Abstract
The current therapy success of depressive disorders remains in need of improvement due to low response rates and a delay in symptomatic improvement. Reliable functional biomarkers would be necessary to predict the individual treatment outcome. On the basis of the neurotrophic hypothesis of antidepressant's action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy. We studied individual differences in antidepressant drug effects on cell proliferation and gene expression in lymphoblastoid cell lines (LCLs) derived from patients treated for depression with documented clinical treatment outcome. Cell proliferation was characterized by EdU (5-ethynyl-2'-deoxyuridine) incorporation assays following a 3-week incubation with therapeutic concentrations of fluoxetine. Genome-wide expression profiling was conducted by microarrays, and candidate genes such as betacellulin—a gene involved in neuronal stem cell regeneration—were validated by quantitative real-time PCR. Ex vivo assessment of proliferation revealed large differences in fluoxetine-induced proliferation inhibition between donor LCLs, but no association with clinical response was observed. Genome-wide expression analyses followed by pathway and gene ontology analyses identified genes with different expression before vs after 21-day incubation with fluoxetine. Significant correlations between proliferation and gene expression of WNT2B, FZD7, TCF7L2, SULT4A1 and ABCB1 (all involved in neurogenesis or brain protection) were also found. Basal gene expression of SULT4A1 (P=0.029), and gene expression fold changes of WNT2B by ex vivo fluoxetine (P=0.025) correlated with clinical response and clinical remission, respectively. Thus, we identified potential gene expression biomarkers eventually being useful as baseline predictors or as longitudinal targets in antidepressant therapy.
Highlights
The therapy of depression is characterized by response rates around 60% and difficulties in the early evaluation of individual therapy success owing to delayed clinical improvement that may take from weeks up to several months.[1,2] So far, it is not yet possible to predict the individual treatment outcome of depressive patients owing to a lack of predictive biomarkers
In the explorative phase genome-wide gene expression profiling and EdU proliferation phenotyping experiments were carried out in to identify potential gene expression biomarkers and to elucidate a possible association between individual antidepressant-induced lymphoblastoid cell line (LCL) proliferation and clinical response from LCL donors, respectively. Both approaches were combined in an edgegroup approach where the identified tentative gene expression biomarkers were evaluated in extreme cell lines from EdU phenotyping
No association was detected between LCL proliferation rates and LCL donor’s clinical response measured as percentage change in Hamilton score compared between weeks 0 and 8 (Figure 2d)
Summary
The therapy of depression is characterized by response rates around 60% and difficulties in the early evaluation of individual therapy success owing to delayed clinical improvement that may take from weeks up to several months.[1,2] So far, it is not yet possible to predict the individual treatment outcome of depressive patients owing to a lack of predictive biomarkers. According to the neuroplasticity hypothesis of the antidepressants’ action, which is based on both animal and human cell models, antidepressants act—at least in part—by increasing proliferation of neuronal stem cells.[3,4] depressed patients have been reported with volume reductions in hippocampus and other brain regions,[5] which has been observed to be reversed after successful antidepressant therapy, apparently owing to antidepressant-induced triggering of neural plasticity.[6] As cerebral remodeling processes are complex and take many weeks, this explains the observed delay in symptomatic improvement.[7]. The late-onset action of antidepressant drugs in the treatment of depression is hypothesized owing to changes in neuroplasticity resulting from these proliferative effects in the hippocampus.[8]
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