A New Class of Antidepressant Drugs in the Treatment of Psychiatric Disorders: The Triple Reuptake Inhibitors

It is well established that many antidepressant compounds with proven clinical efficacy act on the serotonergic and noradrenergic pathways. The monoaminergic hypothesis of major depression (MD) stipulates that a deficit in brain monoaminergic neurotransmission in various brain areas including the frontal cortex, hippocampus, amygdala or hypothalamus would account for some of signs and symptoms of the pathology (Katz et al., 2010a). For instance, abnormalities in the serotonin (5-HT) transmission are associated with impulsivity, aggressive, and anxious behaviors (Handley et al., 1995), whereas alteration in noradrenergic transmission, with motor activity, attention, and arousal (Morilak and Frazer, 2004). The role of dopamine (DA) on the other hand, attracted less attention in the mechanisms of action underlying MD. However, the observations that reserpine, which depletes catecholamines, results in lowering mood (Schidkrautn 1965) or that an inhibition of tyrosine hydroxylase induces a worsening of depressive symptoms (Miller et al., 1996), strongly suggest that decreasing DA function may be of particular relevance. The fact that several symptoms observed in MD, including impaired motivation, concentration, and pleasure result from an attenuation of dopaminergic neurotransmission, strengthens the hypothesis that DA also regulates mood (Dunlop and Nemeroff, 2007). Most antidepressants approved, such as the selective serotonin reuptake inhibitors (SSRIs), the norepinephrine (NE) reuptake inhibitor (NRIs) or the dual serotonin/norepinephrine reuptake inhibitors (SNRIs), act by enhancing brain 5-HT and/or NE levels. Despite their therapeutic action, residual symptoms remain and may explain the fact that approximately 50% of depressive individuals do not respond adequately to these agents (Berton and Nestler, 2006). The question can be asked as to whether these remaining symptoms are caused by the antidepressants or if they result from dysfunction in other neurotransmitters such as a blunted DA neurotransmission. In this context, a new generation of antidepressant drugs, the triple reuptake inhibitors (TRIs), has been developed with the hope to offer a clinically relevant advantage over singleor dual-acting agents (Guiard et al., 2009). Indeed, since TRIs simultaneously enhance extracellular levels of 5-HT, NE and DA neurotransmissions in various brain regions, this class of antidepressants could exert their therapeutic activity by treating more symptoms of MD and/or by attenuating some side