New antidepressant drugs that do not cross the blood-brain barrier

Stimulation of neurogenesis in the adult brain (i.e. in the hippocampus) has recently been proposed as a putative mechanism of antidepressant action of drugs. This effect of antidepressants may not be achieved by their primary action on proliferating cells, but may involve the drug-triggered mobilization of trophic factors, such as brain-derived neurotrophic factor (BDNF), glia-derived protein S100 beta, or insulin-like growth factor I (IFG-I). Whereas BDNF and S100 beta are produced in the brain, IGF-I is primarily released from peripheral tissues. Administered peripherally, IGF-I increases hippocampal neurogenesis in the adult rat. Because synthesis and release of IGF-I appear to be stimulated by serotonergic mechanisms, we propose that antidepressants that affect serotonergic mechanisms might be rendered more effective by mobilizing IGF-I. Moreover, we suggest that new antidepressant drugs could be designed that would not enter into the brain but would stimulate peripheral mediators such as IGF-I.