Dr. Shelton is assistant professor of psychiatry and head of clinical drug trials in the Mood Disorders Program in the Department of Psychiatry at Case Western Reserve University School of Medicine in Cleveland, Ohio.
Dr. Calabrese is professor of psychiatry and director of the Mood Disorders Program in the Department of Psychiatry at Case Western Reserve University School of Medicine.
Acknowledgments: Drs. Shelton and Calabrese have received grant support and honoraria from Glaxo- SmithKline Pharmaceuticals. No financial support was received for this particular work.
What was the rationale behind the development of lamotrigine (LTG) as a mood stabilizer? Patients demonstrated improvements in mood and sense of well-being during the clinical trials phase of LTG development as an antiepileptic drug. There were theoretical reasons to suppose that LTG might possess mood-stabilizing properties; mood swings may be associated with the kindling process, as are seizures. The different phases of bipolar disorder are not equally amenable to treatment. Pharmacotherapy of bipolar disorder must address both stabilization “from above” and “from below.” Bipolar depression and rapid-cycling bipolar disorder are particularly refractory to treatment with lithium and carbamazepine, and it is evident that further treatment options are needed for refractory mood states. Bipolar I depressed patients receiving LTG dosages of 200 mg/day and 50 mg/day showed significant improvement compared with placebo on several measures of depression. In addition, LTG was shown to be a useful treatment for patients with rapid-cycling bipolar II disorder. Furthermore, LTG was shown to be effective in preventing depressive episodes associated with bipolar I disorder over an 18-month randomized phase. LTG has not been shown to be effective in the treatment of mania or unipolar depression. Primary care providers and psychiatrists have been reluctant to prescribe LTG for bipolar disorder because of the drug’s tendency to cause rash; improved titration schedules have resulted in a dramatic reduction in the incidence of this side effect. A series of controlled studies investigating the use of LTG in bipolar disorder is in progress.
During the clinical development of lamotrigine (LTG) as a treatment for intractable seizures, anecdotal reports of mood improvements in LTG-treated patients were obtained.1,2 In 1994, Smith and colleagues2 pointed out that although reduced seizure frequency is an established benefit of LTG treatment, it remained unclear how to determine whether the reduction justified any inherent toxicity. They reasoned that resources are limited in treatment-refractory epilepsy. Thus, passing up an antiepileptic drug (AED) that might be of value to specifically defined patient subgroups is undesirable. Smith and colleagues concluded that there was a need to evaluate other AED efficacy measures that might be more sensitive than seizure frequency. Reasonable candidates, they thought, might be seizure severity and quality-of-life reports.
Using a crossover design, the investigators administered add-on LTG to 81 patients with various types of epilepsy. The patients were already receiving either enzyme-inducing AEDs (n=56) or both enzyme inducers and valproate (n=25). The principle variable of interest was seizure frequency. Among the secondary response variables were patients’ subjective reports of seizure severity, anxiety, depression, self-esteem, mastery, happiness, and mood. Results indicated no difference in the levels of depression reported by patients receiving LTG and those receiving placebo (PBO), but LTG-treated patients reported significantly higher levels of happiness and mastery, or perceived internal locus of control. There was no correlation between perceived happiness and changes in seizure frequency or severity.
The investigators concluded that LTG has an effect on mood independent of its antiepileptic effect. However, the study was limited by its choice of affective measures and the results were open to interpretation. There was no explanation offered for the fact that improvements were reported in self-esteem, mastery, and happiness, yet no comparable effect was seen on measures of anxiety and depression. The results of the mood analysis were discarded entirely because of a large variance. Because the study was constructed by a “standard design” we presume it was double-blinded, although that was not explicitly stated.
Lamotrigine and Bipolar Depression
To date, there have been approximately 16 open studies of LTG in the treatment of bipolar depression. The largest and most recent3 was an open 48-week trial of LTG as either add-on (n=60) or monotherapy (n=15) in patients with bipolar I and bipolar II disorder. Forty-one of the patients (55%) were rapid cyclers and 34 were not. Improvement from baseline was seen in patients with and without rapid cycling. Rapid cyclers showed less improvement than nonrapid cyclers in severe mania, but about equal improvement in mild-to-moderate mania and depression. Nonrapid cyclers showed greater improvement in severe manic symptoms than in depressive symptoms. This result is consistent with findings on valproate reported from this laboratory in the early 1990s4,5; evidence suggested more antimanic than antidepressant effects.
In the first double-blind, PBO-controlled, parallel-group evaluation of the efficacy of LTG monotherapy in bipolar depression, Calabrese and colleagues6 examined 195 depressed adult outpatients with bipolar I (not bipolar II) disorder for 7 weeks at 12 sites in the United States, 2 sites in the United Kingdom, and 2 sites in Australia. Sixty-six patients received PBO tablets, 63 received LTG 50 mg (25 mg BID), and 66 received LTG 200 mg/day (100 mg BID). Patients were “stratified” to balance the presence or absence of recent treatment with lithium, defined as presence or absence of plasma levels of at least 0.4 mmol/L or dosing of 600 mg/day for at least 1 month.
In contrast to early work by Smith and colleagues,2 response variables consisted of measures customarily used in studies of mood disorders—the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Mania Rating Scale (MRS, consisting of the first 11 items from the Schedule for Affective Disorders and Schizophrenia–Change Version), and the Clinical Global Impression Scales for Severity and Improvement (CGI-S and CGI-I, respectively). Analysis of variance was used to test for group differences in response variables at screening, baseline, day 4 of treatment, and weekly thereafter. A last observation carried forward (LOCF) analysis was also employed at the same points, as well as a responder analysis to detect any differences in the rate of response.
The LOCF analysis corrected any bias introduced by patients who dropped out of the study early, possibly before a drug effect was detectable. Results of the study showed significant differences between groups on most efficacy variables in both the LOCF and the observed endpoint data. Patients on LTG 200 mg showed improvement over PBO on all measures except the LOCF analyses of the 17-item and the 31-item HAM-D, and the 17-item HAM-D-observed analyses. Patients receiving LTG 50 mg also showed responses on major efficacy variables, but not as marked as those shown by the group taking LTG 200 mg. The effect of lithium pretreatment stratification was noncontributory. Importantly, LTG was not associated with switch rates that exceeded those of PBO, suggesting that an antidepressant effect was observed without evidence of destabilization.
Frye and colleagues7 have published the results of a controlled comparative study on the efficacy of LTG and gabapentin compared to PBO. Thirty-one patients with refractory bipolar and unipolar mood disorders were randomly assigned and then crossed over to each of the three 6-week monotherapy evaluations. LTG, but not gabapentin, was shown to possess acute antidepressant properties in depressed patients with bipolar disorder, compared with PBO.
Lamotrigine and Mania
In two separate PBO-controlled multicenter trials, LTG failed to demonstrate efficacy superior to that of PBO in acutely manic patients. The first trial lasted 3 weeks and compared LTG 50 mg with PBO, whereas the second trial employed 6 weeks of blinded augmentation and compared LTG 200 mg with PBO.8
Long-Term Efficacy of Lamotrigine
The long-term mood-stabilizing properties of LTG have been compared with lithium and PBO. Recently, manic patients (N=349) were enrolled in an 18-month maintenance study and randomized to maintenance therapy after stabilization on LTG monotherapy.9 Patients were then randomized to LTG (n=59), lithium (n=46), or PBO (n=70). Both LTG and lithium were shown to be significantly better than PBO in both analysis of survival and time to intervention for a mood episode. However, LTG was primarily effective in the prevention of depressive episodes, whereas lithium was primarily effective in the prevention of manic episodes.
A 27-site randomized, double-blind, PBO-controlled study of LTG prophylaxis in rapid cyclers was recently published,10 constituting the first controlled study of rapid cyclers. A pure cohort of 182 patients with bipolar I and bipolar II disorder was stabilized on LTG adjunctive therapy; the initial and ancillary psychotropic medications were then gradually withdrawn. At that point, 93 patients were randomized to LTG (titrated up to 500 mg/day) and 89 to PBO. Seventy-one percent had bipolar I disorder; stratification ensured a balanced assignment of patients with bipolar I and bipolar II disorder to each treatment group. Efficacy variables were time to a relapse-preventing intervention, survival time in study (time to dropout for any reason, including intervention), the 17-item HAM-D, MADRS, MRS, CGI-S, GAS, and retrospective life charting.
There was no significant difference between LTG and PBO groups in time to intervention, but the median LTG time to intervention was 18 weeks, compared with 12 weeks for PBO. The intergroup survival analysis was significant (P<.04). Median survival times were 14 weeks for LTG and 8 weeks for PBO. Importantly, stratification analyses showed consistently greater affective improvement in patients with bipolar II disorder compared to those with bipolar I disorder—an unexpected result in light of previously documented efficacy of LTG in bipolar I disorder. This finding supports the validity of bipolar II as a legitimate bipolar subtype according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition11 (DSM-IV). It also underscores the observation by Smith and colleagues,2 who suggested that it is important to examine drugs for efficacy in specific patient subgroups, even in the face of possible undesirable side effects.
Lamotrigine and Unipolar Depression
There has been one case study reported12 of a positive response to LTG when added to buspirone. The response was maintained after the discontinuation of buspirone at 6 weeks and for 16 months thereafter. To date, 371 unipolar depressed patients have received LTG monotherapy in three controlled studies.13,14 All three studies failed to show significant LTG treatment effects. One study7 examined the efficacy of LTG and gabapentin in a mixed cohort of 38 patients with treatment-refractory unipolar or bipolar depression, using a double-blind, randomized, crossover design. Patients in the LTG cohort showed significantly more improvement in symptoms than those taking PBO; patients taking gabapentin showed an intermediate degree of improvement. Improvement appeared to increase with increasing bipolarity (ie, unipolar<bipolar II<bipolar I.)
The use of LTG has been shown to be associated with an increased prevalence of benign rash and, rarely, more serious rashes. In all PBO-controlled, multicenter studies comparing LTG (n=979) with PBO (n=935), benign rash rates were 9.4% versus 8.2%, serious rash rates were 0.1% versus 0%, and no cases of Stevens-Johnson syndrome or toxic epidermal necrolysis were observed. Rash occurring within 5 days of beginning treatment is usually benign and often caused by other factors such as contact dermatitis and insect bites. Benign rash (present in 9% of adults) shows no systemic involvement, changes in complete blood cell count, or changes in differential cell count. A reasonable response is to retain or reduce and maintain the current dose for 10–14 days and follow clinically. Loratadine (10 mg/day) plus a topical agent such as 0.5% betamethasone can be used for pruritus. It is important to engage the patient in the treatment process. Patients must report any rash to the psychiatrist, and unexplained rashes should immediately be referred to a dermatologist.
Of greater concern are serious rashes, which necessitate the discontinuation of LTG treatment. Presentations and risk factors in the occurrence of such patients have been described. Initial risk factors include having tested positive for the human immunodeficiency virus (a 100-fold increase in incidence), the presence of systemic lupus erythematosus (a 10-fold higher incidence), corticosteroid treatment (a 4.4-fold increase), and history of a primary relative having manifested a serious rash after LTG treatment (as with other AED hypersensitivity reactions, as much as a 25% increase).15-17 Symptoms include fever, sore throat, malaise, facial involvement (eg, edema, involvement of lips, mouth, or eyes), and cervical lymphadenopathy. The rash may also be generalized (confluent). Hematologic changes may include neutropenia, thrombocytopenia, atypical lymphocytosis, leukocytosis, delayed eosinophilia, a left shift with toxic neutrophils present, and liver function test results that may be three times their normal values. Urinalysis may be remarkable for proteinuria and the presence of white blood cells.18 Treatment is by discontinuation of LTG and any concurrently administered enzyme inhibitor.
During the clinical development of LTG as an AED, anecdotal evidence suggested that the drug might improve the quality of life for many patients. Later, case studies, open trials, and blinded, PBO-controlled, randomized studies demonstrated clearly that LTG is effective in the treatment of bipolar disorder. The drug does not appear to be equally effective in all phases of the illness. Both open and PBO-controlled data suggest that LTG is more effective in the acute and prophylactic management of the depressed phase than in mania; double-blinded, PBO-controlled data suggest that the drug is useful in the treatment of patients with rapid-cycling bipolar disorder, particularly in those with bipolar II. This finding supports the validity of both rapid cycling and bipolar II as valid modifications to the DSM-IV diagnosis of bipolar disorder. The efficacy of LTG monotherapy in these two subgroups may be due to the frequent presentation of such patients in the depressed phase of the illness.
It has long been understood that treatment of bipolar disorder requires “stabilization from above” (ie, amelioration of manic and hypomanic symptoms), and that available medications such as divalproex and lithium are more effective in the treatment of (hypo-) mania than in depression. It is becoming equally clear that treatment must provide “stabilization from below” (ie, improvement in neurovegetative signs), with agents effective in depression.14 There is emerging consensus that complex regimens of combination therapy will be necessary in order to accomplish this in the immediate future. The possibility that there may exist an agent equally effective in the management of both phases of the illness awaits further investigation. PP
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