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Citalopram-induced pathways regulation and tentative treatment-outcome-predicting biomarkers in lymphoblastoid cell lines from depression patients.

ABSTRACT: Antidepressant therapy is still associated with delays in symptomatic improvement and low response rates. Incomplete understanding of molecular mechanisms underlying antidepressant effects hampered the identification of objective biomarkers for antidepressant response. In this work, we studied transcriptome-wide expression followed by pathway analysis in lymphoblastoid cell lines (LCLs) derived from 17 patients documented for response to SSRI antidepressants from the Munich Antidepressant Response Signatures (MARS) study upon short-term incubation (24 and 48?h) with citalopram. Candidate transcripts were further validated with qPCR in MARS LCLs from responders (n?=?33) vs. non-responders (n?=?36) and afterward in an independent cohort of treatment-resistant patients (n?=?20) vs. first-line responders (n?=?24) from the STAR*D study. In MARS cohort we observed significant associations of GAD1 (glutamate decarboxylase 1; p?=?0.045), TBC1D9 (TBC1 Domain Family Member 9; p?=?0.014-0.021) and NFIB (nuclear factor I B; p?=?0.015-0.025) expression with response status, remission status and improvement in depression scale, respectively. Pathway analysis of citalopram-altered gene expression indicated response-status-dependent transcriptional reactions. Whereas in clinical responders neural function pathways were primarily up- or downregulated after incubation with citalopram, deregulated pathways in non-responders LCLs mainly involved cell adhesion and immune response. Results from the STAR*D study showed a marginal association of treatment-resistant depression with NFIB (p?=?0.068) but not with GAD1 (p?=?0.23) and TBC1D9 (p?=?0.27). Our results propose the existence of distinct pathway regulation mechanisms in responders vs. non-responders and suggest GAD1, TBC1D9, and NFIB as tentative predictors for clinical response, full remission, and improvement in depression scale, respectively, with only a weak overlap in predictors of different therapy outcome phenotypes.

SUBMITTER: Barakat AK

PROVIDER: S-EPMC7329820 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Citalopram-induced pathways regulation and tentative treatment-outcome-predicting biomarkers in lymphoblastoid cell lines from depression patients.

Barakat Abdul Karim AK Scholl Catharina C Steffens Michael M Brandenburg Kerstin K Ising Marcus M Lucae Susanne S Holsboer Florian F Laje Gonzalo G Kalayda Ganna V GV Jaehde Ulrich U Stingl Julia Carolin JC

Translational psychiatry 20200701 1

Antidepressant therapy is still associated with delays in symptomatic improvement and low response rates. Incomplete understanding of molecular mechanisms underlying antidepressant effects hampered the identification of objective biomarkers for antidepressant response. In this work, we studied transcriptome-wide expression followed by pathway analysis in lymphoblastoid cell lines (LCLs) derived from 17 patients documented for response to SSRI antidepressants from the Munich Antidepressant Respon ...[more]

PMID: 32612257

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Project description:BACKGROUND:Recent US and UK clinical practice guidelines recommend that second-generation antidepressants should be considered amongst the best first-line options when drug therapy is indicated for a depressive episode. Systematic reviews have already highlighted some differences in efficacy between second-generation antidepressants. Citalopram, one of the first selective serotonin reuptake inhibitors (SSRI) introduced in the market, is one of these antidepressant drugs that clinicians use for routine depression care. OBJECTIVES:To assess the evidence for the efficacy, acceptability and tolerability of citalopram in comparison with tricyclics, heterocyclics, other SSRIs and other conventional and non-conventional antidepressants in the acute-phase treatment of major depression. SEARCH METHODS:We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to February 2012. No language restriction was applied. We contacted pharmaceutical companies and experts in this field for supplemental data. SELECTION CRITERIA:Randomised controlled trials allocating patients with major depression to citalopram versus any other antidepressants. DATA COLLECTION AND ANALYSIS:Two reviewers independently extracted data. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy (the number of patients who responded or remitted), patient acceptability (the number of patients who failed to complete the study) and tolerability (side-effects). MAIN RESULTS:Thirty-seven trials compared citalopram with other antidepressants (such as tricyclics, heterocyclics, SSRIs and other antidepressants, either conventional ones, such as mirtazapine, venlafaxine and reboxetine, or non-conventional, like hypericum). Citalopram was shown to be significantly less effective than escitalopram in achieving acute response (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.08 to 2.02), but more effective than paroxetine (OR 0.65, 95% CI 0.44 to 0.96) and reboxetine (OR 0.63, 95% CI 0.43 to 0.91). Significantly fewer patients allocated to citalopram withdrew from trials due to adverse events compared with patients allocated to tricyclics (OR 0.54, 95% CI 0.38 to 0.78) and fewer patients allocated to citalopram reported at least one side effect than reboxetine or venlafaxine (OR 0.64, 95% CI 0.42 to 0.97 and OR 0.46, 95% CI 0.24 to 0.88, respectively). AUTHORS' CONCLUSIONS:Some statistically significant differences between citalopram and other antidepressants for the acute phase treatment of major depression were found in terms of efficacy, tolerability and acceptability. Citalopram was more efficacious than paroxetine and reboxetine and more acceptable than tricyclics, reboxetine and venlafaxine, however, it seemed to be less efficacious than escitalopram. As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings. Economic analyses were not reported in the included studies, however, cost effectiveness information is needed in the field of antidepressant trials.

Dataset Information

Citalopram-induced pathways regulation and tentative treatment-outcome-predicting biomarkers in lymphoblastoid cell lines from depression patients.

Publications

Citalopram-induced pathways regulation and tentative treatment-outcome-predicting biomarkers in lymphoblastoid cell lines from depression patients.

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