Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 2
- 主要终点
- Positive and Negative Symptom Scores
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 34 Years 至 62 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Carriers of a triplication in the glycine decarboxylase gene
排除标准
- •Not carriers of a triplication in the glycine decarboxylase gene
研究组 & 干预措施
Open label DCS
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule for 8 weeks.
干预措施: D-cycloserine (Drug)
DCS or placebo
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.
干预措施: D-cycloserine (Drug)
DCS or placebo
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.
干预措施: DCS or placebo (Drug)
Second open label DCS
Both participants received second open label exposures to D-cycloserine (seromycin), 50 mg/d capsule for 24 weeks.
干预措施: D-cycloserine (Drug)
结局指标
主要结局
Positive and Negative Symptom Scores
时间窗: 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.
Brief Psychiatric Rating Scale (BPRS) Scores
时间窗: 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.
Clinical Global Impression (CGI) Severity Scores
时间窗: 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.
Mania Symptom Scores
时间窗: 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.
Depression Symptom Scores
时间窗: 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.
次要结局
- Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude)(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)
- Neurocognitive Function(Baseline and Week 8 of open-label DCS treatment)
- Brain Glycine/CR Ratio(Baseline and Week 8 of DCS treatment)
研究者
Deborah L. Levy
Director, Psychology Research Laboratory
Mclean Hospital