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Use of Anticonvulsants and Bipolar Disorder

Posted by MB on July 28, 2003, at 11:32:24

Interesting
MB
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Use of Anticonvulsants and Bipolar Disorder -- Expert Review

Irving Kuo, MD

Introduction

Currently, anticonvulsant medications are some of the primary pharmacologic agents used for the treatment of bipolar affective disorder. Some of the anticonvulsants currently being used for treatment of bipolar disorder include carbamazepine, valproate, lamotrigine, gabapentin, topiramate, oxcarbazepine, zonisamide, tiagabine, felbamate, levatiracetam, phenytoin, and pregabalin. The panel of experts attempted to answer the question of whether anticonvulsants were over- or underutilized in the treatment of bipolar disorder.[1] Lakshmi N. Yatham, MB, FRCPC, Director of the Mood Disorders Clinical Research Unit at the University of British Columbia, made some introductory remarks before allowing the panel to offer their opinions on this question. He related that in the anticonvulsants that were used for the treatment of bipolar disorder, there were differences in their mechanisms of action and there was no "class effect." He related that some of the agents appear to work and some do not. Some appear to be effective on "core bipolar" symptoms and others are more effective on "comorbid" symptoms. He also stated that some work better for mania while others work better for depression, so the question of the choice of anticonvulsants to be used is not a simple one. He felt that some of the issues that needed to be clarified included which anticonvulsant to use, for what indication, and where, geographically, the agents are being used.
Current Concepts in Bipolar Treatment

Charles Bowden, MD,[2] Karren Professor and Chairman, Department of Psychiatry, University of Texas Health Science Center at San Antonio, was the first panelist to comment on this issue. He initially spoke about the current concepts of treatment of bipolar disorder. He related that bipolar disorder is composed of 4-6 behavioral domains, that impulsivity is the closest to a universal symptom complex in bipolar disorder, and that no drug eliminated all the symptoms. He stated that at this time, tolerability of the drug drove drug selection and patient adherence. He also related that the ideal mood stabilizers would be drugs that benefited one or more of the primary aspects of bipolar disease, were effective in acute and maintenance face treatments, and did not worsen any aspects of the illness. He related that at times, anticonvulsants might be used too much. He felt that doses often were pushed so high that side effects would begin to prevail, and this caused treatment noncompliance. Other examples of anticonvulsant overuse included trying to rely on monotherapy with an anticonvulsant to do "everything," or using these medications in an irrational, polypharmacy manner. Likewise, Dr. Bowden felt that at times the anticonvulsants were underutilized. He cited examples such as when no mood stabilizers were used in the treatment of bipolar patients or when there was an unrealistic fear of adverse defense based on an inadequate knowledge of the effects of the drugs. He related that from a pragmatic standpoint, these drugs should be used when and where they work, and not used where they don't. He also felt that drugs that were being poorly tolerated by patients should not be continued.

Dr. Bowden then examined a series of studies[3-5] looking at the effectiveness of divalproex both as monotherapy and adjunctive treatment in the treatment of bipolar disorder. He cited several studies examining divalproex as an add-on treatment to haloperidol, olanzapine, and selective serotonin reuptake inhibitor antidepressants in the acute treatment of bipolar disorder, either in the manic phase or as prevention of dropouts from treatment due to depressive episodes. In each study, divalproex did appear to significantly help in the treatment of acute bipolar symptoms. He also looked at several maintenance treatment studies[6,7] that examined divalproex's role in helping with the recurrence of bipolar episodes, and the studies also seem to indicate efficacy in the use of divalproex for decreasing recurrence rates.

The next speaker was Giovanni Cassano, MD,[8] Professor of Psychiatry at the University of Pisa in Italy, who spoke about "The Use of Anticonvulsants and the Present Broadening of Bipolar Spectrum." Dr. Cassano related that there are few data available concerning the current range of use of anticonvulsants in several subtypes of bipolar disorder, including bipolar II disorder, cyclothymia, and antidepressant-triggered mania. Although anticonvulsants are used in these situations, there is little evidence in the literature of their efficacy. He also related that anticonvulsants are used in the depressive or dysthymic states associated with subsyndromal manic or mixed symptoms or associated with a family history of bipolar illness. Anticonvulsants are also used in highly recurrent and early-onset depressions; in psychotic depressions in substance abusers with a history of bipolar symptoms; in decreasing alcohol craving; in the treatment of anxiety and eating disorders with patients with a history of a bipolar background, borderline personality disorder, impulse control, and PTSD states; as well as in schizoaffective and schizophrenic form disorders. Dr. Cassano also felt that reimbursement issues were critical in the choice of mood stabilizers and might mitigate against off-label usages before the anticonvulsant medications. He felt that long-term studies on the treatment of bipolar spectrum disorders with anticonvulsants are needed because otherwise a great number of severe bipolar patients will receive ungrounded therapies.
Anticonvulsants in Bipolar Depression

Dr. Guy Goodwin, MD,[9] W.A. Handley Professor of Psychiatry at the University of Oxford, then gave his overview of the use of anticonvulsant medications in bipolar depression. He initially asked why we use anticonvulsants in bipolar disorder and related that one reason was because pathophysiologically and pharmacologically, they make some sense. Anticonvulsants generally increase the action of GABA and decrease the action of glutamate, thus preventing high-frequency repetitive discharges in cells by direct effects on membrane ion channels and enhancing the system's stability. He speculated that the facilitation of GABA functioning may be "bad" for depression because GABA-ergic medications like gabapentin, divalproex, and benzodiazepines can cause sedation, fatigue and cognitive slowing.[10] He felt that diminishing glutamate activity could have an antidepressant effect, as demonstrated by medications such as lamotrigine and topiramate, which possibly have antidepressant, "activating," and weight loss properties. He also stated that anticonvulsants should be used in bipolar affective disorder because they have been demonstrated to work. He related that lamotrigine monotherapy has been demonstrated to have significant efficacy in the treatment of bipolar depression compared with placebo.[11] He also cited a study of divalproex compared with placebo in the treatment of bipolar depression that showed that in the maintenance phase, divalproex seemed to have a positive effect on preventing depressive recurrence.

Ultimately, the panel agreed that while there was some evidence for the efficacy of anticonvulsant medications in the treatment of bipolar disorder, much more evidence is needed in order to clarify which parts of the illness are best treated with these agents, their effectiveness in the maintenance phase of bipolar disease, and the issue of the use of anticonvulsant monotherapy vs using anticonvulsants in conjunction with other pharmacologic agents for maximum efficacy while minimizing adverse effects.
References

1. Yatham LN, Bowden CL, Cassano G, Goodwin G. Use of anticonvulsants and bipolar disorder (too much or too little?). Program and Abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Interactive Sessions: Ask the Experts.
2. Bowden, CL. Use of anticonvulsants and bipolar disorder (too much or too little?). Program and Abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Interactive Sessions: Ask the Experts.
3. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group.[comment][erratum appears in JAMA 1994 Jun 15;271(23):1830]. JAMA. 1994;271:918-924. Abstract
4. Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Pattern of response to divalproex, lithium, or placebo in four naturalistic subtypes of mania. Neuropsychopharmacology. 2002;26:530-536. Abstract
5. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.[comment]. Arch Gen Psychiatry. 2002;59:62-69. Abstract
6. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.[comment]. Arch Gen Psychiatry. 2000;57:481-489. Abstract
7. Tohen M, Chengappa KN, Suppes T, et al. Olanzapine combined with mood stabilizers in prevention of recurrence in bipolar disorder: an 18-month study. Program and abstracts of the XXIIIrd Congress of the Collegium Internationale Neuro-Psychopharmacologicum; July 23-27, 2002; Montreal, Canada. Abstract P.2.E.061.
8. Cassano G. The use of anticonvulsants and the present broadening of bipolar spectrum. Program and Abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Interactive Sessions: Ask the Experts.
9. Goodwin G. Use of anticonvulsants and bipolar disorder (too much or too little?). Program and Abstracts of the 5th International Conference on Bipolar Disorder; June 12-14, 2003; Pittsburgh, Pennsylvania. Interactive Sessions: Ask the Experts.
10. Ketter TA. Post RM. Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(5 suppl 2):S53-S67.
11. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E. Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79-88. Abstract


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