Bottomline: An antidepressant medication known to trigger mania in bipolar patients is found to increase arachidonic acid metabolism in the brain, which has been linked to mania. Mol Psychiatry. 2008 Nov 4. [Epub ahead of print]

Background: Many antidepressants, particularly tricyclic antidepressants and serotonin selective reuptake inhibitors (SSRI’s), are known to induce episodes of mania or increase cycle frequency or symptom intensity in bipolar patients. Since mania mood stabilizers have been shown to decrease the arachidonic acid cascade, the NIH research team theorized that mania-triggering antidepressants might induce the mood switch via up regulating omega-6 metabolism in the brain.

Summary: Researchers compared the impact of administering imipramine versus bupropion on biomarkers of arachidonic acid metabolism in the brain, because imipramine but not bupropion, increases mania switching in bipolar patients.  As predicted, imipramine caused an increase of arachidonic metabolism and biomarkers, including an increase of the enzyme (phospholipase-A2  or phospho-cPLA2), which is a key enzyme that releases arachidonic acid from the cell membrane, as shown in the figure below:

Study Quote: "The results of this study taken with published data on fluoxetine treatment, suggest that antidepressant
agents that increase switching of bipolar depressed patients to a manic state do so by increasing arachidonic acid metabolism in the brain."

Comment: This study adds to a growing body of evidence implicating excess arachidonic acid in the brain as part of the pathology in neuropsychiatric disorders, including Alzheimer's disease.   For example, many of the mania medications (lithium, valproate and carbamazepine) work by lowering arachidonic acid in the brain (Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):239-46); and valproate was shown to heal brain cells and improve memory in an animal model of Alzheimer's disease (See Bipolar Drug Improves Alzheimer's Disease Symptoms).

Recently, arachidonic acid gone awry, was demonstrated in the first human brain imaging study in patients with Alzheimer's disease (See Brain Image Study Shows Increased Arachidonic Acid in Alzheimer's Patients ).  And
higher levels of this omega-6 fat are associated with increased severity of symptoms in bipolar patients (See Arachidonic Acid-The Omega-6 Fat Connection to Bipolar Mood Disorder ).

Link to Study:

Lee HJ, Rao JS, Chang L, Rapoport SI, Kim HW.
Chronic imipramine but not bupropion increases arachidonic acid signaling in rat
brain: is this related to 'switching' in bipolar disorder? Mol Psychiatry. 2008 Nov 4. [Epub ahead of print]