Anticonvulsants bipolar disorders

Control of early withdrawal symptoms, which prevents their progression to more serious symptoms, is the indication for which medications are most widely prescribed in the treatment of alcohol dependence. The most commonly used agents to treat alcohol withdrawal are the benzodiazepines, a class of drugs that, by virtue of their agonist activity at the GABA receptor complex, suppress the hyperexcitability associated with alcohol withdrawal. With widespread use of anticonvulsant medications for bipolar disorder and other disorders associated with behavioral disinhibition and CNS hyperexcitability, anticonvulsants have also been examined for use in the treatment of alcohol withdrawal. 

The evidence base for clinical decisions based on cost-effectiveness for the affective disorders is less clear than for schizophrenia. In bipolar disorder the primary effectiveness of the mainstay treatments, lithium and anticonvulsant pharmacotherapy, is undergoing considerable revision (Bowden et al, 2000). Until this is clarified, cost-effectiveness studies are probably premature. Nevertheless the cost burden in bipolar disorder is qualitatively similar to that in schizophrenia, with in-patient costs being the primary burden and associated social costs in treated patients. The drug costs are even less than those for schizophrenia. In Chapter 5 John Cookson suggests there is little economic evidence to drive prescribing decisions. The in-patient burden does not seem to have altered with the introduction of lithium. The only drug-related study (Keck et al, 1996) showed an obvious difference in treatment costs only when lithium was compared with sodium valproate. Since these are both cheap drugs this is unlikely to influence clinical decisions. The main question is what impact... 

TABLE 36-5. Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder... 

Anticonvulsant A drug used in the treatment of epilepsy, and to reduce the risk of seizures during detoxification from sedative-hypnotics. More recently these drugs have been used in the clinical management of bipolar disorders. 

Nimodipine may be more effective than verapamil for rapid-cycling bipolar disorder because of its anticonvulsant properties, high lipid solubility, and good penetration into the brain. 

Anticonvulsants. Finally, several antiseizure medications have been tried. These include valproic acid (Depakote, Depakene), carbamazepine (Tegretol), Lamotrig-ine (Lamictal), and gabapentin (Neurontin). The anticonvulsants are effective treatments for bipolar disorder. Their use for major depression needs to be studied further. Please refer to Section 3.4 Bipolar Disorders. 

Anticonvulsdnts. An early observation that BN patients may have abnormal electroencephalogram (EEG) resnlts led to specnlation that binge eating may represent an atypical behavioral presentation of seiznre activity. Thus, the first controlled medication study for the treatment of BN evaluated the use of the antiseizure medication phenytoin (Dilantin). Phenytoin was not found to be significantly superior to placebo, and the earlier reports of EEG abnormalities were not confirmed. The results of a subsequent trial of carbamazepine (Tegretol), an anticonvulsant that has been reported to be effective in the treatment of bipolar disorder, were also disappointing. As a result, anticonvulsants are not routinely used in the treatment of BN. 

According to the Expert Consensus Panel for Mental Retardation Rush and Frances, (2000), the mainstays of the pharmacological treatment of acute mania or bipolar disorder in adults are anticonvulsant medications (divalproex, valproic acid, or carbamazepine) or lithium. Both divalproex or valproic acid and lithium were preferred treatments for classic, euphoric manic episodes. Divalproex or valproic acid was preferred over lithium and carbamazepine for mixed or dysphoric manic episodes and rapid-cycling mania. For depressive episodes associated with bipolar disorder, the addition of an antidepressant (SSRI, bupropion, or venlafaxine) was recommended. According to the Expert Consensus Panel, the presence of MR does not affect the choice of medication for these psychiatric disorders in adults. 

Keck PE Jr, McElroy SL, Nemeroff CB Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry 4 395-405, 1992a Keck PE Jr, McElroy SL, Vuckovic A, et al Combined valproate and carbamazepine treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci 4 319-322, 1992b... 

McElroy SL, Keck PE Jr, Pope EIG Jr, et al Valproate in primary psychiatric disorders literature review and clinical experience in a private psychiatric hospital, in Use of Anticonvulsants in Psychiatry Recent Advances. Edited by McElroy SL, Pope HG Jr. Clifton, NJ, Oxford Health Care, 1988b McElroy SL, Keck PE Jr, Pope HG Jr, et al Valproate in the treatment of rapid-cycling bipolar disorder. J Clin Psychopharmacol 8 275-279, 1988c McElroy SL, Sessain EC, Pope HG Jr, et al Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder and schizophrenia. J Clin Psychiatry 52 411-414, 1991a... 

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. 

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. 

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). 

Furthermore, clinical trials are performed in various cultural and geographical settings. Transcultural differences may play a significant role in drug efficacy e.g. oriental populations require much lower doses of antipsychotic drugs compared with Caucasian patient populations. Phase IV trials also may be performed to explore possible novel uses for compounds approved and marketed in other indications (e.g. treatment of anxiety disorders with antidepressants, treatment of bipolar disorder with anticonvulsants, etc.). 

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). 

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. 

The rationale for the use of selected anticonvulsants in the treatment of bipolar disorder is based on the following factors ... 

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