Introduction
Many effective treatments for major depressive disorder (MDD) are currently available, but response and remission rates are low or inconsistent. Approximately 50% of patients fail to respond adequately to initial treatment, and ∼30% achieve the treatment goal of full remission (Warden et al., 2007). Furthermore, among patients achieving remission, there is a considerable risk of relapse (Oestergaard and Moldrup, 2011). Thus, recent studies (Geddes et al., 2003; Kornstein, 2008) and clinical guidelines (Davidson, 2010; National Guideline Clearinghouse, 2013; National Institute for Health and Clinical Excellence, 2010; Rodgers et al., 2012) recommend long-term antidepressant therapy for maintaining response or remission of MDD. In addition, antidepressants may be associated with significant adverse effects that can affect patient acceptance of and adherence to therapy (Millan, 2006; Ginsberg, 2009). Newer effective antidepressive agents with better tolerability offer the potential to improve adherence to treatment and provide clinicians with improved therapeutic options for this debilitating condition (Ratner et al., 2008; Spina et al., 2008).
Vortioxetine (Lu AA21004) is an investigational antidepressant agent currently under development for the treatment of MDD. The mechanism of action of vortioxetine is considered to be related to its multimodal activity, which is a combination of two pharmacological modes of action: direct modulation of receptor activity and inhibition of the serotonin transporter. In-vitro studies indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and an inhibitor of the 5-HT transporter (Bang-Andersen et al., 2011; Westrich et al., 2012). The precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear. However, data from serotonergic receptor and transporter occupancy studies coupled with neuronal firing and microdialysis studies in rats suggest that the targets interact in a complex manner, leading to modulation of neurotransmission in several systems, including serotonin, norepinephrine, dopamine, histamine, and acetylcholine systems within the rat forebrain (Bang-Andersen et al., 2011; Mork et al., 2012). These multimodal pharmacological actions are considered to be responsible for the antidepressant effects of vortioxetine.
The efficacy and safety of vortioxetine has been evaluated in several clinical trials (Alvarez et al., 2012; Baldwin et al., 2012b; Henigsberg et al., 2012; Katona et al., 2012; Mahableshwarkar et al., 2013) and an open-label extension study (Baldwin et al., 2012a). Study participants who completed one of two short-term double-blind randomized trials (NCT00672620 and NCT00735709) (Henigsberg et al., 2012; Mahableshwarkar et al., 2013) were eligible to continue into this long-term study. In the dose-ranging lead-in studies, 45–60% of study participants with MDD responded to therapy after 8 weeks of treatment (with either 2.5, 5, 10 mg/day of vortioxetine, 60 mg of duloxetine, or placebo), defined as at least a 50% decrease from baseline in the 24-item Hamilton Depression Scale (HAM-D24) total score. The primary objective of the current study was to evaluate the long-term safety and tolerability of flexible doses of vortioxetine (2.5, 5, and 10 mg once daily) over a period of 52 weeks in study participants with MDD who completed one of the two acute double-blind studies.