School of Social Sciences and Psychology, Western Sydney University, Sydney 2751, New South Wales, Australia.
Department of Social Sciences, College of Arts and Sciences, Qatar University, P.O. Box 2713, Doha, Qatar.
Rev Neurosci. 2020 Jan 28;31(2):219-232. doi: 10.1515/revneuro-2019-0057.
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.
治疗抵抗性精神分裂症（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，同型半胱氨酸水平升高是由于转硫途径活性降低，导致同型半胱氨酸在合成 L-半胱氨酸时代谢。精神分裂症患者的谷胱甘肽水平较低，表明 L-半胱氨酸短缺和转硫途径活性降低。精神分裂症患者的硫化氢（H2S）水平较低。H2S 由胱硫醚 β-合酶和胱硫醚 γ-裂合酶合成，这两种酶都是转硫途径中的两种酶。含硫铁蛋白从 L-半胱氨酸中获得硫。氧化磷酸化（OXPHOS）途径含有多种含硫铁蛋白。由于 L-半胱氨酸水平低，铁硫簇的形成将失调，导致精神分裂症中 OXPHOS 缺陷。钼辅因子（MoCo）合成需要硫，而硫则来自 L-半胱氨酸。MoCo 合成水平低，钼依赖亚硫酸盐氧化酶（SUOX）的合成水平也会降低。SUOX 可从含硫氨基酸中解毒亚硫酸盐。如果亚硫酸盐不能解毒，就会发生亚硫酸盐毒性。转硫途径代谢硒代蛋氨酸，硒代蛋氨酸中的硒可用于合成硒蛋白。转硫途径活性降低会导致硒蛋白合成减少。谷胱甘肽过氧化物酶（GPX），其中多种 GPX 是硒蛋白，在精神分裂症中含量较低。硒蛋白的失调会导致氧化应激，从而增加基因和组蛋白的甲基化，导致 TRS 的表观遗传改变。针对转硫途径和其他途径的失调，建议在主流抗精神病药物的基础上增加一种针对 TRS 的附加治疗方法。
