Last week, we took you on a journey of discovery and innovation, and this week we’re gonna tell you how the heck it all works. That means a deep dive into the nitty gritty of SSRIs, from what serotonin does (A LOT, as it turns out), to why blocking its uptake has the effects it does, from the different side effects of SSRIs, to how effective they really are. The discourse surrounding this class of drugs is complicated and contradictory, and this episode provides lots of answers and some terrible baseball metaphors to help you make sense of SSRIs.
| SSRI Biology |
| Mechanism of action: |
| Artigas, F., Nutt, D.J. and Shelton, R., 2002. Mechanism of action of antidepressants. Psychopharmacology bulletin, 36, pp.123-132. |
| Sharp, T., 2012. Molecular and cellular mechanisms of antidepressant action. Behavioral Neurobiology of Depression and Its Treatment, pp.309-325. |
| Willner, P., Scheel-Krüger, J. and Belzung, C., 2013. The neurobiology of depression and antidepressant action. Neuroscience & biobehavioral reviews, 37(10), pp.2331-2371. |
| Duman, R.S. and Voleti, B., 2012. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends in neurosciences, 35(1), pp.47-56. |
| Davis, L.L., Yonkers, K.A., Trivedi, M., Kramwer, G.L. and Petty, F., 1999. The mechanism of action of SSRIs, a new hypothesis. Selective Serotonin Reuptake Inhibitors (SSRIs): Past, Present and Future, pp.171-185. |
| Depression and Anxiety as disorders: |
| Goodwin, R.D., Dierker, L.C., Wu, M., Galea, S., Hoven, C.W. and Weinberger, A.H., 2022. Trends in US depression prevalence from 2015 to 2020: the widening treatment gap. American Journal of Preventive Medicine, 63(5), pp.726-733. |
| Malhi, G.s., Mann, J.J. 2018. Seminar. Depression. The Lancet, 392(10161) pp24-30. |
| Roach, A., Sureshkumar, D.S., Elliot, K., Hidalgo-Padilla, L., van Loggerenberg, F., Hounsell, L., Jakaite, Z., Esnal, F., Donaghy, J., Bird, V.J. and Priebe, S., 2023. One-year recovery rates for young people with depression and/or anxiety not receiving treatment: a systematic review and meta-analysis. BMJ open, 13(7), p.e072093. |
| Stein, M.B. and Sareen, J., 2015. Generalized anxiety disorder. New England Journal of Medicine, 373(21), pp.2059-2068. |
| Ruhé, H.G., Mason, N.S. and Schene, A.H., 2007. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Molecular psychiatry, 12(4), pp.331-359. |
| Guideline papers: |
| Eder, J., Dom, G., Gorwood, P., Kärkkäinen, H., Decraene, A., Kumpf, U., Beezhold, J., Samochowiec, J., Kurimay, T., Gaebel, W. and De Picker, L., 2023. Improving mental health care in depression: a call for action. European Psychiatry, 66(1), p.e65. |
| American Psychiatric Association Workgroup on Major Depressive Disorder. 2010. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. [https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf] |
| American Psychological Association, 2019. Clinical practice guideline for the treatment of depression across three age cohorts [https://www.apa.org/depression-guideline/guideline.pdf] |
| National Collaborating Centre for Mental Health 2011, updated 2020. Generalised anxiety disorder in adults: management in primary, secondary and community care. British Psychological Society. |
| Efficacy and effectiveness studies: |
| Cipriani, A., Furukawa, T.A., Salanti, G., Chaimani, A., Atkinson, L.Z., Ogawa, Y., Leucht, S., Ruhe, H.G., Turner, E.H., Higgins, J.P. and Egger, M., 2018. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 391(10128), pp.1357-1366. |
| Jakubovski, E., Johnson, J.A., Nasir, M., Müller‐Vahl, K. and Bloch, M.H., 2019. Systematic review and meta‐analysis: Dose–response curve of SSRIs and SNRIs in anxiety disorders. Depression and anxiety, 36(3), pp.198-212. |
| Saelens, J., Gramser, A., Watzal, V., Zarate Jr, C.A., Lanzenberger, R. and Kraus, C., 2025. Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials. Neuropsychopharmacology, 50(6), pp.913-919. |
| Warden, D., Rush, A.J., Trivedi, M.H., Fava, M. and Wisniewski, S.R., 2007. The STAR* D Project results: a comprehensive review of findings. Current psychiatry reports, 9(6), pp.449-459. |
| Pigott, H.E., Kim, T., Xu, C., Kirsch, I. and Amsterdam, J., 2023. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR* D study’s patient-level data with fidelity to the original research protocol. BMJ open, 13(7), p.e063095. |
| McCormack, J. and Korownyk, C., 2018. Effectiveness of antidepressants. BMJ, 360. |
| Cipriani, A., Furukawa, T.A., Salanti, G., Geddes, J.R., Higgins, J.P., Churchill, R., Watanabe, N., Nakagawa, A., Omori, I.M., McGuire, H. and Tansella, M., 2009. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The lancet, 373(9665), pp.746-758. |
| Perlis, R.H. and Fava, M., 2022. Is it time to try sequenced treatment alternatives to relieve depression (STAR* D) again?. JAMA psychiatry, 79(4), pp.281-282. |
| Cuijpers, P., Karyotaki, E., Ciharova, M., Miguel, C., Noma, H. and Furukawa, T.A., 2021. The effects of psychotherapies for depression on response, remission, reliable change, and deterioration: A meta‐analysis. Acta Psychiatrica Scandinavica, 144(3), pp.288-299. |
| Gartlehner, G., Dobrescu, A., Chapman, A., Toromanova, A., Emprechtinger, R., Persad, E., Affengruber, L., Pieh, C., Klerings, I. and Wagner, G., 2023. Nonpharmacologic and pharmacologic treatments of adult patients with major depressive disorder: a systematic review and network meta-analysis for a clinical guideline by the American College of Physicians. Annals of internal medicine, 176(2), pp.196-211. |
| Placebo-responses: |
| Krogsbøll, L.T., Hróbjartsson, A. and Gøtzsche, P.C., 2009. Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC medical research methodology, 9, pp.1-10. |
| Furukawa, T.A., Cipriani, A., Atkinson, L.Z., Leucht, S., Ogawa, Y., Takeshima, N., Hayasaka, Y., Chaimani, A. and Salanti, G., 2016. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. The Lancet Psychiatry, 3(11), pp.1059-1066. |
| Rutherford, B.R. and Roose, S.P., 2013. A model of placebo response in antidepressant clinical trials. American Journal of Psychiatry, 170(7), pp.723-733. |
| Jones, B.D., Razza, L.B., Weissman, C.R., Karbi, J., Vine, T., Mulsant, L.S., Brunoni, A.R., Husain, M.I., Mulsant, B.H., Blumberger, D.M. and Daskalakis, Z.J., 2021. Magnitude of the placebo response across treatment modalities used for treatment-resistant depression in adults: a systematic review and meta-analysis. JAMA network open, 4(9), pp.e2125531-e2125531. |
| Bschor, T., Nagel, L., Unger, J., Schwarzer, G. and Baethge, C., 2024. Differential outcomes of placebo treatment across 9 psychiatric disorders: a systematic review and meta-analysis. JAMA psychiatry, 81(8), pp.757-768. |
| Meister, R., Jansen, A., Härter, M., Nestoriuc, Y. and Kriston, L., 2017. Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis. Journal of affective disorders, 215, pp.288-298. |
| Cuijpers, P., Karyotaki, E., Weitz, E., Andersson, G., Hollon, S.D. and Van Straten, A., 2014. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: a meta-analysis. Journal of affective disorders, 159, pp.118-126. |
| Children and adolescents: |
| WHO Mental Health of Adolescents. Oct 2024. Factsheet. https://www.who.int/news-room/fact-sheets/detail/adolescent-mental-health#:~:text=Emotional%2520disorders%26text=Depression%2520is%2520estimated%2520to%2520occur,affect%2520school%2520attendance%2520and%2520schoolwork |
| Weersing, V.R., Goger, P., Schwartz, K.T., Baca, S.A., Angulo, F. and Kado-Walton, M., 2025. Evidence-Base Update of Psychosocial and Combination Treatments for Child and Adolescent Depression. Journal of Clinical Child & Adolescent Psychology, 54(1), pp.1-51. |
| Cipriani, A., Zhou, X., Del Giovane, C., Hetrick, S.E., Qin, B., Whittington, C., Coghill, D., Zhang, Y., Hazell, P., Leucht, S. and Cuijpers, P., 2016. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet, 388(10047), pp.881-890. |
| Walkup, J.T., 2017. Antidepressant efficacy for depression in children and adolescents: industry-and NIMH-funded studies. American Journal of Psychiatry, 174(5), pp.430-437. |
| Strawn, J.R., Mills, J.A., Sauley, B.A. and Welge, J.A., 2018. The impact of antidepressant dose and class on treatment response in pediatric anxiety disorders: a meta-analysis. Journal of the American Academy of Child & Adolescent Psychiatry, 57(4), pp.235-244. |
| Wang, Z., Whiteside, S.P., Sim, L., Farah, W., Morrow, A.S., Alsawas, M., Barrionuevo, P., Tello, M., Asi, N., Beuschel, B. and Daraz, L., 2017. Comparative effectiveness and safety of cognitive behavioral therapy and pharmacotherapy for childhood anxiety disorders: a systematic review and meta-analysis. JAMA pediatrics, 171(11), pp.1049-1056. |
| Locher, C., Koechlin, H., Zion, S.R., Werner, C., Pine, D.S., Kirsch, I., Kessler, R.C. and Kossowsky, J., 2017. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA psychiatry, 74(10), pp.1011-1020. |
| Long term data: |
| Wiles, N.J., Thomas, L., Turner, N., Garfield, K., Kounali, D., Campbell, J., Kessler, D., Kuyken, W., Lewis, G., Morrison, J. and Williams, C., 2016. Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial. The Lancet Psychiatry, 3(2), pp.137-144. |
| Hughes, S. and Cohen, D., 2009. A systematic review of long-term studies of drug treated and non-drug treated depression. Journal of affective disorders, 118(1-3), pp.9-18. |
| Reid, S. and Barbui, C., 2010. Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants. Bmj, 340. |
| Fournier, J.C., DeRubeis, R.J., Amsterdam, J., Shelton, R.C. and Hollon, S.D., 2015. Gains in employment status following antidepressant medication or cognitive therapy for depression. The British Journal of Psychiatry, 206(4), pp.332-338. |
| Cuijpers, P., Hollon, S.D., Van Straten, A., Bockting, C., Berking, M. and Andersson, G., 2013. Does cognitive behaviour therapy have an enduring effect that is superior to keeping patients on continuation pharmacotherapy? A meta-analysis. BMJ open, 3(4), p.e002542. |
| Back and forths regarding placebo effect: |
| Naudet, F., Millet, B., Charlier, P., Reymann, J.M., Maria, A.S. and Falissard, B., 2013. Which placebo to cure depression? A thought-provoking network meta-analysis. BMC medicine, 11, pp.1-10. |
| Cipriani, A. and Geddes, J.R., 2014. Placebo for depression: we need to improve the quality of scientific information but also reject too simplistic approaches or ideological nihilism. BMC medicine, 12, pp.1-3. |
| Munkholm, K., Paludan-Müller, A.S. and Boesen, K., 2019. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ open, 9(6), p.e024886. |
| N Fountoulakis, K., S McIntyre, R. and F Carvalho, A., 2015. From randomized controlled trials of antidepressant drugs to the meta-analytic synthesis of evidence: methodological aspects lead to discrepant findings. Current neuropharmacology, 13(5), pp.605-615. |
| Untreated depression: |
| Mekonen, T., Ford, S., Chan, G.C., Hides, L., Connor, J.P. and Leung, J., 2022. What is the short-term remission rate for people with untreated depression? A systematic review and meta-analysis. Journal of Affective Disorders, 296, pp.17-25. |
| Whiteford, H.A., Harris, M.G., McKeon, G., Baxter, A., Pennell, C., Barendregt, J.J. and Wang, J., 2013. Estimating remission from untreated major depression: a systematic review and meta-analysis. Psychological medicine, 43(8), pp.1569-1585. |
| Roach, A., Sureshkumar, D.S., Elliot, K., Hidalgo-Padilla, L., van Loggerenberg, F., Hounsell, L., Jakaite, Z., Esnal, F., Donaghy, J., Bird, V.J. and Priebe, S., 2023. One-year recovery rates for young people with depression and/or anxiety not receiving treatment: a systematic review and meta-analysis. BMJ open, 13(7), p.e072093. |
| Epidemiology: |
| GBD 2019 Mental Disorders Collaborators, 2022. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry, 9(2), pp.137-150. |
| Vos, T., Lim, S.S., Abbafati, C., Abbas, K.M., Abbasi, M., Abbasifard, M., Abbasi-Kangevari, M., Abbastabar, H., Abd-Allah, F., Abdelalim, A. and Abdollahi, M., 2020. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The lancet, 396(10258), pp.1204-1222. |
| Mythbusting: |
| Hall, R.C.W., Friedman, S.H., Sorrentino, R., Lapchenko, M., Marcus, A. and Ellis, R., 2019. The myth of school shooters and psychotropic medications. Behavioral Sciences & the Law, 37(5), pp.540-558. |
| Hall, R.C.W. and Friedman, S.H., 2013, November. Guns, schools, and mental illness: potential concerns for physicians and mental health professionals. In Mayo Clinic Proceedings (Vol. 88, No. 11, pp. 1272-1283). Elsevier. |
| Whyte, I.M., Dawson, A.H. and Buckley, N.A., 2003. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Qjm, 96(5), pp.369-374. |
| Li, K., Zhou, G., Xiao, Y., Gu, J., Chen, Q., Xie, S. and Wu, J., 2022. Risk of suicidal behaviors and antidepressant exposure among children and adolescents: a meta-analysis of observational studies. Frontiers in psychiatry, 13, p.880496. |
| Boschloo, L., Hieronymus, F., Lisinski, A., Cuijpers, P. and Eriksson, E., 2023. The complex clinical response to selective serotonin reuptake inhibitors in depression: a network perspective. Translational Psychiatry, 13(1), p.19. |
| The controversial serotonin paper: |
| Moncrieff, J., Cooper, R.E., Stockmann, T., Amendola, S., Hengartner, M.P. and Horowitz, M.A., 2023. The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular psychiatry, 28(8), pp.3243-3256. |
| And all of the responses to it: |
| Jacobsen, J.P.R., 2023. Serotonin and depression—an alternative interpretation of the data in Moncrieff et al. Molecular Psychiatry, 28(8), pp.3158-3159. |
| El-Mallakh, R.S., Doroodgar, M., Elsayed, O.H. and Kidambi, N., 2023. The serotonin theory of depression. Molecular Psychiatry, 28(8), pp.3157-3157. |
| Almulla, A.F. and Maes, M., 2023. Although serotonin is not a major player in depression, its precursor is. Molecular Psychiatry, 28(8), pp.3155-3156. |
| Moncrieff, J., Cooper, R.E., Stockmann, T., Amendola, S., Hengartner, M.P., Plöderl, M. and Horowitz, M.A., 2023. The serotonin hypothesis of depression: both long discarded and still supported?. Molecular Psychiatry, 28(8), pp.3160-3163. |
| Jauhar, S., Arnone, D., Baldwin, D.S., Bloomfield, M., Browning, M., Cleare, A.J., Corlett, P., Deakin, J.W., Erritzoe, D., Fu, C. and Fusar-Poli, P., 2023. A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression. Molecular Psychiatry, 28(8), pp.3149-3152. |
| Bartova, L., Lanzenberger, R., Rujescu, D. and Kasper, S., 2023. Reply to:“The serotonin theory of depression: a systematic umbrella review of the evidence” published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0). Molecular Psychiatry, 28(8), pp.3153-3154. |
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