In the past two decades there has been a search for drugs that could be alternatives for lithium in treating effectively and safely patients who: a) may not be lithium candidates because of age (elderly), pregnancy, or renal or cardiac disorders; b) are unresponsive to lithium; and c) react adversely to lithium. The first alternative was suggested by Okuma who, in 1973 and several times thereafter, reported that the anticonvulsant carbamazepine (CBZ) has both therapeutic and prophylactic efficacy in bipolar affective disorders.1-3 In his pioneer work, Okuma demonstrated that CBZ's antimanic effect was achieved with 400 mg to 1,200 mg daily at blood levels of 6 to 12 µg/ml and that its prophylactic effect was achieved with 200 mg to 600 mg/day at blood levels around 6 µg/ml. Kishimoto et al studied the prophylactic effects of carbamazepine in 32 patients with affective disorder who were receiving long-term therapy with CBZ.4 Kishimoto and colleagues observed complete remission of both manic and depressive symptoms in four cases and reduction of symptoms in 20 cases when CBZ was administered alone. In the ten cases where lithium was added to the CBZ therapy no noticeable improvement was shown. These findings were soon confirmed by Post and colleagues at NIMH. Their publications on CBZ's antimanic and prophylactic efficacy were largely responsible for stimulating additional research around the world on the use of CBZ and other anticonvulsants in the treatment of affective disorders.57 Even more recently, Post and associates observed seven lithium non-responders receiving carbamazepine therapy for an average of 1.7 years to assess CBZ's prophylactic efficacy.8 Three of the patients were treated with CBZ alone and four received carbamazepine in combination with neuroleptics, tricyclic antidepressants or lithium carbonate. An average blood level of 11.3 µg/ml was achieved with an average dose of 1 ,285 mg/day of CBZ. Post reports that of the seven patients, six showed a good overall prophylactic response to carbamazepine.
At the VII World Congress of Psychiatry (Vienna, July 1983), additional data were presented by speakers from Europe, North America and Japan attesting to CBZ's safety and efficacy, especially for those unresponsive to or intolerant of lithium.9-18 In addition, several clinicians described the use of other anticonvulsants for acute and prophylactic therapies of affective disorders.
The keto-analogue of CBZ, oxcarbazepine (OxCBZ), has pharmacological properties almost identical to CBZ. According to Ernrich of the Max Planck Institute for Psychiatry,19 Ox-CBZ has antimanic effects similar to CBZ but causes fewer side effects. Ox-CBZ's efficacy in acute mania also was attested to by Müller who reported improvement in 43 of 48 patients treated with 600 mg to 3,000 mg/day.20 Ox-CBZ was well-tolerated by these patients. Muller also reported that in two haloperidol-controlled, double-blind trials with OxCBZ in mania, Ox-CBZ was as antimanic as haloperidol and well-tolerated. Greil et al21 reported that in their comparison of Ox-CBZ and CBZ, the former was equi-effective and better tolerated, causing only mild, transient side effects (drowsiness, dizziness). They also reported that the combination of Ox-CBZ with lithium, antidepressants and/or neuroleptics seems to be as safe as the co-administration of these drugs with CBZ. Although evaluations of Ox-CBZ's prophylactic efficacy have not been completed, the preliminary evidence indicates that it is as efficacious as lithium and CBZ.
The anticonvulsant dipropylacetamide is another alternative for lithium. Lambert, a French pioneer in psychopharmacotherapy, reported that dipropylacetamide, alone and in combination with neuroleptics, has antimanic effects comparable to or slightly less than lithium's.22 Furthermore, he reported that as a prophylaxis for bipolar patients, dipropylacetamide is as effective as lithium with the added advantage that it is better tolerated and does not require the biological supervision necessary for lithium therapy.
Describing his comparison of dipropylacetamide with lithium prophylaxis, Venkowsky stressed that dipropylacetamide's prophylactic efficacy was similar to lithium's but, most important, prophylactic dipropylacetamide was much better tolerated.23 Adverse lithium effects (polydypsia, polyuria, diabetes insipidus, gastrointestinal reactions} occurred in 55% of the patients, whereas undesirable side effects (nausea, vomiting) occurred in only 7.5% of dipropylacetamide patients.
The acute and prophylactic efficacy of dipropylacetamide stimulated trials of another anticonvulsant, sodium valproate, alone and in combination with lithium. In 1980, Emrich reported that a placebo-controlled, ???-design trial had established that sodium valproate exerts an antimanic effect, and at the World Congress of Psychiatry he reported that a prophylactic action of this drug has been verified.24 Brennan and Sandyk of Boston City Hospital reported that six of eight acutely manic patients they had treated with sodium valproate had an unequivocal response to a maximum dose of 3.6 g/day in three divided doses.25 Three other patients with recurrent manic and depressive episodes resistant to lithium have been treated with prophylactic sodum valproate (900 mg to 1 ,500 mg/d) from nine to 33 months. All have remained practically free of affective symptoms.
Two Polish investigators reported that a longterm trial (30 to 52 months) involving 75 patients with bipolar and schizoaffective disorders showed that valproic acid amide "exerts strong antimanic and prophylactic action."26
To date there has been a single report of another anticonvulsant, the benzodiazepine clonazepam, having antimanic efficacy. At the 1982 meeting of the Society of Biological Psychiatry (Toronto), Chouinard and his associates at McGiII reported that their double-blind cross-over controlled comparison of clonazepam with lithium in the treatment of 12 newly admitted, acutely manic patients, revealed that clonazepam was more efficacious than lithium.27 Lithium was given in the range of 900 mg/day to 2,100 mg/day (mean 1,691 mg/day) and clonazepam in the range of 4 mg/day to 16 mg/day (mean 10.4 mg/day). Although clonazepam is highly sedative, it was well-tolerated in high doses by the manic patients. Prior to Chouinard's report, Lechin's investigations also reported the antimanic effects of clonazepam in manic and schizoaffective patients.28 Lechin presupposed that the clonazepam antimanic efficacy could be due to its ability to inhibit dopamine release from dopamine terminals.
In summary, it is now evident that there are a number of anticonvulsants that are suitable alternatives for lithium, These drugs have acute antimanic and prophylactic effects, often with fewer side effects than lithium and without as much monitoring being required. They offer hope for rapid cyclers and for the 25% of partial lithium responders and the 25% of lithium non-responders. They also offer hope for a subgroup of depressives who, if responsive, will experience an antidepressant effect at about the same time as with a tricyclic or other antidepressants, that is, within two to three weeks. Finally, studies of the mechanism of action of these anticonvulsants alone and with other drugs may lead to new and better understanding of the basic mechanisms of affective dysregulation.
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