Following the discovery in 1949 of lithium's efficacy in BD (Cade, 1949
), divalproex and carbamazepine were approved by the FDA for bipolar mania, and lamotrigine was approved for delaying the appearance of the different mood states. Lithium and divalproex also are recommended for maintenance therapy. Atypical antipsychotics are especially useful for acute mania. One, quetiapine, is approved for bipolar depression and maintenance therapy adjunctive to lithium or divalproex, and aripiprazole and olanzapine are approved for maintenance monotherapy in Bipolar I. Depression is 3 times more common than mania in BD, but depression is generally inadequately treated. Some antidepressants if administered as monotherapy or with mood stabilizers increase “switching” to mania.
Multiple risk alleles, each with a small individual contribution, are consistent with a polygenic threshold inheritance of BD. To date, however, genetic findings have shown poor replication and have not consistently identified defective brain cascades as likely therapeutic targets. In contrast, a “top down” approach based on identifying a common mechanism of action of agents that have been shown in controlled clinical trials to work or not to work in BD has been more informative, and is the focus of this review. Two hypotheses that have been generated by this approach are the “myo-inositol depletion” and “GSK-3 targeting” hypotheses. While each might explain lithium's mechanism of action, neither convincingly accounts for the actions of the other mood stabilizers or, moreover, why some antidepressants enhance switching from bipolar depression to mania.
The “AA cascade hypothesis,” which is closely considered in this review, identifies a common target of the four approved mood stabilizers as the brain AA cascade, and tentatively explains why some antidepressants increase switching of bipolar depression to mania. This hypothesis was derived largely from studies in unanesthetized rats chronically administered FDA-approved mood stabilizers, as well as the clinically-proven ineffective topiramate for comparison. Lithium, carbamazepine and sodium valproate were shown to downregulate AA turnover in brain phospholipids, without changing DHA or palmitic acid turnover. Lamotrigine reduced AA incorporation coefficients k* in brain phospholipids. The effect on AA turnover of lithium and carbamazepine was ascribed to reduced expression of AA-selective cPLA2 and of its AP-2 transcription factor, whereas valproate's effect was ascribed to its inhibition of an AA-selective microsomal acyl-CoA synthetase. Each of the four agents depressed rat brain COX-2 expression and, when measured, the concentration of the COX-2 - derived AA metabolite, PGE2. Topiramate, which had been proposed as a mood stabilizer based on initial trials, but later failed Phase III trials, did not alter any brain AA cascade marker. Thus, the AA cascade hypothesis corresponds to proven clinical efficacy of the tested drugs.
The AA cascade hypothesis is consistent with evidence that BD symptoms arise from excessive dopaminergic and glutamatergic but reduced cholinergic signaling, provided that the signaling uses AA as a second messenger. Thus, imaging in unanesthetized rats showed that lithium upregulated muscarinic cholinergic M1,3,5
receptor signaling involving AA; lithium and carbamazepine blocked D2
-like receptor-initiated AA signaling; and lithium, valproate and carbamazepine each blocked NMDA receptor-initiated AA signaling (). The NMDA effects may explain much of the global effects of the mood stabilizers on the AA cascade, since most brain synapses are excitatory and glutamatergic (Attwell and Laughlin, 2001
; Raichle and Gusnard, 2002
More research is needed to examine disease progression and deterioration in BD, which only recently is being addressed. Progression may be a trait feature, but it also may be determined by factors such as diet, substance abuse, obesity, and bipolar disorder drugs. Postmortem studies indicate the presence of neuroinflammation, excitotoxicity and apoptosis in the BD brain, processes that can underlie progression (Kim et al., 2007a
; Kim et al., 2008
; Rao et al., In press
). Chronic administration of atypical antipsychotics has been shown to cause atrophy and astrocyte loss in monkey brain, and chronic lithium produced neuronal death in rat brain (Section 4.3.
). On the other hand, mood stabilizers and antipsychotics have been reported to be neuroprotective in animal models of neuroinflammation and excitotoxicity, in some cases by downregulating the brain AA cascade.
Observations that mood stabilizers selectivity downregulate the rat brain AA cascade at therapeutically relevant plasma concentrations, and that antidepressants that increase switching of bipolar depression to mania upregulate the cascade, suggest that an upregulated brain AA cascade contributes to BD symptoms, particularly bipolar mania. Cascade-suppressing drugs, as well as dietary n-3 PUFA supplementation (Section 11.)
might be used to test the relation between disturbed behavior and disturbed AA metabolism in animal models with disturbances of both behavior and AA metabolism (). Additionally, cascade parameters can be measured in such pathological models, as well as in the normal rat, to screen for new and potentially clinically relevant therapeutic agents for BD. Based on this review and prior suggestions (Chang et al., 1996
; Chang et al., 1999
; Rapoport and Bosetti, 2002
), one would predict efficacy in BD from NMDA transmission modifiers, inhibitors of cPLA2
or of COX-2 synthetase, such as non-steroidal anti-inflammatory agents including COX inhibitors and aspirin (which can acetylate COX-2 to form specific anti-inflammatory derivatives of AA and DHA) (Breitner, 2003
; Farooqui et al., 2006
; Ketterer et al., 1996
; Rapoport and Bosetti, 2002
; Serhan, 2006
; Stolk et al., Submitted for publication), other promoters of brain DHA conversion to resolvins and neuroprotectins (Basselin et al., Unpublished observations
; Serhan, 2006
) including dietary n-3 PUFA supplementation, and inhibitors of AA-selective acyl-CoA synthetase, including valproate-like compounds (Bazinet et al., 2006b
; Bialer and Yagen, 2007
). These predictions could be tested by direct clinical trials or by analyzing relevant databases (Stolk et al., Submitted for publication).
In addition, the presence of an upregulated brain AA cascade in BD patients could be tested for directly by imaging regional brain AA incorporation parameters (k
* and Jin
) during manic, euthymic and depressive phases of the disease, with the help of positron emission tomography. Increased AA incorporation associated with neuroinflammation has been measured in this way in patients with Alzheimer disease (Esposito et al., 2007
; Esposito et al., 2008
; Giovacchini et al., 2004