The treatment of bipolar depression

Depressive episodes occur more frequently in most patients with BD, and may account for a significant proportion of functional impairment attributed to this illness. Even in euthymia, residual depressive symptoms are common leading to a significant reduction in quality of life and functioning. Currently, the treatment of bipolar depression is a clinical challenge because available options are relatively limited (Citrome, 2014).

The US Food and Drug Administration (FDA) has approved new strategies for the treatment bipolar depression in the last ten years. The FDA approved quetiapine (immediate or extended release), a olanzapine-fluoxetine combination (OFC), and more recently, lurasidone for the acute treatment of bipolar depression (McIntyre et al., 2013). Quetiapine is indicated both for mania and depression in BD and its extended-release formulation enables a single daily administration, although residual sedation may be burdensome for some patients. Some studies suggest the efficacy of the OFC in bipolar depression. Side effects of OFC include sedation, weight gain, and metabolic disturbances. The new atypical antipsychotic lurasidone was approved for use in monotherapy or adjunctively to lithium or valproate in bipolar I depression, and EPS/akathisia may be frequent, but this agent seems to have a relatively safe profile regarding metabolic disturbances (Yatham et al., 2013; McIntyre et al., 2013). These findings indicate that lurasidone could be included as a first-line treatment for bipolar depression in future guidelines (Yatham et al., 2013; Franklin et al., 2015).

Lithium has a prominent role in the prophylaxis of new episodes and in the reduction of suicidal behaviour, although there are few trials that have had evaluated its role in bipolar depression in monotherapy (Selle et al., 2014; Cipriani et al., 2013a). However, lithium either in monotherapy or in combination remains a first-line option for the treatment of bipolar depression. When lithium alone fails, it is possible to combine it with other drugs, especially valproate, atypical antipsychotics (e.g. quetiapine or lurasidone), antidepressants (SSRI and bupropion as first-choice, and venlafaxine and tricyclic as third-line choices), carbamazepine, and lamotrigine (Jeong et al., 2015; Yatham et al., 2013; Grunze et al., 2010).

Anticonvulsants have a limited role in the acute treatment of bipolar depression. There are two positive double-blind studies of lamotrigine in BD and a positive metaanalysis (Geddes et al., 2009), although a recent network meta-analysis found no evidence of efficacy for lamotrigine (McIntyre et al., 2013; Taylor et al., 2014). Lamotrigine studies are hamstrung by the need for a six-week titration phase in eight-week studies, leaving only two weeks to display efficacy. Valproate seems to have efficacy for the treatment of bipolar depression based on a small number of studies. Evidence does not support the use of carbamazepine and topiramate for bipolar depression (Selle et al., 2014, Vieta et al., 2002).

Significant controversy remains regarding the use of antidepressants for the acute treatment of bipolar depression. There are significant concerns relative to the propensity of these agents to promote affective switches, cycle acceleration, and even the emergence of suicidality (McElroy et al., 2006; Vazquez et al., 2013). Thus, most guidelines recommend the use of antidepressants for the treatment of BD when associated with a classic mood stabilizer or an antipsychotic. Among antidepressants, tricyclic agents and venlafaxine seem to carry a greater risk of treatment emergent affective switches, while bupropion and SSRIs have the lowest (except paroxetine) (Yatham et al., 2013; Vazquez et al., 2013). The patient must be advised to notify his/her clinician of any abrupt changes in mood during the use of an antidepressant (Vazquez et al., 2013).

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