The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants

The monoamine hypothesis of depression posits that an imbalance in monoaminergic neurotransmission is causally related to the clinical features of depression. Antidepressants influencing serotonin mainly aim at raising serotonin concentrations, thereby increasing serotonergic transmission at the level of the synapse, for example by inhibiting the serotonin transporter. However, the serotonin system is multifaceted. Different serotonin receptor subtypes turn the serotonergic system into a complex neurochemical arrangement that influences diverse neurotransmitters in various brain regions. Classical antidepressants as well as other psychopharmacological agents have various crucial effects on serotonin receptors. We aim at providing a clinically useful characterization of serotonin receptor subtypes in the treatment of depression. Clarifying the mode of action and the interplay of serotonin receptors with pharmacological agents should help antidepressant mechanisms and typical side effects to be better understood. Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile.