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Lamictal: Miraculous? Not Quite
Lamictal (lamotrigine) has been approved! The only problem is that few people can quite comprehend what it's been approved for. A close reading of the the FDA's approval reveals more hedging than you'll find in a formal English garden. They seem to be saying that Lamictal is effective at delaying the occurrence of any mood episode in Bipolar I Disorder, but only when added to "standard therapy." But they take extra pains to assure us that they are not approving it for the treatment of depression.
As any astute follower of the psychiatric literature can surmise, such a lukewarm endorsement implies spotty research support, and this is true in the case of Lamictal. Let's take a peak.
Bipolar Depression. Lamictal is the only medication on the planet other than lithium (see TCR 1:7) to have demonstrated better efficacy than placebo for this condition. The 1999 study in question (1) was also the largest controlled study ever conducted in bipolar depression. Calabrese and colleagues randomly assigned 195 outpatients with bipolar I depression to three groups: Lamictal 100 mg BID, Lamictal 25 mg BID, and placebo. The trial lasted for 7 weeks, and at that point both doses of Lamictal outperformed placebo on the Hamilton Depression Scale, with the 200 mg dose working more quickly and robustly than the 50 mg dose.
"So," you ask, "why is Lamictal not approved for bipolar depression?" Because two other, even larger, studies could find no significant antidepressant efficacy for Lamictal when compared with placebo. Neither of these studies were published, but the results are available from the manufacturer if you ask your drug reps for them. As we all know, negative studies rarely get published, an unfortunate social and economic reality which probably leads to inappropriate drug prescribing.
Rapid-Cycling Bipolar Disorder. In 2000, the "Lamictal 614 Study Group" published what TCR will describe momentously as "The World's First And Only Placebo-Controlled Study Of Rapid-Cycling Bipolar Disorder." (2) Well, it's true! Open label studies have been done on other anticonvulsants in rapid cycling bipolar disorder, but none incorporated either a placebo group or random assignment. The results of this study? Forty one percent of the 45 patients taking Lamictal monotherapy were stable at the 6 month mark, versus only 26% of the 49 taking placebo (p = 0.03). Not a bad result, and since nothing else apprears to work in rapid cycling bipolar disorder (see TCR 1:8), you might as well give Lamictal a spin.
Also in 2000, a study was published comparing Lamictal, Neurontin, and placebo for the treatment of 31 hospitalized patients with "refractory mood disorders," most of whom were rapid cycling bipolar patients; all had failed prior trials of mood stabilizers (3). At the 6 week endpoint, 52% of the Lamictal monotherapy group (mean dose: 274 mg QD) responded, vs. only 26% of the Neurontin group (mean dose: 3,987 mg QD-really!) and 23% for placebo. This was a small study, but it certainly adds to our sense that Lamictal provides something special for rapid cycling bipolar patients.
Maintenance Treatment. Recently, a study was published in the Archives of General Psychiatry showing that Lamictal beat placebo in preventing relapse to depression over an 18 month period, though it did not do any better at preventing manic or hypomanic episodes (4). In this study, 349 manic or hypomanic bipolar patients were enrolled, and they were all given open label Lamictal for 8 to 16 weeks (100-200 mg QD). Half of these patients responded to Lamictal, and these 175 patients were randomized to three different possible groups for 18 months of maintenance treatment: Lamictal (100-400 mg QD), lithium (levels 0.8-1.1 mEq/L), or placebo. Before we get to the punchline, you might have noticed that this study was already "stacked" in favor of Lamictal. How? By only randomizing those patients who already responded to Lamictal; that is, patients whose particular version of bipolar disorder was the Lamictal-responsive kind.
Now that we've gotten our skeptical introduction out of the way, on to the results! Lamictal indeed prolonged time to a depressive episode, while lithium prolonged time to a manic, hypomanic, or mixed episode. That's the good news. The bad news is that only 50% of Lamictal patients survived the open label phase, and of these, only 52% survived the double blind phase without needing more meds. Thus, over the entire 21 months of the study, only 25% of Lamictal treated patients made it to the other end on Lamictal alone without needing an intervention.
This may not be as grim a statistic as it might seem. None of us would realistically expect a bipolar patient to be completely stable over the course of almost two years on only one medication. And the fact that 25% of Lamictal-treated patients achieved this goal seems in itself pretty impressive.
The Rash Problem. In general, the most common Lamictal side effects are headache, insomnia, sedation, GI side effects, and rash. Many of you are hesitant to prescribe it because of the risk of Stevens-Johnson syndrome. However, two sources of data give TCR a fairly warm and fuzzy feeling about the Lamictal rash risk. The first is a study published in 2002 by Calabrese and colleagues, who analyzed all of the available GlaxoSmithKline data on the use of Lamictal in mood disorders (5). A total of 2681 patients were analyzed (1198 on Lamictal, 1056 on placebo, 280 on lithium, and 147 on desipramine). In the controlled trials, not a single case of Stevens-Johnson Syndrome, or any other serious rash, occurred in Lamictal-treated patients; one case of serious rash occurred in the placebo group. What about benign rashes? The overall rate in the Lamictal group was 8.3%, not statistically different from the placebo rate of 6.4%. The other reassuring evidence comes from Germany, where a special registry exists to track cases of serious rashes. This data set reports a risk of Lamictalinduced SJ syndrome of only 2.0/10,000 for adults, not statistically different from the risk with Tegretol, Dilantin, or phenobarbital.
The bottom line on Lamictal seems to be that it helps to delay depressive relapses in bipolar patients, and that it may be as good as any molecule under the sun for treating rapid-cycling patients, especially those who have failed prior treatments. Lamictal is also worth a try for acute bipolar depression, but the data is mixed. Don't use it as monotherapy for acute mania, however, since two unpublished studies have shown it to be ineffective for this (6).
TCR VERDICT:
Lamictal: A Nice Addition, But no Cure-All
1. Calabrese JR, Bowden CL, Sachs GS, et al. A double- blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
2. Calabrese JR, Suppes T, Bowden CL, et al. A double- blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61:841-850.
3. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo- controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.
4. Bowden CL, Calabrese JR, Sachs G, et al. A placebo- controlled 18 month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psych. 2003;60:392-400.
5. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood disorders: Clinical relevance and management. J Clin Psychiatry. 2002;63:1012-1019.
6. Data on file, GlaxoSmithKline
General PsychiatryAs any astute follower of the psychiatric literature can surmise, such a lukewarm endorsement implies spotty research support, and this is true in the case of Lamictal. Let's take a peak.
Even the FDA can’t seem to decide what Lamictal is most useful for.
Bipolar Depression. Lamictal is the only medication on the planet other than lithium (see TCR 1:7) to have demonstrated better efficacy than placebo for this condition. The 1999 study in question (1) was also the largest controlled study ever conducted in bipolar depression. Calabrese and colleagues randomly assigned 195 outpatients with bipolar I depression to three groups: Lamictal 100 mg BID, Lamictal 25 mg BID, and placebo. The trial lasted for 7 weeks, and at that point both doses of Lamictal outperformed placebo on the Hamilton Depression Scale, with the 200 mg dose working more quickly and robustly than the 50 mg dose.
"So," you ask, "why is Lamictal not approved for bipolar depression?" Because two other, even larger, studies could find no significant antidepressant efficacy for Lamictal when compared with placebo. Neither of these studies were published, but the results are available from the manufacturer if you ask your drug reps for them. As we all know, negative studies rarely get published, an unfortunate social and economic reality which probably leads to inappropriate drug prescribing.
Rapid-Cycling Bipolar Disorder. In 2000, the "Lamictal 614 Study Group" published what TCR will describe momentously as "The World's First And Only Placebo-Controlled Study Of Rapid-Cycling Bipolar Disorder." (2) Well, it's true! Open label studies have been done on other anticonvulsants in rapid cycling bipolar disorder, but none incorporated either a placebo group or random assignment. The results of this study? Forty one percent of the 45 patients taking Lamictal monotherapy were stable at the 6 month mark, versus only 26% of the 49 taking placebo (p = 0.03). Not a bad result, and since nothing else apprears to work in rapid cycling bipolar disorder (see TCR 1:8), you might as well give Lamictal a spin.
Also in 2000, a study was published comparing Lamictal, Neurontin, and placebo for the treatment of 31 hospitalized patients with "refractory mood disorders," most of whom were rapid cycling bipolar patients; all had failed prior trials of mood stabilizers (3). At the 6 week endpoint, 52% of the Lamictal monotherapy group (mean dose: 274 mg QD) responded, vs. only 26% of the Neurontin group (mean dose: 3,987 mg QD-really!) and 23% for placebo. This was a small study, but it certainly adds to our sense that Lamictal provides something special for rapid cycling bipolar patients.
Maintenance Treatment. Recently, a study was published in the Archives of General Psychiatry showing that Lamictal beat placebo in preventing relapse to depression over an 18 month period, though it did not do any better at preventing manic or hypomanic episodes (4). In this study, 349 manic or hypomanic bipolar patients were enrolled, and they were all given open label Lamictal for 8 to 16 weeks (100-200 mg QD). Half of these patients responded to Lamictal, and these 175 patients were randomized to three different possible groups for 18 months of maintenance treatment: Lamictal (100-400 mg QD), lithium (levels 0.8-1.1 mEq/L), or placebo. Before we get to the punchline, you might have noticed that this study was already "stacked" in favor of Lamictal. How? By only randomizing those patients who already responded to Lamictal; that is, patients whose particular version of bipolar disorder was the Lamictal-responsive kind.
Now that we've gotten our skeptical introduction out of the way, on to the results! Lamictal indeed prolonged time to a depressive episode, while lithium prolonged time to a manic, hypomanic, or mixed episode. That's the good news. The bad news is that only 50% of Lamictal patients survived the open label phase, and of these, only 52% survived the double blind phase without needing more meds. Thus, over the entire 21 months of the study, only 25% of Lamictal treated patients made it to the other end on Lamictal alone without needing an intervention.
Lamictal Dosing Guidelines
- Usual Dosing — 25 mg QD X 1 week, increase by 25 mg per week
- Dosing with Depakote or in patients with a history of any drug rash — 5 mg QD X 1 week, increase by 12.5 mg per week
- Rash risk — is maximal during first few months of treatment
This may not be as grim a statistic as it might seem. None of us would realistically expect a bipolar patient to be completely stable over the course of almost two years on only one medication. And the fact that 25% of Lamictal-treated patients achieved this goal seems in itself pretty impressive.
The Rash Problem. In general, the most common Lamictal side effects are headache, insomnia, sedation, GI side effects, and rash. Many of you are hesitant to prescribe it because of the risk of Stevens-Johnson syndrome. However, two sources of data give TCR a fairly warm and fuzzy feeling about the Lamictal rash risk. The first is a study published in 2002 by Calabrese and colleagues, who analyzed all of the available GlaxoSmithKline data on the use of Lamictal in mood disorders (5). A total of 2681 patients were analyzed (1198 on Lamictal, 1056 on placebo, 280 on lithium, and 147 on desipramine). In the controlled trials, not a single case of Stevens-Johnson Syndrome, or any other serious rash, occurred in Lamictal-treated patients; one case of serious rash occurred in the placebo group. What about benign rashes? The overall rate in the Lamictal group was 8.3%, not statistically different from the placebo rate of 6.4%. The other reassuring evidence comes from Germany, where a special registry exists to track cases of serious rashes. This data set reports a risk of Lamictalinduced SJ syndrome of only 2.0/10,000 for adults, not statistically different from the risk with Tegretol, Dilantin, or phenobarbital.
The bottom line on Lamictal seems to be that it helps to delay depressive relapses in bipolar patients, and that it may be as good as any molecule under the sun for treating rapid-cycling patients, especially those who have failed prior treatments. Lamictal is also worth a try for acute bipolar depression, but the data is mixed. Don't use it as monotherapy for acute mania, however, since two unpublished studies have shown it to be ineffective for this (6).
TCR VERDICT:
Lamictal: A Nice Addition, But no Cure-All
1. Calabrese JR, Bowden CL, Sachs GS, et al. A double- blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
2. Calabrese JR, Suppes T, Bowden CL, et al. A double- blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61:841-850.
3. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo- controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.
4. Bowden CL, Calabrese JR, Sachs G, et al. A placebo- controlled 18 month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psych. 2003;60:392-400.
5. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood disorders: Clinical relevance and management. J Clin Psychiatry. 2002;63:1012-1019.
6. Data on file, GlaxoSmithKline
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