Fig. 1 Working model showing potential routes by which stressors and cytokines could influence depressive state. Stressors and cytokines may promote several common neurochemical changes, and it is suggested that they may act synergistically in affecting some neurochemical processes. Moreover, stressors and cytokines may result in the sensitization of neurochemical processes, resulting in exaggerated responses to subsequent challenges. Both cytokines and stressors, as depicted in the figure, increase the release of corticotropin-releasing hormones (CRH) in hypothalamic and extrahypothalamic sites, although, in the case of stressors, this outcome may involve activation of bombesin-like peptides (neuromedin B and gastrin-releasing peptide). In addition to activating hypothalamic–pituitary–adrenal function, corticotropin-releasing hormones may influence serotonin (5-HT) processes, and γ-aminobutyric acid receptor A (GABAA) activity may act as a mediator in this regard. The 5-HT variations (as well as those of other amines) may influence depression directly or may do so through other processes. In this regard, an alternative, although not necessarily mutually exclusive, pathway involves cytokine/stress activation of either nuclear factor-κB (NFκB), mitogen-activated protein (MAP) kinases or janus kinase/signal transducer and transcription (JAK-STAT) activator pathway signalling. These would influence oxidative or apoptotic mechanisms, leading to altered growth factor expression (e.g., brain-derived neurotrophic factor [BDNF]), again favouring impaired neuroplastic processes and culminating in major depression. ACTH = adrenocorticotropic hormone; AVP = arginine vasopressin; CORT = cortisol; DA = dopamine; GRP = gastrin-releasing peptide; IL = interleukin; NE = norepinephrin; NMB = neuromedin B; TNF = tumour necrosis factor. Reprinted from Anisman et al. (4) Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 2008;85:1–74, with permission from Elsevier.