linoleic-acid and Schizophrenia

The purpose of this article is to provide a comprehensive review of metabolomics studies for psychosis, as a means of biomarker discovery. Manuscripts were selected for review if they involved discovery of metabolites using high-throughput analysis in human subjects and were published in the last decade. The metabolites identified were searched in Human Metabolome Data Base (HMDB) for a link to psychosis. Metabolites associated with psychosis based on evidence in HMBD were then searched using PubMed to explore the availability of further evidence. Almost all of the studies which underwent full review involved patients with schizophrenia. Ten biomarkers were identified. Six of them were reported in two or more independent metabolomics studies: N-acetyl aspartate, lactate, tryptophan, kynurenine, glutamate, and creatine. Four additional metabolites were encountered in a single metabolomics study but had significant evidence (two supporting articles or more) for a link to psychosis based on PubMed: linoleic acid, D-serine, glutathione, and 3-hydroxybutyrate. The pathways affected are discussed as they may be relevant to the pathophysiology of psychosis, and specifically of schizophrenia, as well as, constitute new drug targets for treatment of related conditions. Based on the biomarkers identified, early diagnosis of schizophrenia and/or monitoring may be possible.

Topics: 3-Hydroxybutyric Acid; Aspartic Acid; Biomarkers; Bipolar Disorder; Creatine; Female; Glutamic Acid; Glutathione; Humans; Kynurenine; Lactic Acid; Linoleic Acid; Male; Metabolome; Metabolomics; Psychotic Disorders; Schizophrenia; Serine; Tryptophan

There is now convincing evidence that membrane phospholipid metabolism is abnormal in schizophrenic patients. Our own studies, consistent with those of other research groups, have shown marked depletion of essential fatty acids, particularly arachidonic acid and docosahexanoic acid, in red blood cell membranes from schizophrenic patients relative to healthy control subjects. We also present preliminary evidence that similar abnormalities are present in first degree relatives of schizophrenic patients. Furthermore, it appears that changes in diet, which modify membrane levels of fatty acids, can have significant effects upon symptoms of schizophrenia and tardive dyskinesia (TD). Thus, we have found that schizophrenic patients who eat more (n-3) fatty acids in their normal diet have less severe symptoms. In a pilot study of (n-3) fatty acid supplementation we observed significant improvement in both schizophrenic symptoms and tardive dyskinesia over a 6 week period.

Topics: Arachidonic Acids; Docosahexaenoic Acids; Erythrocyte Membrane; Family; Fatty Acids, Essential; Fatty Acids, Omega-3; Food, Fortified; Humans; Linoleic Acid; Linoleic Acids; Membrane Lipids; Pilot Projects; Schizophrenia

Two recent meta-analyses showed decreased red blood cell (RBC) polyunsaturated fatty acids (FA) in schizophrenia and related disorders. However, both these meta-analyses report considerable heterogeneity, probably related to differences in patient samples between studies. Here, we investigated whether variations in RBC FA are associated with psychosis, and thus may be an intermediate phenotype of the disorder.. For the present study, a total of 215 patients (87% outpatients), 187 siblings, and 98 controls were investigated for multiple FA analyses. Based on previous studies, we investigated docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), linoleic acid (LA), nervonic acid (NA), and eicasopentaenoic acid (EPA). On an exploratory basis, a large number of additional FA were investigated. Multilevel mixed models were used to compare the FA between the 3 groups.. Compared to controls, both patients and siblings showed significantly increased DHA, DPA, AA, and NA. LA was significantly higher in siblings compared to controls. EPA was not significantly different between the 3 groups. Also the exploratory FA were increased in patients and siblings.. We found increased RBC FA DHA, DPA, AA, and NA in patients and siblings compared to controls. The direction of change is similar in both patients and siblings, which may suggest a shared environment and/or an intermediate phenotype. Differences between patient samples reflecting stage of disorder, dietary patterns, medication use, and drug abuse are possible modifiers of FA, contributing to the heterogeneity in findings concerning FA in schizophrenia patients.

Topics: Adult; Arachidonic Acid; Docosahexaenoic Acids; Eicosapentaenoic Acid; Erythrocytes; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Healthy Volunteers; Humans; Linoleic Acid; Male; Psychotic Disorders; Schizophrenia; Siblings; Young Adult

Disturbances of lipid metabolism have been implicated in psychiatric illnesses. We previously reported an association between the gene for fatty acid binding protein 7 (FABP7) and schizophrenia. Furthermore, we identified and reported several rare non-synonymous polymorphisms of the brain-expressed genes FABP3, FABP5 and FABP7 from schizophrenia and autism spectrum disorder (ASD), diseases known to part share genetic architecture. Here, we conducted further studies to better understand the contribution these genes make to the pathogenesis of schizophrenia and ASD. In postmortem brains, we detected altered mRNA expression levels of FABP5 in schizophrenia, and of FABP7 in ASD and altered FABP5 in peripheral lymphocytes. Using a patient cohort, comprehensive mutation screening identified six missense and two frameshift variants from the three FABP genes. The two frameshift proteins, FABP3 E132fs and FABP7 N80fs, formed cellular aggregates and were unstable when expressed in cultured cells. The four missense mutants with predicted possible damaging outcomes showed no changes in intracellular localization. Examining ligand binding properties, FABP7 S86G and FABP7 V126L lost their preference for docosahexaenoic acid to linoleic acid. Finally, mice deficient in Fabp3, Fabp5 and Fabp7 were evaluated in a systematic behavioral test battery. The Fabp3 knockout (KO) mice showed decreased social memory and novelty seeking, and Fabp7 KO mice displayed hyperactive and anxiety-related phenotypes, while Fabp5 KO mice showed no apparent phenotypes. In conclusion, disturbances in brain-expressed FABPs could represent an underlying disease mechanism in a proportion of schizophrenia and ASD sufferers.

Topics: Amino Acid Sequence; Animals; Anxiety; Behavior, Animal; Brain; Carrier Proteins; Child Development Disorders, Pervasive; Docosahexaenoic Acids; Exploratory Behavior; Fatty Acid Binding Protein 3; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Frameshift Mutation; Humans; Linoleic Acid; Lymphocytes; Mice; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Neoplasm Proteins; Nerve Tissue Proteins; Schizophrenia; Sequence Alignment; Tumor Suppressor Proteins

White matter (WM) abnormalities have been implicated in schizophrenia, yet the mechanisms underlying these abnormalities are not fully understood. Several lines of evidence suggest that polyunsaturated fatty acids (PUFAs) play a role in myelination, and there is substantial evidence documenting decreased PUFA concentrations in schizophrenia. We therefore hypothesized that lower membrane PUFA concentrations may be related to reduced WM integrity in schizophrenia and related disorders.. In 30 male patients with a recent-onset psychotic disorder, erythrocyte membrane PUFA concentrations were assessed and diffusion tensor imaging was performed with voxelwise analysis.. Lower total PUFA concentration was associated with lower fractional anisotropy (FA) throughout the corpus callosum and bilateral parietal, occipital, temporal and frontal WM (P < .05, corrected). Of the individual PUFAs, lower arachidonic acid concentration, and to a lesser extent, lower nervonic acid, linoleic acid, and docosapentaenoic acid concentration were significantly associated with lower FA. PUFA concentrations were inversely associated with radial diffusivity but showed little association with axial diffusivity. Greater severity of negative symptoms was associated with lower nervonic acid concentration and lower FA values.. Membrane PUFA concentrations appear to be robustly related to brain WM integrity in early phase psychosis. These findings may provide a basis for studies to investigate the effects of PUFA supplementation on WM integrity and associated symptomatology in early psychosis.

Topics: Adult; Anisotropy; Arachidonic Acid; Cerebral Cortex; Corpus Callosum; Diffusion Tensor Imaging; Erythrocyte Membrane; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Image Processing, Computer-Assisted; Linoleic Acid; Male; Myelin Sheath; Nerve Fibers, Myelinated; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

Platelets were found to emit a burst of chemiluminescence during incubation with arachidonic or linoleic acid. This chemiluminescence response may indicate activation of the enzyme prostaglandin synthase in the arachidonate-induced platelet chemiluminescence as it is inhibited by aspirin. Stimulation of platelets with arachidonic acid and linoleic acid induced a concentration dependent chemiluminescence response. Platelets from drug naive schizophrenic subjects showed significantly increased arachidonic acid metabolism compared to control subjects. No significant difference was observed between schizophrenic and control subjects in the chemiluminescence response to linoleic acid. In schizophrenic subjects treated with neuroleptic drugs the overactive arachidonic acid response was normalized. Linoleic acid chemiluminescence response was unaffected by neuroleptic treatment. Hyperactive cyclooxygenase activity may reflect a similar condition in the brain and implicates prostaglandin pathway abnormalities in the pathogenesis of schizophrenia.

Topics: Adult; Antipsychotic Agents; Arachidonic Acid; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Activation; Female; Humans; Linoleic Acid; Luminescent Measurements; Male; Prostaglandin-Endoperoxide Synthases; Schizophrenia; Sulpiride; Time Factors

At least two groups of schizophrenics will be described. One such group may have a mutant delta-6-desaturase which prefers the omega-6-series essential fatty acids over the omega-3 series essential fatty acids resulting in low cis-linoleic acid blood levels. This subgroup may be related to the low histamine type schizophrenia. In contrast, we describe the possible existence of another group of schizophrenic patients with elevated cis-linoleic acid blood levels, elevated fasting insulin levels, elevated EGOT and urinary kryptopyrolle termed "delta-6-pyroluria." The etiology of this group may be due to a block instead of a mutant delta-6-desaturase. The elevated fasting insulin level may be an attempt to overcome the malfunctioning pathway.

Topics: Alprostadil; Aspartate Aminotransferases; Fatty Acid Desaturases; Fatty Acids, Essential; Humans; Insulin; Linoleic Acid; Linoleic Acids; Linoleoyl-CoA Desaturase; Mutation; Prostaglandins; Pyrroles; Schizophrenia; Syndrome

Three long-stay, hospitalised schizophrenics who had failed to respond adequately to conventional drug therapy were treated with gamma-linolenic acid and linoleic acid in the form of evening primrose oil. They became substantially worse and electroencephalographic features of temporal lobe epilepsy became apparent. In all three the clinical state dramatically improved when carbamazepine, the conventional therapy for temporal lobe epilepsy was introduced. It can be extremely difficult to distinguish on clinical grounds between schizophrenia and temporal lobe epilepsy, and electroencephalographic studies do not always reveal an abnormality in the temporal lobe syndrome, unless additional procedure such as sphenoidal electroencephalography is undertaken. A trial of therapy with gamma-linolenic acid may prove of considerable value in distinguishing between these two states, so allowing specific therapy to be introduced.

Topics: Adult; Carbamazepine; Diagnosis, Differential; Electroencephalography; Epilepsy, Temporal Lobe; Female; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Male; Middle Aged; Schizophrenia