The role of the monoamines serotonin and noradrenaline in mental illnesses including depression is well recognized. All antidepressant drugs in clinical use increase acutely the availability of these monoamines at the synapse either by inhibiting their neuronal reuptake, inhibiting their intraneuronal metabolism, or increasing their release by blocking the α-sub-2 auto- and heteroreceptors on the monoaminergic neuron. This acute increase in the amount of the monoamines at the synapse has been found to induce long-term adaptive changes in the monoamine systems that end up in the desensitization of the inhibitory auto- and heteroreceptors including the presynaptic α-sub-2 and 5-HT-sub(1B) receptors and the somatodendritic 5-HT-sub(1A) receptors located in certain brain regions. The desensitization of these inhibitory receptors would result in higher central monoaminergic activity that coincides with the appearance of the therapeutic response. These adaptive changes responsible for the therapeutic effect depend on the availability of the specific monoamine at the synapse, as depletion of the monoamines will either reverse the antidepressant effect or causes a relapse in the state of drug-free depressed patient previously treated with antidepressant drugs. Furthermore, blocking the somatodendritic 5-HT-sub(1A) or nerve terminal α-sub-2 receptors proved to increase the response rate in the treatment of major and treatment-resistant depression, providing further support to the assumption that the antidepressant effect results from the long-term adaptive changes in the monoamine auto- and heteroregulatory receptors. On the other hand, the chronic treatment with antidepressants resulted in D-sub-2 receptors supersensitivity in the nucleus accumbens. This supersensitivity might play a role in the mechanisms underlying antidepressant induced mood switch and rapid cycling.