[Antidepressant and tolerance: Determinants and management of major side effects].

Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy, it takes several weeks for antidepressants to demonstrate full effectiveness, and adverse effects occur more quickly or (quicker) which can be a source of poor compliance. This latest aspect often leads to dose reduction and/or change of molecule that have the effect of delaying remission. This review attempts to present, from the pharmacological properties of the major classes of antidepressants (monoamine oxidase inhibitor [MAOI], tricyclic antidepressants [TCA], selective serotonin reuptake inhibitor [SSRI] and serotonin and noradrenaline reuptake inhibitor [SNRI]), to the pharmacological mechanisms involved in adverse effects by focusing on sexual dysfunction, nausea/vomiting, and weight changes and sleep disruption. If the activation of dopamine D1/2  or norepinephrine receptors through the autonomic nervous system controls and facilitates sexual desire, increasing serotoninergic transmission through 5-HT1B/2A/2C receptors activation inhibits this process. The pharmacological properties of drugs inducing nausea/vomiting activate opiate receptors μ, increase dopaminergic and serotoninergic transmission activating the dopamine D2  and serotonin 5-HT3  receptors, respectively. Among the causes responsible for weight gain under antidepressant therapy, monoamine neurotransmission still plays an important role. The blockade of serotonin 5-HT2C or histamine H1  receptors is directly responsible for weight gain. Finally, the activation of 5-HT1A/1B/3/7 serotoninergique receptors modulates wakefulness, raid eyes movement or sleep duration. In conclusion, if antidepressant activity of SERT or MAO inhibitors is an indirect consequence of postsynaptic 5-HT, DA, NA receptor activation, it is also responsible for side effects, causes of poor compliance and hence therapeutic failures. Finally, we need to take into account the key role of the nocebo effect in the occurrence of adverse effects. The next generation of antidepressant would aim to have a rapid efficacy in patients unresponsive or resistant to drugs currently available while improving certain effects of tolerance through an optimization of their psychopharmacological properties leading to a reduction of their side effects.