TABLE 2.

Clinical studies of ER stress proteins in schizophrenia patients treated with or without antipsychotics.

References	Study location	Study design	ER stress-related protein/genes	Findings	Antipsychotic treatment
Kim et al., 2021	United States	UPR protein expression in the DLPFC of 22 matched pairs of elderly control subjects and subjects with SCZ was analyzed by WB and RT-qPCR.	sXBP1/uXBP1 ↑ GRP78/BiP ↑	1. In SCZ, BiP expression was increased, p-IRE1α expression was decreased, and PERK expression positively related to age was decreased. 2. There were decreased p-JNK2 and increased sXBP1, and IRE1α increased XBP1 mRNA splicing and drove upregulation of sXBP1 protein expression.	YES
Kakiuchi et al., 2004	Japan	The XBP1-116C/G polymorphism in 234 unrelated patients was genotyped by PCR, and Fisher’s exact test was used to examine the differences in genotype and allele frequencies.	XBP1-116C/C ↓	1. The XBP1-116C/C genotype, a protective factor for bipolar disorder and schizophrenia, is decreased in patients with SCZ.	NO
Cheng et al., 2014	Asia	The XBP1-116C/G polymorphism was analyzed in different databases for case-control studies up to July 31, 2014.	XBP1-116C/G ↑	The XBP1-116C/G polymorphism is associated with an increased risk of psychiatric illness including bipolar disorder in the Asian population.	NM
Chen et al., 2004	China	The XBP1-197C/G polymorphism in unrelated patients (374 cases and 371 controls) was genotyped by PCR.	XBP1-197C/G ↑	1. XBP1-197C/G was significantly associated with SCZ, and the GG genotype frequency was higher than controls. 2. The G allele was significantly higher in the SCZ male groups; there were no significant changes in female groups.	NO
Kim et al., 2008	Korea	Five SNPs of HSP70 in patients with SCZ (294 cases and 288 controls) were genotyped by using pyrosequencing method.	HSP70- rs2075799*G/A ↑	1. The rs2075799*G/A genotype was more represented in SCZ. 2. The T-A haplotype of rs2227956 and rs2075799 was significantly associated with SCZ.	NM
Kowalczyk et al., 2014	Poland	Polymorphisms of the HSP-1 and HSP-2 genes were genotyped by PCR-RFLP in drug-naïve patients with SCZ (203 cases and 243 controls) to examine the differences in genotype and allele frequencies.	HSP-1 +190CC ↑	1. The HSP-1+190CC genotype and +190C allele were more represented in patients with SCZ. 2. Female patients with the HSP-1+190CC genotype have a higher risk of developing paranoid schizophrenia than male patients.	NO
Pae et al., 2005	Korea	Polymorphisms of the HSP-1 and HSP-2 were genotyped by PCR-RFLP in inpatients (161cases and 165 controls) to examine the differences in genotype and allele frequencies.	HSP-2 ↑	1. HSP-2 polymorphism contributed to the development of schizophrenia in a gene dose–dependent manner. 2. The HSP-2 polymorphism conferred some susceptibility to schizophrenia in the Korean population.	YES

BiP, binding immunoglobulin protein; DLPFC, dorsolateral prefrontal cortex; GRP78, glucose regulatory protein 78; HSP, heat shock protein; PCR, polymerase chain reaction; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; p-JNK2, phosphorylated-c-Jun N-terminal kinase 2; RT-qPCR, real-time quantitative polymerase chain reaction; SCZ, schizophrenia; sXBP1, spliced X-box binding protein 1; UPR, unfolded protein response; WB, western blotting; XBP1, X-box binding protein 1; NM, not mentioned.