In this article, clinically relevant research is briefly discussed and, perhaps more important, a few tips on how to read and interpret research studies are presented. Your feedback, suggestions, and questions are eagerly solicited at [email protected].
More efficacious treatments are sorely needed for the treatment of the major depressive episodes of bipolar I and bipolar II disorders (“bipolar depression”). For example, lamotrigine has been found to be more effective than placebo for delaying occur-rence of both depressive and, to a lesser extent, manic episodes during 18 months in patients with bipolar I disorder (who were recently or currently in a manic, mixed, or depressive episode and whose condition was first stabilized with the use of lamotrigine).1 Its efficacy in the acute phase of bipolar depression is, however, much less clear.
The published literature on the treatment of acute bipolar depression with lamotrigine was somewhat misleading until recently. One clinical trial found lamotrigine to be more efficacious than placebo on at least some of the outcome measures.2
The American Psychiatric Association’s practice guideline for bipolar disorder advocates using lamotrigine as one of the first-line options for bipolar depression.3 However, 4 other randomized, placebo-controlled clinical trials (similar in size to the published one) were not published (although the results of 1 of these 4 were mentioned as part of a review article). These 4 trials did not find lamotrigine to be more efficacious than placebo on most of the outcome measures. This was a prominent example of publication bias in which studies that fail to find a treatment to be effective are much less likely to be published, thus significantly biasing the published literature in favor of the proposed treatment.4
TIP: In assessing whether a particular treatment is efficacious for a particular disorder, or reading a review or meta-analysis that attempts to do this, it is essential that all randomized, controlled clini-cal trials on the topic be taken into consideration. Unfortunately, this is commonly not done, so readers must be vigilant for this.
Finally, in 2008 the results of all 5 randomized, placebo-controlled studies of the efficacy of lamotrigine monotherapy for acute bipolar depression were published in a single article.5
These studies randomized about 200 patients each and lasted for 7 to 10 weeks. Three of the studies included only patients with bipolar I disorder, 1 included only those with bipolar II disorder, and 1 included patients with both. The final dosage of lamotrigine was 200 mg/d in 3 studies, 1 study compared 50 mg/d and 200 mg/d with placebo, and 1 study used a flexible dosage between 100 and 400 mg/d.
In each study, 1 of the 2 clinician-rated depression severity scales that were completed in all 5 studies (Hamilton Depression Rating Scale [HDRS] and the Montgomery-Asberg Depression Rating Scale) was identified as the “primary” outcome measure. Other outcome measures (for example, the Clinical Global Impression–Severity scale, and the Clinical Global Impression–Improvement scale) were considered “secondary” outcome measures.
TIP: Why have multiple outcome measures? In clinical trials, it is standard practice to measure the same outcome by more than 1 method and to evaluate a variety of outcomes. This is because different outcome measures may capture a different aspect of change and to a different extent. For example, rating scales for severity of depression that cover a specified list of symptoms in a specified way may reach different conclusions from the Clinical Global Impression–Improvement scale in which clinicians assess patients and simply rate the patient as being “minimally improved,” “much improved,” “very much improved,” and so on.
TIP:Why would 1 of the measures be identified as the “primary” outcome measure? Statistical testing is based on probability. The more times you flip a coin, the more chances that there will be at least 1 tail. Similarly, if multiple statistical tests are done to compare several different outcome measures, this increases the likelihood that at least 1 of the tests will be “statistically significant” just by chance. Therefore, researchers should identify in advance that 1 of the comparisons is the “primary” outcome measure.
The difference in improvement in severity of depression between patients treated with lamotrigine or placebo, on the basis of the depression rating scale that was the predefined primary outcome measure for that study, was not statistically significant in any of the 5 studies (ie, was not such that it was unlikely to have been due to chance). In 1 study, lamotrigine was statistically significantly better than placebo on improvement as assessed by important secondary outcome measures.2,5 In the other 4 studies, however, lamotrigine was not statistically significantly better than placebo even on the secondary outcome measures.5
TIP: When a treatment is found not to be statistically significantly more efficacious than placebo, this could be because either (1) the patients receiving the drug were not improving much, or (2) the patients receiving the placebo were improving almost as much as those receiving the drug. This distinction should be obvious but is commonly ignored.
Looking at the mean improvement on the various outcome measures in these 5 studies, it appears that the mean improvement with lamotrigine in all 5 studies was broadly similar; however, in 4 of the studies, patients who received placebo also improved nearly as much, thus largely obliterating the drug-placebo difference.
TIP: When drug-placebo differences are small, or when different studies on the same question don’t agree—both of which were true in this case—one approach may be to combine the data from all patients in all the studies. This is called a “pooled analysis.”
A pooled analysis of individual data of the 1072 patients who had participated in these 5 trials was in fact performed and published in 2009.6 On the basis of a 50% reduction in the HDRS score, 44% of patients who received lamotrigine were “responders” compared with 35% who received placebo, and this difference was statistically significant (ie, unlikely to be due to chance).
TIP: In assessing how well a treatment works, having large numbers of patients in a study or pooling data from various studies may allow us to conclude—even for small differences between the treatment groups—that these differences are probably real. We must keep in mind, however, that such statistically significant differences may nevertheless be of too small a magnitude to be of clinical significance.
In this pooled analysis, there was only a 9% difference in the proportion of patients who were responders (had a 50% or more reduction in the severity of depression) in the lamotrigine and the placebo groups.
TIP: In all instances, it is very important that we assess the efficacy of a treatment not only for the patient group as a whole but also for clinically relevant subgroups on the basis of our knowledge of the disorder. In many cases, a subgroup can be identified that is much more likely to respond to a particular treatment. Clinicians may then think differently about the proposed treatment for each of the subgroups.
In a planned subgroup analysis for patients with more severe depression (HDRS score ≥ 23), lamotrigine was statistically significantly better than placebo. In this subgroup, 46% of the patients in the lamotrigine group were responders compared with 30% in the placebo group, a 16% difference. On the other hand, a higher proportion of patients with less severe depression (ie, HDRS ≤ 24) responded to placebo (45%) and there was no statistically significant difference between the proportion of responders who received lamotrigine (48%) and the proportion of those who received placebo.
TIP: Since post hoc subgroup analyses can be a way of trying to salvage a study that failed to find a statistically and/or clinically significant effect, it is important to see whether a subgroup analysis was planned (as in this study) or was part of a “fishing expedition” after the study. If it was not planned, we should (1) think about whether the subgroup makes sense on the basis of our knowledge of the disorder; and (2) consider the findings of the subgroup analyses to be tentative or “hypothesis generating,” with verification in future studies being essential.
Putting the results into clinical context
A key factor in considering the potential use of lamotrigine to treat acute bipolar depression is that lamotrigine takes several weeks to titrate. On the one hand, in 7- to 10-week studies this reduces the amount of time that patients receive the final dose of lamotrigine being tested. On the other- hand, a longer duration increases the chances that patients in the placebo group may improve as well, because of spontaneous improvement, or the supportive experience of being in a clinical trial, or both.
A 9% drug-placebo difference overall is just below what is commonly considered to be clinically meaningful. (A 10% to 20% drug-placebo difference is commonly considered clinically meaningful, depending on the seriousness of the disorder, cost and adverse effects of the treatment, and so on.) However, the drug-placebo difference was more substantial in patients who had more severe depression.
While this article focuses mainly on lamotrigine, medications recommended as first-line treatment options for acute bipolar depression also include lithium, quetiapine, olanzapine, and the SSRIs.7 Of these, the olanzapine/fluoxetine combination (OFC) and quetiapine have received FDA approval for use in bipolar depression. Critical review of the data that support the efficacy of these and other treatments is beyond the purview of this article. It seems that some of these alternative treatments may be effective. For example, the proportion of responders in the initial 2 quetia-pine trials was 61% versus 39% for those who received placebo, a difference we would consider clinically meaningful.8 However, there is a paucity of what the clinician sorely needs—unbiased studies that compared the efficacy of these treatments in the same study (“head-to-head”). I am unaware of any study that compares the efficacy of lamotrigine with that of quetiapine for acute bipolar depression.
TIP: Since study samples and study design can vary considerably, it is highly inadvisable to do a simple comparison of the efficacy results for 2 medications if they were from 2 different studies. One medication should be considered more efficacious than the other only if the 2 were directly compared in the same study and the study design was not substantially biased in favor of 1 of the medications.
Lamotrigine and OFC were directly compared in the same clinical trial after 7 and 25 weeks of treatment.9,10 OFC was found to be statistically significantly more efficacious than lamotrigine on several, but not all, outcome measures. At the end of 6 months, the proportion of patients who were responders was 64.4% for OFC and 55% for lamotrigine. This difference, while statistically significant, is again just below the threshold usually accepted as being clinically significant. On the other hand, OFC also had more treatment-emergent adverse effects and a greater incidence of clinically significant weight gain (defined by convention as 7% or more of the patient’s baseline weight; 34% with OFC vs 2% with lamotrigine) and of new-onset hypercholesterolemia (16% with OFC vs 4% with lamotrigine).
When all is said and done, should we use lamotrigine as one of the treatment options for acute bipolar depression? First, not all potential treatments for acute bipolar depression are as effective as quetiapine and OFC seem to be. Second, in addition to data on efficacy of these medications, the considerable differences in the incidence of adverse effects that may be medically serious is critical to the choice of the medication for a particular patient. Finally, if a particular medication has already been considered as the one that a particular patient will probably take for maintenance treatment, while this is not absolute, this is an important factor in support of its use for the acute depression as well. Thus, lamotrigine is appropriately considered by various practice guidelines as one of the first-line options for acute bipolar depression.
Dr Mago is director of the Mood Disorders Program at Thomas Jefferson University in Philadelphia.
1. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65:432-441.
2. 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.
3. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
4. Nassir Ghaemi S, Shirzadi AA, Filkowski M. Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder. Medscape J Med. 2008;10:211. http://www.medscape.com/viewarticle/579046. Accessed February 4, 2010.
5. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10:323-333.
6. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4-9.
7. Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11:225-255.
8. Weisler RH, Calabrese JR, Thase ME, et al. Efficacy of quetiapine monotherapy for the treatment of depressive episodes in bipolar I disorder: a post hoc analysis of combined results from 2 double-blind, randomized, placebo-controlled studies. J Clin Psychiatry. 2008;69:769-782.
9. Brown EB, McElroy SL, Keck PE Jr, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry. 2006;67:1025-1033.
10. Brown E, Dunner DL, McElroy SL, et al. Olanzapine/fluoxetine combination vs lamotrigine in the 6-month treatment of bipolar I depression. Int J Neuropsychopharmacol. 2009;12:773-782.