Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

NCT01720316 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 2012p001597R21MH097470-01A1
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Schizo-affective Disorder; Bipolar Disorder

Keywords

Glycine; Glycine decarboxylase; Psychosis; Mutation

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (8)

• 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

• 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

• 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

• 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

• Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.

  6 weeks per treatment arm

Study Arms (3)

glycine

ACTIVE COMPARATOR

Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind

Drug: Glycine

Placebo

PLACEBO COMPARATOR

placebo, TID dosing, 6 weeks Double-blind

Drug: placebo

glycine, open-label

ACTIVE COMPARATOR

glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks

Drug: Glycine

Interventions

Glycine DRUG

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

glycine; glycine, open-label

placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Triplication of glycine decarboxylase gene

You may not qualify if:

• Normal glycine decarboxylase copy number

Sponsors & Collaborators

• Mclean Hospital: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

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  PMID: 31279534 DERIVED

MeSH Terms

Conditions

Psychotic Disorders; Bipolar Disorder; Hyperglycinemia, Nonketotic

Interventions

Glycine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Bipolar and Related Disorders; Mood Disorders; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Deborah L. Levy
• Organization: McLean Hospital

dlevy@mclean.harvard.edu

617-855-2854

Study Officials

• Deborah L Levy, PhD

  Mclean Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: October 30, 2012
• First Posted: November 2, 2012
• Study Start: December 10, 2012
• Primary Completion: May 31, 2017
• Study Completion: May 31, 2017
• Last Updated: September 19, 2017
• Results First Posted: April 18, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)