Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications

Previous studies have observed significant abnormalities in the fatty acid composition of peripheral tissues from drug-na?ve first-episode schizophrenic (SZ) patients relative to normal controls, including deficits in omega-3 and omega-6 polyunsaturated fatty acids, which are partially normalized following chronic antipsychotic treatment. We hypothesized that postmortem cortical tissue from patients with SZ would also exhibit deficits in cortical docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA; 20:4n-6) relative to normal controls, and that these deficits would be greater in drug-free SZ patients. We determined the total fatty acid composition of postmortem orbitofrontal cortex (OFC) (Brodmann area 10) from drug-free and antipsychotic-treated SZ patients (n=21) and age-matched normal controls (n=26) by gas chromatography. After correction for multiple comparisons, significantly lower DHA (-20%) concentrations, and significantly greater vaccenic acid (VA) (+12.5) concentrations, were found in the OFC of SZ patients relative to normal controls. Relative to age-matched same-gender controls, OFC DHA deficits, and elevated AA:DHA, oleic acid:DHA and docosapentaenoic acid (22:5n-6):DHA ratios, were found in male but not female SZ patients. SZ patients that died of cardiovascular-related disease exhibited lower DHA (-31%) and AA (-19%) concentrations, and greater OA (+20%) and VA (+17%) concentrations, relative to normal controls that also died of cardiovascular-related disease. OFC DHA and AA deficits, and elevations in oleic acid and vaccenic acid, were numerically greater in drug-free SZ patients and were partially normalized in SZ patients treated with antipsychotic medications (atypical>typical). Fatty acid abnormalities could not be wholly attributed to lifestyle or postmortem tissue variables. These findings add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of SZ, and suggest that abnormalities in OFC fatty acid composition may be gender-specific and partially normalized by antipsychotic medications.     

Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult mice: prevention by chronic lithium treatment

OBJECTIVES: Emerging data suggests that omega-3 fatty acid deficiency may be a risk factor for bipolar disorder. In the present study, we determined the effects of chronic dietary-induced omega-3 fatty acid deficiency and/or concomitant chronic lithium chloride (LiCl) treatment on amphetamine (AMPH)-induced behavioral sensitization, a phenomenon that may recruit neuroplastic mechanisms relevant to the pathophysiology of bipolar disorder. METHOD: Adult male C57BL/6J mice were randomly assigned to one four diets: Control (alpha-linolenic-fortified), Control+LiCl (0.255%), alpha-linolenic-Deficient, or Deficient+LiCl (0.255%), and behavioral testing initiated 65 days later. Locomotor activity was determined following 3 intermittent (separated by 7d) injections of amphetamine (AMPH) (1mg/kg). After behavioral testing, red blood cell (RBC) and regional brain (prefrontal cortex, hippocampus, ventral striatum) fatty acid composition was determined by gas chromatography. RESULTS: Each diet group exhibited comparable locomotor activity following acute AMPH treatment. However, the development of sensitization following repeated AMPH treatment was significantly augmented in Deficient mice relative to controls, and this augmented response was prevented by chronic LiCl treatment. Relative to controls, Deficient mice exhibited deficits in RBC and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition, reciprocal elevations in vaccenic acid (18:1n-7), arachidonic acid (AA, 20:4n-6), and docosapentaenoic acid (DPA, 22:5n-6) compositions, and elevations in AA:DHA, oleic acid:DHA, and DPA:DHA ratios. The fatty acid abnormalities in Deficient mice were not altered by concurrent chronic lithium treatment. Mice fed the Control+LiCl diet exhibited a significant increase in AA composition in RBC and all brain regions, and an elevated AA:DHA ratio in the prefrontal cortex and hippocampus, relative to Controls. Fatty acid composition in RBC and different brain regions were predominantly positively correlated. Within the ventral striatum, DHA composition was inversely correlated, and AA:DHA and oleic acid:DHA ratios positively correlated, with total distance traveled following the final AMPH treatment. CONCLUSION: These data indicate that alterations in fatty acid composition resulting from dietary-induced omega-3 fatty acid deficiency augment the development of AMPH-induced behavioral sensitization in a manner that is prevented by chronic lithium treatment. The implications of these findings for understanding the contribution of omega-3 fatty acid deficiency to the pathophysiology and progression of bipolar disorder are discussed.     

Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder.

BACKGROUND: Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls. METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann's Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography. RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables. CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.     

Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: evidence for augmented biosynthesis

Prior clinical studies suggest that chronic treatment with atypical antipsychotic medications increase erythrocyte and postmortem prefrontal cortex (PFC) omega-3 fatty acid composition in patients with schizophrenia (SZ). However, because human tissue phospholipid omega-3 fatty acid composition is potentially influenced by multiple extraneous variables, definitive evaluation of this putative mechanism of action requires an animal model. In the present study, we determined the effects of chronic treatment with the atypical antipsychotic risperidone (RISP, 3.0 mg/kg/d) on erythrocyte and PFC omega-3 fatty acid composition in rats maintained on a diet with or without the dietary omega-3 fatty acid precursor, alpha-linolenic acid (ALA, 18:3n-3). Chronic RISP treatment resulted in therapeutically-relevant plasma RISP and 9-OH-RISP concentrations (18+/-2.6 ng/ml), and significantly increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3, +22%, p=0.0003) and docosapentaenoic acid (22:5n-3, +18%, p=0.01) composition, and increased PFC DHA composition (+7%, p=0.03) in rats maintained on the ALA+ diet. In contrast, chronic RISP did not alter erythrocyte or PFC omega-3 fatty acid composition in rats maintained on the ALA- diet. Chronic RISP treatment did not alter erythrocyte or PFC arachidonic acid (AA, 20:4n-6) composition. These data suggest that chronic RISP treatment significantly augments ALA-DHA biosynthesis, and preferentially increases peripheral and central membrane omega-3 fatty acid composition. Augmented omega-3 fatty acid biosynthesis and membrane composition represents a novel mechanism of action that may contribute in part to the efficacy of RISP in the treatment of SZ.     

Abnormal fatty acid pattern in the superior temporal gyrus distinguishes bipolar disorder from major depression and schizophrenia and resembles multiple sclerosis

This study investigated the fatty acid composition of the postmortem superior temporal gyrus (STG), a cortical region implicated in emotional processing, from normal controls (n=15) and patients with bipolar disorder (BD, n=15), major depressive disorder (MDD, n=15), and schizophrenia (SZ, n=15). For comparative purposes, STG fatty acid composition was determined in a separate cohort of multiple sclerosis patients (MS, n=15) and normal controls (n=15). Compared with controls, patients with BD, but not MDD or SZ, exhibited abnormal elevations in the saturated fatty acids (SFA) palmitic acid (16:0), stearic acid (18:0), the polyunsaturated fatty acids (PUFA) linoleic acid (18:2n-6), arachidonic acid (20:4n-6), and docosahexaenoic acid (22:6n-3), and reductions in the monounsaturated fatty acid (MUFA) oleic acid (18:1n-9). The total MUFA/SFA and 18:1/18:0 ratios were lower in the STG of BD patients and were inversely correlated with total PUFA composition. MS patients exhibited a pattern of fatty acid abnormalities similar to that observed in BD patients including elevated PUFA and a lower 18:1/18:0 ratio. Collectively, these data demonstrate that BD patients exhibit a pattern of fatty acid abnormalities in the STG that is not observed in MDD and SZ patients and closely resembles MS patients.     

Phospholipid profile in the postmortem hippocampus of patients with schizophrenia and bipolar disorder: No changes in docosahexaenoic acid species

Previous studies with postmortem brain tissues showed abnormalities not only in n-3 long-chain polyunsaturated fatty acids (PUFA) but also in phospholipid metabolism in the cortex of individuals with schizophrenia and mood disorder. In this study we investigated whether there is similar abnormality in n-3 long-chain PUFAs and/or in phospholipid profile in the hippocampus of schizophrenia and bipolar disorder patients compared to unaffected controls. Using high-performance liquid chromatography/electrospray ionization-mass spectrometry (LC/MS), the phospholipid contents in the postmortem hippocampus from 35 individuals with schizophrenia, 34 individuals with bipolar disorder and 35 controls were evaluated. Unlike the previous findings form orbitofrontal cortex, we found no significant differences in either n-3 long-chain PUFA or total phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC). However, docosapentaenoic acid (n-6, 22:5n-6)-PS and 22:5n-6-PC were significantly lower in individuals with schizophrenia or bipolar disorder than the controls. When fatty acid contents were estimated from PS, PE and PC, 22:5n-6 was significantly lower in both patient groups compared to the controls. From these results we concluded that DHA loss associated with these psychiatric disorders may be specific to certain regions of the brain. The selective decrease in 22:5n-6 without affecting DHA contents suggests altered lipid metabolism, particularly n-6 PUFA rather than n-3 PUFA, in the hippocampus of individuals with schizophrenia or bipolar disorder.     

Fatty acid composition in the postmortem amygdala of patients with schizophrenia, bipolar disorder, and major depressive disorder

Previous studies with postmortem brain tissues showed abnormalities in n-3 polyunsaturated fatty acids (PUFAs) in the orbitofrontal cortex of individuals with schizophrenia and mood disorders. However, in the hippocampus, we were not able to find any significant differences in PUFAs except for small differences in n-6 PUFAs. In the present study we investigated levels of PUFAs in the amygdala of postmortem brains from patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD) compared with those of unaffected controls. Amygdala samples from patients with schizophrenia (n = 15), bipolar disorder (n = 15), or MDD (n = 15), and controls matched for age, sex, and five other confounding factors (n = 15) were analyzed for fatty acid composition by gas chromatography. In contrast to previous studies of the orbitofrontal cortex and hippocampus, we were unable to find any significant differences in major PUFAs. The relative compositions of docosahexaenoic acid (DHA), the major n-3 PUFA, were 10.0 ± 1.1%, 10.0 ± 1.3%, 9.3 ± 1.3%, and 9.7 ± 1.1%, respectively, in patients with schizophrenia, bipolar disorder, and MDD and unaffected controls (not significantly different). The corresponding relative compositions of arachidonic acid (AA), the major n-6 PUFA, were 9.0 ± 0.8%, 9.2 ± 0.5%, 9.4 ± 0.7%, and 9.4 ± 0.7%, respectively (not significantly different). Significant differences were found in some of the other fatty acids. In particular, we found a 6.5% increase in palmitic acid and 6.2% decrease in oleic acid in patients with MDD compared to controls. With regard to schizophrenia, there was an 8.0% decrease in docosatetraenoic acid compared to controls. In conclusion, the changes in DHA and/or AA seen in orbitofrontal cortex and hippocampus were not observed in amygdala. These changes may be specific to particular brain regions.     

Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain

Polyunsaturated fatty acids (PUFA), which comprise 25-30% of the fatty acids in the human brain, are necessary for normal brain development and function. PUFA cannot be synthesized de novo and must be supplied to the brain by the plasma. It is necessary to know the PUFA content and composition of the various plasma lipids and lipoproteins in order to understand how these fatty acids are taken up and metabolized by the brain. Human plasma free fatty acid (FFA) ordinarily contains about 15% linoleic acid (18:2n-6) and 1% arachidonic acid (AA) (20:4n-6). Plasma triglycerides, phospholipids, and cholesterol esters also are rich in linoleic acid, and the phospholipids and cholesterol esters contain about 10% AA. These findings suggest that the brain probably can obtain an adequate supply of n-6 PUFA from either the plasma FFA or lipoproteins. By contrast, the plasma ordinarily contains only one-tenth as much n-3 PUFA, and the amounts range from 1% alpha-linolenic acid (18:3n-3) in the plasma FFA to 2% docosahexaenoic acid (22:6n-3, DHA) in the plasma phospholipids. The main n-3 PUFA in the brain is DHA. Therefore, if the plasma FFA is the primary source of fatty acid for the brain, much of the DHA must be synthesized in the brain from n-3 PUFA precursors. Alternatively, if the brain requires large amounts of preformed DHA, the phospholipids contained in plasma lipoproteins are the most likely source.     

Plasma levels of n-3 fatty acids in bipolar patients: Deficit restricted to DHA

Epidemiological studies suggest that n-3 polyunsaturated fatty acid (n-3 FA) deficiency is a risk factor for bipolar disorders (BDs). The aim of this study was to determine whether such a deficit does exist in patients with BD and to characterize the overall plasma fatty acid (FA) profile in these patients. Using gas chromatography/mass spectrometry, we measured fasting plasma levels of 15 FAs in 42 patients diagnosed with BD according to DSM-IV criteria and in 57 age- and gender-matched healthy controls. Plasma docosahexaenoic acid (DHA) levels were significantly decreased in bipolar patients (p < 0.001 versus healthy controls). Compared with controls, patients had higher plasma levels of all other FAs, including arachidonic acid (AA, p < 0.001), alpha-linolenic acid (ALA, p < 0.001), and eicosapentaenoic acid (EPA) (p < 0.001). Although in the present study we observed significant DHA deficits in the plasma of bipolar patients our findings do not support the therapeutic use of ALA and/or EPA supplementation. DHA may provide a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle. Finally, measurement of FA levels in plasma seems to be more reliable and reproducible than assays of erythrocyte FA content.     

Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: Relationship with liver delta6-desaturase expression

Polyunsaturated fatty acids (PUFA), a lipid family comprised of omega-3 (n-3) and n-6 fatty acids, are a critical component of cellular membranes, and recent in vitro studies have found that antipsychotic medications up-regulate genes responsible for PUFA biosynthesis. To evaluate this effect in vivo, rats were treated with risperidone (1.5, 3, 6mg/kg/day), paliperidone (1.5, 3, 6mg/kg/day), olanzapine (2.5, 5, 10mg/kg/day), quetiapine (5, 10, 20mg/kg/day), haloperidol (1, 3mg/kg/day) or vehicle through their drinking water for 40day. Effects on liver Fads1, Fads2, Elovl2, and Elovl5 mRNA expression, plasma indices of n-3 (plasma 22:6/18:3 and 20:5/18:3 ratios) and n-6 (plasma 20:4/18:2 and 20:3/18:2 ratios) biosynthesis, and peripheral (erythrocyte, heart) and central (frontal cortex) membrane PUFA composition were determined. Only risperidone and its metabolite paliperidone significantly and selectively up-regulated liver delta-6 desaturase (Fads2) mRNA expression, and robustly increased plasma indices of n-3 and n-6 fatty acid biosynthesis. In risperidone- and paliperidone-treated rats, plasma indices of n-3 and n-6 fatty acid biosynthesis were all positively correlated with liver Fads2 mRNA expression, but not Fads1, Elovl2, or Elovl5 mRNA expression. All antipsychotics at specific doses increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3) composition, and all except quetiapine increased arachidonic acid (AA, 20:4n-6) composition. Risperidone, paliperidone, and olanzapine increased heart DHA and AA composition, and no antipsychotic altered frontal cortex DHA or AA composition. These in vivo data demonstrate that augmentation of PUFA biosynthesis is not common to all antipsychotic medications, and that risperidone and paliperidone uniquely increase delta-6 desaturase (Fads2) mRNA expression and most robustly increase PUFA biosynthesis and peripheral membrane composition.