MOOD STABILIZERS USED FOR BIPOLAR DISORDER TARGET BRAIN ARACHIDONIC ACID CASCADE One approach to understanding and treating bipolar disorder (BD) may be to identify a common mechanism of action of the FDA-approved mood stabilizers used in its treatment. In two critical reviews, we proposed that the common mechanism is downregulation of the brain """"""""arachidonic acid (AA) cascade."""""""" Thus, chronic administration to rats of lithium, carbamazepine, valproate, and lamotrigine downregulate AA turnover in brain phospholipids, prostaglandin E formation, and expression of AA cascade enzymes, including cytosolic phospholipase A2, cyclooxygenase-2 and acyl-CoA synthetase. The changes are selective for AA, as docosahexaenoic or palmitic acid metabolism is unaffected. Antidepressants that increased switching of bipolar depression to mania upregulated the rat brain AA cascade, consistent with the hypothesis. The conclusions are supported by our postmortem studies on the BD brain (Rapoport et al., 2009;Rao et al 2009). MANIA CAUSED BY CERTAIN ANTIDEPRESSANTS IN BIPOLAR DEPRESSED PATIENTS MAY BE RELATED TO INCREASED BRAIN ARACHIDONIC ACID METABOLISM Some antidepressants (e.g. fluoxetine, imipramine) when given to depressed bipolar disorder (BD) patients increase frequency of switching to mania, whereas others (e.g. bupropion) do not. Consistent with our hypothesis that BD, particularly the manic phase, is associated with upregulated brain AA metabolism, we showed in rats that chronic (but not acute) fluoxetine or imipramine increased brain AA metabolic markers, but bupropion did not (Lee et al. 2010). CHRONIC LITHIUM DAMPENS NEUROINFLAMMATION BY MODIFYING BRAIN ARACHIDONIC AND DOCOSAHEXAENOIC ACID METABOLISM Neuroinflammation characterizes many progressive human brain brain diseases, including Alzheimer disease, bipolar disorder and HIV-1 dementia that we are studying. Neuroinflammation involves activation of brain microglia, cytokine and nitric oxide release by them, and upregulation of brain arachidonic acid (AA) metabolism and metabolic enzymes. We reported that administration of lithium to rats in which neuroinflammation was induced by 6 days of brain infusion of bacterial lipopolysaccharide (LPS) suppressed the upregulated LPS-induced expression of AA metabolizing enzymes, AA metabolism, and synthesis of the pro-inflammatory AA metabolite, prostaglandin E2. Lithium also induced formation of 17-hydroxy docosahexaenoic acid (17-OH-DHA), a precursor of antiinflammatory neuroprotectins. 17-OH-DHA also can be formed after aspirin acetylates cyclooxygenase-2. Thus, an antiinflammatory synergy between lithium and aspirin is likely, and this is supported by our clinical epidemiological data (see below). Lithium's antiinflammatory action may account for its efficacy against bipolar disorder, and suggests that it would be of use in other neuroinflammatory diseases, such as Alzheimer disease and HIV-1 dementia (Basselin et al 2010). ASPIRIN ENHANCES LITHIUM EFFICACY IN BIPOLAR DISORDER: AN EPIDEMIOLOGICAL STUDY Using a pharmacological database, we confirmed our hypothesis that aspirin (see above) would enhance the bipolar effects of lithium, which was based on their common effects on suppressing brain arachidonic acid (AA) metabolism and increasing docosahexaenoic acid metabolism in rats. We used a pharmacological database with a pharmacoepidemiological analysis to show that low dose aspirin significantly reduced the number of medical events (dose increase or addition of antipsychotic agent) in patients treated with lithium, whereas other nonsteroidal antiinflammatory drugs and glucocorticoids did not. These findings support our proposal of upregulated brain AA metabolism in bipolar disorder, and suggest that lithium plus aspirin might be considered for this disease as will neuroinflammatory human brain diseases such as Alzheimer disease (Stolk et al. 2010).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
Zip Code
Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika et al. (2016) Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment. J Psychiatr Res 76:59-65
Blanchard, Helene C; Taha, Ameer Y; Rapoport, Stanley I et al. (2015) Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fatty Acids 96:25-30
Blanchard, Helene; Chang, Lisa; Rezvani, Amir H et al. (2015) Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression. Neurochem Res 40:2293-303
Yuan, Zhi-Xin; Rapoport, Stanley I (2015) Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice. Prostaglandins Leukot Essent Fatty Acids 101:9-14
Rapoport, Stanley I (2014) Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem Neurosci 5:459-67
Modi, Hiren R; Basselin, Mireille; Rapoport, Stanley I (2014) Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4. Bipolar Disord 16:875-80
Ramadan, Epolia; Blanchard, Helene; Cheon, Yewon et al. (2014) Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice. Prostaglandins Leukot Essent Fatty Acids 90:191-7
Modi, Hiren R; Taha, Ameer Y; Kim, Hyung-Wook et al. (2013) Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability. J Neurochem 124:376-87
Modi, Hiren R; Basselin, Mireille; Taha, Ameer Y et al. (2013) Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder. Biochim Biophys Acta 1831:880-6
Kim, Hyung-Wook; Cheon, Yewon; Modi, Hiren R et al. (2012) Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain. Psychopharmacology (Berl) 222:663-74

Showing the most recent 10 out of 25 publications