Anticonvulsants as mood stabilizers

Post RM, Ketter TA, Pazzaglia PJ, et al New developments in the use of anticonvulsants as mood stabilizers. Neuropsychobiology 27 132-137, 1993c... 

In the Expert Consensus survey (Rush and Frances, 2000), the respondents identified newer atypical anti-psychotics and anticonvulsants or mood stabilizers as first-line treatments for self-injury. Antidepressants, naltrexone, and conventional antipsychotics were given ratings at least midway or higher on the scale provided. 

Lithium, several (but not all) anticonvulsants, and most of the atypical antipsychotic medications are approved by the U.S. Food and Drug Administration (FDA) for the treatment of one of more phases of bipolar disorder. These medications are referred to as mood stabilizers, and they are the foundation of treatment for bipolar disorders. However, the skillful treatment of bipolar disorder requires not only the knowledge of how to prescribe one or more of these medications but also the understanding that some medications are preferred for one phase of the illness but not the other or for long-term use but not necessarily acute use. In this chapter, we first review the clinical use of lithium and the anticonvulsants that are definite or probable mood stabilizers. The general properties of atypical anti-psychotics are reviewed in Chapter 4. In this chapter, we expand on the use of these compounds for the treatment of bipolar disorder. Discussion of the treatment of each phase of bipolar disorder concludes the chapter. 

For example carbamazepine is both a substrate and an inducer of 3A4. Thus as treatment becomes chronic, 3A4 is induced and carbamazepine blood levels fall (Fig. 6—19)- Failure to recognize this effect and to increase carbamazepine dosage to compensate for it may lead to a failure of anticonvulsant or mood-stabilizing efficacy, with breakthrough symptoms. 

Drugs can not only be substrates for a cytochrome P450 enzyme or an inhibitor of a P450 enzyme, they can also be inducers of a cytochrome P450 enzyme and thereby increase the activity of that enzyme. This was discussed in Chapter 6 for CYP450 3A4, and the induction of 3A4 activity by the anticonvulsant and mood stabilizer carbamazepine was given as an example (Fig. 6—19). Since mood stabilizers may be frequently mixed with atypical antipsychotics, it is possible that carbamazepine may be added to the regimen of a patient previously stabilized on clozapine, quetiapine, ziprasidone, or sertindole. If so, the doses of these atypical antipsychotics may need to be increased over time to compensate for the induction of 3A4 by carbamazepine. 

To review the mechanism of action of lithium and five anticonvulsants used as mood stabilizers (valproic acid, carbamazepine, lamotrigine, gabapentin and topiramate). 

Tegretol (carbamazepine) A common medication referred to as a mood stabilizer. This anticonvulsant medication is used as mood stabilizer for the following reasons (a) inadequate response or intolerance to antipsy-chotics or lithium (b) manic symptoms (c) rapid cycling of the condition ... 

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

Lithium was the first established mood stabilizer and is still considered a first-line agent for acute mania and maintenance treatment of both bipolar I and II disorders. It is the only bipolar medication approved for adults and children 12 years and older. Long-term use of lithium reduces suicide risk. Patients with rapid cycling or mixed states may not respond as well to lithium monotherapy as to some anticonvulsants. 

TDM has improved the performance of anticancer, antidementia, antidepressant, antiepileptic, anticonvulsant, antifungal, antimicrobial, antipsychotic, antiretroviral, anxiolytic, hypnotic, cardiac, addiction treatment, immunosuppressant, and mood stabilizer drags for more than 30 years.2-9 Many analytical procedures evolved as analytical techniques and instrumentation have advanced. This chapter briefly reviews the different types of analytical methods the applications of high-throughput techniques in TDM are discussed in detail. 

Lithium remains the treatment of choice for bipolar patients who experience classic euphoric episodes of mania. Current evidence suggests that those with mixed episodes or rapid cycling episodes respond preferably to anticonvulsants or atypical antipsychotic drugs. In addition to its use as a mood stabilizer, lithium is effective in converting unipolar antidepressant nonresponders to responders. Finally, lithium may also be an effective treatment for patients with clnster headaches. 

Alternate treatments. Mood-stabilization and control of manic or hy-pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively. 

These data suggest that there is more available information for use of lithium than for other mood stabilizers, and that adolescents hospitalized with adolescent-onset, acute mania have rates of response between 50% and 80%. Supplementation with sedating medication appears to be common but not systematically evaluated. Children hospitalized with mania also respond to lithium, but their comorbid disorders often need separate attention. Open trials with DVP in hospitalized adolescents are also supported. There is much less information on CBZ and there are no data on newer anticonvulsants such as lamotrigine, topiramate, or gabapentin. These data are largely consistent with data from studies of hospitalized adults with classic mania. 

Virtually all anticonvulsants are or have been of interest for the treatment of bipolar disorder. However, the importance of controlled data cannot be understated. For example, gabapentin, an anticonvulsant that initially received much attention as a potential mood stabilizer, was compared with placebo and did not appear to stabilize mood (Frye et al. 2000 Pande et al. 2000). Similar negative results were seen with topiramate in placebo-controlled trials for the treatment of mania. Although these medications might be useful adjuncts in some patients, given the currently expanded pharmacopoeia of medications with positive controlled trial data in bipolar disorder, we do not recommend the primary use of agents that have only case reports as an evidence base or controlled studies with predominantly negative results. 

Anticonvulsants, such as lamotrigine, valproate, or CBZ, with or without other mood stabilizers... 

Lithium Versus Anticonvulsants. A number of trials have also compared lithium to various anticonvulsant mood stabilizers such as VPA and CBZ ( 83, 99, 100). The results will be discussed in more detail in the sections on these specific agents. In general, lithium has been found to be comparable, but some data support better efficacy for agents such as VPA and CBZ in certain subgroups (e.g., mixed states, rapid cyclers). It is not clear, however, whether these agents have the same antisuicidal effects as lithium. 

Typical doses of clonazepam have been in the range of 2 to 16 mg/day given on a once or twice per day schedule due to its longer half-life. A major advantage of this anticonvulsant is its relative lack of adverse effects and freedom from laboratory monitoring in comparison with CBZ and VPA. Clonazepam may be more useful when combined with lithium or CBZ rather than as a specific antimanic agent, perhaps supplanting the need for antipsychotics. In this sense, it can be viewed as a behavioral suppressor, rather than a true mood stabilizer (121). 

Because lithium has long been the standard treatment for bipolar disorder, it is often the drug of first choice. Increasingly, however, VPA has emerged as a viable alternate first-line therapy. CBZ, marketed as an anticonvulsant, has also been studied and used for its mood-stabilizing properties. There has never been a definitive controlled study, however, comparing the efficacy of lithium with other mood stabilizers in difficult-to-treat manic patients. 

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