Schizo-affective DisorderPhase 2NCT01720316

Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

A Phase 2 study testing Glycine in people with Schizo-affective Disorder and Bipolar Disorder, run by Mclean Hospital at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Schizo-affective Disorder, Bipolar Disorder
What is being tested?: Glycine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 2 participants
Where: 1 siteUnited States
Study dates: 10 Dec 2012to 31 May 2017
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Triplication of glycine decarboxylase gene

Who cannot join

Normal glycine decarboxylase copy number

Trial locations and contacts

1 site in 1 country.

United States1 site

McLean Hospital
Belmont, Massachusetts, 02478

Other trials in United States

About this study

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

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.

Read the 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).

Conditions: Schizo-affective Disorder, Bipolar Disorder
Being tested: Glycine, placebo
Keywords: Glycine, Glycine decarboxylase, Psychosis, Mutation
Medical subject headings: Psychotic Disorders, Bipolar Disorder, Hyperglycinemia, Nonketotic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

GlycineDrug
Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
placeboDrug

Study groups in NCT01720316
Study group	Role	What they receive
glycine	Active comparator	Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind Receives: Drug: Glycine
Placebo	Placebo comparator	placebo, TID dosing, 6 weeks Double-blind Receives: Drug: placebo
glycine, open-label	Active comparator	glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Receives: Drug: Glycine

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period

Secondary outcomes (8)

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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Recordings at baseline and week 6 of glycine

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

10 Dec 201231 May 2017

First posted2 Nov 2012 (estimated)
Study start10 Dec 2012
Primary completion31 May 2017
Study completion31 May 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (34)Papers the sponsor has linked to this study.
Other trials for Schizo-affective DisorderStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 2 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01720316
Sponsor's protocol ID: 2012p001597
Other IDs: R21MH097470-01A1
Status last verified: Sep 2017
First submitted: 30 Oct 2012
Last updated: 19 Sep 2017
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Butler PD, Schechter I, Zemon V, Schwartz SG, Greenstein VC, Gordon J, Schroeder CE, Javitt DC. Dysfunction of early-stage visual processing in schizophrenia. Am J Psychiatry. 2001 Jul;158(7):1126-33. doi: 10.1176/appi.ajp.158.7.1126.
PubMed 11431235
Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, Heresco-Levy U, Carpenter WT. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007 Oct;164(10):1593-602. doi: 10.1176/appi.ajp.2007.06081358.
PubMed 17898352
Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):365-84. doi: 10.1007/s10571-006-9062-8. Epub 2006 Jun 14.
PubMed 16773445
Duncan EJ, Szilagyi S, Schwartz MP, Bugarski-Kirola D, Kunzova A, Negi S, Stephanides M, Efferen TR, Angrist B, Peselow E, Corwin J, Gonzenbach S, Rotrosen JP. Effects of D-cycloserine on negative symptoms in schizophrenia. Schizophr Res. 2004 Dec 1;71(2-3):239-48. doi: 10.1016/j.schres.2004.03.013.
PubMed 15474895
Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G. The kynurenic acid hypothesis of schizophrenia. Physiol Behav. 2007 Sep 10;92(1-2):203-9. doi: 10.1016/j.physbeh.2007.05.025. Epub 2007 May 21.
PubMed 17573079
Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. 2000 May;157(5):826-8. doi: 10.1176/appi.ajp.157.5.826.
PubMed 10784481
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. doi: 10.1176/ajp.153.12.1628.
PubMed 8942463
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. doi: 10.1016/s0006-3223(98)00367-9.
PubMed 10071726
Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciute 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, Kalviainen R, Eriksson K, Kantanen AM, Dorn T, Hansen J, Kramer 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.
PubMed 20398883
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. doi: 10.1192/bjp.169.5.610.
PubMed 8932891
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. doi: 10.1001/archpsyc.56.1.29.
PubMed 9892253
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. doi: 10.1016/s0006-3223(03)00707-8.
PubMed 14732596
Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69-108. doi: 10.1016/S0074-7742(06)78003-5.
PubMed 17349858
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.
PubMed 11806864
Jensen JE, Licata SC, Ongur 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.
PubMed 19388001

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 19 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase
ClinicalTrials.gov ID: NCT01720316
Acronym / sponsor ID: 2012p001597
Conditions: Schizo-affective Disorder, Bipolar Disorder
Keywords: Glycine, Glycine decarboxylase, Psychosis, Mutation
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 2 participants (actual)
Lead sponsor: Mclean HospitalUniversity, hospital or other
Collaborators: National Institute of Mental Health (NIMH)
Study start: 10 Dec 2012 (actual)
Primary completion: 31 May 2017 (actual)
Study completion: 31 May 2017 (actual)
First posted: 2 Nov 2012 (estimated)
Results: Posted 18 Apr 2017

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
glycine	Active comparator	Drug: GlycineGlycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind
Placebo	Placebo comparator	Drug: placeboplacebo, TID dosing, 6 weeks Double-blind
glycine, open-label	Active comparator	Drug: Glycineglycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

Triplication of glycine decarboxylase gene

Key exclusion criteria (1 listed)

Normal glycine decarboxylase copy number

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
GlycineDouble-blind placebo controlled trial of glycine or placebo, followed by open-label glycine	Drug	glycine, glycine, open-label
placebo	Drug	Placebo

Primary outcome

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
Time frame: 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.
Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine
Time frame: 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.
Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine
Time frame: At baseline, during glycine treatment, during placebo treatment and during open-label glycine
Plasma glycine levels; normal range is 122-467 nM/mL
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
Time frame: 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.
Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Time frame: 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.
Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Time frame: 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).
Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Time frame: 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.
Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
Time frame: 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.

8 secondary outcomes

Brain Glycine/CR Ratio
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
Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
Time frame: 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
Time frame: 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
Time frame: Recordings at baseline and week 6 of glycine
Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Recordings at baseline and week 6 of glycine

Results and safety

Results posted to the registry on 18 Apr 2017, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Glycine, Then Placebo	1	1
Placebo, Then Glycine	1	1

Primary outcome: 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

Time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period. Number. Unit: units on a scale

Measure	Glycine, Then Placebo n = 1	Placebo, Then Glycine n = 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

Primary outcome: Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine

Time frame: At baseline, during glycine treatment, during placebo treatment and during open-label glycine. Number. Unit: units on a scale

Measure	Baseline n = 2	Composite Score on Glycine, Double-blind n = 2	Composite Score on Placebo n = 2	Composite Score on Glycine, Open-label n = 2
Participant 1	45	52	52	49
Participant 2	48	52	55	46

Population analysed: Data provided for each participant separately.

Primary outcome: Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine

Time frame: At baseline, during glycine treatment, during placebo treatment and during open-label glycine. Number. Unit: nM/mL

Measure	Glycine Then Placebo n = 1	Placebo Then Glycine n = 1
Baseline	216	271
Glycine double-blind	410	761
Placebo	194	347
Glycine open-label	516	634

Primary outcome: 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

Time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period. Number. Unit: units on a scale

Measure	Glycine, Then Placebo n = 1	Placebo, Then Glycine n = 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

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: 26 weeks. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Glycine	0 of 2 (0%)	2 of 2 (100%)	0 of 2
Placebo	0 of 2 (0%)	0 of 2 (0%)	0 of 2

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2017.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 11431235Butler PD, Schechter I, Zemon V, Schwartz SG, Greenstein VC, Gordon J, Schroeder CE, Javitt DC. Dysfunction of early-stage visual processing in schizophrenia. Am J Psychiatry. 2001 Jul;158(7):1126-33. doi: 10.1176/appi.ajp.158.7.1126.
Background: PubMed 17898352Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, Heresco-Levy U, Carpenter WT. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007 Oct;164(10):1593-602. doi: 10.1176/appi.ajp.2007.06081358.
Background: PubMed 16773445Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):365-84. doi: 10.1007/s10571-006-9062-8. Epub 2006 Jun 14.
Background: PubMed 15474895Duncan EJ, Szilagyi S, Schwartz MP, Bugarski-Kirola D, Kunzova A, Negi S, Stephanides M, Efferen TR, Angrist B, Peselow E, Corwin J, Gonzenbach S, Rotrosen JP. Effects of D-cycloserine on negative symptoms in schizophrenia. Schizophr Res. 2004 Dec 1;71(2-3):239-48. doi: 10.1016/j.schres.2004.03.013.
Background: PubMed 17573079Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G. The kynurenic acid hypothesis of schizophrenia. Physiol Behav. 2007 Sep 10;92(1-2):203-9. doi: 10.1016/j.physbeh.2007.05.025. Epub 2007 May 21.
Background: PubMed 10784481Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. 2000 May;157(5):826-8. doi: 10.1176/appi.ajp.157.5.826.
Background: PubMed 8942463Goff 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. doi: 10.1176/ajp.153.12.1628.
Background: PubMed 10071726Goff 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. doi: 10.1016/s0006-3223(98)00367-9.
Background: PubMed 20398883Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, Walley NM, Nicoletti P, Ge D, Catarino CB, Duncan JS, Kasperaviciute 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, Kalviainen R, Eriksson K, Kantanen AM, Dorn T, Hansen J, Kramer 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.
Background: PubMed 8932891Heresco-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. doi: 10.1192/bjp.169.5.610.
Background: PubMed 9892253Heresco-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. doi: 10.1001/archpsyc.56.1.29.
Background: PubMed 14732596Heresco-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. doi: 10.1016/s0006-3223(03)00707-8.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Deborah L Levy, PhD principal investigator

Mclean Hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Glycine in people with Schizo-affective Disorder and Bipolar Disorder, run by Mclean Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Apr 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01720316, which also lists 34 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2017.