Other Anticonvulsants

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. 

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Succinimides. Ethosuximide [77-67-8] C2H22NO2 (41) and the related succinknide, methsuximide [77-41-8] C22H23NO2 (42) are used in absence seizure treatment. Like the other anticonvulsants discussed, the mechanism of action of the succinirnides is unclear. Effects on T-type calcium channels and -ATPase activity have been reported (20). Ethosuximide has significant CNS and gastrointestinal (GI) side effect HabiUties (13). 

The oxa2ohdinedione trimethadione [127-48-0] C H NO (50), at one time the dmg of choice for the treatment of absence sei2ures, has been replaced by ethosuximide (41) and valproate (49). (50) has a distinct profile from that of phenytoin but causes photophobia and night blindness in approximately 30% of the patients taking it and has the CNS and sedative properties seen for other anticonvulsants together with moderate neutropenia, hepatitis, and skin rashes (13). Trimethadione does not appear to produce its effects via modulation of GABA-mediated responses. 

MISSELLANEOUS ANTICONVULSANTS. Valproic acid (Depakene) is unrelated chemically to the other anticonvulsants. This drug is absorbed rapidly when taken orally Tablets should not be chewed but swallowed whole to avoid irritation to the mouth and throat. The capsules may be opened and the drug sprinkled on a small amount of food, such as pudding or applesauce This mixture must be swallowed whole immediately and not chewed. Zonisamide is administered orally once a day or in divided doses. The dose may be increased by 100 mg day every 1 to 2 weeks until control of the seizures is obtained or the patient reaches the maximum dosage of 600 mg/d. 

OXAZOLIDINEDIONES. Drowsiness is the most common adverse reaction and, as with the other anticonvulsants, tends to subside with continued use Visual disturbances may also occur. The patient with a visual disturbance is assisted with ambulation and oriented carefully to the environment. The nurse ensures that the environment is safe The patient may be especially sensitive to bright lights and may want the room light to be kept dim. Because photosensitivity can occur, the nurse must keep the patient out of the sun. The nurse instructs the patient to use sunscreens and protective clothing until the individual effects of the drug are known. 

Other anticonvulsants, such as gabapentin and topiramate, are also being used by some clinicians, but controlled trials are lacking. 

Toxicological problems among infants are relatively common. For example, it is now routine to follow the course of changes in Dilantin levels of patients who are being treated for various convulsive disorders (12). It is also important to be able to detect and assay for other drugs that are used in the newborn, such as various other anticonvulsants, salicylates, and a host of others. 

Following acute exposure to cyclodiene organochlorine pesticides, seizures and respiratory depression may occur (Ellenhom 1988 Proctor et al. 1988). Benzodiazepines (e.g., diazepam or lorazepam) or other anticonvulsant medications (e.g., phenobarbital) have been commonly used to control seizures (Ford 1993). Organochlorines may sensitize the myocardium to the proarrhythmic effects of adrenergic amines, potentially resulting in initiation of ventricular fibrillation (TOMES 1994). 

Other anticonvulsants snch as oxcarbazepine, gabapentin, and lamotrigine may also be helpful in treating the affective lability and impulsivity seen in BPD, though little data is available. Each of these medications is discussed in Chapter 3. 

Valproic acid (VPA) is gaining increasing acceptance as a first-line drug it is less sedating than other anticonvulsants. Tremor, gastrointestinal upset, and weight gain are frequently observed reversible hair loss is a rarer occurrence. Hepatotoxicity may be due to a toxic catabolite (4-en VPA). 

Valproate, carbamazepine, and other anticonvulsants pose teratogenic risks. Despite this, treatment should continue during pregnancy, as the potential threat to the fetus by a seizure is greater However, it is mandatory to administer the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may... 

Carbamazepine, phenytoin, pheno-barbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticonvulsants or with other drugs may result in clinically important interactions (plasma level monitoring ). 

Regular monitoring of blood phenytoin levels provides a valuable contribution to the management of patients with epilepsy. The value of determining the blood level of other anticonvulsant drugs is unconfirmed. At present such work should be undertaken only as prospective research procedures combining clinical and biochemical methods of assessment and patient-management. 

Adults and children 8 to 30 mg/kg/day in divided doses. The optimum range is 375 to 1000 mg/day. When given in combination with other anticonvulsants, the starting dose is 250 mg once daily. 

Epilepsy For control of grand mal, psychomotor, or focal epileptic seizures, either alone or with other anticonvulsants. It may control grand mal seizures refractory to other anticonvulsants. 

Patients already receiving other anticonvulsants Start primidone at 100 to 125 mg at bedtime gradually increase to maintenance level as the other drug is gradually decreased. When therapy with primidone alone is the objective, the transition should not be completed in less than 2 weeks. 

Combination therapy - Wr en adding to existing anticonvulsant therapy, do so gradually while other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased. 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

Tiagabine is an anti-convulsive medication also used in the treatment for panic disorder as are a few other anticonvulsants. It does appear to operate as a selective GABA reuptake inhibitor. Tiagabine s most common side effects include confusion, difficulty speaking clearly/stuttering and mild sedation. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Used in combination with other anticonvulsant agents for management of partial seizures in adults and children... 

Gabapentin is used in combination with other anticonvulsant agents in the management of partial seizures (Bruni, 1998) with or without secondary generalization (Morris, 1999). A few (McElroy et al., 1997 Knoll et ah, 1998), but not all (Dimond et al., 1996), preliminary reports suggested that gabapentin may have an-timanic efficacy in adults with BD. 

More recently, gabapentin has been added to the arsenal of medications used for the treatment of chronic pain, along with other anticonvulsant drugs, such as carbamazepine and clonazepam, as used in the treatment of neuropathies in children (Berde et ah, 1993 Green and Kowalik 1994). 

Valproate metabolism may be induced by other anticonvulsants, including carbamazepine, phenytoin, primidone, and phenobarbital, resulting in an increased total clearance of valproate and perhaps decreased efficacy. 

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). 

ADVERSE EFFECTS OF LITHIUM, VALPROATE, AND OTHER ANTICONVULSANTS... 

Because CBZ and valproate have been used for many years to treat seizure disorders in children and adolescents, more systematic knowledge about their clinical pharmacology in this age group is available than there is about lithium. However, pediatric patients with epilepsy are often on concomitant therapy with other anticonvulsants. That fact complicates attempts to extrapolate from this experience to the use of CBZ or valproate as monotherapy for childhood or adolescent bipolar disorder. For example, the risk of serious and potentially fatal hepatotoxicity with valproate occurs almost exclusively in children younger than age 10 years (usually 2 years or younger) who are on multiple anticonvulsants for congenital seizure disorders. How or whether this risk translates to children or adolescents who are on monotherapy with valproate for bipolar disorder is unknown. Nonetheless, clinicians need to be aware of this possible risk and take the following steps to increase the likelihood of early detection in case this problem arises ... 

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