A series of candidate mechanisms for lithium's psychotropic (mood-stabilizing) actions have been suggested over the last 40 years:

• effects on enzymes and biosynthetic pathways (1950s)

• effects on presynaptic adrenergic release and reuptake mechanisms (1960s)

• effects on postsynaptic receptor modulation and impact on receptor supersensitivity (1970s)

• effects on adenylate cyclase and subsequently G-protein mediators of transduction systems (1980s)

• most recently, effects on phosphoinositol turnover, transcriptional regulation, and its downstream targets on neurotrophic and other factors regulating neuroprotection versus cell death (1990s).

Several of these candidate mechanisms are summarized in Fig 1 and Fig 2, and are compared with the mechanisms of some of the other mood-stabilizing anticonvulsants such as carbamazepine and valproate. Lithium's effects on G proteins (2.9 are conceptually intriguing in relation to lithium's ability to modulate overactive systems, and preliminary support for adenylate cyclase effects has been based on validating studies with adenylate cyclase inhibitors in acute mania. (2I> Similarly, recent studies implicating the ability of lithium and valproate to inhibit protein kinase C has been preliminarily validated with the demonstration of possible antimanic effects of the protein kinase C inhibitor tamoxifen. (22>

Fig. 1 Common and differential mechanism of mood stabilizers: PI, phosphoinositol; AC, adenylate cyclase; IMPase, inositol monophosphatase; PLC, phospholipase C; cAMP, cyclic adenosine monophosphate; NPY, neuropeptide Y; ACH, acetylcholine; Gas, G protein alpha (s) subunit; DA, dopaminergic; Ne, noradrenergic; PKC, protein kinase C; A1 R, adenosine A1 receptors; T4, thyroxine; Gap 43, growth-associated protein 43; CRE, cyclic response element; CBZ, carbamazepine; TRH, thyrotrophin-releasing hormone; CREB, cyclic response element binding protein; VPA, valproate; SRIF, somatostatin; t.o., turnover.

Fig. 2 Mechanisms of mood stablization. Depicted schematically at the top of the figure is a synapse with various types of channels, neurotransmitters, and proteins associated with the mechanisms of action of the mood stabilizers listed in the table below. Row headings: Li, lithium; CBZ, carbamazepine; VPA, valproate; LTG, lamotrigine; GPN, gabapentin; TPM, topiromate. Column headings: K+ efflux; Na+ influx; EAA, excitatory amino acids; GABA, g-aminobutyric acid; GABA t.o., GABA turnover; Tryp, tryptophan; 5-HT, serotonin; NMDA Ca2+; L-type Ca2+; G, G protein; cAMP, cyclic adenosine monophosphate; IPtase, inositol phosphatase; AP-1, activator protein 1; Sub P, substance P; SRIF, somatostatin. Arrows indicate increases or decreases in substance/activity.

Most recently, lithium has emerged as a possible neurotrophic and neuroprotective factor via inhibition of calcium influx through the M-methyl-D-aspartate receptor(23> and its ability to change the ratio of neurotrophic versus cell death factors, such as increasing Bcl-2 and brain-derived neurotrophic factor while decreasing the apoptotic factor BAX.(2 24) Much work remains to be done to implicate or rule out these changes in the psychotrophic actions of lithium. However, it is clear that lithium increases white blood cell count and platelets by increasing granulocyte-macrophage colony-stimulating factor. (25> This effect is sufficient to overcome the benign white count suppression of carbamazepine.(2 2 and 28

The potential clinical relevance of this finding is also evidenced by the data that pretreatment with lithium can decrease the size of a cerebral infarct following middle cerebral artery ligation and decrease the amount of neurological deficit. (29) Given the new findings of altered size of crucial structures involved in emotion regulation in the affective and post-traumatic stress disorders, including amygdala,(3,31.) and hippocampus/3 32> one can only wonder whether lithium's neuroprotective effects could alter some of these putative neuronal- or glial-based changes in central nervous system substance.

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