Relationship of Mania Symptomatology to Maintenance Treatment Response with Divalproex, Lithium, or Placebo

Abstract

Euphoric and mixed (dysphoric) manic symptoms have different response patterns to divalproex and lithium in acute mania treatment, but have not been studied in relationship to maintenance treatment outcomes. We examined the impact of initial euphoric or dysphoric manic symptomatology on maintenance outcome. Randomized maintenance treatment with divalproex, lithium, or placebo was provided for 372 bipolar I patients, who met improvement criteria during open phase treatment for an index manic episode. The current analysis grouped patients according to the index manic episode subtype (euphoric or dysphoric), and evaluated the impact on maintenance treatment outcome. The rate of early discontinuation due to intolerance during maintenance treatment was higher for initially dysphoric patients (N ¼ 249) than euphoric patients (N ¼ 123; 15.7 vs 7.3%, respectively; p ¼ 0.032). Both lithium (23.2%) and divalproex (17.1%) were associated with more premature discontinuations due to intolerance than placebo (4.8%; p ¼ 0.003 and 0.02, respectively) in the initially dysphoric patients. Among initially euphoric patients, treatment with lithium was associated with significantly more premature discontinuations due to intolerance compared to placebo (18.2 vs 0%; p ¼ 0.03), and divalproex was significantly (p ¼ 0.05) more effective than lithium, but not placebo in delaying time to a depressive episode. Initial euphoric mania appeared to predispose to better outcomes on indices of depression and overall function with divalproex maintenance than with either placebo or lithium. Dysphoric mania appeared to predispose patients to more side effects when treated with either divalproex or lithium during maintenance therapy.

The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm

“…There are some data in favor of a superiority of lithium in the treatment of more “classic” patients, but in the rest of patients the 2 agents seem to be comparable. Lithium was also comparable to valproate in terms of prevention of mood episodes (Bowden et al, 2000; Calabrese et al, 2005a) and suicidality (Oquendo et al, 2011) to olanzapine (Tohen et al, 2005) and also to aripiprazole (El-Mallakh et al, 2012)…”

“…The data so far suggest that olanzapine prolongs time to relapse into any episode in patients with an index mixed episode (Tohen et al, 2006, 2009) while on the contrary, lithium and valproate had negative results in patients with a dysphoric manic index episode (Bowden et al, 2005a). Additionally, the data are in support of the combination of quetiapine plus lithium or valproate (Vieta et al, 2008a; Suppes et al, 2009) but are negative concerning aripiprazole in patients with an index mixed episode (Yatham et al, 2013a).…”

“…The studies comparing valproate with lithium have already been discussed above (Bowden et al, 2000; Calabrese et al, 2005a; Oquendo et al, 2011). Two trials suggested valproate is comparable with olanzapine (Tohen et al, 2003a) and with a similar cost to healthcare system (Zhu et al, 2005).…”

“…For the prevention phase, the data so far suggest that divalproex is not more effective than lithium (Calabrese et al, 2005a) and also that the combination of lithium plus divalproex is not better than lithium alone (Kemp et al, 2009). One small study reported that the combination of lithium plus carbamazepine did better than either agent alone (Denicoff et al, 1997).…”

Pharmacological Treatments for Bipolar Disorder: Present Recommendations and Future Prospects

“…Although several studies of acute mania indicate less benefit with lithium treatment than with valproate, and second-generation studies report equivalent outcomes in mixed and manic subjects, the lack of samples selected strictly for mixed mania limits conclusions applicable to practice settings. The major study of treatment outcomes in maintenance care noted that patients with mixed states had less overall benefit with regard to efficacy and tolerability than did manic patients, regardless of whether they were treated with lithium or valproate (Bowden et al 2005). Examination of these results suggests that mixed states are principally more difficult to treat because their overall severity of illness is higher that strictly depressed or manic patients, and that they are associated with poor tolerability of regimens.…”