Bipolar disorder and mechanisms of action of mood stabilizers

Abstract

Bipolar disorder (BD) is a major medical and social burden, whose cause, pathophysiology and treatment are not agreed on. It is characterized by recurrent periods of mania and depression (Bipolar I) or of hypomania and depression (Bipolar II). Its inheritance is polygenic, with evidence of a neurotransmission imbalance and disease progression. Patients often take multiple agents concurrently, with incomplete therapeutic success, particularly with regard to depression. Suicide is common. Of the hypotheses regarding the action of mood stabilizers in BD, the "arachidonic acid (AA) cascade" hypothesis is presented in detail in this review. It is based on evidence that chronic administration of lithium, carbamazepine, sodium valproate, or lamotrigine to rats downregulated AA turnover in brain phospholipids, formation of prostaglandin E(2), and/or expression of AA cascade enzymes, including cytosolic phospholipase A(2), cyclooxygenase-2 and/or acyl-CoA synthetase. The changes were selective for AA, since brain docosahexaenoic or palmitic acid metabolism, when measured, was unaffected, and topiramate, ineffective in BD, did not modify the rat brain AA cascade. Downregulation of the cascade by the mood stabilizers corresponded to inhibition of AA neurotransmission via dopaminergic D(2)-like and glutamatergic NMDA receptors. Unlike the mood stabilizers, antidepressants that increase switching of bipolar depression to mania upregulated the rat brain AA cascade. These observations suggest that the brain AA cascade is a common target of mood stabilizers, and that bipolar symptoms, particularly mania, are associated with an upregulated cascade and excess AA signaling via D(2)-like and NMDA receptors. This review presents ways to test these suggestions.

Figure 1. Prevalence ratio of bipolar disorder increases with risk allele burden

A combination of more than any 15 of risk alleles significantly increases the risk for BD above the risk (1.0) in the general population, whereas a combination of any 19 increases the risk 3.8 fold. From (Baum et al., 2008).

Figure 2

Chemical structures of FDA-approved mood stabilizers

Figure 3. Model of brain arachidonic acid cascade initiated at synapse

AA is liberated from the stereospecifically numbered (sn)-2 position of a phospholipid by activation (star) of phospholipase A₂ (PLA₂). A fraction is converted to bioactive eicosanoid, while the remainder diffuses to the endoplasmic reticulum bound to a fatty acid binding protein (FABP). There, it is converted to arachidonoyl-CoA by acyl-CoA synthetase with the consumption of 2 ATPs, then re-esterified into an available lysophospholipid by acyltransferase, or β-oxidized in mitochondria. AA in the endoplasmic reticulum exchanges freely with unesterified unbound AA in plasma, into which labeled AA (AA*) has been infused. Other metabolic pathways are not shown. J_in, the rate of incorporation of unesterified unlabeled AA into brain, equals the net rate of loss by metabolism, since AA cannot be synthesized de novo in brain. Adapted from (Rapoport and Bosetti, 2002).

Figure 4. Mood stabilizers downregulate the rat brain arachidonic acid cascade during neurotransmission at different levels

The first level is at the neuroreceptor itself, the second its coupling mechanism with cPLA₂. cPLA₂ also can be transcriptionally downregulated by drug action on its transcription factor, AP-2 (lithium and carbamazepine), whereas reincorporation of AA can be slowed by drug inhibition of an AA-selective acyl-CoA synthetase (valproate). These effects are correlated with reduced turnover of AA in membrane phospholipids. Drugs also can inhibit formation of PGE₂ and/or TXB₂ by downregulating activity and/or transcription of COX-2 (and expression of NF-κB) and COX-1 respectively. See Text and Table 4 for detailed effects. Adapted from (Rao et al., 2008).

Figure 5. MK-801 and chronic lithium block NMDA stimulation of arachidonic acid signal in rat brain

AA incorporation coefficients k* in autoradiographs of coronal brain sections. Two left columns: rats on a control diet, that had been injected i.p. with saline or 50 mg/kg NMDA. Two central columns: rats on a control diet injected with MK-801 or NMDA following MK-801; Two right columns: rats on a LiCl diet injected with saline or NMDA. NMDA increased k* in rats on the control diet, but not in rats pretreated with MK-801 or in rats fed the LiCl diet. Fr 8 and 10, frontal cortex 8 and 10; Mot, Som, motor and somatosensory cortex; Acg, anterior cingulate cortex; CPu, caudate putamen; Hipp, hippocampus. From (Basselin et al., 2006a).

Figure 6. Coronal autoradiographs of brain showing effects of 5-HTT genotype on regional arachidonic acid incorporation coefficients k* in mice

Acg, anterior cingulate cortex; Aud, auditory cortex; CPu, caudate-putamen; Hipp, hippocampus; IPC, interpeduncular nucleus; Mot, motor cortex; SN, substantia nigra; Thal, thalamus; Vis, visual cortex. Adapted from (Basselin et al., 2009).