Tryptophan-Kynurenine Pathway Metabolism in the Pathophysiology of Cognitive Impairment in Schizophrenia.
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- TRP-KYN pathway candidate plasma metabolite levels
研究概览
简要总结
Schizophrenia is a common, long-term mental illness. It causes problems with thoughts, feelings, and behavior, including positive symptoms (hallucinations, delusions), negative symptoms (lack of emotion, motivation), and cognitive impairment (trouble with thinking, memory, and attention). While antipsychotic drugs effectively treat positive symptoms, they don't help much with cognitive impairment.This study will examine how the tryptophan-kynurenine pathway in the brain contributes to cognitive problems in people having their first episode of schizophrenia and treated with a single antipsychotic. Our goal is to create models for early detection of cognitive impairment in schizophrenia and find potential targets for new treatments to improve thinking and memory.
详细描述
This single-center, prospective study will recruit 100 treatment-naïve, first-episode schizophrenia (SZ) patients at Tianjin Anding Hospital for an 8-week follow-up. All patients will receive monotherapy with risperidone and undergo baseline and week 8 assessments including clinical rating scales and the MATRICS Consensus Cognitive Battery (MCCB), along with peripheral blood sample collection. Concurrently, 100 age-, sex-, and education-matched healthy controls (HCs) will be recruited. Prior data from 300 medication-naïve SZ patients and 100 HCs will be selectively included in the final analysis (totaling 300 SZ patients and 200 HCs). We hypothesize that dysregulation of the tryptophan-kynurenine (TRP-KYN) pathway in SZ patients, leading to an imbalanced ratio of neuroprotective kynurenic acid (KYNA) to neurotoxic quinolinic acid (QUIN), affects inflammatory markers and NMDA receptor (NMDAR) levels, ultimately causing cognitive impairment. Specifically, we will analyze the association between cognitive function and plasma TRP-KYN pathway metabolites in medication-naïve FES patients; relationship between cognitive function and TRP-KYN pathway gene polymorphisms and mRNA expression in medication-naïve FES patients; and changes in cognitive function post-8-week treatment with plasma TRP-KYN pathway mRNA expression and metabolite levels.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy volunteers matched to the patient group on sex, age, and education level;
- •Ethnic Han Chinese;
- •Able and willing to provide written informed consent.
排除标准
- •Significant comorbid medical or neurological conditions;
- •Any DSM-5-defined psychiatric disorder;
- •Family history of psychiatric illness spanning three or more generations;
- •Current use of psychoactive medications;
- •Refusal to provide informed consent/participate.
研究组 & 干预措施
Schizophrenic Patients
100 eligible individuals will meet DSM-5 criteria for schizophrenia or schizoaffective disorder, be Han Chinese aged 18-55 years, presenting with a first episode of illness ≤ 5 years duration. Prior antipsychotic exposure must be ≤ 4 weeks cumulatively, or patients must be treatment-naïve. Informed consent will be obtained from patients and their families.
Healthy Control
100 healthy, age-, gender-, and education-matched Han Chinese volunteers, with informed consent.
结局指标
主要结局
TRP-KYN pathway candidate plasma metabolite levels
时间窗: Baseline, week8
Plasma levels of tryptophan-kynurenine (TRP-KYN) pathway candidate metabolites, including kynurenine, kynurenic acid, kynurenic quinolinic acid, quinolinic acid, tryptophan, indole-3-acetic acid, and indole-3-propionic acid, were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sample information was registered in MetLIMS software, with designated positions for samples of interest, blanks, standards, and quality control samples. Samples were added to corresponding wells in a 96-well plate provided in the kit. Subsequently, derivatization was performed by adding a 5% phenylisothiocyanate solution. Finally, target analytes were extracted with an organic solvent and diluted. The pre-processed sample extracts underwent High-Performance Liquid Chromatography-Mass Spectrometry detection. Each sample was analyzed in two parts: the first involved signal acquisition in flow injection analysis mode, and the second in liquid chromatography-mass spectrometry mode.
Cognitive Function
时间窗: Baseline, week8
All participants underwent cognitive function assessment based on the MATRICS Consensus Cognitive Battery (MCCB). The MCCB is a standardized instrument for assessing cognitive function in schizophrenia. It comprises nine subtests primarily evaluating seven cognitive domains: processing speed, attention/alertness, working memory, verbal learning, visual memory, reasoning and problem-solving, and social cognition. The MCCB scoring procedure generates standardised T-scores that are corrected for age, gender, and educational level. Higher T-scores indicate better cognitive function.
Candidate gene mRNA expression levels
时间窗: Baseline, week8
Whole blood was collected in BD PAXgene® Blood RNA tubes (2.5 mL from antecubital veins) and gently inverted to mix. Samples were incubated vertically at room temperature for 2 hours, then stored at -20°C overnight before transfer to -80°C for RNA extraction. Extracted RNA was reverse transcribed to synthesize cDNA. Gene expression levels of TDO, IDO, KMO, KAT-II, KYNU, and 3HAO were determined by RT-qPCR with gel electrophoresis for product validation and densitometric scanning using a gel imaging system.
次要结局
- Psychiatric Symptoms(Baseline, week8)
- Depressive Symptoms(Baseline, week8)
- Anxiety Symptoms(baseline, week 8)
- Clinical Global Impression of Efficacy(baseline, week 8)