	5	2
Depression symptoms at 6 weeks intervention 2	7	1
Depression symptoms, end of washout2	3	1
Depression symptoms at 2 weeks open label	2	1
Depression symptoms at 4 weeks open label	2	1
Depression symptoms at 6 weeks open label	1	1
Depression symptoms, end of washout3	2	0

9. Secondary Outcome

Title	Brain Glycine/CR Ratio
Description	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
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Subject1: Brain Glycine/CR Ratio at Baseline/Week 6 of Glycine	Subject 2:Brain Glycine/CR Ratio at Baseline/Week 6 of Glycine
Arm/Group Description	Brain glycine/CR ratio at baseline and week 6 of glycine for one participant: Subject 1	Brain glycine/CR ratio at baseline and week 6 of glycine for one participant
Measure Participants	1	1
Baseline - pre-challenge drink	0.2558	0.5691
Baseline 60 minutes post challenge drink	0.6157	0.3918
Baseline 80 minutes post challenge drink	0.6631	0.6428
Baseline 100 minutes post challenge drink	0.5938	0.6363
Baseline 120 minutes post challenge drink	0.6953	0.9559
Week 6 of glycine - pre-glycine dose	0.6573	0.3235
Week 6 of glycine - 60 minutes post glycine dose	0.2983	0.3807
Week 6 of glycine - 80 minutes post glycine dose	0.4577	0.5591
Week 6 of glycine - 100 minutes post glycine dose	0.5751	0.4142
Week 6 of glycine - 120 minutes post glycine dose	0.3842	0.3545

10. Secondary Outcome

Title	Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
Description	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.
Time Frame	baseline and week 6 of glycine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Subject1: Brain Glutamate/CR Ratio- Baseline/Week 6 of Glycine	Subject2: Brain Glutamate/CR Ratio- Baseline/Week 6 of Glycine
Arm/Group Description	Brain glutamate/CR ratio at baseline and week 6 of glycine for one participant: Subject 1	Brain glutamate/CR ratio at baseline and week 6 of glycine for one participant: Subject 2
Measure Participants	1	1
Baseline brain glutamate/Cr ratio	0.98	2.053
Week 6 brain glutamate/Cr ratio	0.84	1.13

11. Secondary Outcome

Title	Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
Description	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.
Time Frame	Baseline and week 6 of glycine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Subject1: Brain GABA/CR Ratio- Baseline/Week 6 of Glycine	Subject2: Brain GABA/CR Ratio- Baseline/Week 6 of Glycine
Arm/Group Description	Brain GABA/CR ratio at baseline and week 6 of glycine for one participant: Subject 1	Brain GABA/CR ratio at baseline and week 6 of glycine for one participant: Subject 2
Measure Participants	1	1
Baseline GABA/Cr	0.16	0.27
Week 6 of glycine tx GABA/Cr	0.22	0.24

12. Secondary Outcome

Title	Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE
Description	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.
Time Frame	Recordings at baseline and week 6 of glycine

Outcome Measure Data

Analysis Population Description

Only one subject received these procedures because normal hearing is required.

Arm/Group Title	Auditory ERPs Latency (ms) Baseline: Subject 1	Auditory ERPs Latency (ms) 6 Weeks of Glycine: Subject 1	Auditory ERPs Latency (ms) Baseline: Subject 2	Auditory ERPs Latency (ms) 6 Weeks of Glycine: Subject 2
Arm/Group Description	Subject1: Auditory ERPs (latency) baseline	Subject1: Auditory ERPs (latency) week 6 of glycine	Subject2: Auditory ERPs (latency) baseline	Subject2: Auditory ERPs (latency) week 6 of glycine
Measure Participants	0	0	1	1
P300 latency at fz	279.3	300.78
P300 latency at cz	279.3	293
P300 latency at pz	279.3	294.92
N100 latency at fz	97.66	94
N100 latency at cz	91.8	94
P200 latency at fz	197.27	205
P200 latency at cz	193.4	203

13. Secondary Outcome

Title	Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.
Description	functional magnetic resonance imaging
Time Frame	6 weeks per treatment arm

Outcome Measure Data

Analysis Population Description

Data not collected.

Arm/Group Title	Glycine	Placebo
Arm/Group Description	Glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks glycine powder: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine	placebo, TID dosing, 6 weeks placebo
Measure Participants	0	0

14. Secondary Outcome

Title	Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
Description	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.
Time Frame	Recordings at baseline and week 6 of glycine

Outcome Measure Data

Analysis Population Description

Only one subject received these procedures because normal hearing is required.

Arm/Group Title	Auditory ERPs Amplitude (Deg) Baseline: Subject 1	Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 1	Auditory ERPs Amplitude (Deg) Baseline: Subject 2	Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 2
Arm/Group Description	Subject1: Auditory ERPs (amplitude) baseline	Subject1: Auditory ERPs (amplitude) week 6 of glycine	Subject2: Auditory ERPs (amplitude) baseline	Subject2: Auditory ERPs (amplitude) week 6 of glycine
Measure Participants	0	0	1	1
P300 amplitude at fz	-0.635	3.74
P300 amplitude at cz	6.53	6.6
P300 amplitude at pz	5.34	5.57
N100 amplitude at fz	-3.93	-4.71
N100 amplitude at cz	-3.62	-3.89
P200 amplitude at fz	1.662	6.29
P200 amplitude at cz	6.59	7.8
P50 S1 amplitude	2.76	2.2
P50 S2 amplitude	1.23	0.78
MMN amplitude at fz	-3.356	-1.004
MMN amplitude at cz	-4.13	-1.322

15. Secondary Outcome

Title	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
Description	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.
Time Frame	Recordings at baseline and week 6 of glycine

Outcome Measure Data

Analysis Population Description

Only one subject received these procedures because normal hearing is required.

Arm/Group Title	Auditory ERPs Gamma Baseline: Subject 1	Auditory ERPs Gamma 6 Weeks of Glycine: Subject 1	Auditory ERPs Gamma Baseline: Subject 2	Auditory ERPs Gamma 6 Weeks of Glycine: Subject 2
Arm/Group Description	Subject1: Auditory ERPs (gamma phase locking) baseline	Subject1: Auditory ERPs (gamma phase locking) week 6 of glycine	Subject2: Auditory ERPs (gamma phase locking) baseline	Subject2: Auditory ERPs (gamma phase locking) week 6 of glycine
Measure Participants	0	0	1	1
G40 fz	0.135	0.255
G40 cz	0.168	0.29
G20 fz	0.023	0.107
G20 cz	0.03	0.108
G30 fz	0.19	0.177
G30 cz	0.163	0.242

16. Secondary Outcome

Title	Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
Description	Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment.
Time Frame	Recordings at baseline and week 6 of glycine

Outcome Measure Data

Analysis Population Description

Only one subject received these procedures because normal hearing is required.

Arm/Group Title	Auditory ERPs Amplitude (Deg) Baseline: Subject 1	Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 1	Auditory ERPs Amplitude (Deg) Baseline: Subject 2	Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 2
Arm/Group Description	Subject1: Auditory ERPs (amplitude) baseline	Subject1: Auditory ERPs (amplitude) week 6 of glycine	Subject2: Auditory ERPs (amplitude) baseline	Subject2: Auditory ERPs (amplitude) week 6 of glycine
Measure Participants	0	0	1	1
Number [ratio]	44.51	35.67

Adverse Events

Time Frame	26 weeks
Arm/Group Title	Glycine		Placebo
Arm/Group Description	Glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks glycine powder: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine		placebo, TID dosing, 6 weeks placebo
All Cause Mortality
	Glycine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Glycine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Glycine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		0/2 (0%)
Gastrointestinal disorders
nausea	2/2 (100%)		0/2 (0%)
vomiting	2/2 (100%)		0/2 (0%)
diarrhea	2/2 (100%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.