In this study, we found that (1) OLA significantly increased plasma LysoPE concentrations and improved cognitive functions in FEP patients; (2) different LysoPE species have different functions in SCZ patients. In this cohort study, baseline LysoPE(16:1) concentration may serve as a predictor for cognitive effect of OLA; (3) changes in LysoPE(22:1) were associated with cognitive improvement after treatment, suggesting that LysoPE exerts a pivotal effect on cognitive improvement after OLA treatment in SCZ.
LysoPE is a bioactive molecule with pleiotropic impact on neurons. Our longitudinal follow-up study supports previous findings of improved cognitive functions after treatment with OLA, especially in domains of immediate memory, delayed memory [40]. Consistent with other studies, cognitive improvements after treatment were independent of the reductions in clinical symptoms. In addition, OLA significantly increased the concentrations of LysoPEs in patients with SCZ. Our study is superior to other studies in that most of other studies about LysoPE analysis used chronic patients with SCZ treated with several types of antipsychotics, rather than first-episode drug-naïve patients. Considering that antipsychotic medications are known to have an impact on the metabolites in SCZ patients [41–43], thus, only OLA was used to treat patients in this study, which is also advantageous to other studies.
We found significant increase in 8 LysoPE species at 4 weeks of follow-up, suggesting that most LysoPE concentrations were dynamic during the disease progression of SCZ. However, only an increase in LysoPE(22:1) was associated with cognitive improvement in patients with SCZ, indicating that LysoPE(22:1) was involved in the pathophysiology of cognitive function in SCZ. We speculated that the increase in plasma LysoPE concentrations after OLA treatment could enhance cognitive function in patients with SCZ. LysoPE is a minor constituent of cell membranes, which has been shown to activate cell signaling cascades such as mitogen-activated protein kinase (MAPK) or intracellular Ca2+ signaling [44–46]. It has also been reported to be associated with oxidative stress, inflammatory response and mitochondrial functions in vivo, all of which have been linked to the potential neuroprotective roles of SGA [47, 48]. Noteworthy, structurally different LysoPE species have different fatty acid lengths and saturation degrees in mammals. Changes in different types of LysoPE concentration have been found in animals with glutamate-induced neuronal death or other pathophysiological conditions such as animal models of AD [28]. Studies from animal model of global ischemia have revealed a fatty acid composition imbalance constituted of LysoPE18:0, 18:1, 20:4 and 22:6 in long-term postischemia parenchyma related to cognitive decline [49]. Our study is the first to report an association between LysoPE and cognitive improvement in patients with SCZ. It should be noted that many confounding factors, such as sex, age, smoking status, and different types of antipsychotic medications, can affect cognitive function, as well as the concentration of LysoPE. In this study, to control for these factors, we recruited drug-naïve female patients treated with monotherapy and were nonsmokers with normal weight. Thus, the association between changes in LysoPE concentrations and cognitive improvement may be an intrinsic link, rather than an association caused by confounding factors.
Furthermore, we found that baseline LysoPE concentrations were significantly associated with cognitive improvement after treatment in patients. Patients with higher baseline LysoPE concentrations showed greater improvement in cognitive functions compared to those with lower LysoPE. Plasma LysoPE(22:1) concentration may be a more sensitive biomarker for cognitive improvement in the early stage of SCZ. Until now, the role of LysoPE in the brain is complex and remains unclear. There is accumulating evidence for a dual role of LysoPE in CNS. Different types of LysoPE either protect brain from pathophysiological condition, or are involved in the development of pathophysiological conditions [28]. For example, LysoPE 18:1 has been reported to play a protective role of against glutamate-induced excitotoxicity in AD model mice, traumatic brain injury rat mode and global cerebral ischaemia rat, while LysoPE 22:6 has been reported to have a deteriorating effect [29, 31, 50]. In agreement with our findings, Liano et al. reported that serum LysoPE concentrations can identify AD patients from control subjects and predict the progression of mild cognitive decline [51]. However, our results were preliminary. It is warranted to confirm the associations between LysoPE concentrations and cognitive improvements in a large size of sample.
Our study has some limitations. First, it remains unclear whether plasma concentrations of LysoPE can reflect the concentrations in CSF. Therefore, we cannot make a conclusion that LysoPE concentrations were increased in the brain of patients with SCZ. Second, the relatively small sample size increases the possibility of Type II error. Most of the associations between plasma LysoPE levels and cognitive improvement presented in this study were not significant, which might be due to the low statistical power. Third, control subjects were not recruited in this study. We do not know whether baseline LysoPE concentrations were abnormal, as well as whether OLA increased their concentrations to normal levels.
In conclusion, we found that OLA treatment regulated plasma LysoPE concentrations, which was further associated with cognitive improvements in patients with SCZ. In addition, baseline LysoPE can predict cognitive response to 4 weeks of OLA monotherapy. So far, the function of LysoPE species in patients with SCZ remains unclear. The findings of this study provide a basis for further investigation of the role of LysoPEs in patients with SCZ. Our findings were preliminary and further longitudinal studies are needed to understand the physiological and pathological roles of each LysoPE in cognitive functions in patients with SCZ and to elucidate their association with antipsychotic medications.