mood stabilizers is not clearly understood. Lithium directly inhibits two signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. GSK-3 is a component of diverse intracellular signaling pathways. These include signaling via insulin/insulin-like growth factor, brain-derived neurotrophic factor (BDNF), and the Wnt pathway. Lithium-induced inhibition of GSK-3 results in reduction of phosphorylation of β-catenin, which allows β-catenin to accumulate and translocate to the nucleus. There, β-catenin facilitates transcription of a variety of proteins. The pathways that are facilitated by the accumulation of β-catenin via GSK-3 inhibition modulate energy metabolism, provide neuroprotection, and increase neuroplasticity.
Studies on the enzyme prolyl oligopeptidase and the sodium myoinositol transporter support an inositol depletion mechanism for mood-stabilizer action. Valproic acid may indirectly reduce GSK-3 activity and can up-regulate gene expression through inhibition of histone deacetylase. Valproic acid also inhibits inositol signaling through an inositol depletion mechanism. There is no evidence of GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol depletion mechanism, as seen with lithium and valproic acid. The mood stabilizers may also have indirect effects on neurotransmitters and their release.
A. Effects on Electrolytes and Ion Transport
Lithium is closely related to sodium in its properties. It can substitute for sodium in generating action potentials and in Na+-Na+ exchange across the membrane. At therapeutic concentrations (~1 mEq/L), it does not significantly affect the Na+-Ca2+ exchanger or the Na+/K+-ATPase pump.
B. Effects on Second Messengers
Some of the enzymes affected by lithium are listed in Table 29–6. One of the best-defined effects of lithium is its action on inositol phosphates. Early studies of lithium demonstrated changes in brain inositol phosphate levels, but the significance of these changes was not appreciated until the second-messenger roles of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) were discovered. As described in Chapter 2, inositol trisphosphate and diacylglycerol are important second messengers for both α-adrenergic and muscarinic transmission. Lithium inhibits inositol monophosphatase (IMPase) and other important enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 (inositol diphosphate) to IP1 (inositol mono-phosphate) and the conversion of IP1 to inositol (Figure 29–4). This block leads to a depletion of free inositol and ultimately of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell diminish in proportion to the amount of activity in the PIP2-dependent pathways. The activity of these pathways is postulated to be markedly increased during a manic episode. Treatment with lithium would be expected to diminish activity in these circuits.
TABLE 29–6 Enzymes affected by lithium at therapeutic concentrations.
AMP, adenosine monophosphate; IP3, inositol 1,4,5-trisphosphate.