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Balance efficacy, safety in bipolar depression.

The popularity of lamotrigine took a hit this year when the results of five randomized, double-blind, placebo-controlled trials showed that it had no efficacy as monotherapy in primary measures of acute bipolar depression (Bipolar Disord. 2008;10:323-33).

Though not approved for this indication, lamotrigine had been considered by many clinicians to be one of "the big four" options for treating bipolar depression, largely because of its good tolerability. The others are two approved treatments--quetiapine (Seroquel) or a combination of olanzapine and fluoxetine (Symbyax)--and another unapproved option, lithium.

Don't count lamotrigine out yet, though, because it still has a role among the options for treating bipolar depression, several experts said in interviews. Each of the physicians in this article has received research funding from the maker of lamotrigine, GlaxoSmithKline, and been an adviser, consultant, or

speaker for the company and

many others.

"I'm not a good enough clinician to rely on any one medication," said

Dr. Joseph R. Calabrese, director of the mood disorders program at Case Western Reserve University, Cleveland, and lead author of the damaging review of lamotrigine trials. "Our patients are very complicated."

He firmly believes that almost all patients with bipolar disorder need medication to stabilize mood plus psychotherapy to learn how to manage leftover symptoms. Most patients require two medications: one to address mania and one to address depression, he added.

Dr. Calabrese opts for lithium in many patients, usually with another antimanic agent. The second that a patient seems to be cycling down, he adds a drug for depression, usually lamotrigine or quetiapine. He tends to prefer lamotrigine for patients who have psychomotor-retarded, tired, slowed-down depressions because the drug causes little or no sedation, which is a side effect of quetiapine in 30%-40% of patients. Lamotrigine causes a benign rash in about 10% of patients but does not cause weight gain, another potential side effect of quetiapine. Some studies have shown that quetiapine also may negatively affect glucose metabolism, but none of those studies was designed to detect new or exacerbated cases of diabetes, he noted. On the other hand, for patients who have lots of anxiety, agitation, restlessness, or psychotic symptoms, Dr. Calabrese might try quetiapine first because of its sedative side effects. Quetiapine works for type I and type II bipolar depression, for rapid and nonrapid cyclers, and in anxious and nonanxious patients, he said. With lamotrigine, an additional anxiolytic usually is needed in anxious patients.

For any phase of the illness, Dr. Terence A. Ketter starts by considering the two approved treatments, which have the greatest evidence of efficacy and a number needed to treat in single digits. Compared with placebo, four patients would need to be treated for bipolar depression with Symbyax to achieve one greater response, or five patients would need to be treated with quetiapine. In comparison, the number needed to treat with lamotrigine is 13, said Dr. Ketter, chief of the bipolar disorder clinic at Stanford (Calif.) University.

The two approved treatments also have a number needed to harm in single digits. Few physicians choose Symbyax because of side effects--the weight gain and metabolic effects, he added. Compared with placebo, treating six patients with Symbyax will harm one by increasing body weight by 7% or more. Treating five patients with quetiapine would "harm" one by producing sedation. For lamotrigine, the number needed to harm is 44 patients treated to get a nonserious rash in 1. Dr. Ketter employs number-needed-to- treat and number-needed-to-harm analyses in psychiatric decision making in his upcoming book "Clinical Manual of Bipolar Depression," to be published soon by American Psychiatric Publishing Inc.

"If it's an extremely urgent situation where you're willing to take a hit for tolerability because you need quick efficacy, you will lean toward the approved treatments" for bipolar depression, he reasoned. "But if a patient is not severely depressed and is skittish about sedation or weight gain, lamotrigine may be a tradeoff worth making" for greater safety but lesser efficacy

One he ad-to-head trial of Symbyax and lamotrigine suggested that 12 patients would need to be treated with Symbyax to give 1 patient benefits greater than those seen with lamotrigine. For every five patients on Symbyax, one would increase body weight by more than 7%, compared with lamotrigine therapy "So if you treat 12 patients, you would expect 1 more responder with the olanzapine/fluoxetine combination, but you would expect 2 patients with weight gain," he said.

Dr. Ketter said the data from the five trials reported by Dr. Calabrese showed lamotrigine was superior to placebo when grouped in a meta-analysis presented at a conference earlier this year by Dr. John R. Geddes of the University of Oxford (England). "You had to have about 500 patients in each group" to show a significant difference from placebo, he explained. Response rates were around 50% with lamotrigine and 41% with placebo.

When using medication for bipolar depression, Dr. Charles L. Bowden favors lamotrigine or quetiapine. Most often, he adds lamotrigine to a more antimanic mood stabilizer such as lithium, divalproex, or an antipsychotic. He might not choose lamotrigine if the patient has had an unsuccessful prior experience with it or is taking another drug that might predispose to rash, such as carbamazepine, said Dr. Bowden, chair of psychiatry at the University of Texas, San Antonio.

Monoamine oxidase inhibitors (MAOIs), unlike other antidepressants, have consistent evidence of benefit in treating bipolar depression but are underused out of concerns that patients won't heed warnings of potential chemical reactions with some foods, leading to severely high blood pressure, Dr. Bowden said. Review articles in recent years, however, suggest that the risk is minimal.

The MAOI tranylcypromine "is a pretty high drug on my list" of alternatives, Dr. Bowden said.

In addition to his association with the maker of lamotrigine, Dr. Ketter has been a consultant or speaker for, or received funds from, Abbot Laboratories, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Co., Cephalon Inc., Corcept Therapeutics Inc., Elan Pharmaceuticals Inc., Eli Lilly & Co., Forest Laboratories Inc., Janssen Pharmaceuticals Products LP, Jazz Pharmaceuticals, Merck 8c Co., Novartis Pharmaceuticals, Pfizer Inc., Shire Pharmaceuticals Inc., Solvay Pharmaceuticals Inc., UCB Pharmaceuticals, and Wyeth Pharmaceuticals. Some of these companies make medications for bipolar. Dr. Calabrese also has received funding from or been a speaker or consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma Co., Forest Labs, Janssen, Organon USA Inc., Ortho-McNeil Inc., Repligen Corp., Servier Laboratories, Solvay Pharmaceuticals Inc. /Wyeth Pharmaceuticals, and Supernus Pharmaceuticals Inc., some of which make drugs for bipolar disorder.

Dr. Bowden also has received funding from or been a speaker or consultant for Abbot, AstraZeneca, Bristol-Myers Squibb, Elan Pharmaceuticals, Janssen, Eli Lilly, Parke-Davis, Pfizer, Sanofi Synthelabo Inc., SmithKline Beecham, and UCB, some of which make drugs for bipolar disorder.

By Sherry Boschert, San Francisco Bureau
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Author:Boschert, Sherry
Publication:Clinical Psychiatry News
Date:Oct 1, 2008
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