Review: Drug Interactions Between Depression and Epilepsy Therapy
DOI:
https://doi.org/10.70392/jpns.v3i2.48Keywords:
Depression, Epilepsy , Drug Interaction, Antidepressants, Antiepileptic DrugsAbstract
Background: Managing comorbid depression and epilepsy is challenging due to complex drug-drug interactions (DDIs). Objective: This systematic review evaluates clinically significant pharmacokinetic and pharmacodynamic interactions between antidepressants and antiepileptic drugs (AEDs). Methods: A systematic search was conducted across PubMed, ScienceDirect, and Google Scholar (2010–2025) following PRISMA guidelines. Results: Of 377 identified records, 24 studies met the inclusion criteria. Pharmacokinetic interactions (n=18; 75%) primarily involve the CYP450 enzyme system, notably CYP2D6 inhibition by fluoxetine and induction by carbamazepine. Significant pharmacodynamic risks include serotonin syndrome (n=3) and lowered seizure thresholds. Conclusion: While modern therapies offer better safety profiles, specific combinations like valproate-lamotrigine or SSRI-tramadol require rigorous monitoring. Clinical Implications: Pharmacists must prioritize screening for enzyme-inducing AEDs to prevent therapeutic failure or toxicity in neuropsychiatric care.
References
Spina, E., Leon, J.D. Potentially clinically relevant pharmacodynamic interactions between antiepileptic drugs and psy-chotropic drugs: an update. Current Pharmaceutical Design 2017, 23(37), 5625-5638. DOI: https://doi.org/10.2174/1381612823666170809102258
Rachmaini, F., Juwita, D.A., Abdillah, R., Afrianti, R.D., Wahyuni, F.S. Interaction between Fluoxetine and Risperidone and Its Association with Clinical Outcomes in Schizophrenic Patients. Pharmaceutical Sciences and Research 2023, 10(1), 1. DOI: https://doi.org/10.7454/psr.v10i1.1266
Puspitasari, A.W., Angeline, L. Analisis potensi interaksi obat golongan antidepresan pada pasien Skizofrenia di rumah sakit jiwa Dr. Soeharto Heerdjan tahun 2016. Pharmaceutical Sciences and Research 2019, 6(1), 2. DOI: https://doi.org/10.7454/psr.v6i1.4196
Novella, A., Elli, C., Pasina, L. Selective Serotonin Reuptake Inhibitors and Risk of Serotonin Syndrome as Consequence of Drug-Drug Interactions: Analysis of the FDA Adverse Event Reporting System. Medical Principles and Practice 2025. DOI: https://doi.org/10.1159/000546109
Jin, G., Stokes, P. Drug interaction between a selective serotonin reuptake inhibitor and a triptan leading to serotonin toxicity: a case report and review of the literature. Journal of Medical Case Reports 2021, 15(1), 371. DOI: https://doi.org/10.1186/s13256-021-02946-8
de Brabander, E., Schaars, K.K., van Amelsvoort, T. Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review. Journal of psychiatric research 2024, 174, 137-152. DOI: https://doi.org/10.1016/j.jpsychires.2024.04.001
Kane, C.M., Mulvey, M.R., Wright, S., Craigs, C., Wright, J.M., Bennett, M.I. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: systematic review and meta-analysis. Palliative medicine 2018, 32(1), 276-286. DOI: https://doi.org/10.1177/0269216317711826
Arthy, C.c., Lubis, R.A. Mood Stabilizer Induced Steven Johnson Syndrome: A Case Report. In Proceedings of the 7th International Conference on Neuroscience, Neurology, and Psychiatry Universitas Sumatera Utara 2024, 83, 37. Springer Nature. DOI: https://doi.org/10.2991/978-94-6463-616-1_6
Rizkifani, S., Susanti, R., Febiani, T. Kajian interaksi obat antidepresan dan antipsikotik pada pasien skizofrenia di Rumah Sakit Jiwa Daerah Sungai Bangkong Pontianak. Medical Sains: Jurnal Ilmiah Kefarmasian 2023, 8(1), 163-172. DOI: https://doi.org/10.37874/ms.v8i1.532
Mikami, A., Hori, S., Ohtani, H., Sawada, Y. Analysis of the mechanism of prolonged persistence of drug interaction between terbinafine and amitriptyline or nortriptyline. Biological and Pharmaceutical Bulletin 2017, 40(7), 1010-1020. DOI: https://doi.org/10.1248/bpb.b16-01004
Sandson, N.B., Marcucci, C., Bourke, D.L., Smith-Lamacchia, R. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug-drug interactions. American Journal of Psychiatry 2006, 163(11), 1891-1896. DOI: https://doi.org/10.1176/ajp.2006.163.11.1891
Putri, R.H., Putranti, A.H. Efek Samping Polifarmasi Asam Valproat dan Topiramat Dibandingkan Monofarmasi Asam Valproat pada Pasien Epilepsi. Sari Pediatri 2021, 23(4), 247-54. DOI: https://doi.org/10.14238/sp23.4.2021.247-54
Besag, F.M., Berry, D., Vasey, M.J., Patsalos, P.N. Drug-drug interactions between antiseizure medications and antipsy-chotic medications: a narrative review and expert opinion. Expert Opinion on Drug Metabolism & Toxicology 2023, 19(11), 829-847. DOI: https://doi.org/10.1080/17425255.2023.2278676
Zaccara, G., Franco, V. Pharmacokinetic interactions between antiseizure and psychiatric medications. Current neuro-pharmacology 2023, 21(8), 1666-1690. DOI: https://doi.org/10.2174/1570159X20666220524121645
Luszczki, J. J., Mazurkiewicz, L. P., Wroblewska-Luczka, P., Wlaz, A., Ossowska, G., Szpringer, M., Zolkowska, D., Florek-Luszczki, M. Combination of phenobarbital with phenytoin and pregabalin produces synergy in the mouse ton-ic-clonic seizure model: An isobolographic analysis. Epilepsy Research 2018, 145, 116-122. DOI: https://doi.org/10.1016/j.eplepsyres.2018.06.003
Brodie, M.J., Mintzer, S. Interactions between antiepileptic drugs: mechanisms and clinical significance. Epilepsy & Be-havior 2019, 97, 253–262.
Candeloro, S. Drug Interaction between the Carbamazepine and Phenytoin. J. Phar. Res. Clin. Pra 2023, 6(2), 37–39
Eltalal, S., El Ayouty, M., El-Said, A., Wahba, Y. CYP2C9 (* 2&* 3) and CYP2C19 (* 2&* 3) polymorphisms among children with nonlesional epilepsy: a single-center study. Acta Neurologica Belgica 2021, 121(6), 1623-1631. DOI: https://doi.org/10.1007/s13760-020-01442-y
Liu, S., Xu, Y. MD Investigation on the Interaction between Carbamazepine and Two CYP Isoforms, CYP3A4 and CYP3A5. International Journal of Molecular Sciences 2023, 24(3), 2188. DOI: https://doi.org/10.3390/ijms24032188
Teomete, M., Cabuk, D., Korkmaz, T., Seber, S., Ozturk, O. F., Aver, B., Karaalp, A., Basaran, G. Recommendations for cyclin‑dependent kinase 4/6 inhibitor treatments in the context of co‑morbidity and drug interactions. Oncology Letters 2024, 27(4), 145. DOI: https://doi.org/10.3892/ol.2024.14278
Johannessen Landmark, C., Johannessen, S.I., Patsalos, P.N. Therapeutic drug monitoring of antiepileptic drugs: current status and future prospects. Expert opinion on drug metabolism & toxicology 2020, 16(3), 227-238. DOI: https://doi.org/10.1080/17425255.2020.1724956
Mishra, A., Mishra, B.R., Mohapatra, D., Srinivasan, A., Maiti, R. Interaction between Carbamazepine and Concomitant Levetiracetam Therapy in Patients with Epilepsy. Canadian Journal of Hospital Pharmacy 2025, 78(4), e3864. DOI: https://doi.org/10.4212/cjhp.3846
Tolbert, D., Bekersky, I., Chu, H.M., Ette, E.I. Drug‐metabolism mechanism: knowledge–based population pharmaco-kinetic approach for characterizing clobazam drug‐drug interactions. The Journal of Clinical Pharmacology 2016, 56(3), 365-374. DOI: https://doi.org/10.1002/jcph.603
Quintero, G.C. Review about gabapentin misuse, interactions, contraindications and side effects. Journal of experimental pharmacology 2017, 9, 13-21. DOI: https://doi.org/10.2147/JEP.S124391
Qi, X. Neuropharmacology of Neurotransmitter Systems: Current Drugs and Their Effects on Neural and Neuroendocrine Pathways. Asia Pacific Journal of Clinical Medical Research 2025, 1(1), 1-10. DOI: https://doi.org/10.62177/apjcmr.v1i1.336
Montejo, A.L., Prieto, N., de Alarcón, R., Casado-Espada, N., de la Iglesia, J., Montejo, L. Management strategies for antidepressant-related sexual dysfunction: a clinical approach. Journal of clinical medicine 2019, 8(10), 1640. DOI: https://doi.org/10.3390/jcm8101640
Alborghetti, M., Barbieri, M.A., Nicoletti, F., Spina, E. Exploring drug interactions between newer antidepressants and medications used to treat neurological disorders. Expert Opinion on Drug Metabolism & Toxicology 2025, 21(10), 1169-1193. DOI: https://doi.org/10.1080/17425255.2025.2566692
Das, B., Ramasubbu, S.K., Kumar, B., Rawat, V.S. Top 20 drug−drug interactions, polypharmacy and analysis of the nature of risk factors due to QT interval prolonging drug use in elderly psychiatry outpatients. Journal of Family Medicine and Primary Care 2020, 9(12), 6023-6040. DOI: https://doi.org/10.4103/jfmpc.jfmpc_1060_20
Khurana, K., Acharya, S., Sadh, K., Pantbalekundri, N., Toshniwal, S. Complete Heart Block Secondary to Concomitant Use of Metoprolol and Fluoxetine in a Case of Chronic Depression and Systemic Hypertension: A Case Report. Journal of Clinical & Diagnostic Research 2024, 18(3), p. 18. DOI: https://doi.org/10.7860/JCDR/2024/68236.19205
Strawn, J.R., Whitsel, R., Nandagopal, J.J., DelBello, M.P. Atypical Stevens-Johnson syndrome in an adolescent treated with duloxetine. Journal of child and adolescent psychopharmacology 2011, 21(1), 91. DOI: https://doi.org/10.1089/cap.2010.0071
Pinkhasov, A., Xiong, G., Bourgeois, J. A., Heinrich, T. W., Huang, H., Coriolan, S., Annamalai, A., Mangal, J.P., Frankel, S., Lang, M., Raj, Y.P., Dandois, M., Barth, K., Stewart, A.L., Rado, J., Pesek, J., Sanders, A., Spear-man-McCarthy, E.V., Gagliardi, J., Fiedorowicz, J.G. Management of SIADH-related hyponatremia due to psychotropic medications–An expert consensus from the Association of Medicine and Psychiatry. Journal of psychosomatic research 2021, 151, 110654. DOI: https://doi.org/10.1016/j.jpsychores.2021.110654
Nikbakhat, M. R., Arabzadeh, S., Zeinoddini, A., Khalili, Z., Rezaei, F., Mohammadinejad, P., Ghaleiha, A., Akhon-dzadeh, S. Duloxetine add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. Pharmacopsychiatry 2016, 49(4), 162-169. DOI: https://doi.org/10.1055/s-0042-101557
Dołoto, A., Bąk, E., Batóg, G., Piątkowska-Chmiel, I., Herbet, M. Interactions of antidepressants with concomitant medications—safety of complex therapies in multimorbidities. Pharmacological Reports 2024, 76(4), 714-739. DOI: https://doi.org/10.1007/s43440-024-00611-7
Spadaro, A., Scott, K.R., Koyfman, A., Long, B. High risk and low prevalence diseases: Serotonin syndrome. The Amer-ican Journal of Emergency Medicine 2022, 61, 90-97. DOI: https://doi.org/10.1016/j.ajem.2022.08.030
Koleva, K., Nikolov, R. Antidepressants-induced serotonin syndrome: literature review. Pharmacia 2018, 65(1), 64-70.
Li, H., Cheng, Y., Ahl, J., Skljarevski, V. Observational study of upper gastrointestinal tract bleeding events in patients taking duloxetine and nonsteroidal anti-inflammatory drugs: a case-control analysis. Drug, Healthcare and Patient Safety 2014, 6, 167-174. DOI: https://doi.org/10.2147/DHPS.S66835
Xu, T., Gao, N., Li, Y., Wang, R., Chen, B., Hu, G., Zhang, X. Inhibitory effects of fluoxetine and duloxetine on the pharmacokinetics of metoprolol in vivo and in vitro. Fundamental & clinical pharmacology 2022, 36(6), 1057-1065. DOI: https://doi.org/10.1111/fcp.12795
Edinoff, A.N., Swinford, C.R., Odisho, A.S., Burroughs, C.R., Stark, C.W., Raslan, W.A., Cornett, E.M., Kaye, A.M., Kaye, A.D. Clinically relevant drug interactions with monoamine oxidase inhibitors. Health psychology research 2022, 10(4), 39576. DOI: https://doi.org/10.52965/001c.39576
Gronich, N. Central nervous system medications: pharmacokinetic and pharmacodynamic considerations for older adults. Drugs & aging 2024, 41(6), 507-519. DOI: https://doi.org/10.1007/s40266-024-01117-w
Aliyu, H., Ayo, J.O., Ambali, S.F., Suleiman, M.M., Kobo, P.I., Tauheed, A.M., Sinkalu, V.O. Alteration of neurobe-havioural activities by carbamazepine, phenytoin and their combination in Wistar rats: A mini review. Journal of Neuro-science and Behavioral Health 2017, 4(1), 25-30. DOI: https://doi.org/10.5455/JNBS.1481879445
Susanti, R., Latiefah, A.D., Nafisah, R. Kajian Interaksi Obat pada Resep Pasien Epilepsi Rawat Jalan di RSUD dr. Slamet Garut. Jurnal Ilmiah Farmako Bahari 2025, 16(2), 182-192. DOI: https://doi.org/10.52434/jifb.v16i2.42775
Hagemann, A., Herting, A., Klimpel, D., Bien, C.G., Polster, T. Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction. Epilepsia 2024, 65(6), e73-e78. DOI: https://doi.org/10.1111/epi.17952
Candeloro, M., Eikelboom, J.W., Chan, N., Bhagirath, V., Douketis, J.D., Schulman, S. Carbamazepine, phenytoin, and oral anticoagulants: Drug‐drug interaction and clinical events in a retrospective cohort. Research and practice in thrombosis and haemostasis 2022, 6(2), e12650. DOI: https://doi.org/10.1002/rth2.12650
Shah, K., Kamrai, D., Srinivas, S., Veluri, N., Chaudhari, G., Trivedi, C., Mansuri, Z. Benzodiazepine interaction with COVID-19 drugs. The Primary Care Companion for CNS Disorders 2021, 23(6), 37719. DOI: https://doi.org/10.4088/PCC.21br03081
Petrucelli, N., Hayes, B.D., Shelat, N., Elshaboury, R.H., Pearson, J.C., Koehl, J.L. Evaluating clinical sequelae of the carbapenem-valproate interaction: A retrospective analysis. In Open Forum Infectious Diseases 2024, 11(3), p. e130. DOI: https://doi.org/10.1093/ofid/ofae130
Liu, R., Xiao, L., Hu, Y., Yan, Q., Liu, X. Rescue strategies for valproic acid overdose poisoning: Case series and litera-ture review. Clinical Case Reports 2024, 12(1), e8367. DOI: https://doi.org/10.1002/ccr3.8367
Downloads
Published
Data Availability Statement
Issue
Section
License
Copyright (c) 2026 Erwin Samsul, Sandrina Nur Yulianda, Rahmawati Eka Sari, Dina Nurfauziah Rahmi, Rahma Nur Afifah, Risma Nur Ramadhani, Annisa Azhalia Syakina, Selvina Nirmaya Saputri, Listra Febrina Taruk (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
How to Cite
