Effectiveness and Weight Effects of Open-Label Lamotrigine With and Without Concomitant Psychotropic Medications in Patients With Bipolar I Disorder

Michael N. ZarZar, MD; Jay Graham, PharmD; Jeremy Roberts; Thomas Thompson, MD; Kevin Nanry

In This Article


In a 12-week, open-label study, lamotrigine demonstrated a favorable clinical response and was not associated with weight gain in 1137 patients with bipolar I disorder. The results of the present post-hoc analysis are consistent with previous findings that lamotrigine was associated with improved mood symptoms[7] and quality-of-life scores[20] in patients with bipolar I disorder. The post-hoc analysis also suggests that the effects of lamotrigine are maintained in the presence of various concomitant medications. In the present analysis, patients who began taking lamotrigine as monotherapy and patients already receiving treatment who began taking lamotrigine as adjunctive therapy had similar degrees of clinical improvement over 12 weeks. Additionally, patients taking and not taking concomitant valproate, lithium, antipsychotics, or antidepressants experienced statistically significant improvement from baseline in their mean CGI-BP scores over 12 weeks of open-label lamotrigine treatment, with no statistically significant differences between groups.

All groups experienced improvement in quality-of-life scores (recorded as percentage of the maximum possible Q-LES-Q score) over 12 weeks of treatment with lamotrigine, with a mean improvement of 10.1 ± 20.07 percentage points in the ITT population. Patients receiving lamotrigine monotherapy had greater numerical mean improvement in quality-of-life scores compared with all other groups, although the difference in improvement between the lamotrigine monotherapy group (12.0 ± 20.13) and the adjunctive lamotrigine group (9.7 ± 20.04) was not statistically significant. Placebo-controlled studies are necessary to confirm the positive effect of lamotrigine on quality-of-life scores in patients with bipolar disorder. In a recent 8-week, placebo-controlled study of patients with bipolar I or bipolar II depression, quetiapine (300 and 600 mg/d) increased mean Q-LES-Q scores (as percentage of maximum possible score) by approximately 11 percentage points, and placebo improved Q-LES-Q scores by 6.4 percentage points (both doses of quetiapine significantly superior to placebo, P < .001).[21] In the present study, significantly greater improvement was observed in patients not taking concomitant antipsychotics than in those who were receiving antipsychotics, even after control for baseline clinical severity and quality of life, age, sex, and region, with an adjusted mean difference of 3.62 percentage points. The clinical relevance of these findings is not known.

Obesity is more prevalent in patients with bipolar disorder than in the general population.[22] Obesity is associated with a number of cardiovascular and other health problems[23,24,25] and appears to be correlated with poorer outcomes of treatment of bipolar I disorder.[26] In addition, medications used to treat bipolar disorder may contribute to weight gain and obesity. Specifically, weight gain has been associated with valproate;[27] the atypical antipsychotics clozapine and olanzapine, and to a lesser extent, risperidone and quetiapine;[28] and tricyclic antidepressants.[29,30] In the present study, patients taking concomitant valproate or antipsychotics weighed significantly more at baseline than patients not taking these medications. Patients did not gain additional weight after beginning lamotrigine treatment, regardless of whether they were taking concomitant valproate, lithium, antipsychotics, or antidepressants. These findings are consistent with other evidence of lamotrigine's overall neutral effect on weight.[14]

Long-term treatment with lamotrigine has been associated with weight loss in obese adult patients without psychiatric or seizure disorders[31] and obese patients with bipolar disorder.[32] The present analysis supports the earlier findings, as slight, nonsignificant weight loss was consistently observed in obese patients after 12 weeks of lamotrigine treatment, with or without various concomitant medications. Obese patients taking adjunctive lamotrigine and those taking concomitant antidepressants experienced a small but statistically significant weight loss over the course of the study. Long-term prospective studies in patients with bipolar disorder are needed to examine the effect on weight of lamotrigine given as monotherapy and as adjunctive therapy.

Patient satisfaction with medication may affect adherence to the treatment regimen, which is critical for preventing relapse in patients with bipolar disorder. Overall, about 70% more patients were satisfied with lamotrigine as their treatment for bipolar disorder (58%) than with their previous medication (34%). The percentage of patients who were satisfied with lamotrigine was similar regardless of whether the patient was taking concomitant valproate, lithium, antipsychotics, or antidepressants.

Large, open-label trials, such as the prospective study from which these data were drawn, provide information about clinical response and tolerability that cannot be derived from registration trials. Because of strict inclusion and exclusion criteria, patients enrolled in registration trials may not be representative of the clinical population receiving treatment with the medication once it is approved. Thus, results from the current analysis may apply more broadly to the clinic-based population of patients who are being treated for bipolar I disorder.

Findings from the present analysis should be considered within the context of the study. The demographic composition of the study sample (for example, 90% were white) may limit generalizability to patients of other ethnicities. Furthermore, results must be interpreted in light of the open-label study design and lack of a control group. Patients were not randomly assigned to concomitant medications, and selection biases may have affected the results of the present analysis. Data were not available about the patients' symptoms and quality of life before treatment with their concomitant medications or about the duration of treatment with these medications. In addition, the clinical significance of the changes from baseline in quality-of-life scores is not known. The effect of the coadministration of individual antipsychotics and antidepressants on the response to lamotrigine was not evaluated. Finally, many patients were taking multiple concomitant medications, some of which may have affected weight or clinical response.

Randomized, controlled, double-blind studies are needed to further examine the safety and efficacy of lamotrigine in patients taking various concomitant medications. Long-term studies are also needed. Furthermore, clinical trials are indicated to evaluate the safety and efficacy of switching to lamotrigine monotherapy for bipolar I patients who are still symptomatic during treatment with other psychotropic medications or are experiencing intolerable adverse effects of medication.

In summary, the results of the current analysis are consistent with the results of other studies showing that short-term treatment with lamotrigine improved overall clinical response and quality of life in patients with bipolar disorder and suggest that these benefits extend to patients taking concomitant valproate, lithium, antipsychotics, or antidepressants. Lamotrigine did not induce additional weight gain in patients taking psychotropic medications that increase weight. The majority of patients were satisfied with lamotrigine as treatment for their bipolar disorder. The results of this open-label study suggest that clinicians should consider lamotrigine as an alternative adjunctive therapy in appropriate patients with bipolar I disorder who are taking other psychotropic medications and continue to have symptoms. When lamotrigine is used as an adjunctive medication, the dosage should be adjusted in accordance with the prescribing information to account for pharmacokinetic interactions with valproate and carbamazepine or other medications.


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