Pharmacological treatment of bipolar depression

Bipolar disorder is a disabling, largely episodic, recurrent illness associated with severe functional impairment, psychiatric and somatic comorbidity, and premature mortality from both suicide and medical illnesses (Baldessarini 2010a,b; Sanders 2010). Lifetime prevalence of bipolar disorder in the general population, taking into account both type I (with mania) and type II (with hypomania) disorder, is at least 1–2% (Merikangas 2011), and up to 10% if broad diagnostic criteria include major depression with subthreshold hypomania (Zimmermann 2009). Depressive, dysthymic and mixed (dysphoric/ agitated) states contribute to the total illness burden in bipolar disorder. These morbidity factors are strongly associated with, and predicted by, similar first lifetime episodes (Baldessarini 2010a, 2012). In several longitudinal studies of the treatment of bipolar disorder by community standards, the mean proportion of weeks in morbid states was 68% and three-quarters of that unresolved morbidity is accounted for by depressive illness (Baldessarini 2010a; Tondo 2013). Depressive components of bipolar disorder are associated not only with a high proportion of unresolved (treatment-resistant) morbidity, but also with psychiatric and medical comorbidity, disability and mortality from suicide in young patients and from co-occurring medical disorders in older patients – all resulting in very high levels of clinical and economic burden for patients, families and society (Ösby 2001; Tondo 2007; Crump 2013). Despite the high prevalence and major clinical, public health and economic significance of depression in bipolar disorder, few treatments have proved to be highly and consistently effective in acute episodes, and there is even less evidence of means of providing substantial long-term protection from recurrent episodes. In particular, there is considerable controversy about the value and risks of antidepressant drugs in treating bipolar depression (Pacchiarotti 2013; Vázquez 2013). In turn, lack of highly effective treatments encourages widespread empirical trials of combination therapies (polytherapy) that are largely untested for effectiveness and safety. It is likely that the paucity of therapeutic studies for bipolar depression reflects a broadly accepted view that major depression is similar in its clinical characteristics as well as its responses to treatment in patients with bipolar as well as unipolar mood disorder (Baldessarini 2013a). Instead, there is considerable evidence that bipolar and unipolar mood disorders differ in many ways, including family history, gender distribution, age at onset, long-term diagnostic stability, episode duration, recurrence rates and response to treatment (Baldessarini 2013b). These considerations indicate that bipolar depression remains a leading clinical problem and one of the most critical unsolved challenges Pharmacological treatment of bipolar depression