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[41] Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. InMayo Clinic Proceedings 2006 Oct 1 (Vol. 81, No. 10, pp. 1361-1367). Elsevier

[42] Laugesen K, Farkas DK, Vestergaard M, Jørgensen JOL, Petersen I, Sørensen HT. Glucocorticoid use and risk of suicide: a Danish population-based case-control study. World Psychiatry. 2021 Feb;20(1):142-143.

[43] Ricoux A, Guitteny-Collas M, Sauvaget A, Delvot P, Pottier P, Hamidou M, Vanelle JM. Troubles psychiatriques induits par la corticothérapie orale: mise au point sur la nature, l'incidence, les facteurs de risque et le traitement. La Revue de médecine interne. 2013 May 1;34(5):293-302.

[44] Pedro Fong et al., Association of suicidal ideation and depression with the use of proton pump inhibitors in adults: a cross-sectional study, Sci Rep. 2022 Nov 14;12(1):19539. doi: 10.1038/s41598-022-24244-z. https://pubmed.ncbi.nlm.nih.gov/36376493/

[45] A. Laudisio et al., Use of proton-pump inhibitors is associated with depression: a population-based study, Int Psychogeriatr, 2018 Jan;30(1):153-159 : https://pubmed.ncbi.nlm.nih.gov/28899441/

[46] Y-H. Wang, V. Wintzell, Jonas F. Ludvigsson, H. Svanström, Björn Pasternak, Proton pump inhibitor use and risk of depression and anxiety in children: nationwide cohort study, Clin Transl Sci. 2022 May; 15(5): 1112–1122 : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099128/

[47] T. Makunts, H. Joulfayan, K. Ta, R. Abagyan, Depression events associated with proton-pump inhibitors in postmarketing drug surveillance data, June 05, 2023: https://www.medrxiv.org/content/10.1101/2023.06.03.23290931v1.full

[48] Laird E, O'Halloran AM, Molloy AM, et al. Low vitamin B. Br J Nutr. Dec 13 2021:1–22. doi:10.1017/S0007114521004748
[40] Amine, Laffinti Mahmoud, et al. "Corticoïdes et culture: un cas d'épisode psychotique aigu cortico-induit." *The Pan African Medical Journal* 33 (2019)

[41] Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. InMayo Clinic Proceedings 2006 Oct 1 (Vol. 81, No. 10, pp. 1361-1367). Elsevier

[42] Laugesen K, Farkas DK, Vestergaard M, Jørgensen JOL, Petersen I, Sørensen HT. Glucocorticoid use and risk of suicide: a Danish population-based case-control study. World Psychiatry. 2021 Feb;20(1):142-143.

[43] Ricoux A, Guitteny-Collas M, Sauvaget A, Delvot P, Pottier P, Hamidou M, Vanelle JM. Troubles psychiatriques induits par la corticothérapie orale: mise au point sur la nature, l'incidence, les facteurs de risque et le traitement. La Revue de médecine interne. 2013 May 1;34(5):293-302.

[44] Pedro Fong et al., Association of suicidal ideation and depression with the use of proton pump inhibitors in adults: a cross-sectional study, Sci Rep. 2022 Nov 14;12(1):19539. doi: 10.1038/s41598-022-24244-z. https://pubmed.ncbi.nlm.nih.gov/36376493/

[45] A. Laudisio et al., Use of proton-pump inhibitors is associated with depression: a population-based study, Int Psychogeriatr, 2018 Jan;30(1):153-159 : https://pubmed.ncbi.nlm.nih.gov/28899441/

[46] Y-H. Wang, V. Wintzell, Jonas F. Ludvigsson, H. Svanström, Björn Pasternak, Proton pump inhibitor use and risk of depression and anxiety in children: nationwide cohort study, Clin Transl Sci. 2022 May; 15(5): 1112-1122 : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099128/

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[50] Derom ML, Sayón-Orea C, Martínez-Ortega JM, Martínez-González MA. Magnesium and depression: a systematic review. Nutr Neurosci. Sep 2013;16(5):191–206. doi:10.1179/1476830512Y.0000000044

[51] Cheungpasitporn W, Thongprayoon C, Mao MA, et al. Hypomagnesaemia linked to depression: a systematic review and meta-analysis. Intern Med J. Apr 2015;45(4):436–40. doi:10.1111/imj.12682

[52] Floris Imhann et al., Proton pump inhibitors affect the gut microbiome Gut. 2016 May; 65(5): 740–748. doi: 10.1136/gutjnl-2015-310376

[53] Jeremy Appleton, The Gut-Brain Axis: Influence of Microbiota on Mood and Mental Health Integr Med (Encinitas). 2018 Aug; 17(4): 28–32.

[54] George Monks, Ryan Rivera-Oyola, and Mark Lebwohl, The Psoriasis Decision Tree, J Clin Aesthet Dermatol. 2021 Apr; 14(4): 14–22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142826/

[55] Ortega-Albás JJ, López-Bernabé R, Serrano García AL, Díaz Gómez JR. Suicidal ideation secondary to sodium oxybate. J Neuropsychiatry Clin Neurosci. 2010;22:352r.e26.

[56] Rossetti AO, Heinzer RC, Tafti M, Buclin T. Rapid occurrence of depression following addition of sodium oxybate to modafinil. Sleep Med. 2010;11:500–1

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[62] FDA approved Labeling Text for NDA 020796, Novartis – COMTAN® (entacapone) tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020796s15lbl.pdf

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[72] Witte Janet et al. A Randomized, Controlled, Pilot Study of Acamprosate Added to Escitalopram in Adults With Major Depressive Disorder and Alcohol Use Disorder. *Journal of clinical psychopharmacology* 32, n° 6 (décembre 2012): 787-96.
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[73] FDA, Highlights of prescribing information, CAMPRAL® (acamprosate calcium) Delayed-Release Tablets, revised: January 2012: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021431s015lbl.pdf

[74] Legendre, T., C. Boudebesse, C. Henry, et B. Etain. « Antibiomania : penser au syndrome maniaque secondaire à une antibiothérapie ». L'Encéphale 43, no 2 (2017): 183. https://doi.org/10.1016/j.encep.2015.06.008

[75] Edith Paula Meszaros et al., « Antibiomania: a case report of clarithromycin and amoxicillin-clavulanic acid induced manic episodes separately ». BMC Psychiatry 21, no 1 (11 août 2021): 399. https://doi.org/10.1186/s12888-021-03397-7.

[76] Xinji Liu et al., Antibiotic exposure and potential risk of depression in the Chinese elderly: a biomonitoring-based population study, Environ Sci Pollut Res Int. 2021 Jun;28(21):26794-26806. doi: 10.1007/s11356-021-12560-2. https://pubmed.ncbi.nlm.nih.gov/33501576/

[77] Katherine Dinan, Timothy Dinan, Antibiotics and mental health: The good, the bad and the ugly, J Intern Med. 2022 Dec; 292(6): 858-869. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796968/
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[82] Gyu Nam Park, Joo O Kim, Jae Won Oh, San Lee, Association between anemia and depression: The 2014, 2016, and 2018 Korea National Health and Nutrition Examination Survey, J Affect Disord, 2022 Sep 1;312:86-91. doi: 10.1016/j.jad.2022.06.015.

[83] Kamilla W Miskowiak, Maj Vinberg et al., Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder, Trials. 2010; 11: 97 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967509/

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[85] D. Keshishi, T. Makunts, R. Abagyan, Common osteoporosis drug associated with increased rates of depression and anxiety, Scientific Reports, 11(1), Dec 2021: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671447/

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[82] Gyu Nam Park, Joo O Kim, Jae Won Oh, San Lee, Association between anemia and depression: The 2014, 2016, and 2018 Korea National Health and Nutrition Examination Survey, J Affect Disord, 2022 Sep 1;312:86-91. doi: 10.1016/j.jad.2022.06.015.

[83] Kamilla W Miskowiak, Maj Vinberg et al., Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder, Trials. 2010; 11: 97 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967509/

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# Effets dépressogènes des médicaments et risque suicidaire : analyse de cas régionaux à partir d'une base de données nationale de pharmacovigilance

Thèse d'université n° 2023 – 147 – Université de Picardie Jules Vernes, Faculté de médecine Océane Fourrier ; directrice de thèse : Mme le Dr Valérie GRAS-CHAMPEL

**Résumé** : La dépression et les conduites suicidaires (CS) sont des affections très fréquentes et certains médicaments ont été décrits comme induisant ou aggravant ces conditions. Nous avons analysé les cas régionaux d'une base de données nationale de pharmacovigilance concernés par un effet indésirable de type dépression ou CS à l'aide d'une extraction via les termes associés du MedDRA et nous avons comparé les résultats aux données renseignées dans les Résumés des Caractéristiques du Produit (RCP) des médicaments suspects dans ces effets. Les facteurs de risque individuels de CS ont également été relevés. Les résultats ont été marqués par un taux très important de déclarations concernant le LEVOTHYROX® NF ainsi que le MIRENA®. Parmi les autres thérapeutiques, on retrouve majoritairement des classes pharmacologiques pour lesquelles le risque de dépression ou de CS est déjà connu. Quelques cas ont cependant été retrouvés parmi des classes thérapeutiques pour lesquelles ce risque n'est pas listé dans leur RCP, et trois médicaments représentent de potentiels signaux de pharmacovigilance (néfopam, zolédronate et emtricitabine). Le reste des résultats est concordant avec les connaissances actuelles. L'étude est limitée par les biais protopathiques et de sous-notification ainsi que l'effet de notoriété. La dépression ayant une origine multifactorielle avec des intrications complexes, il est difficile de déterminer le rôle propre d'un médicament dans sa survenue. Cependant, il reste indispensable que les professionnels de santé soient alertés du potentiel effet dépressogène ou suicidogène de certains médicaments afin de les prendre en compte dans la prise en charge des patients.

**Abstract:** Depression and suicidal behaviors are very common conditions, and some medications have been described as inducing or worsening these conditions. We analyzed regional cases from a national pharmacovigilance database related to adverse effects of depression or suicidal behavior using the related Standardized MedDRA Queries (SMQs) from MedDRA. We compared the results to the information provided in the Summary of Product Characteristics (SmPC) of the drugs implicated in these effects. Individual risk factors for events related to suicidal behavior were also noted. The results were marked by a high rate of reports of depression and, to a lesser extent, suicidal ideation with the new formulation of LEVOTHYROX® and MIRENA®. Among other therapies, many belong to pharmacological classes for which the risk of developing or exacerbating depression or suicidal behavior is already known. However, a few cases were found among pharmacological classes for which the risk of depression or suicidal behavior is not listed in their SmPC despite strong pharmacological evidence. Three medications have also been highlighted as potential pharmacovigilance signals (nefopam, zoledronate and emtricitabine). The rest of the results are consistent with current knowledge. The study is limited by underreporting biases, protopathic biases, and notoriety effect. Since depression has a multifactorial origin with complex interplay, it is impossible to determine the exact role of a medication in its development. However, it remains essential for healthcare professionnals to be alerted to the potential depressogenic or suicidogenic effects of certain medications in order to consider them in patient management.
# Effets dépressogènes des médicaments et risque suicidaire : analyse de cas régionaux à partir d'une base de données nationale de pharmacovigilance

Thèse d'université n° 2023 – 147 – Université de Picardie Jules Vernes, Faculté de médecine Océane Fourrier ; directrice de thèse : Mme le Dr Valérie GRAS-CHAMPEL

**Résumé** : La dépression et les conduites suicidaires (CS) sont des affections très fréquentes et certains médicaments ont été décrits comme induisant ou aggravant ces conditions. Nous avons analysé les cas régionaux d'une base de données nationale de pharmacovigilance concernés par un effet indésirable de type dépression ou CS à l'aide d'une extraction via les termes associés du MedDRA et nous avons comparé les résultats aux données renseignées dans les Résumés des Caractéristiques du Produit (RCP) des médicaments suspects dans ces effets. Les facteurs de risque individuels de CS ont également été relevés. Les résultats ont été marqués par un taux très important de déclarations concernant le LEVOTHYROX® NF ainsi que le MIRENA®. Parmi les autres thérapeutiques, on retrouve majoritairement des classes pharmacologiques pour lesquelles le risque de dépression ou de CS est déjà connu. Quelques cas ont cependant été retrouvés parmi des classes thérapeutiques pour lesquelles ce risque n'est pas listé dans leur RCP, et trois médicaments représentent de potentiels signaux de pharmacovigilance (néfopam, zolédronate et emtricitabine). Le reste des résultats est concordant avec les connaissances actuelles. L'étude est limitée par les biais protopathiques et de sous-notification ainsi que l'effet de notoriété. La dépression ayant une origine multifactorielle avec des intrications complexes, il est difficile de déterminer le rôle propre d'un médicament dans sa survenue. Cependant, il reste indispensable que les professionnels de santé soient alertés du potentiel effet dépressogène ou suicidogène de certains médicaments afin de les prendre en compte dans la prise en charge des patients.

**Abstract:** Depression and suicidal behaviors are very common conditions, and some medications have been described as inducing or worsening these conditions. We analyzed regional cases from a national pharmacovigilance database related to adverse effects of depression or suicidal behavior using the related Standardized MedDRA Queries (SMQs) from MedDRA. We compared the results to the information provided in the Summary of Product Characteristics (SmPC) of the drugs implicated in these effects. Individual risk factors for events related to suicidal behavior were also noted. The results were marked by a high rate of reports of depression and, to a lesser extent, suicidal ideation with the new formulation of LEVOTHYROX® and MIRENA®. Among other therapies, many belong to pharmacological classes for which the risk of developing or exacerbating depression or suicidal behavior is already known. However, a few cases were found among pharmacological classes for which the risk of depression or suicidal behavior is not listed in their SmPC despite strong pharmacological evidence. Three medications have also been highlighted as potential pharmacovigilance signals (nefopam, zoledronate and emtricitabine). The rest of the results are consistent with current knowledge. The study is limited by underreporting biases, protopathic biases, and notoriety effect. Since depression has a multifactorial origin with complex interplay, it is impossible to determine the exact role of a medication in its development. However, it remains essential for healthcare professionnals to be alerted to the potential depressogenic or suicidogenic effects of certain medications in order to consider them in patient management.