Anticonvulsant agents carbamazepine

Carbamazepine (CBZ) and divalproex sodium (DVP) are the most common anticonvulsant agents prescribed for adult BD (Bowden et ah, 1994) Post et ah, 1998b) and pediatric epileptic disorders (Trimble, 1990 Dunn et al., 1998). As a consequence of their documented efficacy in these populations, their use has been extended to pediatric behavioral and mood disorders (Biederman et ah, 1998). We review here their mechanisms of action, pharmacokinetics, side effects, and pediatric uses. The multiple cytochrome P450 (CYB)-mediated potential drug interactions of CBZ and DVP are not covered in detail in this chapter. For a comprehensive review of this subjects the reader is referred to a recent publication by Flockhart and Oesterheld (2000). 

Support is scant for the efficacy of anticonvulsant agents in the treatment of OCD (Jenike 1990 Joffe and Swinson 1987). If there is a role for carbamazepine in OCD, it may be in patients with clinical or electroen-cephalographic evidence of a seizure disorder (Jenike and Brotman 1984 Khanna 1988). The anti-OC efficacy of combined SRI-carbamazepine treatment has not been adequately studied. Sodium valproate was found ineffective in two cases of OCD (McElroy and Pope 1988 McElroy et al. 1987). However, one author has suggested that sodium valproate may be a useful pretreatment for patients with OCD who might otherwise tolerate SRIs poorly (Deltito 1994). The anticonvulsant clonazepam is discussed earlier in this chapter. 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

D. Anticonvulsants (carbamazepine and phenytoin) and theophylline may delay the onset and shorten the duration of action of some nondepolarizing agents. Carbamazepine has additive effects, and reduction of the neuromuscular blocker dose may be required. 

Pseudoallergic reactions resemble allergic reactions clinically but are not immunologically mediated. Examples include asthma and rashes caused by aspirin and maculopapular erythematous rashes due to ampicillin or amoxicillin in the absence of penicillin hypersensitivity. Few other entities that can initiate this reaction are sulfonamides, anticonvulsants (phenytoin, carbamazepine and phenobarbital), NSAIDs (aspirin, naproxen, nabumetone and keto-profen), antiretroviral agents and cephalosporins [1 ]. 

Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-... 

Well known for their clinical role as antimanic agents, anticonvulsants such as carbamazepine and valproate have also been used in both bipolar and unipolar TRD (Post et al. 1994a, 1994b). In one series. Post et al. (1994a) found a greater response in patients with bipolar (15/40) versus those with unipolar (2/17) TRD. Open studies of valproate also suggest limited antidepressant efficacy, but only a paucity of data with anticonvulsants on TRD exists. More recently, in open trials, lamotrigine (a partial anticonvulsant that inhibits glu-... 

Other agents with anticonvulsant properties that may be of use m the treatment of bipolar disorder include topiramate, gabapentin, tiagabine and carbamazepine (Janicak et al., 2001). 

Several controlled trials have shown that lithium is efficacious in the maintenance treatment of bipolar disorder, with higher serum levels (0.8 1 mol/1) being more indicative of successful prophylaxis (Keck and McElroy. 2002). Valproic acid also appears to have efficacy in maintenance therapy, specifically in bipolar patients with mixed mania and rapid cycling (Bowden et al., 1995). The results concerning carbamazepine s efficacy as a maintenance medication are controversial (Stuppaeck et al., 1994). Other potential agents with some evidence of good maintenance value include clozapine and olanzapine. A combination of lithium and carbamazepine or other anticonvulsants is recommended under certain conditions if an adequate preventive effect cannot be obtained with the substances individually (Bauer et al., 2002). 

Like adults, some adolescents do not respond to lithium, and clinicians often try an anticonvulsant, such as valproate or carbamazepine. The use of these agents is based primarily on their antimanic activity in adults because only a limited number of case reports about the treatment of bipolar adolescents with CBZ are available (207). There are 29 reports in the world literature, however, examining the efficacy of CBZ in the treatment of behavioral dyscontrol or high activity level in children. Of... 

For patients with bipolar affective disorder (manic-depressive illness) lithium, usually in the form of lithium carbonate, has been the main prophylactic agent for the last forty years. However, during the last ten years certain anticonvulsants (carbamazepine and sodium valproate) have also been found to be effective. 

FIGURE 11—51. The enzyme CYP450 3A4 can be induced by the anticonvulsant and mood stabilizer carbamazepine. If this agent is stopped in a patient who is receiving an atypical antipsychotic that is a substrate for this same enzyme (i.e., clozapine, quetiapine, ziprasidone, or sertindole), the doses of these antipsychotics may need to be reduced because the autoinduction of 3A4 by carbamazepine will reverse over time once it is discontinued. 

Carbamazepine is itself a second-line augmenting agent for numerous other anticonvulsants, lithium, and atypical antipsychotics in treating bipolar disorder... 

True hypersensitivity reactions to phenytoin are related to the "aromatic" anticonvulsants. Thus, in patients in whom a reaction is suspected, other arene anticonvulsants such as carbamazepine, oxcarbazepine, phenobarbital, or primidone should be avoided, as there is a high rate of cross-reactivity (estimated as high as 80%). Valproic acid is an agent that can be safely used as an alternative anticonvulsant in such patients. 

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