Abstract
The neurotrophic hypothesis of depression suggests an association between effects on neuroplasticity and clinical response to antidepressant drug therapy. We studied individual variability in antidepressant drug effects on cell proliferation in lymphoblastoid cell lines (LCLs) from n=25 therapy-resistant patients versus n=25 first-line therapy responders from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Furthermore, the variability in gene expression of genes associated with cell proliferation was analyzed for tentative candidate genes for prediction of individual LCL donor’s treatment response. Cell proliferation was quantified by EdU (5-ethynyl-2′-deoxyuridine) assays after 21-day incubation of LCLs with fluoxetine (0.5 ng μl−1) and citalopram (0.3 ng μl−1) as developed and described earlier. Gene expression of a panel of candidate genes derived from genome-wide expression analyses of antidepressant effects on cell proliferation of LCLs from the Munich Antidepressant Response Signature (MARS) study was analyzed by real-time PCR. Significant differences in in vitro cell proliferation effects were detected between the group of LCLs from first-line therapy responders and LCLs from treatment-resistant patients. Gene expression analysis of the candidate gene panel revealed and confirmed influence of the candidate genes ABCB1, FZD7 and WNT2B on antidepressant drug resistance. The potential of these genes as tentative biomarkers for antidepressant drug resistance was confirmed. In vitro cell proliferation testing may serve as functional biomarker for individual neuroplasticity effects of antidepressants.
Highlights
Depressive disorders are among the leading causes of disability worldwide[1] with a lifetime prevalence of more than 16%.2Depression contributes to decreased quality of life including morbidity, loss of productivity and suicidal thoughts.[3]The neurotrophic hypothesis of depression suggests a chronic hyperactivity of the hypothalamic–pituitary–adrenal axis leading to a lowered growth factor expression and trophic changes in the brain.[4]
Recently identified tentative gene expression biomarkers for neuroplasticity in antidepressant drug response will be studied for confirmation in this independent cohort from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study: In a genome-wide approach using patientderived lymphoblastoid cell line (LCL) from the Munich Antidepressant Response Signature (MARS) study, we identified five potential gene expression biomarkers that have been associated with cell proliferative effects of antidepressants or with LCL donor’s clinical response/remission in antidepressant drug therapy: transcription factor 7-like 2 (TCF7L2), frizzled class receptor 7 (FZD7), winglesstype MMTV integration site family member 2B (WNT2B), p-glycoprotein (P-GP, ABCB1) and sulfotransferase 4A1 (SULT4A1)
We found significant elevated basal gene expression levels of the genes WNT2B (ΔCT difference of 4.96) and ABCB1 (ΔCT difference of 2.31) in the LCLs derived from patients with antidepressant treatment resistance relative to responder-derived ones
Summary
Depressive disorders are among the leading causes of disability worldwide[1] with a lifetime prevalence of more than 16%.2. The neurotrophic hypothesis of depression suggests a chronic hyperactivity of the hypothalamic–pituitary–adrenal axis leading to a lowered growth factor expression and trophic changes in the brain.[4] The hippocampus, a cerebral structure involved in emotion processing and stress response seems to be the most affected area in depression-associated neurotrophic changes.[5] A recent meta-analysis considering 8927 samples from 15 different magnetic resonance imaging studies confirmed significant lower hippocampal volumes in depressed patients compared with healthy controls.[6] Antidepressant treatment has been shown to be associated with reversing hippocampal atrophy by the enhancement of neuronal proliferation and synaptic plasticity.[7] treatment efficacy in patients with smaller hippocampus volume has been observed to be delayed over the time of 3–4 weeks,[8] which is usually the earliest time for reliable evaluation of treatment efficacy.[9] This phenomenon, together with the usually low (o 30%) response rates to first-line antidepressant medications,[10,11] point to a need to identify response or non-response biomarkers for the prediction of individual antidepressant treatment effects
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