In this 16-week, single-blind monotherapy study of lamotrigine versus lithium for the acute treatment of bipolar II depression, both groups showed significant improvement on depression and hypomania scores while maintaining a low switch rate. This trial is one of the largest bipolar II disorder, acute phase depression studies ever completed. The baseline to endpoint improvement was substantial across both groups, though between group differences were not noted on the primary outcome or secondary measure symptom assessments. Clinical results did not differ between those patients with or without rapid cycling. A striking number of patients met response and remission criteria, with more than 65% of the LTG group and more than 55% of the Li group meeting criteria on both. A very small number of patients in either group showed evidence of switch in this four month study. As statistical improvement was noted as well on the manic symptom assessment, it is reasonable to consider that patients demonstrated overall improvement in stability and not only a decrease of depressive symptoms.
In order to provide more direct comparison of our findings from those in shorter duration studies, we assessed the changes in symptoms at week 8 of the study. Both item analyses and assessment of clinical symptoms at week 8 showed significant improvement with continued gains over the remaining 8 weeks of the study. This is also pertinent in that it suggests improvements observed were not simply the natural course of illness but reflective of response to medication.
The completion rate for the study was at 44%. Patients showed reasonable tolerability, with stated dropout from study about the same across groups. Patients in the Li group reported a greater number of side effects, and significant differences were noted for the development of side effects with Li relative to LTG. Side effect symptoms were consistent with our understanding of each of these medications and what other studies have reported.
Due to the lack of a placebo arm, definitive statements cannot be made regarding treatment efficacy, though results support the efficacy of both lithium and lamotrigine in the treatment of BDII depression. Patients who received lithium showed significant improvement over the course of the study. Although there are no published randomized acute or maintenance treatment trials of BDII only using Li, these findings support early acute and maintenance findings for a role for Li in the treatment of bipolar depression (Kane et al, 1982
; Zornberg and Pope, 1993
; Greil and Kleindienst, 1999
), suggesting an early acute efficacy maintained into the continuation treatment of bipolar II depression.
These results also support that lamotrigine may be effective in the treatment of BDII acute depression. It is possible that the long titration schedule required for lamotrigine limits the time for response in more usual shorter duration acute depression trials. In this study, the 16-week design provided 8 weeks for the titration of lamotrigine followed by 8 weeks of therapeutic dosing. Patients receiving LTG showed improvement consistent with positive findings in shorter acute trials (Frye et al, 2000
). The continuous improvement over the course of the full 16 week trial is also consistent with a longer (26-week) trial (Calabrese et al, 2000
This study is limited by its single-blind design and lack of a placebo-controlled arm. Of note, the relative degree of improvement on either Li or LTG was consistent with that seen on drug for the recently reported placebo-controlled, acute depression studies of quetiapine in BDI and BDII (Calabrese et al, 2005
; Thase et al, 2006
). In particular, the degree of improvement is similar to that observed in the pooled BDII data from quetiapine studies (n=351, Suppes et al, 2007
). While supportive that overall improvement in mood stability noted was not a placebo response, further studies, including a placebo-controlled arm, are needed to rule out the possibility results reflect course of illness. Without a placebo control results cannot be absolutely ascribed to medication effects. However, as with other BDII populations, the history of depression in this population studied was one of persistent symptoms, regardless of cycling status. Thus while conclusions must be cautionary, the overall course of illness in a well-defined BDII population supports that results reflected a medication effect.
In the analyses of patients with rapid cycling bipolar II disorder, similar outcomes were seen. These results are interesting as previous lithium research has suggested that lithium is less effective in rapid cycling populations. In a recent double-blind study of Li monotherapy and divalproex (DVP) monotherapy in patients with rapid-cycling bipolar disorder, Li performed as well as DVP suggesting that overall, rapid-cycling is difficult to successfully stabilize (Calabrese et al, 2000
). The results from this study also support that Li has a place in treatment consideration, as well as other agents, with patients recently depressed or rapid cycling.
The percentage of the population reporting a course of illness consistent with DSM-IV-TR rapid cycling criteria was high. As this was not an exclusion or inclusion criteria we do not know why this percentage was higher than usual BDI trials. Possible reasons include that a higher percentage of BDII are rapid cycling at any given time, patients with BDII may show more monthly variations in mood, patients with BDII may be more susceptible to seasonal variations and changes in photoperiod, and most subjects volunteered in early winter or late summer, seasons associated with the fastest changes in photoperiod (Friedman et al, 2006
). Regardless of cycling status, the patients reported long term and persistent depressive symptoms over the years preceding the trial.
The findings from this research support the use of both lithium and lamotrigine in the treatment of BDII depression. Significant improvement was observed from baseline depression and hypomanic symptoms, though limited between group differences were noted. Patients receiving Li reported significantly more side effects, but discontinuation from side effects was not significant between groups. Further studies are needed to confirm results in a placebo controlled trial and elucidate relative differences between treatments including the role of atypical antipsychotics, antidepressants and the relative role of lithium, lamotrigine, and other anticonvulsants in BDII depression.
The number of individuals estimated to have bipolar II disorder is significant. Our knowledge base of appropriate acute and longer term treatments is extremely limited and is a critical area of needed future study.