Our findings based on a well-phenotyped cohort of twin pairs discordant for schizophrenia and healthy controls independently associate specific lipid abnormalities with schizophrenia and with genetic liability to schizophrenia as well as with specific intermediate phenotypes obtained from brain imaging and neurocognitive testing.
The observed elevation of triglycerides in schizophrenia patients in comparison to their healthy co-twins is in agreement with earlier findings that schizophrenia is associated with elevated fasting total triglycerides and insulin resistance [27
]. This metabolic abnormality has been usually attributed to antipsychotic drug-specific side effects. However, there is growing evidence that elevated circulating insulin and insulin-related peptides and abnormal insulin response to glucose can be identified already in drug-naïve first-episode patients [29
], suggesting that insulin signaling is impaired in schizophrenia [30
In a recent lipidomic study of different lipoprotein fractions in people with varying degrees of insulin resistance we found that the lipids observed in LC5 are abundant in liver-produced very low density lipoprotein particles and are associated with insulin resistance [33
]. In agreement with this, schizophrenia patients in the present study were insulin resistant. Additionally, the twins from pairs discordant for schizophrenia had a higher HOMA-IR index compared to healthy controls (Table ), implying that these differences may not be due to antipsychotic medication use.
One should bear in mind that atypical antipsychotics used by a majority of patients in our study (Table ) are known to have a strong effect on serum lipidomic profiles [34
]. Consequently, with the data from the current study alone we are not able to control for the effect of antipsychotic medication used on lipidomic profiles, specifically on the elevated triglycerides in the patients. However, we have already shown in our earlier study that triglycerides are significantly elevated in schizophrenia patients even after correcting for antipsychotic medication use and metabolic co-morbidity [27
]. Furthermore, previous studies finding elevated insulin and related peptides have been done on antipsychotic-naïve first-episode patients [29
]. Together, our data indicate that schizophrenia is characterized by insulin resistance and consequently enhanced hepatic very low density lipoprotein production [35
] and elevated serum concentrations of specific triglycerides.
LysoPCs were diminished in schizophrenia patients compared to their co-twins and to healthy controls. These changes were associated with decreased cognitive speed. The observed changes are particularly remarkable because elevated lysoPCs commonly positively associate with obesity and insulin resistance, as we have shown in a study of monozygous twins pairs discordant for weight [36
]. Despite having measured lysoPC from serum, its observed variation may have direct implications for the lipid metabolism in the brain since lysoPC is a preferred carrier of polyunsaturated fatty acids across the blood-brain barrier [37
]. Polyunsaturated fatty acids are important for the development of normal brain function [3
]. In individuals at ultra-high risk of a psychotic disorder, dietary intake of long chain ω-3 fatty acids also reduces the risk of progression to the disease [38
One potential clue about the pathogenic relevance of our findings comes from the negative association of rheumatoid arthritis with schizophrenia. Oken and Schulzer [39
] performed a meta-analysis of 16 studies encompassing over 70,000 patients with schizophrenia and over 350,000 patients with other major psychiatric conditions and concluded that rheumatoid arthritis 'occurs among schizophrenia patients at a rate of only 29 percent of the corresponding prevalence in other psychiatric patients' and is even lower than 29% when compared to the general population. Such negative association with schizophrenia led to the 'prostaglandin deficiency' hypothesis, which postulated that defective enzyme systems converting essential fatty acids to prostaglandins lead to diminished levels of prostaglandins [7
], which as a consequence may lead to altered monoaminergic neurotransmission. Prostaglandins are-along with lysoPCs-byproducts of PC hydrolysis by phospholipase A2. In contrast to schizophrenia, lysoPC is increased in rheumatoid arthritis [40
], thus supporting the view that prostaglandins and perhaps also lysoPC as a byproduct may play a protective role in schizophrenia. As an alternative hypothesis, based also on the evidence that infections in early life may play a role in etiology of schizophrenia [41
], Torrey and Yolken [42
] suggested that rheumatoid arthritis and schizophrenia 'share a common infectious and/or immune etiology and that once a person gets one of the diseases then they are relatively immune to the other'. In fact, these two hypotheses may be related. Prolonged low levels of lysoPC in early life increases susceptibility to infection [43
]. Recent research in sepsis has also shown that lysoPC inversely correlates with the severity of infection [44
] and that lysoPC administration to mouse models of sepsis protects them against lethality [45
LysoPC is a major component of oxidized low density lipoprotein [46
], but varying serum lysoPC concentrations may also be due to changes in high density lipoprotein (HDL) metabolism. LysoPC is particularly abundant in persons with high HDL cholesterol [47
] and diminished levels of HDL cholesterol have been observed in patients with schizophrenia in a general population cohort [48
]. Together, due to many sources influencing lysoPC concentration in blood, which may depend on the individual's genotype and lifestyle, it may be challenging to detect disease-specific changes of lysoPCs in the general population, such as in our recent study in a general population cohort [27
]. The twin study design such as ours is a more suitable setting where genetic and environmental factors are better separated, and specific factors directly associated with the disease pathogenesis may be more sensitively detected.
As a potential limitation of our study, the imaging and neurocognitive data were collected on average 5 years prior to blood sampling for this specific study. However, there is recent evidence that correlation between age and cortical thickness is similar in patients and controls [49
]. In a two-year longitudinal study of first-episode psychoses, neurocognitive deficits were found in place by onset of psychosis and remained stable over the course of the study [50
]. We therefore consider that brain structure and cognitive performance would not change within this span to a degree or in a direction that would affect the conclusions being drawn from the data. However, the fact that the imaging data were available for only 34 out of 73 participants weakened the power of the association analysis of image data with other variables. Another potential limitation is the cross-sectional design of our study. Due to many sources affecting lysoPC concentration, longitudinal research in prodromal and early psychosis is needed to further elucidate its role in psychotic disorders. Finally, a more decisive separation of genetic versus environmental effects would have come from examining the monozygous twin pairs separately, but the numbers are too small to permit this.