Valproate and carbamazepine are options in the treatment of mania, mixed states and those with rapid cycling illness and comorbid substance abuse ( Greil 1998 Bowden and Singh 2005), but lack full support in prophylaxis and the treatment of bipolar depression. However, its side effect profile and lesser efficacy in certain subgroups ( Calabrese and Woyshville 1995) have led to investigations of second generation anticonvulsants and atypical antipsychotics as alternative treatments. Lithium undoubtedly retains the broadest evidence base, with substantiated efficacy in treating manic and depressive phases, prophylaxis ( Tondo et al 19) and the reduction of suicide risk ( Baldessarini et al 2003). The pharmacological management of bipolar disorder is rising in complexity, with the continual refining of the illness spectrum and an expanding pharmacopeia of medication options that, in monotherapy or in combination, may provide more sophisticated means of targeting phasic symptoms, polarity changes, and subclinical or minor symptoms. These findings indicate a need for treatments directed towards the alleviation and prevention of depression, and milder albeit still disabling subthreshold depressive symptoms in bipolar disorder. In bipolar II disorder, symptomatic illness has been estimated to be present over 53.9% of the 13.4-year follow-up, with depression evident for 50.3% of total follow-up time, during which subsyndromal and minor symptoms dominated over major depression ( Judd et al 2003). Paykel et al (2006) reported comparable trends in 204 patients with bipolar I disorder, studied over 18 months. Frequent changes in symptom levels and polarity, and the predominance of subsyndromal and minor symptoms were also demonstrated. Significantly, depressive symptoms (present over 31.9% of the total follow-up period) predominated over symptoms of any other phases. Judd and colleagues ( Judd et al 2002) have demonstrated that over the course of 12.8 years, their cohort of 146 patients with bipolar I disorder were symptomatic 47.3% of the time. In particular, more recent understanding of the natural course of bipolar disorder has highlighted its disease burden and challenged its historical conceptualization as an episodic illness with full inter-episode recovery ( Kraepelin 2002). The highly recurrent course of bipolar disorder ( Angst and Sellaro 2000), its poor functional outcomes ( Mitchell et al 2004) and over-representation in the completed suicide population ( Rihmer and Kiss 2002) have been well-documented in the literature. Further randomized controlled trials are required to consolidate the available findings and to explore the boundaries of lamotrigine’s efficacy, which may encompass the soft spectral disorders.īipolar disorder has been estimated to have a population lifetime prevalence of between 0.3%–1.5% ( Weissman et al 1996), but this figure based on DSM-III criteria may belie the extent of the full spectrum. The designation of lamotrigine as first-line treatment for bipolar depression prophylaxis should be done in cognizance of this context, and it would seem prudent to await greater evidence of efficacy before designating lamotrigine as first-line treatment for other bipolar indications. However, this relative inadequacy compares favorably with the alternative treatment options for bipolar depression, which are marked by poor efficacy or risk of polarity switch. The total number of published well designed trials is small, even the maintenance evidence is derived from two studies. While the data supports its tolerability and safety, the strongest evidence for its efficacy lies in the prevention of bipolar depression, with weaker evidence for the treatment of acute bipolar depression, refractory unipolar and bipolar depression, and rapid cycling bipolar disorder. This review examines the published clinical trials of lamotrigine in bipolar treatment. Lamotrigine has emerged with a distinct place in the pharmacological treatment of bipolar disorder, with the potential to treat and prevent bipolar depression, which is the dominant and arguably most disabling and under-treated phase of the illness.
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