Schizophrenia is a serious neuropsychiatric disorder, yet a clear pathophysiology has not been identified. To date, neither the objective biomarkers for diagnosis nor specific medications for the treatment of schizophrenia are clinically satisfactory. It is well accepted that lipids are essential to maintain the normal structure and function of neurons in the brain and that abnormalities in neuronal lipids are associated with abnormal neurodevelopment in schizophrenia. However, lipids and lipid-like molecules have been largely unexplored in contrast to proteins and their genes in schizophrenia. Compared with the gene- and protein-centric approaches, lipidomics is a recently emerged and rapidly evolving research field with particular importance for the study of neuropsychiatric disorders such as schizophrenia, in which even subtle aberrant alterations in the lipid composition and concentration of the neurons may disrupt brain functioning. In this review, we aimed to highlight the lipidomics of the brain, retina, and biofluids in both human and animal studies, discuss aberrant lipid alterations in correlation with schizophrenia, and propose future directions from the biological landscape towards potential clinical applications in schizophrenia. Recent studies are in support of the concept that aberrations in some lipid species [e.g. phospholipids, polyunsaturated fatty acids (PUFAs)] lead to structural alterations and, in turn, impairments in the biological function of membrane-bound proteins, the disruption of cell signaling molecule accessibility, and the dysfunction of neurotransmitter systems. In addition, abnormal lipidome alterations in biofluids are linked to schizophrenia, and thus they hold promise in the discovery of biomarkers for the diagnosis of schizophrenia.

Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.