This Review evaluates the
arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of
lithium and other FDA-approved mood stabilizers in
bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered
lithium,
carbamazepine,
valproate, or
lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain
phospholipids,
cyclooxygenase-2 expression, and
prostaglandin E2 concentration.
Lithium and
carbamazepine also reduced expression of cytosolic
phospholipase A2 (cPLA2) IVA, which releases AA from membrane
phospholipids, whereas
valproate uncompetitively inhibited in vitro
acyl-CoA synthetase-4, which recycles AA into
phospholipid.
Topiramate and
gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical
antipsychotics olanzapine and
clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic
NMDA and dopaminergic D2 receptor activation, while
lithium enhanced the signal during
cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the
antidepressants fluoxetine and
imipramine, which tend to switch BD depression to
mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD
mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose
aspirin reduced morbidity in patients taking
lithium, and that high n-3 and/or low n-6
polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and
migraine patients.