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CHAPTER 29 Antipsychotic Agents & Lithium 525

mood stabilizers is not clearly understood. Lithium directly inhib- TABLE 29–6 Enzymes affected by lithium at
its two signal transduction pathways. It both suppresses inositol therapeutic concentrations.
signaling through depletion of intracellular inositol and inhibits
glycogen synthase kinase-3 (GSK-3), a multifunctional protein Enzyme Enzyme Function; Action of Lithium
kinase. GSK-3 is a component of diverse intracellular signaling Inositol The rate-limiting enzyme in inositol
pathways. These include signaling via insulin/insulin-like growth monophosphatase recycling; inhibited by lithium, resulting in
factor, brain-derived neurotrophic factor (BDNF), and the Wnt depletion of substrate for IP 3 production
pathway. Lithium-induced inhibition of GSK-3 results in reduc- (Figure 29–4)
tion of phosphorylation of β-catenin, which allows β-catenin Inositol polyphos- Another enzyme in inositol recycling;
to accumulate and translocate to the nucleus. There, β-catenin phate 1-phosphatase inhibited by lithium, resulting in depletion
of substrate for IP 3 production (Figure 29–4)
facilitates transcription of a variety of proteins. The pathways that
are facilitated by the accumulation of β-catenin via GSK-3 inhibi- Bisphosphate Involved in AMP production; inhibited
by lithium; may be target that results in
nucleotidase
tion modulate energy metabolism, provide neuroprotection, and lithium-induced nephrogenic diabetes
increase neuroplasticity. insipidus
Studies on the enzyme prolyl oligopeptidase and the sodium Fructose Involved in gluconeogenesis; inhibition by
myoinositol transporter support an inositol depletion mecha- 1,6-biphosphatase lithium of unknown relevance
nism for mood-stabilizer action. Valproic acid may indirectly Phosphoglucomutase Involved in glycogenolysis; inhibition by
reduce GSK-3 activity and can up-regulate gene expression lithium of unknown relevance
through inhibition of histone deacetylase. Valproic acid also Glycogen synthase Constitutively active enzyme that appears
inhibits inositol signaling through an inositol depletion mecha- kinase-3 to limit neurotrophic and neuroprotective
nism. There is no evidence of GSK-3 inhibition by carbamaze- processes; lithium inhibits
pine, a second antiepileptic mood stabilizer. In contrast, this AMP, adenosine monophosphate; IP 3 , inositol 1,4,5-trisphosphate.
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 Studies of noradrenergic effects in isolated brain tissue indicate
and their release. that lithium can inhibit norepinephrine-sensitive adenylyl cyclase.
Such an effect could relate to both its antidepressant and its anti-
A. Effects on Electrolytes and Ion Transport manic effects. The relationship of these effects to lithium’s actions
Lithium is closely related to sodium in its properties. It can on IP mechanisms is currently unknown.
3
substitute for sodium in generating action potentials and in Because lithium affects second-messenger systems involving
+
+
Na -Na exchange across the membrane. At therapeutic concentra- both activation of adenylyl cyclase and phosphoinositol turnover,
2+
+
tions (~1 mEq/L), it does not significantly affect the Na -Ca it is not surprising that G proteins are also found to be affected.
+
+
exchanger or the Na /K -ATPase pump. Several studies suggest that lithium may uncouple receptors from
their G proteins; indeed, two of lithium’s most common side
B. Effects on Second Messengers effects, polyuria and subclinical hypothyroidism, may be due to
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 inosi-
tol phosphates. Early studies of lithium demonstrated changes Receptor
in brain inositol phosphate levels, but the significance of these
changes was not appreciated until the second-messenger roles of PIP PIP 2 G
inositol-1,4,5-trisphosphate (IP ) and diacylglycerol (DAG) were PI PLC DAG
3
discovered. As described in Chapter 2, inositol trisphosphate Inositol
and diacylglycerol are important second messengers for both IP 3
α-adrenergic and muscarinic transmission. Lithium inhibits ino- IP 1 IP 2
sitol monophosphatase (IMPase) and other important enzymes in −
the normal recycling of membrane phosphoinositides, including − Effects
(inositol diphosphate) to IP (inositol mono-
conversion of IP 2 1 Lithium
phosphate) and the conversion of IP to inositol (Figure 29–4).
1
This block leads to a depletion of free inositol and ultimately FIGURE 29–4 Effect of lithium on the IP 3 (inositol trisphosphate)
of phosphatidylinositol-4,5-bisphosphate (PIP ), the membrane and DAG (diacylglycerol) second-messenger system. The schematic
2
precursor of IP and DAG. Over time, the effects of transmit- diagram shows the synaptic membrane of a neuron. (PI, inorganic
3
phosphate; PIP 2 , phosphatidylinositol-4,5-bisphosphate; PLC, phos-
ters on the cell diminish in proportion to the amount of activity pholipase C; G, coupling protein; Effects, activation of protein kinase
in the PIP -dependent pathways. The activity of these pathways C, mobilization of intracellular Ca , etc.) Lithium, by inhibiting the
2+
2
is postulated to be markedly increased during a manic episode. recycling of inositol substrates, may cause the depletion of the
Treatment with lithium would be expected to diminish activity second-messenger source PIP 2 and therefore reduce the release of IP 3
in these circuits. and DAG. Lithium may also act by other mechanisms (see text).