Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder

Abstract

Previous antemortem and postmortem tissue fatty acid composition studies have observed significant deficits in the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) in red blood cell (RBC) and postmortem cortical membranes of patients with unipolar depression. In the present study, we determined the fatty acid composition of postmortem orbitofrontal cortex (OFC, Brodmann area 10) of patients with bipolar disorder (n=18) and age-matched normal controls (n=19) by gas chromatography. After correction for multiple comparisons, DHA (-24%), arachidonic acid (-14%), and stearic acid (C18:0) (-4.5%) compositions were significantly lower, and cis-vaccenic acid (18:1n-7) (+12.5%) composition significantly higher, in the OFC of bipolar patients relative to normal controls. Based on metabolite:precursor ratios, significant elevations in arachidonic acid, stearic acid, and palmitic acid conversion/metabolism were observed in the OFC of bipolar patients, and were inversely correlated with DHA composition. Deficits in OFC DHA and arachidonic acid composition, and elevations in arachidonic acid metabolism, were numerically (but not significantly) greater in drug-free bipolar patients relative to patients treated with mood-stabilizer or antipsychotic medications. OFC DHA and arachidonic acid deficits were greater in patients plus normal controls with high vs. low alcohol abuse severity. These results add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of bipolar disorder.

Figures

Figure 1

(A) Comparison of total saturated fatty acid compostion (ΣSFA), total polyunsaturated fatty acid composition (ΣPUFA), and total monounsaturated fatty acid composition (ΣMUFA) in the OFC of normal controls and patients with bipolar disorder. (B) Comparison of principal fatty acid composition in the OFC of bipolar patients and age-matched normal controls. After correction for multiple comparisons, stearic acid (C18:0), arachidonic acid (20:4n-6), and DHA (22:6n-3) composition are significantly lower, and cis-vaccenic acid (18:1n-7) composition significantly higher, in the OFC of bipolar patients relative to normal controls (**P≤0.0056 vs. normal controls). (C) OFC fatty acid composition in normal controls (n=19), bipolar patients that committed suicide (n=11), and bipolar patients that did not die from suicide (n=7). Note that DHA (22:6n-3) is the only fatty acid that is lower in the OFC of BP patients relative to normal controls (-16%, p=0.03 vs. normal controls). (D) OFC fatty acid composition in normal controls (n=19), bipolar patients with (n=12) and without (n=6) a history of psychosis. Note that alterations in fatty acid composition are greater in bipolar patients with a history of psychosis than BP patients without a history of psychosis. In (A), (C) and (D), *P≤0.05, **P≤0.01, ***P≤0.001 vs. normal controls. Data are expressed as mean fatty acid composition (μg fatty acid/100 μg fatty acids) ± S.E.M.

Figure 2

Correlations between OFC DHA (22:6n-3) composition (wt % total fatty acids) and the adrenic acid:arachidonic acid ratio (A), the DPA:adrenic acid ratio (B), the oleic acid (OA, 18:1n-9):stearic acid (SA) ratio (C), the palmitioleic acid (PLM, 16:1n-7):palmitic acid (PA) ratio (D), and the cis-vaccenic acid (VA):palmitic acid (PA) ratio (E) among normal controls (open circles) and bipolar patients (closed circles)(N=37). Associated Pearson correlation coefficients and p-values (2-tail) are presented.

Figure 3

Comparison of OFC DHA composition (A), arachidonic acid composition (B), the adrenic acid composition (C), the adrenic acid:arachidonic acid ratio (D), docosapentaenoic acid (DPA, 22:5n-6) composition (E), the DPA:adrenic acid ratio in normal controls (n=19), drug-free bipolar patients (DF, n=3), and bipolar patients treated with lithium (Li, n=6), valproic acid (VPA, n=6), or antipsychotics (AP, n=10) at time of death. Note that the deficits in DHA, arachidonic acid, DPA, and the DPA:adrenic acid ratio, and elevations in adrenic acid:arachidonic acid ratio, are numerically (but not significantly) greater in drug-free bipolar patients relative to bipolar patients treated with lithium, valproic acid, or antipsychotic medications. Data are expressed as mean ± S.E.M. wt % of total fatty acids. Effect size is expressed as mean percent difference from normal controls and associated p-values (unpaired t-test, two-tail).

Figure 4

(A) Comparison of OFC docosahexaenoic acid (DHA) and arachidonic acid (AA) composition (wt % total fatty acids) in combined normals+bipolar patients with low alcohol abuse severity (n=14) and normals+bipolar with high alcohol abuse severity (n=7). Note that OFC DHA and arachidonic acid composition are significantly lower in normals+bipolar with high versus low alcohol abuse severity. (B) Comparison of OFC docosahexaenoic acid (DHA) and arachidonic acid (AA) composition in combined normals+bipolar patients with low substance abuse severity (n=14) and normals+bipolar with high substance abuse severity (n=7). Effect size is expressed as mean percent difference from normal controls and associated p-values (unpaired t-test, two-tail).