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Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy

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Abstract

Rationale

There is a substantial unmet need for biomarkers to predict treatment response in major depressive disorder (MDD). Evidence has converged on activation of the inflammatory response system as a fundamental mechanism underlying MDD.

Objectives

By investigating circulating leukocyte subsets quantified by fluorescence-activated cell sorting (FACS) analysis before treatment, we aim to predict antidepressant response.

Methods

Forty medication-free inpatients with melancholic, non-psychotic depression before treatment with either venlafaxine or imipramine and 40 age- and gender-matched healthy controls were included. Leukocyte subsets were quantified by FACS analysis using frozen peripheral blood mononuclear cells (PBMC) collected prior to and after 7 weeks of treatment with either venlafaxine (375 mg/day) or imipramine (blood level 200–300 ng/ml). Response was defined as at least 50 % reduction of the baseline Hamilton Rating Scale for Depression (HAM-D) score.

Results

Prior to treatment, MDD patients showed reduced percentages of CD4+CD25highFoxp3+ T regulatory (Treg) cells when compared with controls (1.5 ± 0.6 vs. 1.8 ± 0.6, p = .037). After treatment, robust rises in Treg cells were observed in patients (1.8 ± 0.7, p < .001), yet Treg cells were not predictors of the clinical outcome of treatment. Antidepressant non-responders showed increased CD8+ cytotoxic T cell percentages (24.0 ± 8.6 vs. 15.9 ± 5.9, p = .004) and decreased natural killer (NK) cell percentages (14.0 ± 6.9 vs. 21.4 ± 11.9, p = .020) compared with responders before treatment. Both lymphocyte levels were not significantly modulated by treatment.

Conclusion

In melancholic MDD, FACS analysis of circulating leukocyte subpopulations might help to discriminate between patients with high or low responsiveness to antidepressant treatment.

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Acknowledgments

We greatly appreciate Jan Bruijn for the design of the treatment trial, Annemarie Wijkhuijs, Harm de Wit, Thomas Hoogenboezem, and Angelique van Rijswijk for their technical assistance, Walter van den Broek and Esther Pluijms for their clinical care, and Siska Verploegh and Alfredo Ortigosa Aguilera for their management and database assistance.

Funding and disclosure

This study was supported by European Union EU-FP7-HEALTH-F2-2008-222963 “MOODINFLAME”. Laura Grosse was funded by EU-FP7-PEOPLE-2009-IAPP “PSYCH-AID”. Livia A. Carvalho was supported by British Council-Partek Partnership, by the British Heart Foundation, and by an ECNP Young Investigator Award. Tom K. Birkenhager receives study support and speakers' fees from Lundbeck. Hemmo A. Drexhage has received grants from the Netherlands Organisation for Health Research and Development, the European Union, the Dutch Diabetic Foundation and the JDRF; he serves/has served in advisory boards of the Netherlands Organisation for Health Research and Development and the European Union. Veerle Bergink is supported by an Erasmus University fellowship and has received funding from the Netherlands Organisation for Scientific Research (NWO, Rubicon incentive). These supporters had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Immunology, Erasmus Medical Center, Wijtemaweg 80, 3015CN, Rotterdam, The Netherlands

    Laura Grosse & Hemmo A. Drexhage

  2. Department of Psychiatry, University of Muenster, Muenster, Germany

    Laura Grosse

  3. Department of Epidemiology and Public Health, University College London, London, UK

    Livia A. Carvalho

  4. Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands

    Tom K. Birkenhager, Witte J. Hoogendijk, Steven A. Kushner & Veerle Bergink

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  1. Laura Grosse
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  2. Livia A. Carvalho
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  4. Witte J. Hoogendijk
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  6. Hemmo A. Drexhage
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  7. Veerle Bergink
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Correspondence to Laura Grosse.

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Laura Grosse and Livia A. Carvalho share first authorship

Hemmo A. Drexhage and Veerle Bergink share last authorship

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Grosse, L., Carvalho, L.A., Birkenhager, T.K. et al. Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy. Psychopharmacology 233, 1679–1688 (2016). https://doi.org/10.1007/s00213-015-3943-9

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