A Randomized Open-Label 6 Month Acute and Maintenance Trial of Lamotrigine vs. Standard of Care Sodium Valproate Monotherapy for Treatment of Mixed Mania.

Mixed mania is a clinically distinct affective state which is likely to be more severe than classical euphoric mania and to have longer episode duration. Mixed mania is associated with longer duration of illness, suicidality, and poor outcome (McElroy et al, 1995). Although at present there is no universally agreed on definition for mixed states, 40-60% of patients in acute manic states also meet criteria for either major depression or dysphoria (Dilsaver et al,1999; Calabrese et al, 1999; Secunda et al,1985; Sporn and Sacks,1997). Dilsaver at al (1999) in their factor analytic study of manic symptoms were able to differentiate dysphoric and depressed mania. Patients with depressed mania (30% of all patients with mania) were as manic as patients with euphoric mania and also met criteria for the Major depressive disorder. Patients with dysphoric mania were less manic and less depressed, but more irritable than both depressed and euphoric manic patients.

At present there is no accepted treatment algorithms for mixed affective states including depressed and dysphoric mania in Dilsaver definition. Currently used antimanic agents (lorazepam, typical antipsychotics, olanzapine) and mood stablizers (lithium, divlaproex sodium) have little or no antidepressant activity. Therefore, treatment of mixed mania frequently results in emergence of bipolar depression that is often treatment-refractory. Thus is an urgent need for effective treatment of mixed mania that will not result in bipolar depression.

Lamotrigine is an anticonvulsant that prolongs the refractory phase of voltage sensitive channels, an action that is associated with antimanic properties (Hurly, 2002; Sporn and Sacks, 1997; Calabrese et al; 1999, Normann et al; 2002). Lamotrigine was postulated to decrease glutamate release by acting at voltage-sensitive sodium channel in their refractory phase, stabilizing presynaptic neuronal membranes and inhibiting pathologic release of glutamate. As abnormalities in glutamatergic system have been implicated in depression, and NMDA receptor antagonists reverse anxiety or depression in various stress models, lamotrigine could act as an antidepressant. . Thus, lamotrigine has a potential to have both antimanic and antidepressant activity (for refs, see Sporn and Sacks, 1997), and in theory should be uniquely effective for mixed mania (Dilsaver et al, 1999). Indeed, clinical trials reviewed in detail by Hurley (2002), demonstrated that lamotrigine is somewhat effective an antimanic agent, and has significant antidepressant activity in bipolar depression. Lamotrigine was used in a combination with other agents or as monotherapy, and the response rates for depressed, mixed and rapid cycling states were similar, ranging from 52% to 63%. With slow dose titration (6 weeks), side effects were few and the incidence of exfoliative dermatitis was 1 in 500. Of note, although Sporn and Sachs (1997) reported a switch from depression to rapid cycling, such incidences were few. In our institution, lamotrigine was effective for treatment of mixed mania and bipolar depression in patients receiving standard maintenance treatment for Bipolar Mood Disorder. Lamotrigine did worsen agitation in two elderly patients with symptoms of irritable mania.

Based on the above evidence, it appears that lamotrigine, either in combination with a proven antimanic agent or in monotherapy, is uniquely suited to be the agent of choice for treatment of mixed mania. Therefore, we here propose a randomized open-label trial of lamotrigine vs. standard of care sodium valpoate for treatment of mixed mania. Within this framework, the following are the study's hypotheses and objectives:

Hypothesis/Objectives Objective One. To compare the efficacy of the lamotrigine with sodium valproate (standard of care) for treatment of depressive symptoms of acute mania in patients with Bipolar Mood Disorder.