NAME OF RESEARCHER
Giulia Lombardo
NAME OF SUPERVISOR
1st Supervisor, Professor Carmine Maria Pariante
2nd Supervisor, Professor Valeria Mondelli
PROJECT TITLE:
Identifying sex-specific biological differences in Major Depressive Disorder and Treatment Resistant Depression
CLINICAL ACADEMIC GROUP:
Department of Psychological Medicine – King’s College London
START & FINISH DATES:
1st October 2018 – 30th December 2022 - Awarded on the 1st of September 2022
PROJECT DESCRIPTION
Sex differences in major depressive disorder (MDD) are well-known in clinical practice and in research. For instance, women are more likely to develop depression, whereas men are more at risk of completed suicides. The differences expand to other areas like treatment response, and the type of clinical symptoms. Inflammation has recently caught attention as a possible biological factor associated with the etiopathogenesis of depression. Inflammation is our defense mechanism against pathogens and other threats. However, in some patients with depression, the immune system (that is the system that fights those threats) is hyperactivated, resulting in increased levels of inflammatory biomarkers (e.g., C-Reactive Protein (CRP)). Inflammatory levels are even higher in those patients who do not improve with common antidepressants (i.e., treatment resistant depression (TRD)) than responders. The investigation of sex hormones and their relationship with the immune system is a valid path to take to better understand sex differences in depression.
To investigate this, my project is split between two complementary studies.
In the Biomarkers in Depression (BIODEP) Study, I investigated sex hormones and inflammatory biomarkers in male and female patients with depression separately, stratified by inflammatory levels (low vs. high).
The Minocycline and Depression (MINDEP) study is a clinical drug trial testing minocycline (that is an antibiotic with anti-inflammatory and antidepressant proprieties) in MDD-TRD patients. I explored sex differences in response to add-on minocycline treatment, and sex -specific relevance of inflammatory levels at the baseline in modulating treatment response.
What this research has shown.
In the past year, I have completed the analyses for my PhD project, and I obtained my PhD - awarded on the 1st of September 2022. I have recently published my PhD results on the MINDEP clinical trial on Brain, Behavior & Immunity - Health (please, see below).
The main results of my PhD analyses highlight the need to study biological sex to better understand sex differences in depression, and in treatment response.
In the BIODEP study, sex hormones exhibited an interplay with the immune system in patients with depression. Male MDD patients showed an imbalance of gonadal hormone levels with higher inflammation showed decreased testosterone levels and testosterone to estradiol ratio than those with lower inflammation.
In the MINDEP clinical trial, we detected sex differences in the relevance of CRP and interleukin-6 (IL-6) in modulating the response to minocycline treatment. In fact, female TRD patients with low-grade inflammation (CRP ≥ 3 mg/L) showed clinical improvement after minocycline treatment whereas CRP levels did not affect treatment response in male TRD patients. We then detected a relevant role of increased IL-6 levels in predicting treatment response to this compound in both sexes.
Implications
My PhD results raise the possibility of new approaches in investigating the role of the immune system in depression. These findings highlight the need to deepen our knowledge on the immunomodulator proprieties of sex hormones in patients with depression, and on the sex-specific characteristics in terms of treatment response to anti-inflammatory compound (i.e., minocycline) in TRD patients. This new perspective opens the gates to new future tailored treatments in a view of a sex-specific medicine.
PUBLICATIONS & CONFERENCES ATTENDED:
Publications - First Author:
Lombardo, G., Nettis, M. A., Hastings, C., Zajkowska, Z., Mariani, N., Nikkheslat, N., Worrell, C., Enache, D., McLaughlin, A., Kose, M., Bogdanova, A., Sforzini, L., Cleare, A. J., Young, A. H., Dazzan, P., Mondelli, V., & Pariante, C. M. (2022). Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response. Brain, behavior, & immunity - health, 26, 100561. https://doi.org/10.1016/j.bbih.2022.100561
Lombardo G. New frontiers in suicide vulnerability: immune system and sex hormones. Brain Behav Immun Health. 2021 Nov 10;18:100384. doi: 10.1016/j.bbih.2021.100384. PMID: 34841283; PMCID: PMC8607160.
Lombardo, G., Mondelli, V., Dazzan, P., & Pariante, C. M. (2021). Sex hormones and immune system: A possible interplay in affective disorders? A systematic review. Journal of affective disorders, 290, 1–14. https://doi.org/10.1016/j.jad.2021.04.035
Lombardo, G., Enache, D., Gianotti, L., Schatzberg, A. F., Young, A. H., Pariante, C. M., & Mondelli, V. (2019). Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis. Psychoneuroendocrinology, 110, 104420. https://doi.org/10.1016/j.psyneuen.2019.104420
Publications - Second Author
Nettis, M. A., Lombardo, G., Hastings, C., Zajkowska, Z., Mariani, N., Nikkheslat, N., Worrell, C., Enache, D., McLaughlin, A., Kose, M., Sforzini, L., Bogdanova, A., Cleare, A., Young, A. H., Pariante, C. M., & Mondelli, V. (2021). Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 46(5), 939–948. https://doi.org/10.1038/s41386-020-00948-6
Other Publications while the PhD project
Nettis, M. A., Lawrence, A. J., Wood, T., Mariani, N., Nikkheslat, N., Lombardo, G., Enache, D., Veronese, M., Turkheimer, F. E., Dazzan, P., Pariante, C. M., & Mondelli, V. (2021). Using quantitative MRI to study brain responses to immune challenge with interferon-α. Brain, behavior, & immunity - health, 18, 100376. https://doi.org/10.1016/j.bbih.2021.100376
McLaughlin, A. P., Nikkheslat, N., Hastings, C., Nettis, M. A., Kose, M., Worrell, C., Zajkowska, Z., Mariani, N., Enache, D., Lombardo, G., Pointon, L., NIMA Consortium, Cowen, P., Cavanagh, J., Harrison, N., Bullmore, E., Pariante, C. M., & Mondelli, V. (2021). The influence of comorbid depression and overweight status on peripheral inflammation and cortisol levels. Psychological medicine, 1–8. Advance online publication. https://doi.org/10.1017/S0033291721000088
Nikkheslat, N., McLaughlin, A. P., Hastings, C., Zajkowska, Z., Nettis, M. A., Mariani, N., Enache, D., Lombardo, G., Pointon, L., Cowen, P. J., Cavanagh, J., Harrison, N. A., Bullmore, E. T., NIMA Consortium, Pariante, C. M., & Mondelli, V. (2020). Childhood trauma, HPA axis activity and antidepressant response in patients with depression. Brain, behavior, and immunity, 87, 229–237. https://doi.org/10.1016/j.bbi.2019.11.024
Nettis, M. A., Veronese, M., Nikkheslat, N., Mariani, N., Lombardo, G., Sforzini, L., Enache, D., Harrison, N. A., Turkheimer, F. E., Mondelli, V., & Pariante, C. M. (2020). PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers. Translational psychiatry, 10(1), 89. https://doi.org/10.1038/s41398-020-0768-z
Cattaneo, A., Ferrari, C., Turner, L., Mariani, N., Enache, D., Hastings, C., Kose, M., Lombardo, G., McLaughlin, A. P., Nettis, M. A., Nikkheslat, N., Sforzini, L., Worrell, C., Zajkowska, Z., Cattane, N., Lopizzo, N., Mazzelli, M., Pointon, L., Cowen, P. J., Cavanagh, J., … Pariante, C. M. (2020). Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study. Translational psychiatry, 10(1), 232. https://doi.org/10.1038/s41398-020-00874-7
Blog Publications
I am interested in spreading scientific knowledge in an accessible way, thus I have been publishing on Inspire the Mind (https://www.inspirethemind.org/ ) the following blogs:
20th of December 2022 - “From One-Size-Fits-all to Precision Medicine” https://www.inspirethemind.org/post/from-one-size-fits-all-to-precision-medicine
6th of April 2022 - “Beyond the Veil of a Male Phenomenon: Sex hormones & the immune system in suicide vulnerability” https://www.inspirethemind.org/post/beyond-the-veil-of-a-male-phenomenon-sex-hormones-the-immune-system-in-suicide-vulnerability
29th of July 2021 – “The interplay between sex hormones and immune system: an
undiscovered path in the affective disorder maze?” https://www.inspirethemind.org/blog/the-interplay-between-sex-hormones-and-immune-system
8th of January 2020 – “Mindfulness: How to become a Jedi?” https://www.inspirethemind.org/blog/mindfulness-how-to-become-a-jedi
20th of March 2019 – “Sex differences in mental health: a reflection” https://www.inspirethemind.org/blog/2019/03/20/sex-differences-in-mental-health-a-reflection
CONFERENCES ATTENDED IN THE PAST YEAR (2021 - 2022):
July 2022 - British Association for Psychopharmacology (BAP) - Summer meeting BAP 2022
June 2022 - Psychoneuroimmunology Research Society (PNIRS) Annual Meeting 2022
April 2022 - Society of Biological Psychiatry (SOBP) Annual Meeting 2022 - (USA)
September 2021- International Society of Psychoneuroendocrinology (ISPNE) Conference 2021
July 2021- British Association for Psychopharmacology (BAP) - Summer meeting BAP 2021
May 2021 - PsychoNeuroImmunology Research Society (PNIRS) Conference 2021