Journal
NEUROPSYCHOPHARMACOLOGY
Volume 38, Issue 3, Pages 377-385Publisher
SPRINGERNATURE
DOI: 10.1038/npp.2012.191
Keywords
antidepressant; depression; glucocorticoid receptor; inflammation; neuroplasticity; treatment response; personalised medicine
Categories
Funding
- European Commission Framework 6 grant [LSHB-CT-2003-503428]
- Commission of European Communities Seventh Framework Programme [22963]
- Clinician Scientist Fellowship from the Medical Research Council, UK [G108/603]
- NARSAD young investigator award
- Psychiatry Research Trust, UK
- Italian Ministry of Health (Ricerca Corrente)
- Regione Lombardia [17387Sal-13]
- National Institute for Health Research Mental Health Biomedical Research Centre at South London
- Maudsley NHS Foundation Trust
- King's College London
- Medical Research Council [G108/603, G9817803B, MR/J002739/1] Funding Source: researchfish
- MRC [G108/603] Funding Source: UKRI
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To improve the 'personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants (predictors'), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment ('targets'). In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1 alpha, IL-1 beta, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-alpha), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n = 34) and depressed patients (n = 74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels of IL-1 beta (+33%), MIF (+48%), and TNF-alpha (+39%). Antidepressants reduced the levels of IL-1 beta (-6%) and MIF (-24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (-9%) and of FKBP5 (-11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)-that is, response was associated with changes in genes that did not predict, at the baseline, the response. Our findings indicate a dissociation between 'predictors' and 'targets' of antidepressant responders. indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect. Neuropsychopharmacology (2013) 38, 377-385; doi:10.1038/npp.2012.191; published online 19 September 2012
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