Lamotrigine is an anticonvulsant that appears to have some mood-stabilizing properties and may even have some modest antidepressant effect. Lamotrigine’s mechanism of action is unknown. Animal models of self-injurious behaviour suggest glutamatergic interactions, and lamotrigine may inhibit neuronal glutamate release.
The initial dosage of lamotrigine is generally 25 mg once or twice daily, and this can be increased by 25 or 50 mg every week or 2 weeks. If a patient is taking valproate, start lamotrigine at 12.5 mg daily and increase the dosage by 12.5 or 25 mg every 2 weeks because of the drug–drug interaction: valproate doubles the plasma level of lamotrigine, and lamotrigine decreases the level of valproate by 25%. If a patient is taking carbamazepine, somewhat larger dosages and more rapid dosage increases are possible: carbamazepine lowers the concentration of lamotrigine in the blood, and lamotrigine increases the level of carbamazepine and its metabolites. Some patients may require a total dosage of up to 400 mg daily to benefit from this medication. Salzman has suggested that a dosage of 25 to 75 mg daily will probably be effective (1).
Open-label studies, case series, and individual reports indicate that lamotrigine may be efficacious in treating various psychiatric conditions, including posttraumatic stress disorder (PTSD) and bipolar disorder (BD). The manufacturer of lamotrigine is conducting several large multicentre studies of mania, bipolar depression, and maintenance treatment.
A double-blind placebo-controlled study has shown lamotrigine to be effective in treating acute bipolar depression: 195 patients were randomized into 3 groups (placebo, lamotrigine monotherapy 50 mg daily, or lamotrigine monotherapy 200 mg daily). Results indicated that patients randomized to lamotrigine 200 mg daily showed significantly greater improvement, compared with those randomized to placebo (2).
There are 3 case reports of lamotrigine use in patients with BD. In an open trial, Fogelson and Sternbach used lamotrigine to treat 5 women and 2 men, aged 28 to 54 years, for treatment-refractory BD (3). After 8 weeks of lamotrigine 200 to 400 mg daily, 3 patients (all with rapid-cycling BD) showed marked improvement, 2 showed moderate improvement , and 2 were unchanged. Two patients had monotherapy with lamotrigine, and the other 5 had concomitant psychotropic medications. One patient discontinued lamotrigine after 8 weeks, owing to nausea.
Calabrese and colleagues describe another patient with rapid-cycling BD who responded to lamotrigine (4). This 49-year-old man had failed to respond satisfactorily to individual trials of lithium, fluoxetine, and carbamazepine. After 8 weeks of lamotrigine monotherapy up to 200 mg daily, his depression symptoms decreased by about 80%. He continued taking lamotrigine and remained euthymic for 11 months.
Maltese reports 2 cases of middle-aged women with treatment-refractory depression who responded when lamotrigine was used as adjunctive therapy (5). The dosage range was 25 to 75 mg daily.
There are 5 open trials of lamotrigine use in patients with BD. In a study of valproate and lamotrigine in 18 normal volunteers, Anderson and colleagues found that valproate markedly increased the half-life of lamotrigine and decreased its clearance, while lamotrigine decreased plasma concentrations of valproate to a lesser degree (6). The authors recommend reducing lamotrigine dosages in patients taking this combination of antiepileptic drugs.
Walden and others report the case of a 39-year-old man with BD who failed to improve on several different combinations of medications following hospitalization for a manic episode (7). When lamotrigine was added to a regimen of valproic acid and trimipramine, the patient’s condition gradually improved over several weeks. His lamotrigine dosage of 150 mg daily had to be lowered to 100 mg daily when his lamotrigine blood levels increased threefold, presumably as a result of an interaction with valproate.
Sporn reports on lamotrigine’s apparent antidepressant and mood stabilizing effect in 8 of 16 patients (8). In this study, patients were taking other psychotropic medications in conjunction with lamotrigine. In a few cases, patients remained well for a long period of time, which suggests that lamotrigine might have helped the episode of mood disturbance and also might have mood-stabilizing effects.
Fatemi reports that both lamotrigine augmentation therapy and monotherapy appeared to have mood-stabilizing and antidepressant efficacy in the treatment of 5 patients with rapid-cycling BD (9). The effect persisted for an average of 7.5 months. Kusumakar reports on 7 patients with refractory rapid-cycling BD (10). Of this group, 4 patients responded to lamotrigine after 1 to 3 weeks of treatment. One elderly woman in this series was concurrently taking valproate. She developed a rash after 4 weeks, and lamotrigine was subsequently discontinued.
Calabrese and others report on an open trial of 75 patients with BD who were involved in a 48-week open-label prospective study (11). Of the 40 depression patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response with regard to reduced Hamilton Depression Rating Scale (HDRS) scores. Of the 31 patients with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, and nausea. As well, 9% developed a rash, which resulted in drug discontinuation. The mean age of patients in this study was 44 years (range 23 to 70 years).
In 2 unpublished double-blind studies, lamotrigine has been shown to prevent relapse or recurrence of depressive episodes, as well as preventing manic or hypomanic relapses and recurrences (12,13).
There is little in the literature about the use of new anticonvulsants such as gabapentin and lamotrigine in treating elderly patients with BD. We studied the effectiveness of adding lamotrigine to the treatment of inpatient geriatric patients with BD who were in the depressed phase and had been on both lithium and valproate for at least 3 months.
Patients for this study were over age 65 years and diagnosed with BD, based on DSM-IV criteria. They were admitted to a geriatric psychiatry inpatient unit for assessment and management of a depressive episode. There were no exclusion criteria. This trial of lamotrigine was given to the first 5 consecutively admitted patients. The patients had been taking both lithium and valproate for at least 4 months prior to the study. Lamotrigine was added because the depressive episode had not responded to a serotonin reuptake inhibitor (sertraline) or a tricyclic antidepressant (nortriptyline) after 2 months. We obtained informed consent from both patient and family. Lamotrigine was started at a dosage of 25 mg at bedtime, with weekly incremental increases of 12.5 mg daily until a total dosage of either 75 mg or 100 mg daily was obtained. Improvement was measured by clinical interview as well as by HDRS scores, both done by the same psychiatrist. Patients were reassessed at 6 weeks; if the HDRS scores had decreased by at least 50%, they were considered to have improved.
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