Mohammed T. Abou-Saleh

MANAGEMENT OF ACUTE MANIA 485drops to 50% when the full bipolar spectrum is considered 29 . Greilet al. 30,31 have found that carbamazepine may be useful in patientswith non-classical features (mixed or rapid cycling bipolardisorder) or subgroups with depressive or schizophrenia-likefeatures. A few investigators have identified increased benefit withcarbamazepine when they treated patients who had EEGabnormalities associated with symptoms of rage and violentbehavior 32 .Treatment ConsiderationsPrior to starting patients on carbamazepine, the patient’s medicalhistory should be reviewed, with special attention to previousepisodes of blood dyscrasias or liver disease. Laboratory testsshould include a complete blood count (CBC), serum chemistrypanel, and liver function tests [lactate dehydrogenase (LDH),ALT, AST, bilirubin and alkaline phosphatase levels].Dose and AdministrationTreatment in older patients should be initiated with low doses,starting with 200–400 mg/day by mouth. The dose should beincreased gradually and slowly. Carbamazepine therapeutic levelsare in the range 4–12 ng/ml; however, these parameters are basedon the anticonvulsant effect. There is no standard blood levelrecommendation for the treatment of bipolar disorder. The idealtherapeutic blood level is subjectively determined and depends onthe patient’s clinical response and the appearance of side effects.During the initial 6–8 weeks of treatment, blood levels maydecrease despite maintaining a regular dose, due to carbamazepine’sability to induce its own metabolism. Checking blood levelsand adjusting appropriately is important for maintenance of thetreatment effect. Geriatric patients may be able to maintainadequate therapeutic levels on lower doses (400–600 mg) due toslower metabolism.Side EffectsBone marrow depression (aplastic anemia, decreased cell counts,agranulocytosis) and hepatotoxicity can occur with carbamazepine.Risk of bone marrow depression is estimated at 1/125 000.Weekly monitoring of blood counts, liver profile and carbamazepinelevels is indicated during the early weeks of treatment.Idiosyncratic reactions are rare; however, patients should beasked to report immediately reactions such as fever, sore throat orsevere fatigue of sudden onset.The most common adverse effects of carbamazepine aredizziness, drowsiness, vertigo, ataxia, diplopia, nystagmus andblurred vision 9 . These effects are usually dosage-related and maybe minimized by reducing the dose. Skin rash, urticaria, Stevens–Johnson syndrome, Lyell’s syndrome, photosensitivity anddermatitis have also been reported, so that carbamazepine shouldbe discontinued if these symptoms appear.Other side effects include cardiovascular complications, such ascongestive heart failure, hypertension, hypotension, arrhythmias,AV block and thrombophlebitis 33 as may occur with othertricyclic agents. The risk is greatest if patients already haveunderlying cardiovascular disease.Drug InteractionsCarbamazepine interacts with a variety of other medications.Serum carbamazepine concentrations are markedly increasedwhen carbamazepine is given with SSRIs, erythromycin, isoniazid,calcium channel blockers and danazol. Blood levels will alsoincrease to a lesser degree with cimetidine, valproate, phenobarbital,phenytoin and theophylline. Carbamazepine decreasesneuroleptic blood levels, which may lead to a lower efficacy ofthe neuroleptic in combined therapy.Valproate (Valproic Acid)EfficacyValproate is an anticonvulsant also shown to be effective in thetreatment of bipolar disorder in the general adult population. Ithas also been documented to be effective for the elderly bipolarpatient 34–44 . Valproate primarily works through the GABAsystem, and has recently been used to treat patients with acutemania who are resistant to traditional drugs such as lithium andcarbamazepine 36,45 . It remains the drug of choice in patients whohave failed to respond to lithium or carbamazepine or who areunable to tolerate these medications because of their side effects.Valproic acid may be used effectively in combination with lithiumif there is only a partial response to either drug. Likecarbamazepine, valproate causes minimal cognitive side effects,which is of particular advantage in the elderly patient.Treatment ConsiderationsValproate appears to be very well tolerated by elderly patients.Prior to starting patients on valproate, liver function tests and aCBC should be performed. Albumin levels should be performedon the frail elderly. Valproate may be used in combination withlithium, although experience suggests that a trial of monotherapyis usually indicated initially 9 .Dose and AdministrationValproic acid is available in three forms: valproic acid, sodiumvalproate and divalproate sodium. Gastric irritation is notuncommon with valproic acid or sodium valproate treatment.In such patients, the use of divalproate sodium may reducegastrointestinal (GI) irritability. This medication is available inthree strengths, 125 mg, 250 mg and 500 mg. Treatment shouldbegin with low divided doses (125 mg twice a day) and begradually increased to 500–1000 mg/day, depending on tolerance,side effects and blood levels. Most studies evaluating theeffectiveness of valproate in bipolar disorder have used the targetdrug concentrations found effective in the treatment of epilepsy(50–100 mg/ml) 46 . Higher blood levels may sometimes be requiredto achieve optimal clinical response.Valproate is rapidly absorbed from the gastrointestinal systemand has a half-life of 6–16 h in younger patients, although thiscould be longer in geriatric patients. In serum it is predominantlyprotein-bound after absorption. The decrease in serum albuminlevels associated with aging may result in lower dosages beingrequired for elderly patients to achieve adequate blood levels. It ismetabolized in the liver prior to elimination.Side EffectsGastrointestinal side effects of valproate include nausea, vomitingand indigestion. Occasionally abdominal cramps, constipationand diarrhea are reported. Anorexia has also been observed,although weight gain appears more common. These effects are