Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H2S) levels are low in schizophrenia. H2S is synthesized by cystathionine β-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.

中文翻译：

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难治性精神分裂症：关注转硫途径

难治性精神分裂症（TRS）是一种严重的精神分裂症。疾病的严重程度与同型半胱氨酸水平呈正相关，高同型半胱氨酸水平是由于转硫途径的低活性，该途径在合成 L-半胱氨酸时代谢同型半胱氨酸。精神分裂症中谷胱甘肽水平低，这表明 L-半胱氨酸短缺和转硫途径活性低。硫化氢（H2S) 精神分裂症的水平低。H2S由胱硫醚β-合酶和胱硫醚γ-裂合酶合成，这两种酶是转硫途径中的两种酶。铁硫蛋白从 L-半胱氨酸中获得硫。氧化磷酸化 (OXPHOS) 途径具有各种铁硫蛋白。L-半胱氨酸水平低时，铁硫簇的形成将失调，导致精神分裂症中 OXPHOS 的缺陷。钼辅因子 (MoCo) 的合成需要硫，硫是从 L-半胱氨酸中获得的。由于 MoCo 合成水平低，钼依赖性亚硫酸盐氧化酶 (SUOX) 将不会以适当的水平合成。SUOX 从含硫氨基酸中解毒亚硫酸盐。如果亚硫酸盐没有被解毒，可能会产生亚硫酸盐毒性。转硫途径代谢硒代蛋氨酸，由此，来自硒代蛋氨酸的硒可用于硒蛋白的合成。转硫途径的低活性降低了硒蛋白的合成。谷胱甘肽过氧化物酶 (GPX)，各种 GPX 是硒蛋白，在精神分裂症中的含量很低。硒蛋白的失调会导致氧化应激，这会增加基因和组蛋白的甲基化，导致TRS的表观遗传变化。针对 TRS 提出了一种针对主线抗精神病药物的附加治疗，该治疗针对转硫途径的失调和由转硫途径失调引起的其他途径的失调。硒蛋白的失调会导致氧化应激，这会增加基因和组蛋白的甲基化，导致TRS的表观遗传变化。针对 TRS 提出了一种针对主线抗精神病药物的附加治疗，该治疗针对转硫途径的失调和由转硫途径失调引起的其他途径的失调。硒蛋白的失调会导致氧化应激，这会增加基因和组蛋白的甲基化，导致TRS的表观遗传变化。针对 TRS 提出了一种针对主线抗精神病药物的附加治疗，该治疗针对转硫途径的失调和由转硫途径失调引起的其他途径的失调。