Mechanism of Action The mechanism of action of anti-manic drugs is poorly

Mechanism of Action The mechanism of action of anti-manic drugs is poorly

understood. Whereas alterations in monoamine systems are generally believed to be critical for antidepressant response, it is not clear which neurotransmitter systems are involved in the mood stabilization. Indeed, few significant changes in neuro- transmitter levels have been measured following treatment with mood stabilizers. Rather, a range of clinical and preclin- ical studies strongly suggests that the critical site of action for many mood stabilizers occurs at the level of intracellular second-messenger systems.

LITHIUM Lithium is a monovalent cation and appears to exert its clinical effect by directly interacting with intracellular targets. At ther- apeutic serum concentrations, lithium is a direct competitor of magnesium at several important regulatory enzymes, including inositol-monophosphatase (IMPase), which catalyzes the rate limiting step in the phosphoinositol signaling cascade. According to the inositol depletion hypothesis, inhibition of IMPase by lithium reduces myoinositol and phosphoinositide phosphate (PIP-2), thereby reducing G protein mediated signaling, intracellular calcium mobilization and protein kinase

86 HANDBOOK OF PSYCHIATRIC DRUGS

C (PKC) activation. Ultimately, these cascades produce wide- ranging effects on gene transcription, ion channel function and even neuronal structure and synaptic function. It has been postulated that lithium shifts the level of activation in these complex and integrated second messenger systems, providing neurons (and the circuits in which they act) with greater stability and resilience. Magnetic resonance spec- troscopy studies have recently demonstrated that five days of lithium treatment significantly reduces frontal cortex myoinos- itol levels. In support of this system being therapeutically relevant, two PKC inhibitors, tamoxifen and riluzole, have been shown to be effective in treating bipolar mania and depression, respectively. Another enzyme directly inhibited by lithium is glycogen synthase kinase-3 (GSK-3), which has been implicated in a wide range of normal and pathological processes. GSK-3 influences transcription factors and regula- tors of cellular metabolism, impacting upon neuronal resilience and survival. Specific GSK-3 inhibitors are being actively studied for potential therapeutic use in Alzheimer’s disease, diabetes and other disorders.

ANTICONVULSANTS The mechanisms by which some of the anticonvulsants stabi- lize mood are unknown. Valproate acts at sodium channels, at several important steps in GABA metabolism, and on the activity of histone deacetylase (which influences gene transcription). It has also be shown in preclinical studies to produce changes in the phosphoinositol pathway similar to those caused by lithium, including a reduction of PKC activity at clinically relevant serum levels.

Carbamazepine exerts a range of effects on neurotransmitter systems, increasing acetylcholine in the striatum, and decreasing dopamine and GABA turnover, and norepinephrine release. It is not clear which, if any, of these effects are relevant to its therapeutic benefit for bipolar disorder. There has been less study of carbamazepine’s effect on second messenger systems, but it appears to reduce phosphoinositol signaling and the activities of adenylate cyclase and guanylate cyclase.

The anticonvulsant activity of lamotrigine is hypothesized to result from blockade of voltage-sensitive sodium channels,

MOOD STABILIZERS 87 which inhibits the release of the presynaptic excitatory

amino acids aspartate and glutamate. Lamotrigine also blocks high-voltage activated N- and P-type calcium channels and inhibits serotonin reuptake. To date, the influence of lamot- rigine on intracellular signaling cascades is unknown.

ANTIPSYCHOTICS The pharmacology of antipsychotic drugs is described in Chapter 1. Their mechanism of action in the treatment of bipolar disorder is uncertain but may involve the same effects on serotonin and dopamine systems that are believed to underlie the effectiveness of these medications for schizophrenia. Atypical antipsychotics are preferred to older agents due to a reduced risk of tardive dyskinesia, a generally more benign side effect profile, and evidence of some efficacy in the treatment of bipolar depression.