Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine

NCT02304432 | Completed Early Phase 1 Results

• 1 other identifier: 1R21MH105732
• Study Type: interventional
• Target: 2
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to assess the efficacy of d-cycloserine (DCS) as an augmentation strategy in two psychotic patients with a triplication (4 copies) of the glycine decarboxylase (GLDC) gene. Subjects will first undergo an eight-week open-label arm of treatment with DCS (50 mg/d) followed by six 6-week double-blind placebo-controlled exposures to DCS or placebo. The length of each double-blind arm is limited to six weeks to minimize the length of symptom exacerbation experienced by the subjects when they are receiving placebo. The randomization scheme will allow two consecutive exposures to DCS, but will not allow two consecutive exposures to placebo, again to minimize the length of any symptom exacerbation. At the end of the open-label DCS trial, the following procedures will be carried out: structural MRI (3T), proton 1H MRS (4T), fMRI (3T), steady-state auditory evoked potentials, and electroretinogram recordings. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a DCS will be assessed. Baseline data on all of these measures were previously obtained as part of a different study registered in clinical trials.gov - NCT01720316). 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. Pharmaceutical grade DCS) or placebo will be compounded and dispensed by the McLean Hospital Pharmacy. The investigators hypothesize that mutation carriers will have reduced endogenous brain glycine and GABA levels and increased brain glutamate and glutamine levels. DCS administration will increase brain glycine in the two carriers compared to baseline and treatment with glycine (0.8g/kg). 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 DCS, but not placebo, will improve positive, negative and affective symptoms as well as neurocognitive function. The investigators also hypothesize that DCS 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

Schizophrenia; Bipolar Disorder

Keywords

D-cycloserine; Glycine; Psychosis; Mutation; GABA

Outcome Measures

Primary Outcomes (10)

• Positive and Negative Symptom Scores

  Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.

  Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

• Positive and Negative Symptom Scores

  Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.

  Baseline, 2, 4, & 6 weeks (crossover periods)

• Brief Psychiatric Rating Scale (BPRS) Scores

  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 & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

• Brief Psychiatric Rating Scale (BPRS) Scores

  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, 2, 4, & 6 weeks (crossover periods)

• Clinical Global Impression (CGI) Severity Scores

  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.

  Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

• Clinical Global Impression (CGI) Severity Scores

  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.

  Baseline, 2, 4, & 6 weeks (crossover periods)

• Mania Symptom Scores

  Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.

  Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

• Depression Symptom Scores

  Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 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. Higher scores indicate worse depression symptoms.

  Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2

• Mania Symptom Scores

  Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.

  Baseline, 2, 4, & 6 weeks (crossover periods)

• Depression Symptom Scores

  Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 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. Higher scores indicate worse depression symptoms.

  Baseline, 2, 4, & 6 weeks (crossover periods)

Secondary Outcomes (6)

• Neurocognitive Function

  Baseline and Week 8 of open-label DCS treatment

• Brain Glycine/CR Ratio

  Baseline and Week 8 of DCS treatment

• Auditory Evoked Potentials in Latency (Msec)

  Baseline and Week 8 of DCS treatment

• Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts)

  Baseline and Week 8 of DCS treatment

• Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared)

  Baseline and Week 8 of DCS treatment

Study Arms (3)

Open label DCS

EXPERIMENTAL

Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule for 8 weeks.

Drug: D-cycloserine

DCS or placebo

EXPERIMENTAL

Randomized to DCS or placebo. Participants underwent double-blind placebo-controlled exposures to DCS for 6 weeks or placebo for 6 weeks. One participant received exposure to DCS for 6 weeks and then received placebo dosing for 6 weeks. The other participant received exposure to placebo dosing for 6 weeks and then DCS for 6 weeks.

Drug: D-cycloserine; Drug: DCS or placebo

Second open label DCS

EXPERIMENTAL

Both participants received second open label exposures to D-cycloserine (seromycin), 50 mg/d capsule for 24 weeks.

Drug: D-cycloserine

Interventions

D-cycloserine DRUG

Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.

Also known as: Seromycin (d-cycloserine)

DCS or placebo; Open label DCS

DCS or placebo DRUG

Double-blind placebo-controlled exposures to DCS or placebo x 6 weeks. One participant received exposure to DCS x 6 weeks and then received placebo dosing x 6 weeks. The other participant received exposure to placebo dosing x 6 weeks and then DCS x 6 weeks.

Also known as: Seromycin (d-cycloserine) or placebo

DCS or placebo

Eligibility Criteria

• Age: 34 Years - 62 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Carriers of a triplication in the glycine decarboxylase gene

You may not qualify if:

• Not carriers of a triplication in the glycine decarboxylase gene

Sponsors & Collaborators

• Mclean Hospital: lead
• University of Minnesota: collaborator

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  PMID: 15474895 RESULT

• Bodkin JA, Coleman MJ, Godfrey LJ, Carvalho CMB, Morgan CJ, Suckow RF, Anderson T, Ongur D, Kaufman MJ, Lewandowski KE, Siegel AJ, Waldstreicher E, Grochowski CM, Javitt DC, Rujescu D, Hebbring S, Weinshilboum R, Rodriguez SB, Kirchhoff C, Visscher T, Vuckovic A, Fialkowski A, McCarthy S, Malhotra D, Sebat J, Goff DC, Hudson JI, Lupski JR, Coyle JT, Rudolph U, Levy DL. Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene. Biol Psychiatry. 2019 Oct 1;86(7):523-535. doi: 10.1016/j.biopsych.2019.04.031. Epub 2019 May 9.

  PMID: 31279534 DERIVED

MeSH Terms

Conditions

Schizophrenia; Bipolar Disorder; Psychotic Disorders

Interventions

Cycloserine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Bipolar and Related Disorders; Mood Disorders

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

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

dlevy@mclean.harvard.edu

617-855-2854

Study Officials

• Deborah L. Levy, Ph.D.

  Mclean Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: early phase 1
• 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: Director, Psychology Research Laboratory

Study Record Dates

• First Submitted: November 26, 2014
• First Posted: December 2, 2014
• Study Start: September 27, 2015
• Primary Completion: September 30, 2016
• Study Completion: July 31, 2017
• Last Updated: September 19, 2017
• Results First Posted: September 19, 2017

Record last verified: 2017-09