Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report

The growing population of elders is increasing the attention to bipolar disorder (BD) in late life (1, 2). The scant relevant literature highlights the challenges of treating BD in older adults, including greater medical comorbidity and lower tolerance to standard pharmacotherapies than in younger patients (3-6). Evidence specific to geriatric BD is urgently needed (7, 8). While depressive symptoms contribute to reduced quality of life among BD elders (4), there are no published prospective studies of the treatment of geriatric bipolar depression. The challenge of managing bipolar depression in mixed-age populations has been highlighted by previous reports (9-12), and a limited number of medications have been shown to be efficacious for bipolar depression. In addition to the possible precipitation of mania or rapid cycling (13, 14), the addition of multiple psychotropic agents to stabilize mood and treat depression is of concern in older adults due to the risks associated with polypharmacy (15, 16). Lamotrigine was approved by the U.S. Food and Drug Administration for the treatment of epilepsy in 1994, and for the maintenance treatment of BD in 2003. Meta-analysis and meta-regression of monotherapy randomized controlled trials (RCTs) suggest minimal to modest efficacy for lamotrigine in acute bipolar depression (17, 18). However, lamotrigine is widely used in clinical settings for the treatment of bipolar depression, typically in combination with other agents. A recent study of combined lamotrigine and lithium in bipolar depression demonstrated significant improvement and good tolerability in mixed-age adults (19). A literature review and a secondary data-analysis of lamotrigine in older adults with BD (20, 21) suggest that lamotrigine is well tolerated and efficacious, with particular benefit against depressive relapse. The secondary analysis (20) focused on older adults (≥ 55 years) from two placebo-controlled, RCTs evaluating lamotrigine, lithium, and placebo in BD maintenance. There were 638 patients in the double-blind treatment phase including 98 older adults (mean age 61 years, SD = 6.0; range: 55–82 years). Lamotrigine significantly delayed time-to-intervention for depression compared with lithium, while lithium performed better than lamotrigine for time-to-intervention for mania. Side effects for both lamotrigine and lithium were generally time-limited and mild to moderate in intensity, including similar rates of skin rash (3% for lamotrigine, 5% for lithium). Given the positive prospective findings in mixed-age patients and encouraging results in the secondary analysis with older BD patients, we conducted a 12-week, open label trial of lamotrigine in adults age 60 and older with type I or II bipolar depression, assessing its dosing, tolerability, and efficacy. We hypothesized that lamotrigine would be associated with improvement in depressive symptoms and would be well tolerated by these older adults with bipolar depression.