Journal Article
. 2014 Sep;40(3).
doi: 10.1038/npp.2014.226.

Testing the predictive value of peripheral gene expression for nonremission following citalopram treatment for major depression

Jean-Philippe Guilloux 1 Sabrina Bassi 2 Ying Ding 3 Chris Walsh 4 Gustavo Turecki 5 George Tseng 6 Jill M Cyranowski 4 Etienne Sibille 7 
  • PMID: 25176167
  •     35 References
  •     15 citations


Major depressive disorder (MDD) in general, and anxious-depression in particular, are characterized by poor rates of remission with first-line treatments, contributing to the chronic illness burden suffered by many patients. Prospective research is needed to identify the biomarkers predicting nonremission prior to treatment initiation. We collected blood samples from a discovery cohort of 34 adult MDD patients with co-occurring anxiety and 33 matched, nondepressed controls at baseline and after 12 weeks (of citalopram plus psychotherapy treatment for the depressed cohort). Samples were processed on gene arrays and group differences in gene expression were investigated. Exploratory analyses suggest that at pretreatment baseline, nonremitting patients differ from controls with gene function and transcription factor analyses potentially related to elevated inflammation and immune activation. In a second phase, we applied an unbiased machine learning prediction model and corrected for model-selection bias. Results show that baseline gene expression predicted nonremission with 79.4% corrected accuracy with a 13-gene model. The same gene-only model predicted nonremission after 8 weeks of citalopram treatment with 76% corrected accuracy in an independent validation cohort of 63 MDD patients treated with citalopram at another institution. Together, these results demonstrate the potential, but also the limitations, of baseline peripheral blood-based gene expression to predict nonremission after citalopram treatment. These results not only support their use in future prediction tools but also suggest that increased accuracy may be obtained with the inclusion of additional predictors (eg, genetics and clinical scales).

Evidence for an immune response in major depression: a review and hypothesis.
M Maes.
Prog Neuropsychopharmacol Biol Psychiatry, 1995 Jan 01; 19(1). PMID: 7708925
Highly Cited. Review.
A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes.
Roos C Padmos, Manon H J Hillegers, +7 authors, Hemmo A Drexhage.
Arch Gen Psychiatry, 2008 Apr 09; 65(4). PMID: 18391128
The panic-agoraphobic spectrum: a descriptive approach to the assessment and treatment of subtle symptoms.
G B Cassano, S Michelini, +3 authors, E Frank.
Am J Psychiatry, 1997 Jun 01; 154(6 Suppl). PMID: 9167542
A randomized prospective study comparing supportive and dynamic therapies. Outcome and alliance.
D J Hellerstein, R N Rosenthal, +3 authors, A Winston.
J Psychother Pract Res, 1998 Sep 30; 7(4). PMID: 9752637    Free PMC article.
A rating scale for depression.
J Neurol Neurosurg Psychiatry, 1960 Feb 01; 23. PMID: 14399272    Free PMC article.
Highly Cited.
Prognostic meta-signature of breast cancer developed by two-stage mixture modeling of microarray data.
Ronglai Shen, Debashis Ghosh, Arul M Chinnaiyan.
BMC Genomics, 2004 Dec 16; 5(1). PMID: 15598354    Free PMC article.
Merging microarray data from separate breast cancer studies provides a robust prognostic test.
Lei Xu, Aik Choon Tan, Raimond L Winslow, Donald Geman.
BMC Bioinformatics, 2008 Feb 29; 9. PMID: 18304324    Free PMC article.
A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling.
Gregory E Miller, Edith Chen, +5 authors, Steve W Cole.
Biol Psychiatry, 2008 Apr 29; 64(4). PMID: 18440494    Free PMC article.
Highly Cited.
Identifying blood biomarkers for mood disorders using convergent functional genomics.
H Le-Niculescu, S M Kurian, +7 authors, A B Niculescu.
Mol Psychiatry, 2008 Feb 28; 14(2). PMID: 18301394
Ratio adjustment and calibration scheme for gene-wise normalization to enhance microarray inter-study prediction.
Chunrong Cheng, Kui Shen, +2 authors, George C Tseng.
Bioinformatics, 2009 May 06; 25(13). PMID: 19414534    Free PMC article.
A molecular signature of depression in the amygdala.
Etienne Sibille, Yingjie Wang, +6 authors, David A Lewis.
Am J Psychiatry, 2009 Jul 17; 166(9). PMID: 19605536    Free PMC article.
Cytokines and glucocorticoid receptor signaling. Relevance to major depression.
Thaddeus W W Pace, Andrew H Miller.
Ann N Y Acad Sci, 2009 Nov 13; 1179. PMID: 19906234    Free PMC article.
Research domain criteria (RDoC): toward a new classification framework for research on mental disorders.
Thomas Insel, Bruce Cuthbert, +5 authors, Philip Wang.
Am J Psychiatry, 2010 Jul 03; 167(7). PMID: 20595427
Highly Cited.
Elevating the perspective on human stress genomics.
Steve W Cole.
Psychoneuroendocrinology, 2010 Jul 16; 35(7). PMID: 20630660    Free PMC article.
Major depressive disorder: new clinical, neurobiological, and treatment perspectives.
David J Kupfer, Ellen Frank, Mary L Phillips.
Lancet, 2011 Dec 23; 379(9820). PMID: 22189047    Free PMC article.
Highly Cited. Review.
Gene expression biomarkers of response to citalopram treatment in major depressive disorder.
F Mamdani, M T Berlim, +3 authors, G Turecki.
Transl Psychiatry, 2011 Jan 01; 1. PMID: 22832429    Free PMC article.
Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression.
K Pajer, B M Andrus, +9 authors, E E Redei.
Transl Psychiatry, 2012 Jul 27; 2. PMID: 22832901    Free PMC article.
An R package suite for microarray meta-analysis in quality control, differentially expressed gene analysis and pathway enrichment detection.
Xingbin Wang, Dongwan D Kang, +12 authors, George C Tseng.
Bioinformatics, 2012 Aug 07; 28(19). PMID: 22863766    Free PMC article.
Highly Cited.
Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.
R Belzeaux, A Bergon, +12 authors, E C Ibrahim.
Transl Psychiatry, 2012 Nov 15; 2. PMID: 23149449    Free PMC article.
Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline 'predictors' and longitudinal 'targets'.
Annamaria Cattaneo, Massimo Gennarelli, +8 authors, Carmine M Pariante.
Neuropsychopharmacology, 2012 Sep 20; 38(3). PMID: 22990943    Free PMC article.
Highly Cited.
Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study.
G I Papakostas, R C Shelton, +6 authors, J A Bilello.
Mol Psychiatry, 2011 Dec 14; 18(3). PMID: 22158016
Inflammation and depression.
Patricia A Zunszain, Nilay Hepgul, Carmine M Pariante.
Curr Top Behav Neurosci, 2012 May 04; 14. PMID: 22553073
Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool.
Edward Y Chen, Christopher M Tan, +5 authors, Avi Ma'ayan.
BMC Bioinformatics, 2013 Apr 17; 14. PMID: 23586463    Free PMC article.
Highly Cited.
Prediction of the time-course pattern of remission in depression by using clinical, neuropsychological, and genetic variables.
Esteve Gudayol-Ferré, Joan Guàrdia-Olmos, +5 authors, Patricia Martínez-Medina.
J Affect Disord, 2013 Jun 22; 150(3). PMID: 23787408
Panic-agoraphobic spectrum: reliability and validity of assessment instruments.
M K Shear, E Frank, +9 authors, S Banti.
J Psychiatr Res, 2001 Apr 05; 35(1). PMID: 11287057
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).
Ronald C Kessler, Patricia Berglund, +7 authors, National Comorbidity Survey Replication.
JAMA, 2003 Jun 19; 289(23). PMID: 12813115
Highly Cited.
The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.
A John Rush, Madhukar H Trivedi, +10 authors, Martin B Keller.
Biol Psychiatry, 2003 Aug 30; 54(5). PMID: 12946886
Highly Cited.
Neurobiology of suicidal behaviour.
J John Mann.
Nat Rev Neurosci, 2003 Oct 03; 4(10). PMID: 14523381
Highly Cited. Review.
A global measure of perceived stress.
S Cohen, T Kamarck, R Mermelstein.
J Health Soc Behav, 1983 Dec 01; 24(4). PMID: 6668417
Highly Cited.
Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
Ronald C Kessler, Patricia Berglund, +3 authors, Ellen E Walters.
Arch Gen Psychiatry, 2005 Jun 09; 62(6). PMID: 15939837
Highly Cited.
Bias in error estimation when using cross-validation for model selection.
Sudhir Varma, Richard Simon.
BMC Bioinformatics, 2006 Mar 01; 7. PMID: 16504092    Free PMC article.
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
The peripheral-blood transcriptome: new insights into disease and risk assessment.
Steve Mohr, Choong-Chin Liew.
Trends Mol Med, 2007 Oct 09; 13(10). PMID: 17919976
Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study.
C J Murray, A D Lopez.
Lancet, 1997 May 17; 349(9063). PMID: 9164317
Highly Cited.
Blood-based gene expression signatures of medication-free outpatients with major depressive disorder: integrative genome-wide and candidate gene analyses.
Hiroaki Hori, Daimei Sasayama, +7 authors, Hiroshi Kunugi.
Sci Rep, 2016 Jan 06; 6. PMID: 26728011    Free PMC article.
Blood Transcriptomic Markers in Patients with Late-Onset Major Depressive Disorder.
Shigeo Miyata, Masashi Kurachi, +10 authors, Masahiko Mikuni.
PLoS One, 2016 Mar 02; 11(2). PMID: 26926397    Free PMC article.
MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression.
Armaz Aschrafi, Jan M Verheijen, +11 authors, Tamas Kozicz.
J Psychiatry Neurosci, 2016 Apr 06; 41(5). PMID: 27045550    Free PMC article.
Transcriptomics in Interferon-α-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression.
Nilay Hepgul, Annamaria Cattaneo, +11 authors, Carmine M Pariante.
Neuropsychopharmacology, 2016 Apr 14; 41(10). PMID: 27067128    Free PMC article.
Genetic Contributions of Inflammation to Depression.
Jacob Barnes, Valeria Mondelli, Carmine M Pariante.
Neuropsychopharmacology, 2016 Oct 27; 42(1). PMID: 27555379    Free PMC article.
Systematic Review.
Translational Identification of Transcriptional Signatures of Major Depression and Antidepressant Response.
Mylène Hervé, Aurélie Bergon, +8 authors, El Chérif Ibrahim.
Front Mol Neurosci, 2017 Aug 30; 10. PMID: 28848385    Free PMC article.
Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression.
Indira Mendez-David, Céline Boursier, +6 authors, Denis J David.
Front Cell Neurosci, 2017 Sep 02; 11. PMID: 28860968    Free PMC article.
Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry.
Azmeraw T Amare, Klaus Oliver Schubert, Bernhard T Baune.
EPMA J, 2017 Oct 13; 8(3). PMID: 29021832    Free PMC article.
Progress in Elucidating Biomarkers of Antidepressant Pharmacological Treatment Response: A Systematic Review and Meta-analysis of the Last 15 Years.
G Voegeli, M L Cléry-Melin, N Ramoz, P Gorwood.
Drugs, 2017 Nov 03; 77(18). PMID: 29094313
Systematic Review.
Differentially expressed genes related to major depressive disorder and antidepressant response: genome-wide gene expression analysis.
Hye In Woo, Shinn-Won Lim, +2 authors, Soo-Youn Lee.
Exp Mol Med, 2018 Aug 05; 50(8). PMID: 30076325    Free PMC article.
Time Course of Changes in Peripheral Blood Gene Expression During Medication Treatment for Major Depressive Disorder.
Ian A Cook, Eliza Congdon, +4 authors, Andrew F Leuchter.
Front Genet, 2019 Oct 18; 10. PMID: 31620172    Free PMC article.
Epigenome-wide association study of depression symptomatology in elderly monozygotic twins.
A Starnawska, Q Tan, +6 authors, L Christiansen.
Transl Psychiatry, 2019 Sep 04; 9(1). PMID: 31477683    Free PMC article.
Challenges and Future Prospects of Precision Medicine in Psychiatry.
Mirko Manchia, Claudia Pisanu, Alessio Squassina, Bernardo Carpiniello.
Pharmgenomics Pers Med, 2020 May 20; 13. PMID: 32425581    Free PMC article.
Response to fluoxetine in children and adolescents: a weighted gene co-expression network analysis of peripheral blood.
Teresa Torres, Daniel Boloc, +8 authors, Sergi Mas.
Am J Transl Res, 2020 Jun 09; 12(5). PMID: 32509197    Free PMC article.
Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium.
Gara Arteaga-Henríquez, Maria S Simon, +7 authors, Hemmo A Drexhage.
Front Psychiatry, 2019 Jul 30; 10. PMID: 31354538    Free PMC article.