Lamotrigine plus quetiapine combination therapy in treatment-resistant bipolar depression
Department of Neuropsychiatry, Seoul National University Hospital, Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Chongno-Gu, Seoul, Republic of Korea
Department of Psychology, University of Miami, Coral Gables, FL, USA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USATerence A. Ketter, MD
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
BACKGROUND: Lamotrigine and quetiapine are commonly used in bipolar disorder, but there are no published systematic studies of their use in combination for treatment-resistant bipolar depression.
METHODS: We studied 39 trials in outpatients (15 with bipolar I disorder, 22 with bipolar II disorder, and 1 with bipolar disorder not otherwise specified; 1 patient had 2 trials) with depression resistant to quetiapine or lamotrigine who were taking a mean of 1.7 other prescription psychotropic medications. Patients were given either open-label lamotrigine or quetiapine naturalistically, for up to 12 weeks of combination therapy.
RESULTS: Lamotrigine (mean dose, 204.2 mg/d) plus quetiapine (mean dose, 188.5 mg/d) increased the euthymia rate (0.0% to 46.2%), decreased syndromal (79.5% to 30.8%) and subsyndromal (20.5% to 15.4%) depression rates, and improved Clinical Global Impression-Severity (mean change, –1.0) and Global Assessment of Functioning (mean change, +5.9) scores. Approximately one-fifth of patients discontinued therapy (20.5%) or required subsequent additional pharmacotherapy (20.5%). Only 10.3% discontinued due to adverse effects, and there was no significant change in mean body weight.
CONCLUSIONS: The findings of this uncontrolled open pilot study must be viewed with caution. However, randomized, double-blind, placebo-controlled studies are warranted to confirm the possibility that combination therapy with lamotrigine and quetiapine is effective and well tolerated in patients with treatment-resistant bipolar depression.
KEYWORDS: lamotrigine, quetiapine, combination therapy, bipolar depression
ANNALS OF CLINICAL PSYCHIATRY 2011;23(1):17–24
Although bipolar disorder is characterized by recurrent episodes of both depression and mood elevation, depressive symptoms are far more pervasive and treatment resistant than the symptoms of mood elevation.1,2 Furthermore, depressive episodes contribute crucially to morbidity, mortality,3 impaired function, and poor quality of life.4 The past decade has seen important advances in the pharmacotherapy of bipolar disorder,5 yet monotherapies often are inadequate, particularly for depressive symptoms. Consequently, the majority of patients receive combination therapy.6 Combinations of mood stabilizers and atypical antipsychotics are of particular interest, as recent years have brought new options in both therapeutic categories.
The mood-stabilizing anticonvulsant lamotrigine represents an important advance in the pharmacotherapy of bipolar disorder. Lamotrigine has been shown to prevent depressive episodes and has demonstrated good tolerability, aside from the risk of common benign and rare serious rash.7,8 Moreover, limited data suggest that lamotrigine monotherapy yields some benefit in acute bipolar depression,9,10 although to date, lamotrigine lacks an FDA indication for acute bipolar depression.
Adjunctive lamotrigine may be useful in acute treatment-resistant bipolar depression. A recent study included 66 outpatients with bipolar depression resistant to a combination of a mood stabilizer plus at least 1 antidepressant. Patients were randomized to open, adjunctive lamotrigine, inositol, or risperidone for up to 16 weeks. Recovery, defined as euthymia for 8 weeks, was seen in 24%, 17%, and 5% of patients, respectively.11 However, these differences were not statistically significant, perhaps due to limited statistical power related to the small sample size.
The newer atypical antipsychotics provide some advantages over the older typical antipsychotics, as they may relieve12-14 rather than exacerbate15 depressive symptoms. They also are less likely to cause tardive dyskinesia,16 which occurs more often in patients with mood disorders than those with schizophrenia.17 In contrast to antidepressants,18 atypical antipsychotics do not appear to increase the risk of treatment-emergent affective switch.12-14
Among the atypical antipsychotics, quetiapine is of particular interest. Not only is it efficacious for acute mania alone19,20 or in a 2-drug combination therapy with lithium or valproate,21,22 but it also has shown efficacy as monotherapy for acute bipolar depression.13,14 Quetiapine is the first atypical antipsychotic agent approved by the FDA for the treatment of acute depression in patients with bipolar I disorder (BD I) as well as patients with bipolar II disorder (BD II). Also, recent data suggest that quetiapine is superior to placebo for maintenance therapy with a 2-drug combination (added to lithium or valproate).23,24
Although there are substantial data regarding the efficacy of lamotrigine monotherapy and quetiapine monotherapy in the management of bipolar disorder, no published study to date has reported on the combination of quetiapine and lamotrigine in the complex patients encountered in clinical settings. In particular, studies of lamotrigine combined with quetiapine in patients that are already receiving other medications are lacking. We studied the acute effectiveness of lamotrigine plus quetiapine for treatment-resistant syndromal and subsyndromal depressive symptoms in a heterogeneous patient population receiving complex pharmacotherapy for bipolar disorder.
The Stanford Administrative Panel on Human Subjects approved the protocol for the assessment and longitudinal monitoring of naturalistic treatment, and all patients provided verbal and written consent prior to participation. At intake, participants were assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Affective Disorders Evaluation25and the Mini-International Neuropsychiatric Interview (MINI).26 They were followed longitudinally with the STEP-BD Clinical Monitoring Form.27 Between July 1, 2000, and February 28, 2006, we studied outpatients who experienced syndromal or subsyndromal mood symptoms despite treatment with quetiapine or lamotrigine. We evaluated the effects of adding open-label lamotrigine naturalistically to quetiapine therapy or adding quetiapine to lamotrigine.
Participants were adults (age >18) with a primary diagnosis of BD I, BD II, or bipolar disorder not otherwise specified (NOS), who were receiving outpatient treatment at the Stanford University Bipolar Disorder Clinic. Participants had syndromal or subsyndromal depressive symptoms, as defined in the DSM-IV-TR or STEP-BD, respectively. Subsyndromal symptoms consisted of having >2 pervasive DSM-IV-TR depressive symptoms but not meeting criteria for a DSM-IV-TR syndromal depressive, hypomanic, manic, or mixed episode. Patients were excluded if they had a primary diagnosis other than bipolar disorder; were already taking lamotrigine plus quetiapine combination therapy when first seen at the Stanford Clinic and therefore had incomplete baseline (immediately prior to starting combination therapy) data; lacking postbaseline data; taking lamotrigine or quetiapine as needed rather than consistently; and having both lamotrigine and quetiapine started simultaneously. Patients who required additional antidepressants or aripiprazole during lamotrigine plus quetiapine combination therapy were included. However, efficacy parameters for such patients were assessed at the time of adding an antidepressant or aripiprazole in order to avoid overestimating the efficacy of the lamotrigine plus quetiapine combination. In contrast, for such patients, safety and tolerability parameters were assessed at the last visit taking both lamotrigine and quetiapine, in order to avoid overestimating the safety/tolerability of the combination.
The primary effectiveness measure was the change in mood status defined by DSM-IV-TR and STEP-BD from baseline (immediately prior to adding lamotrigine or quetiapine) to the efficacy endpoint (last visit taking lamotrigine plus quetiapine combination therapy or time of adding an antidepressant or aripiprazole). Secondary effectiveness measures included changes from baseline to the efficacy endpoint in the Clinical Global Impression–Severity of Illness scale (CGI-S) and the weekly Global Assessment of Functioning (GAF). The proportions of patients who continued combination therapy with or without adding additional subsequent psychotropic medication(s) were assessed. Information about the time of and reason(s) for discontinuing combination therapy and adding subsequent psychotropic medication(s) was recorded. Safety and tolerability were assessed in participants who reported adverse events of at least moderate severity. Changes in body weight and body mass index (BMI) from baseline to the safety/tolerability endpoint (the last visit at which the patient was taking lamotrigine plus quetiapine) also were assessed.
SPSS version 12 was used for statistical analysis. All measures were analyzed using the last observation carried forward method. Thus, when discontinuation occurred before 12 weeks, data at 12 weeks were imputed from the last postbaseline data. Descriptive statistics were compiled. For changes in mood status, CGI-S, GAF, weight, and BMI, analytic statistics were assessed. χ2 or Fisher exact tests were used for categorical variables, and 95% confidence intervals (95% CIs) were used for continuous variables. All analytic statistical tests were 2-tailed, and results were considered significant if P values were <.05. There was no correction for multiple comparisons.
Thirty-nine trials in 38 patients were included in this study (37 patients had 1 trial, and 1 patient had 2 trials). Ten other trials were excluded due to incomplete baseline data (6 trials), lack of postbaseline data (2 trials), quetiapine being used as needed (1 trial), and both drugs being started simultaneously (1 trial). Among the 39 trials included, quetiapine was added in 26 (66.7%) patients already taking lamotrigine (adjunctive quetiapine group), while in the other 13 (33.3%) trials, lamotrigine was added in patients already taking quetiapine (adjunctive lamotrigine group). One patient having 2 adjunctive trial periods had both an adjunctive quetiapine trial and an adjunctive lamotrigine trial.
Baseline demographic and clinical characteristics of the entire sample and each adjunctive group are presented in TABLE 1. There were imbalances between the adjunctive groups of sufficient magnitude (ie, >10% difference) to raise concerns regarding confounding biases. In particular, the adjunctive lamotrigine group had numerically fewer females (53.8% vs 84.6%) and BD II patients (46.2% vs 65.4%) than the adjunctive quetiapine group. The adjunctive lamotrigine group also had numerically more patients with BD I (46.2% and 34.6%) and history of psychosis (38.5% vs 26.9%).
Baseline demographic and clinical characteristics
||All participants (n=38)a
||Adjunctive quetiapine group (n=26)
||Adjunctive lamotrigine group (n=13)
|Sex, female (%)
|Age (years, mean±SD, 95% CI)
[10.3 to 69.9]
[8.7 to 73.5]
[15.9 to 64.3]
Bipolar disorder I
Bipolar disorder II
Bipolar disorder NOS
|Onset age (years, mean±SD, 95% CI)
[3.4 to 33.4]
[5.6 to 30.4]
[-0.2 to +38.6]
|Duration of illness, years (mean±SD, 95% CI)
[-5.7 to +49.9]
[-8.0 to +54.4]
[0.9 to 40.9]
|Rapid cycling—ever (%)
|Rapid cycling—prior year (%)
|History of psychosis (%)
|History of psychiatric hospitalization (%)
|Comorbid mental disorder (%)
|History of alcohol or substance abuse (%)
|Lamotrigine or quetiapine treatment duration prior to combination (days, mean±SD, 95% CI)
[-588.0 to +1412.0]
|Lamotrigine duration 517.4±566.1
[-614.8 to +1649.6]
|Quetiapine duration 218.8±274.6
[-330.4 to +768.0]
|Lamotrigine or quetiapine dose when starting other agents (mg/d, mean±SD, 95% CI)
||Lamotrigine dose 227.8±146.8
[-65.8 to +521.4]
|Quetiapine dose 207.7±296.4
[-385.1 to +800.5]
Lamotrigine and quetiapine dosing; other psychotropic medications taken concurrently
Immediately prior to adding the adjunctive agent, patients were taking lamotrigine or quetiapine at mean doses of 227.8±146.8 mg/d and 207.7±296.4 mg/d, respectively. The duration of prior lamotrigine was numerically more than twice the duration of prior quetiapine (517.4 days vs 218.8 days, but with overlapping 95% CIs). Our practice of not adding new medications during the first 12 weeks of lamotrigine may have contributed to this result.28 Patients were taking a mean of 1.7±1.1 other prescription psychotropic drugs (other mood stabilizers, other antipsychotics, antidepressants, and anxiolytics) immediately prior to adding lamotrigine or quetiapine. The mean number of other prescription psychotropic drugs decreased numerically at the safety/tolerability endpoint (to 1.5±1.0), but the 95% CIs overlapped. The pattern of concurrent prescription psychotropic drug administration was similar in the 2 adjunctive groups when considered separately.
The mean starting dose of quetiapine was 44.5±36.4 mg/d in the adjunctive quetiapine group, and the mean starting dose of lamotrigine was 18.7±9.9 mg/d in the adjunctive lamotrigine group. Overall, at the safety/tolerability endpoint, quetiapine and lamotrigine doses were 188.5±214.8 mg/d and 204.2±135.6 mg/d, respectively. At the safety/tolerability endpoint, the mean dose of each drug was lower in the group that used it adjunctively. That is, the mean lamotrigine dose was lower in the adjunctive lamotrigine group (98.8±69.3 mg/d; 95% CI, –39.8 to 237.4) than in the adjunctive quetiapine group (256.9±130.3 mg/d; 95% CI, –3.7 to 517.5), with overlapping 95% CIs. Likewise, the mean quetiapine dose was lower in the adjunctive quetiapine group (158.7±161.9 mg/d, 95% CI –165.1 to 482.5) than in the adjunctive lamotrigine group (248.1±292.7 mg/d, 95% CI –337.3 to 833.5), with overlapping 95% CIs.
Change in mood status. At baseline, most patients (79.5%, 31/39) had syndromal depressive symptoms; a minority (20.5%, 8/39) had subsyndromal depressive symptoms. At the efficacy endpoint (last visit taking both lamotrigine and quetiapine or at time of adding an antidepressant or aripiprazole), mood status significantly improved (Fisher exact test-χ2 = 32.96, P < .001). Thus, the proportions of patients with syndromal and subsyndromal depression decreased from 79.5% to 30.8% (from 31/39 to 12/39) and from 20.5% to 15.4% (from 8/39 to 6/39), respectively. The proportion of patients with euthymic mood increased from 0.0% to 46.2% (0/39 to 18/39). In 7/39 trials (17.9%), patients attained recovered status, defined as 8 consecutive weeks euthymic. At the efficacy endpoint, 1/39 (2.6%) patient developed syndromal and 2/39 (5.1%) developed subsyndromal mood elevation. One patient who developed mood elevation had been taking an antidepressant since prior to starting the lamotrigine plus quetiapine combination. None of the patients who developed mood elevation had received additional adjunctive antidepressant medications to that point. The pattern of improvement was similar in the 2 adjunctive groups when considered separately.
Change in CGI-S and GAF. Changes in CGI-S and GAF from baseline to endpoint are summarized in TABLE 2. Overall, both CGI-S and GAF scores improved. Mean CGI-S decreased from 4.00±0.77 to 2.97±1.20 (95% CI for change, –1.37 to –0.63) and mean GAF increased from 56.6±7.0 to 62.5±7.6 (95% CI for change, 3.48 to 8.36). The 95% CIs for change did not cross 0 on the CGI-S or GAF for either treatment group, suggesting significant improvements. Improvements in the CGI-S (mean change, –1.20 vs –0.62) and GAF (mean change, +7.0 vs +3.9) were numerically greater in the adjunctive quetiapine group than in the adjunctive lamotrigine group, but the 95% CIs for change overlapped, suggesting no significant differences.
Discontinuations and additional pharmacotherapy. In 59.0% of trials (23/39) lamotrigine plus quetiapine combination therapy was continued for 12 weeks without the addition of new medications. In 20.5% (8/39) of trials, lamotrigine plus quetiapine combination therapy was continued, but additional psychotropic medication was added after a mean±SD of 35.0±30.4 days. In 17.9% (7/39) of trials, quetiapine was discontinued (after 54.3±24.9 days), while in 2.6% (1/39) of trials lamotrigine was discontinued (after 4 days). The reasons for quetiapine discontinuation included adverse effects of the medication (3 trials: sedation, dizziness, and akathisia in 1 patient each), ineffectiveness (2 trials), and patient choice (2 trials). In 1 patient, lamotrigine was discontinued because of diarrhea. The patterns of the above findings were similar in the 2 adjunctive groups when considered separately.
In 8/39 trials (20.5%) additional psychotropic medication(s) were administered subsequent to starting combination therapy: in 7 patients therapeutic agents were added for persistent depressive symptoms (antidepressants in 5 patients and aripiprazole in 2 patients), and in 1 patient zolpidem was added for insomnia. Exclusion of these 8 trials from the analysis of effectiveness did not alter the pattern of the results.
Adverse effects. Aside from 4/39 (10.3%) patients who discontinued combination therapy due to adverse effects, the combination of lamotrigine plus quetiapine was generally well tolerated. The proportions of patients who reported at least moderate adverse events at baseline and at the safety/tolerability endpoint are summarized in TABLE 3. The only adverse event to increase in frequency was dry mouth (absolute increase of 2.9%).
At the safety/tolerability endpoint, 2/39 (5.1%) patients developed syndromal and 2/39 (5.1%) developed subsyndromal mood elevation. As mentioned in the discussion of efficacy outcomes, 1 patient who developed mood elevation at this point had been taking an antidepressant since before starting the lamotrigine plus quetiapine combination. No patient who developed mood elevation had received additional adjunctive antidepressant medication. One patient developed transient hypomania prior to the addition of aripiprazole.
Body weight and BMI. Overall, from baseline to the safety/tolerability endpoint, mean weight and BMI decreased by 1.7 lbs and 0.29 kg/m2, respectively, but 95% CIs for these changes overlapped 0, suggesting statistical nonsignificance (TABLE 4). Numerically greater decreases in mean weight and BMI were seen in the adjunctive lamotrigine group than in the adjunctive quetiapine group (mean weight change, 2.7 vs 1.2 lbs; mean BMI change, 0.44 vs 0.22 kg/m2). However, the 95% CIs for these changes overlapped, suggesting the results were not statistically significant.
For all of the above analyses, the pattern of findings was similar when the 7 patients who received additional adjunctive antidepressants or aripiprazole were excluded, and when patients with BD I and with BD II/bipolar disorder NOS were considered separately.
Changes in CGI-S and GAF from baseline (immediately prior to lamotrigine plus quetiapine combination therapy) to efficacy endpoint (last observation taking lamotrigine plus quetiapine combination therapy or time of adding antidepressant or aripiprazole)
||95% CI of change
||-1.37 ~ -0.63
||-1.71 ~ -0.69
||-1.14 ~ -0.09
||3.48 ~ 8.36
||3.69 ~ 10.23
||0.21 ~ 7.64
Proportions of patients with at least moderate adverse effects at baseline (immediately prior to starting combination therapy) and safety/tolerability endpoint (last visit taking lamotrigine plus quetiapine)
||Baseline n (%)
||Endpoint n (%)
| Sexual dysfunction
Weight and BMI at baseline (immediately prior to starting combination therapy) and safety/ tolerability endpoint (last visit taking lamotrigine plus quetiapine)
||95% CI of change
||–4.62 to +1.23
||–5.30 to +2.93
|Adjunctive lamotrigine adjunctive
||–6.73 to +1.27
|BMI (kg/ m2)
||–0.76 to +0.18
||–0.87 to +0.43
||–1.09 to +0.21
In this naturalistic study assessing the acute effectiveness of lamotrigine plus quetiapine combination therapy in treatment-resistant bipolar depression, we found significant improvements in mood status, symptom severity, and global functioning. The discontinuation rate was moderate, and subsequent additional psychotropic mediations were not used in most cases. Aside from a modest rate of discontinuation due to adverse central nervous system effects with adjunctive quetiapine, lamotrigine plus quetiapine combination therapy was generally well tolerated and did not alter body weight or BMI.
Poor adherence in bipolar disorder patients often is related to treatment-emergent adverse effects.29 Lamotrigine monotherapy is well tolerated, aside from the risk of a rash that is usually benign, but can be serious.30 Quetiapine monotherapy may yield adverse effects such as sedation and weight gain.31 Our preliminary data extend these observations, suggesting that the lamotrigine plus quetiapine combination could be well tolerated, with only 4/39 (10.3%) patients discontinuing due to adverse effects, comparable pre- and post-treatment rates of adverse effects, and no significant changes in mean weight or BMI. Also, lamotrigine plus quetiapine combination therapy yielded low rates of syndromal (5.1%, 2/39) and subsyndromal (5.1%, 2/39) mood elevation at the safety/tolerability endpoint. Larger controlled studies of longer duration are needed to confirm these preliminary observations.
This study has noteworthy strengths and limitations. The sample was derived from a heterogeneous cohort of bipolar disorder patients with diverse comorbidities and medication regimens, suggesting more generalizability than might be inferred from controlled trials with restrictive inclusion and exclusion criteria. In particular, lamotrigine or quetiapine was added to quetiapine or lamotrigine plus an average of 1.7 other psychotropic medications, reflecting the complex combination pharmacotherapies used in clinical settings when managing treatment-resistant bipolar depression.
However, the findings of this study need to be approached with considerable caution in view of important limitations, including the brief duration (12 weeks), the lack of a control condition, and the small sample size (39 trials). An example of the latter is that only 15 participants had BD I, so that the benefits and risks for such patients may not be adequately represented in this study.
In this observational study, selection bias could contribute to clinical differences encountered with treatment. For example, patients with an inadequate response to quetiapine may have a more treatment-resistant illness than the patients who did not respond to lamotrigine. As a consequence of having more treatment-resistant illness, the quetiapine-resistant individuals (ie, the adjunctive lamotrigine group) showed numerically less improvement with their adjunctive treatment than the patients in the adjunctive quetiapine group, whose illness may be more amenable to treatment. Thus, selection bias could distort the comparison of adjunctive lamotrigine and adjunctive quetiapine.
Additional potentially confounding differences include having fewer females and fewer patients with BD II, and more patients with BD I and more patients with a history of psychosis in the adjunctive lamotrigine group than the adjunctive quetiapine group. Unfortunately, the limited sample size prevented the use of regression modeling to correct for these potential confounders. Moreover, the sample sizes of the adjunctive lamotrigine (n = 13) and adjunctive quetiapine (n = 26) groups were small enough to raise concerns about Type I error when comparing these treatments. Thus, particular caution must be used when considering the effects of adjunctive lamotrigine compared with adjunctive quetiapine.
In spite of the above-mentioned limitations, our observations support the contention that more research is indicated. These preliminary findings suggest that lamotrigine plus quetiapine combination therapy for treatment-resistant bipolar depression may be effective and well tolerated in a clinical setting. Controlled and additional observational studies appear warranted to confirm these results.
ACKNOWLEDGEMENTS: This project was funded by a grant from GlaxoSmithKline, Inc., Research Triangle Park, NC. The data in this article were presented at the 46th Annual Meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, USA, December 9-13, 2007. Abstract III-155.
DISCLOSURES: Dr. Ahn is an advisory committee member for AstraZeneca, Janssen, Pfizer, Inc., and Otsuka Pharmaceuticals, and also received grant/research support or served as a lecturer for AstraZeneca, GlaxoSmithKline, Janssen, L.P., Lundbeck, Pfizer, Inc., and Otsuka Pharmaceuticals. Dr. Bonner is a speaker for Pfizer, Inc. Drs. Culver, Marsh, and Nam report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Ketter has received grant/research support from AstraZeneca Pharmaceuticals LP, Cephalon, Inc., Eli Lilly and Company, Pfizer, Inc., and Sepracor, Inc.; has served as a consultant for Dainippon Sumitomo Pharmaceuticals and Merck; has received lecture honoraria from AstraZeneca Pharmaceuticals LP and GlaxoSmithKline; and has received publishing royalties from American Psychiatric Publishing, Inc. In addition, Dr. Ketter’s spouse, Dr. Nzeera Ketter is an employee and owns stock in Johnson and Johnson.
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CORRESPONDENCE: Terence A. Ketter, MD, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 2124 Stanford, CA 94305 USA E-mail: firstname.lastname@example.org
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