uestion: What is this patient's current medication?

• Lithium (with or without other mood stabilizers)
• Valproate, carbamazepine, or other mood stabilizers such as lamotrigine (with or without other drugs)
• No mood stabilizers

Help: The treatment of this bipolar I depressed patient will depend to some extent on what his/her current medication is. Is this a breakthrough depression in a patient on lithium (plus other mood stabilizers or other drugs)? Or is the patient on other mood stabilizer(s) but not lithium? Or did the depression develop in the context of the patient not being on any mood stabilizer?

• In the algorithm for this subgroup, the first-line intervention is to try to utilize the potential antidepressant efficacy of lithium in bipolar depression.¹ Lithium has demonstrated antidepressant efficacy in bipolar depression,² but other older mood stabilizers do not seem to have an equivalent antidepressant effect. Carbamazepine may possess some weak antidepressant activity, but less than lithium.³ Valproic acid has not to date demonstrated a clear-cut acute antidepressant effect,(4-5) although a controlled study in progress should provide more information. A large placebo-controlled study comparing valproate with lithium for one year of maintenance treatment was recently completed, which showed a very low rate of depressive relapse requiring hospitalization with either of the active treatments.(6) However, the lithium group had the highest rate of suicidal ideation, which raises questions as to the validity of this study. Previous studies have consistently shown that lithium treatment reduces suicidal activity.(7)
• Lamotrigine is an anticonvulsant that may have particular efficacy in bipolar depression. A recent double-blind, placebo-controlled, prospective study of lamotrigine in the treatment of major depressive episodes associated with bipolar I disorder, which included 195 patients, found that 51% of the patients treated with 200 mg/day of lamotrigine showed significant clinical improvement, 41% improved on 50 mg, and 26% improved on placebo.(8) Lamotrigine could become a first-line option in the treatment of bipolar depression, if further studies continue to demonstrate its utility and safety. However, reports of switches to mania indicate it may sometimes behave more like an antidepressant.(8-9) Its efficacy in acute mania and for prevention of recurrences of bipolar mood episodes requires more study. A disadvantage of lamotrigine is the occurrence of potentially serious dermatologic reactions, and there have been rash-associated deaths. According to the package insert, rashes occur in 10% of patients, and the appearance of rash necessitates discontinuation of the medication. The dosage must be increased slowly to minimize the occurrence of these dangerous allergic reactions. Another disadvantage is that improvement in depression may occur rather slowly: 4 to 6 weeks was required in the study cited above. However, lithium may require a similar period to achieve its acute antidepressant efficacy.(10)
• Other anticonvulsants may have some utility in treating bipolar depression. Gabapentin appears to have some weak antidepressant efficacy in bipolar depression.(11-12) The roles of other newer mood-stabilizing agents such as topiramate(13) and tiagabine(14) remain to be defined.

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¹Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The Expert Consensus Guidelines for treating depression in bipolar disorder. J Clin Psychiatry. 1998;59 Suppl 4:73-9.

²Zornberg GL, Pope HG, Jr. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol. 1993;13:397-408.

³Post RM, Uhde TW, Roy-Byrne PP. Antidepressant effects of carbamazepine. Am J Psychiatry. 1986;143:29-34.

(4) Potter WZ. Bipolar depression: specific treatments. J Clin Psychiatry. 1998;59 Suppl 18:30-6. 38.

(5) Sachs G. Is divalproex sodium an appropriate initial treatment for bipolar depression? Psychiatric Ann. 1996;26:S454-S459.

(6) Bowden CL, Calabrese JR, Nemeroff CB, Lydiard RB, McElroy SL. Effects on suicidality of divalproex, lithium, and placebo in randomized one-year maintenance treatment of bipolar disorder, Poster 24. New Clinical Drug Evaluation Unit Conference. Boca Raton, Florida: National Institute of Mental Health; 1998.

(7) Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60[suppl 2]:77-84.

(8) 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. J Clin Psychiatry. 1999;60:79-88.

(9) Sporn J, Sachs G. The anticonvulsant lamotrigine in treatment-resistant manic-depressive illness. J Clin Psychopharmacol. 1997;17:185-9.

(10)A.P.A. Practice guideline for the treatment of patients with bipolar disorder. American Psychiatric Association. Am J Psychiatry. 1994;151:1-36.

(11)Ferrier IN. Lamotrigine and gabapentin. Neuropsychobiology. 1998;38:192-7.

(12)Ghaemi SN, Katzow JJ, Desai SP, Goodwin FK. Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiatry. 1998;59:426-9.

(13)Marcotte D. Use of topiramate, a new anti-epileptic as a mood stabilizer. J Affect Disord. 1998;50:245-51.

(14)Kaufman KR. Adjunctive tiagabine treatment of psychiatric disorders: three cases [In Process Citation]. Ann Clin Psychiatry. 1998;10:181-4.

Recommendation:

If the patient is not on lithium, but is currently on valproic acid, carbamazepine, or another mood stabilizer, the dosage levels should be optimized to minimize the possibility of cycling in preparation for the addition of an antidepressant to the treatment regimen. The valproic acid level should be adjusted to the therapeutic range of 50 to 125 ng/ml,¹ and optimally, if tolerated, to the upper half of that range, and the carbamazepine level should be in the therapeutic range of 4 to 12 ng/ml. If depression persists, an antidepressant should be added. When you finish reading this discussion, click on the bar to go ahead and see the antidepressant recommendations.

If you did not read the Help section of the previous question, press the "back" button on your browser and read it now. It explains our relative lack of confidence in the antidepressant effects of valproate and carbamazepine in this situation. It also discusses lamotrigine. Lamotrigine seems more promising as an antidepressant, but if the patient is on it now and it has not been effective, we have no clear sense yet of how to optimize the dose, so it is left to the clinician to determine when an adequate trial has been completed. When this is done, the patient is ready for our antidepressant recommendations.

Given the doubts about the antidepressant effects of valproate and carbamazepine, and the possibility that they may even induce depressive symptoms in some patients, some clinicians first try lowering rather than increasing the valproate or carbamazepine in this situation. The hope is that the proposed depressogenic effect will be lessened, and the patient may become euthymic or even slightly hypomanic. If this does not work, the dose could be increased as recommended above in preparation for adding an antidepressant. The risk is that the patient could switch into a problematic hypomania or mania.

¹Schaff MR, Fawcett J, Zajecka JM. Divalproex sodium in the treatment of refractory affective disorders. J Clin Psychiatry. 1993;54:380-4.

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