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Completed

NCT Number: NCT02304432

Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine

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.

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Key information

Conditions

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

Age range

34 year–62 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

About this study

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. 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.

There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function. Although many studies have reported positive results in at least one symptom domain, the results of other studies have been negative or ambiguous. 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 and individual differences in brain glycine uptake and metabolism . 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 DCS 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 DCS 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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Carriers of a triplication in the glycine decarboxylase gene

Exclusion criteria

  • Not carriers of a triplication in the glycine decarboxylase gene

Treatment and study plan

D-cycloserine

Drug

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

Other names: Seromycin (d-cycloserine)

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.

Other names: Seromycin (d-cycloserine) or placebo

Primary outcomes

  1. Positive and Negative Symptom Scores

    Time frame: 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 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.

  2. Positive and Negative Symptom Scores

    Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)

    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.

  3. Brief Psychiatric Rating Scale (BPRS) Scores

    Time frame: 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

    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.

  4. Brief Psychiatric Rating Scale (BPRS) Scores

    Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)

    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

    Time frame: 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

    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) Severity Scores

    Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)

    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.

  7. Mania Symptom Scores

    Time frame: 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

    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.

  8. Depression Symptom Scores

    Time frame: 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

    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.

  9. Mania Symptom Scores

    Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)

    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.

  10. Depression Symptom Scores

    Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)

    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.

Secondary outcomes

  1. Neurocognitive Function

    Time frame: Baseline and Week 8 of open-label DCS treatment

    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. Higher scores signify better functioning.

  2. Brain Glycine/CR Ratio

    Time frame: Baseline and Week 8 of DCS treatment

    Proton magnetic resonance spectroscopy at 4T: brain glycine/CR ratio. Participants were assessed at baseline (pre-glycine challenge dose and 60, 80, 100 and 120 minutes post glycine dose) and in week 8 of of open-label DCS treatment: pre-DCS dose, and 60, 80, 100 and 120 minutes post DCS dose. Measured in posterior occipital cortex.

  3. Auditory Evoked Potentials in Latency (Msec)

    Time frame: Baseline and Week 8 of DCS treatment

    Auditory evoked potential latency: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz.

  4. Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts)

    Time frame: Baseline and Week 8 of DCS treatment

    Auditory evoked potential amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2; mismatch negativity (MMN) at fz and cz.

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

    Time frame: Baseline and Week 8 of DCS treatment

    Auditory evoked potential gamma: G40 hz phase locking at fz and cz; G30 hz phase locking at fz and cz; G20 hz phase locking at fz and cz

  6. Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude)

    Time frame: Baseline and Week 8 of DCS treatment

    Auditory evoked potential amplitude: P50 ratio (P50 S2/S1)

Sponsors and collaborators

Lead sponsor

Mclean Hospital

Other

Collaborators

  • University of Minnesota

Registry information

Acronym: DCS

Important dates

Study start
2015
Primary completion
2016
Study completion
2017
First posted
Dec 2, 2014
Registry last updated
Sep 19, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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