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

Abstract

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.

Proteomic investigation of the prefrontal cortex in the rat clomipramine model of depression

“…Still, most of the obtainable and effectively used medications are based on elevation of monoamine levels in line with the monoamine hypothesis of depression [4][5][6]. It is unknown, however, why mood improving effects of the medications appear only after several weeks of treatment, and depression cannot be initiated by reducing the levels of the monoamines in a healthy subject [7].…”

“…It is unknown, however, why mood improving effects of the medications appear only after several weeks of treatment, and depression cannot be initiated by reducing the levels of the monoamines in a healthy subject [7]. A modified hypothesis has been postulated that antidepressant medication may alleviate depression through the desensitization of 5-HT1A, 5-HT3 and 5-HT7 serotonin receptors [4,8].…”

Novel Challenges for the Therapeutics of Depression: Pharmacological Modulation of Interaction between the Intracellular Signaling Pathways Mediated by Ca2+ and cAMP

“…Interestingly, in lammation can impact the glutamatergic system enhancing excitotoxicity and decreasing neuroplasticity. The points of convergence between the in lammatory and glutamatergic hypotheses of depression are not completely established, especially regarding the effects of fast-acting antidepressants [9,10].…”

“…Nonetheless, the monoamine hypothesis of depression continues to dominate the ield and clinical trials, which postulates that an imbalance in monoaminergic neurotransmission is causally related to the clinical features of depression [10]. Anti-depressants in luence serotonin whose main goal consist to raise serotonin concentrations, thereby increasing serotonergic transmission at the level of the synapse, for example by inhibiting the serotonin transporter.…”

“…Clarifying the mode of action, and the interplay of serotonin receptors with pharmacological agents should help elucidate antidepressant mechanisms and typical side effects to better understanding. In addition, clinical medicine featured 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 speci ic effects on certain symptoms of depression as well as a characteristic side-effect pro ile [10].…”