Integrating the monoamine, neurotrophin and cytokine hypotheses of depression--a central role for the serotonin transporter?

Monoamine, in particular serotonergic neurotransmission has long been recognized as an important factor in the aetiology of depression. The serotonin transporter (SERT) is the primary regulator of serotonin levels in the brain and a key target for widely used antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). In realising the limitations of current antidepressant therapy, depression research has branched out to encompass other areas such as synaptic plasticity, neurogenesis and brain structural remodelling as factors which influence mood and behaviour. More recently, the immune system has been implicated in the development of depression and various intriguing observations have inspired the cytokine hypothesis of depression. Over the past two decades evidence of in vitro and in vivo regulation of SERT function by pro-inflammatory cytokines as well as by mechanisms of synaptic plasticity has been accumulating, offering a mechanistic link between the monoamine, neurotrophin and cytokine theories of depression. This review will focus firstly on the interconnected roles of serotonin and neurotrophins in depression and antidepressant therapy, secondly on the impact of the immune system on serotonin transporter regulation and neurotrophin signalling and finally we propose a model of reciprocal regulation of serotonin and neurotrophin signalling in the context of inflammation-induced depression.