Resistance to selective serotonin reuptake inhibitors: role of serotonergic mechanisms

Abstract

SSRIs are the mainstay in the treatment of depression. However, approximately 30% of depressed patients do not respond to antidepressants and the causes of resistance to these drugs are largely unknown. Thus, it is necessary to develop experimental models to investigate the neurobiological changes underlying the response to SSRIs. The approach used in this project was the inter-strain comparison of mice, such as DBA/2 and C57BL/6, differing in serotonin (5-HT) synthesis, due to a spontaneous mutation of tryptophan hydroxylase-2, the rate-limiting enzyme in brain 5-HT synthesis. The genotype-dependent deficit of 5-HT was associated with no response to acute and chronic citalopram and paroxetine in the forced swimming test (FST), an experimental procedure to assess the antidepressant potential of drugs, and with lower basal and citalopram-induced rise of extracellular 5-HT. The administration of the 5-HT precursor, tryptophan, or the blockade 5-HT1A autoreceptors and 5-HT2C receptor-mediated inhibitory feedback reinstated the antidepressant-like effect of citalopram. These findings suggest that boosting 5-HT neurotransmission might be a useful strategy to restore the antidepressant effect in treatment-resistant depressed patients. Further studies suggested that GABAergic inhibition is involved in the mechanism by which 5-HT2C receptor inactivation augments the effects of SSRIs whereas the ability of tryptophan to restore the antidepressant-like effect of SSRIs may involve non-serotonergic mechanisms. Finally, chronic citalopram induced opposite changes in brain-derived neurotrophic factor (BDNF), a neurotrophin linked to the long-term action of antidepressants, in the nucleus accumbens of DBA/2 and C57BL/6 mice. This suggests a possible role of this protein in the lack of response to SSRIs. Overall, these studies provide new insight into the role of 5-HT and BDNF in the response to antidepressant drugs and remark on the inter-strain comparison of mice with a spontaneous tryptophan hydroxylase-2 mutation as a useful tool for understanding the mechanism underlying the response to SSRIs and testing new potential therapeutic strategies