Lipid Alteration Signature in the Blood Plasma of Individuals With Schizophrenia, Depression, and Bipolar Disorder.

Importance: No clinically applicable diagnostic test exists for severe mental disorders. Lipids harbor potential as disease markers. Objective: To define a reproducible profile of lipid alterations in the blood plasma of patients with schizophrenia (SCZ) independent of demographic and environmental variables and to investigate its specificity in association with other psychiatric disorders, ie, major depressive disorder (MDD) and bipolar disorder (BPD). Design, Setting, and Participants: This was a multicohort case-control diagnostic analysis involving plasma samples from psychiatric patients and control individuals collected between July 17, 2009, and May 18, 2018. Study participants were recruited as consecutive and volunteer samples at multiple inpatient and outpatient mental health hospitals in Western Europe (Germany and Austria [DE-AT]), China (CN), and Russia (RU). Individuals with DSM-IV or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of SCZ, MDD, BPD, or a first psychotic episode, as well as age- and sex-matched healthy controls without a mental health-related diagnosis were included in the study. Samples and data were analyzed from January 2018 to September 2020. Main Outcomes and Measures: Plasma lipidome composition was assessed using liquid chromatography coupled with untargeted mass spectrometry. Results: Blood lipid levels were assessed in 980 individuals (mean [SD] age, 36 [13] years; 510 male individuals [52%]) diagnosed with SCZ, BPD, MDD, or those with a first psychotic episode and in 572 controls (mean [SD] age, 34 [13] years; 323 male individuals [56%]). A total of 77 lipids were found to be significantly altered between those with SCZ (n = 436) and controls (n = 478) in all 3 sample cohorts. Alterations were consistent between cohorts (CN and RU: [Pearson correlation] r = 0.75; DE-AT and CN: r = 0.78; DE-AT and RU: r = 0.82; P < 10-38). A lipid-based predictive model separated patients with SCZ from controls with high diagnostic ability (area under the receiver operating characteristic curve = 0.86-0.95). Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were found to be similar to those of SCZ (BPD: r = 0.89; MDD: r = 0.92; P < 10-79). Assessment of detected alterations in individuals with a first psychotic episode, as well as patients with SCZ not receiving medication, demonstrated only limited association with medication restricted to particular lipids. Conclusions and Relevance: In this study, SCZ was accompanied by a reproducible profile of plasma lipidome alterations, not associated with symptom severity, medication, and demographic and environmental variables, and largely shared with BPD and MDD. This lipid alteration signature may represent a trait marker of severe psychiatric disorders, indicating its potential to be transformed into a clinically applicable testing procedure.

Time-Dependent Effect of Sciatic Nerve Injury on Rat Plasma Lipidome.

Neuropathic pain is a condition affecting the quality of life of a substantial part of the population, but biomarkers and treatment options are still limited. While this type of pain is caused by nerve damage, in which lipids play key roles, lipidome alterations related to nerve injury remain poorly studied. Here, we assessed blood lipidome alterations in a common animal model, the rat sciatic nerve crush injury. We analyzed alterations in blood lipid abundances between seven rats with nerve injury (NI) and eight control (CL) rats in a time-course experiment. For these rats, abundances of 377 blood lipid species were assessed at three distinct time points: immediately after, two weeks, and five weeks post injury. Although we did not detect significant differences between NI and CL at the first two time points, 106 lipids were significantly altered in NI five weeks post injury. At this time point, we found increased levels of triglycerides (TGs) and lipids containing esterified palmitic acid (16:0) in the blood plasma of NI animals. Lipids containing arachidonic acid (20:4), by contrast, were significantly decreased after injury, aligning with the crucial role of arachidonic acid reported for NI. Taken together, these results indicate delayed systematic alterations in fatty acid metabolism after nerve injury, potentially reflecting nerve tissue restoration dynamics.

Long-Term Fluoxetine Administration Causes Substantial Lipidome Alteration of the Juvenile Macaque Brain.

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.

Shorter Chain Triglycerides Are Negatively Associated with Symptom Improvement in Schizophrenia.

Schizophrenia is a serious mental disorder requiring lifelong treatment. While medications are available that are effective in treating some patients, individual treatment responses can vary, with some patients exhibiting resistance to one or multiple drugs. Currently, little is known about the causes of the difference in treatment response observed among individuals with schizophrenia, and satisfactory markers of poor response are not available for clinical practice. Here, we studied the changes in the levels of 322 blood plasma lipids between two time points assessed in 92 individuals diagnosed with schizophrenia during their inpatient treatment and their association with the extent of symptom improvement. We found 20 triglyceride species increased in individuals with the least improvement in Positive and Negative Syndrome Scale (PANSS) scores, but not in those with the largest reduction in PANSS scores. These triglyceride species were distinct from the rest of the triglyceride species present in blood plasma. They contained a relatively low number of carbons in their fatty acid residues and were relatively low in abundance compared to the principal triglyceride species of blood plasma.

Reduced purine biosynthesis in humans after their divergence from Neandertals.

We analyze the metabolomes of humans, chimpanzees, and macaques in muscle, kidney and three different regions of the brain. Although several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans.

Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains.

Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans. At the cellular level, astrocytes and oligodendrocyte progenitors displayed more differences in the human evolutionary lineage than the neurons. Comparison of the bulk tissue and single-nuclei sequencing revealed that conventional RNA sequencing did not detect up to two-thirds of cell-type-specific evolutionary differences.

Differences in lipidome and metabolome organization of prefrontal cortex among human populations.

Human populations, despite their overwhelming similarity, contain some distinct phenotypic, genetic, epigenetic, and gene expression features. In this study, we explore population differences at yet another level of molecular phenotype: the abundance of non-polar and polar low molecular weight compounds, lipids and metabolites in the prefrontal cortical region of the brain. We assessed the abundance of 1,670 lipids and 258 metabolites in 146 Han Chinese, 97 Western European, and 60 African American individuals of varying ages, covering most of the lifespan. The statistical analysis and logistic regression models both demonstrated extensive lipid and metabolic divergence of the Han Chinese individuals from the other two populations. This divergence was age-dependent, peaking in young adults, and involved metabolites and lipids clustering in specific metabolic pathways.

Metabolome signature of autism in the human prefrontal cortex.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with yet incompletely uncovered molecular determinants. Alterations in the abundance of low molecular weight compounds (metabolites) in ASD could add to our understanding of the disease. Indeed, such alterations take place in the urine, plasma and cerebellum of ASD individuals. In this work, we investigated mass-spectrometric signal intensities of 1,366 metabolites in the prefrontal cortex grey matter of 32 ASD and 40 control individuals. 15% of these metabolites showed significantly different intensities in ASD and clustered in 16 metabolic pathways. Of them, ten pathways were altered in urine and blood of ASD individuals (Fisher test, p < 0.05), opening an opportunity for the design of new diagnostic instruments. Furthermore, metabolic measurements conducted in 40 chimpanzees and 40 macaques showed an excess of metabolite intensity differences unique to humans, supporting the hypothesized disruption of evolutionary novel cortical mechanisms in ASD.