Abstract
Background
Approximately half of all patients with diagnosed bipolar disorder are prescribed 2 or more psychotropic medications. Lamotrigine was approved in 2003 for the maintenance treatment of bipolar I disorder. This study examined comparative effects of lamotrigine with and without concomitant medications.
Methods
A post hoc analysis of data from a prospective, open-label study of lamotrigine in 1175 patients with bipolar I disorder evaluated the clinical response to and quality-of-life and weight effects of lamotrigine as monotherapy and in patients receiving concomitant valproate, lithium, antipsychotics, or antidepressants. The study was originally designed to assess the rate of rash among patients instructed to use specific dermatologic precautions compared with those receiving usual care. Lamotrigine was administered for 12 weeks, including a 5-week titration, with target dose of 200 mg/d, adjusted as necessary for concomitant medication(s). Evaluations at baseline and week 12 included the severity component of the Clinical Global Impression-Bipolar Version scale, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, and weight and body mass index (BMI).
Results
Efficacy data were available for 1139 patients. Symptoms and quality-of-life mean scores improved following treatment in all patient groups. Quality-of-life scores improved significantly more in patients not receiving than in those receiving concomitant antipsychotics. There were no changes in weight or BMI after lamotrigine monotherapy or adjuvant therapy. Most patients were satisfied with lamotrigine treatment.
Conclusion
Lamotrigine was effective and well tolerated and appeared to have no effect on body weight when given as monotherapy or as adjunctive therapy with valproate, antipsychotics, lithium, or antidepressants to outpatients with bipolar I disorder in a 12-week open-label study.
Introduction
Bipolar disorder is a chronic and disabling condition that affects nearly 4% of American adults at some point during their lives.[1] Several classes of medications have demonstrated efficacy in treating symptoms of bipolar disorder, including lithium, anticonvulsants, antipsychotics, and antidepressants.[2] Patients with bipolar disorder usually require maintenance therapy to reduce the risk for relapse.[3] According to American Psychiatric Association (APA) treatment guidelines for bipolar disorder published in 2002,[3] empirical evidence most strongly supports the use of lithium and valproate for maintenance therapy, and possible alternatives include lamotrigine, carbamazepine, and oxcarbazepine. For patients treated with an antipsychotic agent during an acute manic episode, the APA guidelines recommend discontinuation of the antipsychotic agent after the resolution of the episode unless it is required to control persistent psychosis or to prevent recurrence. There is currently limited evidence demonstrating that antipsychotics are as effective as lithium or valproate for maintenance therapy.[4–6] However, patients who experience persistent subthreshold symptoms or breakthrough mood episodes may benefit from the addition to maintenance therapy of another mood-stabilizing agent, an atypical antipsychotic, or an antidepressant. The use of an antidepressant agent as monotherapy is not recommended for either acute or maintenance treatment because of the risk of precipitating a manic episode.
The anticonvulsant lamotrigine was approved by the US Food and Drug Administration in 2003 for the maintenance treatment of bipolar I disorder in adults and is currently the only medication approved to delay the time to occurrence of depressive as well as manic, hypomanic, and mixed episodes in patients with bipolar I disorder.[7–10] Lamotrigine was also associated with improved completion rates compared with placebo in a study of patients with rapid-cycling bipolar disorder, although most of the difference was seen in patients with bipolar II disorder.[11] The most common treatment-emergent adverse events among patients with bipolar I disorder receiving lamotrigine in 2 clinical trials of maintenance treatment included nausea, insomnia, and somnolence.[7] Unlike some other anticonvulsants and antipsychotics used to treat patients with bipolar disorder, such as valproate and olanzapine, lamotrigine is not associated with changes in body weight.[12–14]
Registration trials of treatments for bipolar disorder typically exclude patients who are taking other psychotropic medications or discontinue these medications before randomization. However, about half of all patients with bipolar disorder are prescribed 2 or more psychotropic medications.[15] Thus, it is important to examine the efficacy and safety of medications for bipolar disorder in patients taking various concomitant psychotropic drugs. A large 12-week, open-label, multicenter trial was conducted to assess the rate of rash among patients instructed to use specific dermatologic precautions compared with those receiving usual care; the primary results have been reported elsewhere.[16] The purpose of this post hoc analysis of data from that trial was to examine patients with bipolar disorder in a naturalistic setting receiving lamotrigine as monotherapy or adjunctive therapy with or without concomitant valproate, lithium, antipsychotics, or antidepressants.
Methods
A prospective multicenter open-label study of lamotrigine in patients with bipolar I disorder (GlaxoSmithKline protocol SCA40917) was performed at 188 sites in the United States. Institutional review board approval was obtained for each site, and all patients provided written informed consent before entering the study.
Patients
Subjects were enrolled on the basis of clinical judgment of the investigators. Patients were eligible to participate if they were 13 years or older and had been given a diagnosis, based on an unstructured clinical interview and review of available medical records, of bipolar I disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. [17] Those currently being treated for bipolar disorder were eligible if they were being treated with a stable regimen of psychotropic medications that did not include lamotrigine and had been initiated at least 2 months before study entry. Mood state was not specified. Patients whom the study investigator judged to have a medical condition or severe psychiatric symptoms that could interfere with study participation were excluded. Female patients of childbearing age who were pregnant or breast-feeding or were capable of bearing children and not using adequate contraceptive methods were also excluded.
Procedures
All participants in the study were to receive lamotrigine for 12 weeks, including a 5-week initiation/titration period and a 7-week continuation phase. Lamotrigine was titrated to a target dosage of 200 mg/d (range, 100-400 mg/d). The target dosage was adjusted as appropriate for patients receiving particular concomitant medications. Patients were given standard titration packs providing 25 mg/d of lamotrigine for the first 2 weeks, 50 mg/d for weeks 3 and 4, and 100 mg/d for week 5. Patients taking valproate and those taking carbamazepine, phenytoin, primidone, or phenobarbital were given special titration packs with those dosages halved and doubled, respectively. The investigator could lower the rate of titration or the dosage of lamotrigine during the 5-week titration period if a patient had difficulty tolerating the titration as scheduled. Although investigators were not permitted to add new medications or increase the dosages of concomitant medications to treat mood symptoms, they could reduce the dosages of concomitant medications to control side effects. Patients who in the investigator's judgment required an additional intervention to control mood symptoms were withdrawn from the study.
Subject visits were scheduled at screening/baseline, at the end of dosage titration (5 weeks), and at study end (12 weeks). Subjects were encouraged to contact the investigator more frequently if needed, and the investigator was able to contact the patient as clinically necessary. An interactive voice response system (IVRS) was used to assess quality of life and patient satisfaction with lamotrigine. Patients were instructed in the use of the IVRS during the baseline visit.
Measures and Statistics
Concurrent medications were recorded at baseline, week 5, and week 12. At these visits the investigators also assessed the patients' clinical response using the Clinical Global Impression-Bipolar Version (CGI-BPI) scale,[18] adapted for this study. Patients used the IVRS to complete the self-rated Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF)[19] at baseline and at the week-12 visit. Q-LES-Q-SF scores were assessed as percentage of the maximum possible score, ie, (total score – minimum score)/(maximum score – minimum score), with at least 5 of the 14 items non-missing. Height was measured at baseline. Weight (kg) was recorded at baseline, week 5, and week 12. Patients rated their satisfaction with their current treatment regimen at baseline and their satisfaction with lamotrigine as a treatment for their bipolar disorder at week 12. Patient satisfaction was rated on a Likert-type scale of 1 (very dissatisfied) to 7 (very satisfied), and the percentage of patients with a score of 6 (satisfied) or 7 (very satisfied) was summarized.
Body mass index (BMI, kg/m2) was calculated, and weight and BMI were summarized, for baseline and week 12. CGI-BP overall severity scores and Q-LES-Q-SF scores at baseline and week 12 were summarized from both observed data and last observation carried forward (LOCF) data. Because results were comparable, only the LOCF data are reported here. Patients who rated their satisfaction with lamotrigine with a score of 6 (satisfied) or 7 (very satisfied) were considered to be satisfied with their medication. The percentage of patients satisfied with their medication was summarized for the total subject sample and for each group of subjects.
Safety data on weight and BMI were summarized for all patients who received at least 1 dose of study medication (ie, the safety population). Clinical response data based on CGI-BP severity and Q-LES-Q-SF scores were summarized for all patients who received at least 1 dose of study medication and provided at least 1 assessment of clinical response during treatment; these patients constituted the intention-to-treat (ITT) population. Both safety and clinical response data were analyzed with paired t tests for comparisons of changes from baseline within groups and analysis of covariance controlling for baseline value, baseline CGI-BP overall severity score, age, sex, and region for comparisons between groups.
Results
Patients
Of the 1175 patients who received at least 1 dose of study medication, 1139 provided at least 1 clinical assessment during treatment. Table 1 summarizes the demographic characteristics of the safety population as well as concomitant psychiatric medication use and patient disposition. The age of patients (mean ± SD) was 42.2 ± 13.1 years, and 96.5% were older than 18 years. The majority of patients were female (64%) and of white ethnicity (90%).
Table 1.
Demographics, Concomitant Psychiatric Medication Use, and Patient Disposition (Safety Population)
| All Patients (N = 1175) | |
|---|---|
| Demographics and Psychiatric Medication Use | |
| Mean age (SD), years | 42.2 (13.1) |
| Female, n (%) | 757 (64) |
| Ethnicity, n (%) | |
| 42 (4) | |
| American Hispanic | 59 (5) |
| Black | 1055 (90) |
| White | 19 (2) |
| Other | |
| Most common concomitant medications,* n (%) | |
| Lithium | 267 (23) |
| Valproate | 260 (22) |
| Bupropion | 249 (21) |
| Quetiapine | 163 (14) |
| Citalopram | 142 (12) |
| Clonazepam | 141 (12) |
| Patient Disposition | |
| Completed study, n (%) | 867 (74) |
| Discontinued study prematurely, n (%) | |
| Adverse event | 180 (15) |
| Voluntary withdrawal (patient's decision) | 42 (4) |
| Lost to follow-up | 38 (3) |
| Protocol violation | 28 (2) |
| Other | 20 (2) |
Patients could be using more than one concomitant medication.
At the start of lamotrigine therapy, patients were taking a mean of 2.38 ± 1.45 prescription psychotropic medications. Of the 1175 patients constituting the safety population, 20% were being treated with lamotrigine monotherapy and 80% were receiving adjunctive lamotrigine (ie, lamotrigine in addition to 1 or more psychotropic drugs, including but not limited to valproate, lithium, antipsychotics, and antidepressants). Patients receiving therapy concomitant with lamotrigine consisted of 778 patients (66%) treated with antidepressants, 352 (30%) taking antipsychotics, 267 (23%) receiving lithium, and 260 (22%) taking valproate. The mean doses of lamotrigine ± SD for completers at week 12 were: 101.1 ± 30.43 for the 179 patients receiving valproate; 191.4 ± 57.51 for the 686 patients who were not taking concomitant valproate; 304.3 ± 108.7 for the 41 patients receiving carbamazepine, phenytoin, primidone, or phenobarbital; 184.1 ± 43.93 for the 646 patients not receiving valproate or carbamazepine (or phenytoin, primidone, or phenobarbital); 174.0 ± 59.98 for the 207 receiving lithium; and 165.3 ± 69.73 for the 659 patients not receiving lithium. Eight hundred sixty-seven patients (74%) completed the study (Table 1). The most common reasons for early withdrawal were adverse events, being lost to follow-up, and voluntary withdrawal (ie, patient's decision).
Clinical Response
On average, patients in the ITT population were mildly to moderately ill at baseline, with a mean CGI-BP overall severity score of 3.4 ± 1.32, and were minimally to mildly ill after 12 weeks of open-label treatment with lamotrigine, with a mean score of 2.4 ± 1.22 (P < .0001 for change from baseline).
Statistically significant improvement from baseline in CGI-BP overall severity mean scores was observed at week 12 in patients receiving lamotrigine monotherapy and adjunctive lamotrigine as well as in those patients taking lamotrigine with and without concomitant valproate, lithium, antipsychotics, or antidepressants (Table 2). Improvement from baseline was similar in patients taking lamotrigine monotherapy vs adjunctive lamotrigine (adjusted mean difference, 0.08; 95% confidence interval [CI], −0.08 to 0.24; P = .3336). There were no significant differences in clinical improvement between patients taking lamotrigine with vs without valproate (adjusted mean difference, −0.11; 95% CI, −0.26 to 0.05; P = .1764), lithium (adjusted mean difference, 0.08; 95% CI, −0.08 to 0.23; P = .3386), antipsychotics (adjusted mean difference, −0.10; 95% CI, −0.24 to 0.04; P = .1657), or antidepressants (adjusted mean difference, −0.02; 95% CI, −0.16 to 0.12; P = .7574).
Table 2.
CGI-BP Overall Severity Scores
| Regimen | Baseline Mean ± SD (n) | Week 12 Mean ± SD (n) | Change From Baseline Mean ± SD (n) |
|---|---|---|---|
| ITT population | 3.4 ± 1.32 (1138) | 2.4 ± 1.22 (1052) | −1.0 ± 1.29* (1051) |
| Lamotrigine monotherapy | 3.6 ± 1.34 (226) | 2.4 ± 1.24 (215) | −1.2 ± 1.33* (215) |
| Lamotrigine polytherapy | 3.4 ± 1.32 (912) | 2.4 ± 1.22 (837) | −1.1 ± 1.26* (837) |
| With concomitant valproate | 3.2 ± 1.43 (249) | 2.3 ± 1.26 (235) | −0.8 ± 1.40* (235) |
| Without concomitant valproate | 3.5 ± 1.29 (889) | 2.4 ± 1.21 (817) | −1.1 ± 1.25* (816) |
| With concomitant lithium | 3.1 ± 1.36 (260) | 2.2 ± 1.22 (241) | −0.9 ± 1.22* (241) |
| Without concomitant lithium | 3.5 ± 1.30 (878) | 2.4 ± 1.22 (811) | −1.1 ± 1.31* (810) |
| With concomitant antipsychotics | 3.4 ± 1.39 (346) | 2.4 ± 1.25 (325) | −1.0 ± 1.31* (324) |
| Without concomitant antipsychotics | 3.5 ± 1.29 (n = 792) | 2.4 ± 1.21 (n = 727) | −1.1 ± 1.28* (n = 727) |
| With concomitant antidepressants | 3.4 ± 1.29 (758) | 2.4 ± 1.22 (694) | −1.0 ± 1.28* (693) |
| Without concomitant antidepressants | 3.5 ± 1.38 (380) | 2.4 ± 1.23 (358) | −1.1 ± 1.32* (358) |
P < .0001 vs baseline.
Quality of Life
In the ITT sample, the Q-LES-Q mean score as a percentage of the maximum possible score increased from 50.6 ± 18.30 at baseline to 60.9 ± 19.48 after 12 weeks of lamotrigine treatment, with a mean increase of 10.1 ± 20.07 points (P < .0001). As shown in Table 3, quality-of-life mean scores improved significantly during open-label lamotrigine monotherapy or adjunctive therapy (P < .0001). Patients receiving lamotrigine with and without valproate (P < .0001), lithium (P < .0001), antipsychotics (P < .0001), and antidepressants (P < .0001) also showed significant improvement in quality-of-life scores. There were no significant differences in change in Q-LES-Q mean score as percentage of the maximum possible score between patients receiving lamotrigine monotherapy and those taking adjunctive lamotrigine (adjusted mean difference, −1.52; 95% CI, −4.41 to 1.38; P = .3039) or between patients receiving lamotrigine with and without valproate (adjusted mean difference, 0.88; 95% CI, −1.94 to 3.70; P = .5399), lithium (adjusted mean difference, 0.44; 95% CI, −2.29 to 3.16; P = .7531), or antidepressants (adjusted mean difference, 0.50; 95% CI, −2.00 to 2.99; P = .6958). However, patients without concomitant antipsychotics experienced greater improvement in quality-of-life scores than those with concomitant antipsychotics (12.7 vs 9.1), with a statistically significant adjusted mean difference of 3.62 (95% CI, 1.16 to 6.08; P = .0040).
Table 3.
Q-LES-Q Scores (% Maximum Possible Score)
| Regimen | Baseline Mean ± SD (n) | Week 12 Mean ± SD (n) | Change From Baseline Mean ± SD (n) |
|---|---|---|---|
| ITT population | 50.6 ± 18.30 (1139) | 60.9 ± 19.48 (914) | 10.1 ± 20.07* (914) |
| Lamotrigine monotherapy | 49.9 ± 18.324 (226) | 61.8 ± 18.65 (184) | 12.0 ± 20.13*† (184) |
| Lamotrigine polytherapy | 50.7 ± 18.30 (n = 913) | 60.9 ± 19.54 (n = 730) | 9.7 ± 20.04*† (n = 730) |
| With concomitant valproate | 53.1 ± 17.97 (249) | 61.3 ± 20.59 (193) | 7.9 ± 20.57* (193) |
| Without concomitant valproate | 49.9 ± 18.34 (890) | 60.8 ± 19.19 (721) | 10.7 ± 19.91* (721) |
| With concomitant lithium | 56.2 ± 18.07 (260) | 63.2 ± 18.21 (217) | 6.8 ± 18.74* (217) |
| Without concomitant lithium | 48.9 ± 18.04 (879) | 60.1 ± 19.81 (697) | 11.2 ± 20.37* (697) |
| With concomitant antipsychotics | 51.7 ± 18.29 (347) | 58.8 ± 19.71 (283) | 7.0 ± 19.83* (283) |
| Without concomitant antipsychotics | 50.1 ± 18.29 (792) | 61.8 ± 19.32 (631) | 11.6 ± 20.03* (631) |
| With concomitant antidepressants | 49.6 ± 18.09 (759) | 60.3 ± 19.63 (613) | 10.4 ± 20.20* (613) |
| Without concomitant antidepressants | 52.4 ± 18.60 (380) | 62.1 ± 19.14 (301) | 9.7 ± 19.83* (301) |
P < .0001 vs baseline;
P < .05 vs without respective concomitant medication(s).
Weight and BMI
In the safety population (N = 1175), lamotrigine treatment was not associated with significant changes in mean weight from baseline (188.1 ± 48.21 lb) to week 12 (188.9 ± 48.41 lb) (Table 4). The mean weight at baseline was significantly higher for patients taking valproate than for those not taking valproate (difference, −14.2 ± 47.77 lb; P < .0001) and in patients taking antipsychotics vs patients not taking antipsychotics (difference, −6.6 ± 48.04 lb; P < .05). However, in all groups, there were no additional changes in weight at week 12 of open-label lamotrigine treatment, and there were no differences in weight change between groups (lamotrigine monotherapy vs adjunctive lamotrigine: adjusted mean difference, −0.58; 95% CI, −1.97 to 0.78; P = .4031; valproate vs no valproate: adjusted mean difference, 0.12; 95% CI, −1.19 to 1.44; P = .8567; lithium vs no lithium: adjusted mean difference, −0.24; 95% CI, −1.49 to 1.02; P = .7106; antipsychotics vs no antipsychotics: adjusted mean difference, 0.36; 95% CI, −0.80 to 1.52; P = .5450; antidepressants vs no antidepressants: adjusted mean difference, −0.19; 95% CI, −1.35 to 0.97; P = .7487). When patients were stratified according to obesity status at baseline, no statistically significant changes in weight were observed at week 12 in nonobese patients (BMI < 30) from the safety population. Furthermore, no statistically significant weight change occurred in nonobese patients taking lamotrigine as monotherapy or adjunctive therapy, or taking lamotrigine with or without concomitant valproate, lithium, antipsychotics, or antidepressants. While no statistically significant change in weight was observed in obese patients from the safety population, obese patients treated with adjunctive lamotrigine, but not those receiving lamotrigine monotherapy, experienced modest but statistically significant weight loss at week 12 relative to baseline (-2.20 ± 19.33 lb, P = .04). No statistically significant changes in weight were observed in obese patients taking open-label lamotrigine with or without valproate, lithium, or antipsychotics or in those taking lamotrigine without antidepressants. However, in obese patients taking concomitant antidepressants, open-label lamotrigine was associated with a statistically significant decrease in weight at week 12 (mean change −1.10 ± 8.75 lb, P < .05).
Table 4.
Mean Weight (lb)
| Regimen | Baseline Mean ± SD (n) | Week 12 Mean ± SD (n) | Change From Baseline Mean ± SD (n) |
|---|---|---|---|
| Safety population | 188.1 ± 48.21 (1174) | 188.9 ± 48.41 (894) | −0.2 ± 8.10 (894) |
| Lamotrigine monotherapy | 181.4 ± 50.00 (238) | 183.6 ± 52.40 (178) | 0.7 ± 9.26 (178) |
| Adjunctive lamotrigine | 190.0 ± 47.62 (936) | 190.5 ± 47.27 (716) | −0.2 ± 7.80 (716) |
| With concomitant valproate | 199.1 ± 49.07 (259) | 199.1 ± 49.34 (190) | −0.2 ± 6.83 (190) |
| Without concomitant valproate | 184.7 ± 47.53 (915) | 186.1 ± 47.82 (704) | −0.0 ± 8.42 (704) |
| With concomitant lithium | 184.8 ± 43.12 (267) | 186.12 ± 43.1 (215) | 0.22±8.76 (215) |
| Without concomitant lithium | 188.32 ± 49.48 (907) | 189.2 ± 49.87 (679) | −0.22 ± 7.88 (679) |
| With concomitant antipsychotics | 192.7 ± 47.31 (351) | 193.8 ± 46.80 (275) | −0.4 ± 8.00 (275) |
| Without concomitant antipsychotics | 186.1 ± 48.48 (823) | 186.7 ± 49.01 (619) | 0.0 ± 8.16 (619) |
| With concomitant antidepressants | 188.5 ± 47.55 (777) | 188.3 ± 48.55 (599) | −0.2 ± 7.69 (599) |
| Without concomitant antidepressants | 187.2 ± 49.52 (397) | 188.7 ± 52.29 (295) | −0.0 ± 8.90 (295) |
P < .05 vs baseline
Similar results were observed for BMI. The mean BMI of the overall sample was 30.1 ± 7.23 kg/m2 at baseline and did not change significantly after 12 weeks of lamotrigine treatment (0.0 ± 1.34 kg/m2). BMI was not significantly altered in patients receiving lamotrigine monotherapy and adjunctive therapy or in patients taking lamotrigine with and without valproate, lithium, antipsychotics, or antidepressants (Table 5). There were no significant differences in change from baseline to week-12 BMI between groups (lamotrigine monotherapy vs adjunctive lamotrigine: adjusted mean difference, −0.08; 95% CI, −0.30 to 0.14; P = .4990; valproate vs no valproate: 0.01; 95% CI, −0.21 to 0.22; P = .9527; lithium vs no lithium: −0.05; 95% CI, −0.25 to 0.16; P = .6654; antipsychotics vs no antipsychotics: adjusted mean difference 0.04; 95% CI, −0.15 to 0.24; P = .6513; antidepressants vs no antidepressants: −0.06; 95% CI, −0.25 to 0.13; P = .5565).
Table 5.
Mean BMI (kg/m2)
| Regimen | Baseline Mean ± SD (n) | Week 12 Mean ± SD (n) | Change From Baseline Mean ± SD (n) |
|---|---|---|---|
| Safety population | 30.1 ± 7.23 (1174) | 30.2 ± 7.25 (894) | −0.0 ± 1.34 (894) |
| Lamotrigine monotherapy | 28.7 ± 7.37 (238) | 28.7 ± 7.71 (178) | 0.1 ± 1.54 (178) |
| Adjunctive lamotrigine | 30.5 ± 7.16 (936) | 30.5 ± 7.09 (716) | −0.1 ± 1.29 (716) |
| With concomitant valproate | 31.4 ± 7.27 (259) | 31.5 ± 7.54 (190) | −0.0 ± 1.41 (190) |
| Without concomitant valproate | 29.8 ± 7.18 (915) | 29.8 ± 7.13 (704) | −0.0 ± 1.07 (704) |
| With concomitant lithium | 1.2 ± 6.08 (267) | 29.4 ± 6.06 (215) | 0.0 ± 1.47 (215) |
| Without concomitant lithium | 30.4 ± 7.52 (907) | 30.4 ± 7.57 (679) | −0.0 ± 1.30 (679) |
| With concomitant antipsychotics | 31.4 ± 7.27 (259) | 31.5 ± 7.54 (190) | −0.1 ± 1.34 (275) |
| Without concomitant antipsychotics | 29.7 ± 7.18 (823) | 29.7 ± 7.19 (619) | 0.0 ± 1.34 (619) |
| With concomitant antidepressants | 30.4 ± 7.16 (777) | 30.4 ± 6.94 (599) | −0.0 ± 1.47 (599) |
| Without concomitant antidepressants | 29.5 ± 7.35 (397) | 29.6 ± 7.82 (295) | −0.0 ± 1.27 (295) |
P < .05 vs baseline.
Patient Satisfaction
The percentage of patients who were satisfied with their treatment improved from 34% with current treatment at baseline to 58% after 12 weeks of lamotrigine treatment (Figure)
The percentage of patients who were satisfied with lamotrigine therapy was similar for patients receiving lamotrigine monotherapy (54%) and adjunctive lamotrigine (60%). Patient satisfaction was also similar in patients receiving lamotrigine with (60%) and without (58%) concomitant valproate, with (60%) and without (58%) concomitant antipsychotics, with (64%) and without (60%) concomitant lithium, and with (59%) and without (56%) concomitant antidepressants.
Adverse Events
Adverse events were reported in 692 patients (59%) overall and were deemed to be drug-related in 452 (38%). Detailed information about adverse events in the overall study population is reported elsewhere.[13] Adverse events thought to be drug-related and reported in 5% or more of any of the patient groups in this analysis were headache, rash, dizziness, and tremor (Table 6). Serious adverse events were reported in 41 patients (3%) and were primarily psychiatric; only 1, a report of mania, was considered to be related to lamotrigine treatment.
Table 6.
Drug-Related Adverse Events (% of Patients) Occurring in 5% or More of Any Group
| Lithium | Lamotrigine | Valproate | Antipsychotics | Antidepressants | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event | All Subjects (N = 1175) | Yes (n = 267) | No (n = 908) | Monotherapy (n = 238) | Adjunctive (n = 937) | Yes (n = 260) | No (n = 915) | Yes (n = 352) | No (n = 823) | Yes (n = 778) | No (n = 397) |
| Headache | 5 | 6 | 5 | 6 | 5 | 4 | 5 | 3 | 6 | 5 | 5 |
| Rash | 4 | 4 | 4 | 6 | 4 | 5 | 4 | 4 | 4 | 3 | 6 |
| Dizziness | 4 | 3 | 4 | 3 | 4 | 5 | 3 | 3 | 4 | 4 | 3 |
| Tremor | 2 | 2 | 2 | 0 | 2 | 5 | 1 | 2 | 2 | 2 | 1 |
| Insomnia | 3 | 5 | 3 | 4 | 3 | 2 | 4 | 4 | 3 | 3 | 4 |
| Nausea | 3 | 5 | 3 | 3 | 3 | 2 | 4 | 3 | 3 | 4 | 3 |
Discussion
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[23–25] 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.
Acknowledgments
Editorial and submission assistance was provided by IntraMed Educational Group. This study was sponsored by GlaxoSmithKline.
Footnotes
Readers are encouraged to respond to the author at mnzarzar@earthlink.net or to Paul Blumenthal, MD, Deputy Editor of MedGenMed, for the editor's eyes only or for possible publication via email: pblumen@stanford.edu
Contributor Information
Michael N. ZarZar, Glenwood Psychiatric Associates, Raleigh, North Carolina Author's Email: mnzarzar@earthlink.net.
Jay Graham, US Clinical Psychiatry, Neurosciences Medicine Development Centre, GlaxoSmithKline, Research Triangle Park, North Carolina.
Jeremy Roberts, GlaxoSmithKline, Research Triangle Park, North Carolina.
Thomas Thompson, Neuroscience-Psychiatry, Medicine Development Center, GlaxoSmithKline, Research Triangle Park, North Carolina.
Kevin Nanry, GlaxoSmithKline, Research Triangle Park, North Carolina.
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