Outlook of Future Serotonergic Drugs and Their Clinical Usefulness: Focused on Schizophrenia and Depression / 대한정신약물학회지

ABSTRACT

Serotonin has been implicated in the etiology and pathophysiology of mental illness such as depression, schizophrenia, anxiety disorder, eating disorder, obsessive compulsive disorder, and panic disorder. Many current used treatments of these disorders are thought to act through the modulation of the serotonergic tone. To improve on the efficacy of antipsychotics that are potent D2 receptor blockers, much interest has evolved around complimenting or replacing D2 dopaminergic antagonism by the action on serotonergic transmission. 5-HT2A receptor blockade, under the condition of weaker D2 receptor antagonism, may contribute to the ability of atypical antipsychotics to increase dopamine release in the medical prefrontal cortex while having a smaller effect on mesolimbic dopamine release. These effects may contribute to their advantage for cognition, negative symptoms and psychotic activity. The use of 5-HT1A receptor agonists may substitute for 5-HT2A antagonism and achieve many of the same benefits in combination with weak D2 receptors blockade. Antagonism of 5-HT2C receptors may also useful for improving cortical function. Thus, 5-HT has joined dopamine as a critical target for developing effective antipsychotics in schizophrenia. In the development of new first-line pharmacological treatment for major depressive disorder, 5-HT system will most likely remain important especially if agents can be developed with improved tolerability, faster onset of response or greater efficacy. The promising area for development of serotonergic antidepressants are agents that target the specific 5-HT receptor subtypes, and agents that affect 5-HT plus one or more of the noradrenaline, CRF, dopamine and glucocorticoids systems. Selective targeting of serotonin receptors such as 5-HT1, 5-HT2, or 5-HT7 may have considerable potential in the treatment of depressive disorders. Trophic agents that increased neuroplasticity or neurogenesis via the activation of cyclic AMP-CREB pathway may be beneficial as a target for novel antidepressants.