Drug Selection Current guidelines by the American Psychiatric Association

Drug Selection Current guidelines by the American Psychiatric Association

list lithium or lamotrigine as first-line monotherapy for acute bipolar depression. Antidepressant monotherapy is not recom- mended except in combination with lithium in severely ill patients. The recommendation for lamotrigine use as a first-line treatment derives from two sources. The first is a large double

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Treatments for Acute Depression in Bipolar Disorder TREATMENT

ADVANTAGES DISADVANTAGES Mood stabilizers

Provide maintenance Antidepressant and antimanic efficacy

efficacy relatively modest for most mood stabilizers

If use of antidepressants Side effects may be becomes necessary,

problematic: should reduce the risk

sedation, weight of switching or cycle

gain/metabolic, acceleration

tremor, etc. Lamotrigine

Significantly more Antimanic efficacy is efficacious than most

relatively modest, so other mood

may not provide stabilizers.

comprehensive No evidence of

treatment as induction of switching

monotherapy for or rapid cycling

bipolar I patients Generally well tolerated Quetiapine

Recent data suggest Side effects may be comparable efficacy

problematic: to lamotrigine

sedation, weight gain/metabolic

May be efficacious for Risk of tardive depression at doses

dyskinesia with lower than those

long-term require for mania,

treatment improving tolerability

At higher doses may be able to provide balanced and strong antidepressant and antimanic efficacy

Antidepressants Probably efficacious in Can trigger switch the acute setting

into mania and increase cycling

ECT Acutely efficacious Cognitive side effects Safe for patients unable

Need for anesthesia to take medication

Maintenance after acute (e.g., pregnancy)

treatment problematic

101 blind, placebo controlled trial of lamotrigine monotherapy

MOOD STABILIZERS

(50 mg vs. 200 mg final dose, after appropriate titration). The response rate with the 200 mg final dose was 56%, which was significantly greater than that of placebo using several clin- ical measures. Though the study was not powered to fully test this, the results of the study suggested that the 200 mg final dose was more effective than 50 mg final dose. The second line of evidence supporting lamotrigine for bipolar depression comes from a larger prospective maintenance study of remitted bipolar I and II patients, comparing lamotrigine monotherapy at 200 mg with lithium monotherapy and with placebo. In this study, lamotrigine was superior to placebo for prophy- laxis of depressive or elevated relapses, but more robustly so for depression. In contrast, lithium was more effective in prevented elevation. Furthermore, unlike with traditional antidepressants, there is no clear evidence of lamotrigine provoking cycling or switching.

Recently, quetiapine has emerged as a second mood stabilizer with potentially robust antidepressant efficacy.

A large multicenter placebo controlled study (There are 2 studies: BOLDER studies) compared quetiapine monotherapy at two doses (300 mg and 600 mg) in bipolar I and II patients in an acute major depression. Response and remission rates for both active groups were identical (58% and 36%, respec- tively) and significantly better than for the placebo group. The effect size for quetiapine in this study was comparable to that of lamotrigine for bipolar depression and significantly greater than that of olanzapine when used as a monotherapy for bipolar depression.

Apart from lamotrigine and quetiapine, there are few data available to stratify the other mood stabilizers in terms of antidepressant efficacy. Lithium, carbamazepine, and olanza- pine appear to be effective for bipolar depression at a much lower rate than lamotrigine or quetiapine, and risperidone, ziprasidone, and aripiprazole have insufficient data to evaluate. Nevertheless, there is reason to consider lithium seriously in patients with persistent, frequent, or severe bipolar depression. Lithium is the only pharmacologic intervention that exhibits

a specific anti-suicide effect, to some degree independent of its mood efficacy within patients. Lithium treatment reduces

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the suicide rate in bipolar patients approximately seven-fold. However, in the same samples, discontinuation of lithium results in a rapid return to previous (or even, transiently, to higher) suicide rates. Moreover, when tapered quickly or abruptly discontinued, a twenty-fold increase in suicides and attempts occurs in the first year. Comparable anti-suicide efficacy in bipolar patients has not been demonstrated for anti- convulsants or antipsychotics, though confirmation of lithium’s uniqueness will require more studies of other agents. In addi- tion, both lithium and anticonvulsants can have a positive impact on impulsivity and aggression, two important suicide risk factors.

Probably all available antidepressant drugs can be effec- tive in treating bipolar depression but we lack sufficient data to stratify them in terms of efficacy. There is some evidence that MAO inhibitors may be somewhat more effec- tive than other classes but they may also be more likely than other classes of antidepressants (except for TCAs) to provoke mood instability. Of course, antidpressants should never be prescribed for bipolar patients in the absence of adequate mood stabilizers, which reduce the risk of switching or cycle acceleration. If mania occurs, the antidepressant medication should be discontinued immediately. It is not clear how long antidepressants should be continued following resolution of an acute major depression. The Expert Consensus Guidelines recommended continuing antidepressants for 18–30 weeks in non-rapid cycling bipolar I patients following resolution of depression and for 9–17 weeks in rapid cycling patients.