Characterization of mechanism of action of antidepressants: comparison of first-generation and newer agents
It is commonly accepted, that endogenous depression can be effectively treated by increasing the function of brain monoaminergic neurotransmitters such as noradrena1ine and serotonin (5-HT). Monoamine oxidase inhibitors (MAO-I) increase noradrenergic and 5-HT neurotransmission by preventing their metabolism. The new generation of MAO-I (e.g. moclobemide) is the selective reversible inhibitors of monoamine oxidase-A (MAO-A). This group is considerably safer than the older nonselective and irreversible MAO-I, in that they produce less hepatoxicity and less interactions with certain drugs and sympathomimetic amines such as tyramine. Tricyclic antidepressants (TAD) enhance noradrenergic and 5-HT transmission by inhibiting, with different selectivities and potencies, monoamine reuptake. Second generation of monoamine reuptake inhibitors comprises selective serotonin reuptake inhibitors (SSRI, e.g. fluoxetine, fluvoxamine, sertraline) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). Certain agents, e.g. nefazodone in addition to 5-HT uptake blockade are capable of blocking postsynaptic 5-HT2 and 5-HT3 receptors. New generation of antidepressants is now available, possessing both 5-HT and noradrenaline reuptake blocking properties (dual uptake blockers, e.g. venlafaxine), but devoid of many other properties common to TAD group (such as M-cholinolytic and antihistaminic effects).
The greater effects of SSRI in combination with 5-HTlA antagonists demonstrate the importance of 5-HTlA autoreceptors in self-inhibition of 5-HT neurons that occurs soon after administration of 5-HT reuptake blockers. Further, serotonin 5-HT-11A partial agonists and 5-HTlA postsynaptic receptor agonists (e.g. flesinoxan) have been demonstrated both preclinical and clinical antidepressant efficacy thus pointing out the role of postsynaptic 5-HTlA receptors in antidepressant effect of drugs.
Despite the ability of antidepressants to enhance monoaminergic transmission soon after administration, clinical effects require prolonged administration. This delay can be attributed to adaptive changes in certain receptors, e.g. desensitization of serotonergic autoreceptors and alpha2 adrenoceptors as well as up-regulation of adrenergic alphal receptors.
Studies of the hypothalamic-pituitary adrenal axis functioning in depression focused interest of researchers on the importance of glucocorticoids in brain function, and mental diseases. There is considerable interest in the possible antidepressant activities of antiglucocorticoids and other compounds inf1uencing the activity of HPA axis and the effects of stress. Most recent findings suggest that antidepressants might work by boosting the production of brain’s neurotrophic factors (e.g. BDNF) thus suggesting a new strategy in pharmacotherapy of depression.