Antimanic treatments

Lithium may facilitate the release of 5-HT, perhaps by increasing tryptophan uptake, enhancing 5-HT release through presynaptic autoreceptors, and/or by increasing activity at postsynaptic 5-HT receptors (i.e., act as a 5-HT agonist). Some data, however, question the long-term effect of lithium on 5-HT enhancement when studied in patients, as opposed to healthy control subjects ( 27). Similar to lithium, clonazepam can increase 5-HT synthesis and cerebrospinal fluid (CSF) levels of its major metabolite, 5-hydroxyindoleacetic acid. Other agents known to enhance 5-HT activity by different mechanisms have also shown initial promise as potential antimanic treatments (e.g., L-tryptophan, a 5-HT precursor). 

The possible antimanic effect of this 5-HT precursor was postulated based on the permissive hypothesis concept of diminished 5-HT activity. When oral doses of L-tryptophan (1 to 4 g) are administered, there is evidence of increased 5-HT synthesis. Three of four double-blind studies yielded positive results, holding the promise of an effective antimanic treatment (275). An advantage of this drug is its relative lack of other adverse effects. 

Dembowski C, Rechlin T. Successful antimanic treatment and mood stabilization with lamotrigine, clozapine, and valproate in a bipolar patient after lithium-induced cerebellar deterioration. A case report. Pharmacopsychiatry 2003 36(2) 83-6. 

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

Typical Antipsychotics. Since their introduction in the 1950s, antipsychotics have played a prominent role in the treatment of bipolar mania. When we recognized that dopamine activity is critical in the brain s reward centers, the notion arose that dopamine hyperactivity may contribute to the euphoria of bipolar mania. Therefore, it was natural to assume that the dopamine-blocking antipsychotics would be effective antimanic medications. 

Lamotngine (Lamictal). Lamotrigine, another anticonvulsant used to treat BPAD, is currently FDA approved for the prevention of both depressive and manic episodes during BPAD maintenance therapy. This represents a shift in the paradigms for BPAD therapy, as medications used to treat acute episodes have also typically been used for antimanic prophylaxis. Lamotrigine is not effective in the acute treatment of mania but has become for many the drug of choice for bipolar depression as well as for prevention of subsequent mood episodes of either polarity. 

Atypical Antipsychotics. The so-called atypical antipsychotics have revolutionized the treatment of schizophrenia and other psychotic disorders since their introduction in the 1990s. Similarly, they are replacing the older antipsychotics in the treatment of BPAD as well. They offer a similar degree of antimanic efficacy without a lessened long-term risk of tardive dyskinesia. For more information regarding the atypical antipsychotics, please refer to Chapter 4 Schizophrenia. 

At the postsynaptic level, lithium has been shown to reduce the function of beta adrenoceptors, presumably by affecting the coupling between the receptor and the secondary messenger system. This effect only becomes apparent following chronic treatment, which may help to explain the delay of several days, or even weeks, before an optimal beneficial effect is observed. All antidepressants are known to reduce the functional activity of postsynaptic beta receptors, which may explain why lithium has both an antimanic and an antidepressant effect in patients with manic-depression. 

In CONCLUSION, lithium is universally accepted as a mood-stabilizing drug and an effective antimanic agent whose value is limited by its poor therapeutic index (i.e. its therapeutic to toxicity ratio). Neuroleptics are effective in attenuating the symptoms of acute mania but they too have serious adverse side effects. High potency typical neuroleptics appear to increase the likelihood of tardive dyskinesia. Of the less well-established treatments, carbamazepine would appear to have a role, particularly in the more advanced stages of the illness when lithium is less effective. 

Topiramate, a sulfamate-substituted derivative of the monosaccharide cf-fructose, is an anticonvulsant agent (AHFS, 2000). The spectrum of topiramate s anticonvulsant activity resembles that of CBZ and phenytoin (Shank et ah, 2000). Topiramate has shown preliminary antimanic (McElroy et al., 2000) and possibly antidepressant efficacy in treatment-refractory, manic patients with BD type I (Calabrese et ah, 1998). 

Several studies suggest that valproate is effective in patients with a history of lithium treatment failure. In the study by Pope et al. [1991), 71% of patients receiving valproate exhibited an antimanic response, even though all of the patients had a history of lithium treatment failure or intolerance. Sixty-four percent of the patients with rapid-cycling bipolar disorder studied by Galabrese and Delucchi [1990) had a history of lithium failure, and the majority of these subsequently responded to valproate. Similarly, the six patients with rapid-cycling bipolar disorder described by McElroy et al. 

Some patients with bipolar disorder will need antidepressants. Although the switch rate into mania or induction of rapid cychng by antidepressants is controversial, these agents do appear to present a risk for some patients, often with devastating consequences. Therefore, when a patient with bipolar disorder is prescribed an antidepressant, it should only be in combination with a medication that has established antimanic properties. Controlled comparative data on the use of specific antidepressant drugs in the treatment of bipolar depression are sparse. Current treatment guidelines extrapolate from these few studies and rely heavily on anecdotal chnical experience. Overah, tricyclic antidepressants should be avoided when other viable treatment options exist. Electroconvulsive therapy should be considered in severe cases. 

Valproic add (Depakote 6 ) is an anticonvulsant with good antimanic action that is especially suited for patients with rapid cycling and mixed episodes (Bowden et id., 1994). However, it is a poor antidepressant, necessitating the use of a low-dose SSRI in the treatment of depression that may occur in the course of bipolar disease. 

In summary, when properly administered, ECT is an effective treatment for the most severe mood and psychotic disorders encountered in clinical practice, especially those warranting hospital care. Its efficacy is even more striking given the fact that 50% of those successfully treated have previously been nonresponsive to one or more adequate courses of medication. Although primarily used for severe depression, it is also an effective antimanic therapy, and may be lifesaving in catatonic states. ECT has also been used successfully to treat special populations, other psychotic disorders, and various organic conditions, such as NMS and Parkinson s disease. 

Kramlinger KG, Post RM. Adding lithium carbonate to carbamazepine antimanic efficacy in treatment-resistant mania. Acta Psychiatr Scand 1989 79 378-385. 

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... 

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