A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression

Sameer Jauhar; Danilo Arnone; David S. Baldwin; Michael Bloomfield; Michael Browning; Anthony j. Cleare; Phillip Corlett; J. F. william Deakin; David Erritzoe; Cynthia Fu; Paolo Fusar-Poli; Guy m. Goodwin; Joseph Hayes; Robert Howard; Oliver D. Howes; Mario f. Juruena; Raymond w. Lam; Stephen m. Lawrie; Hamish Mcallister-Williams; Steven Marwaha; David Matuskey; Robert A. Mccutcheon; David J. Nutt; Carmine Pariante; Toby Pillinger; Rajiv Radhakrishnan; James Rucker; Sudhakar Selvaraj; Paul Stokes; Rachel Upthegrove; Nefize Yalin; Lakshmi Yatham; Allan H. Young; Roland Zahn; Philip J. Cowen

doi:10.1038/s41380-023-02095-y

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression

Sameer Jauhar, Danilo Arnone, David S. Baldwin, Michael Bloomfield, Michael Browning, Anthony j. Cleare, Phillip Corlett, J. F. william Deakin, David Erritzoe, Cynthia Fu, Paolo Fusar-Poli, Guy m. Goodwin, Joseph Hayes, Robert Howard, Oliver D. Howes, Mario f. Juruena, Raymond w. Lam, Stephen m. Lawrie, Hamish Mcallister-Williams, Steven MarwahaDavid Matuskey, Robert A. Mccutcheon, David J. Nutt, Carmine Pariante, Toby Pillinger, Rajiv Radhakrishnan, James Rucker, Sudhakar Selvaraj, Paul Stokes, Rachel Upthegrove, Nefize Yalin, Lakshmi Yatham, Allan H. Young, Roland Zahn, Philip J. Cowen

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Abstract

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this.

Original language	English
Journal	Molecular Psychiatry
Early online date	16 Jun 2023
DOIs	https://doi.org/10.1038/s41380-023-02095-y
Publication status	E-pub ahead of print - 16 Jun 2023

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Jauhar, S., Arnone, D., Baldwin, D. S., Bloomfield, M., Browning, M., Cleare, A. J., Corlett, P., Deakin, J. F. W., Erritzoe, D., Fu, C., Fusar-Poli, P., Goodwin, G. M., Hayes, J., Howard, R., Howes, O. D., Juruena, M. F., Lam, R. W., Lawrie, S. M., Mcallister-Williams, H., ... Cowen, P. J. (2023). A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression. Molecular Psychiatry. https://doi.org/10.1038/s41380-023-02095-y

@article{7fa6b3bc2de94ae5a4cd559726fc43df,

title = "A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression",

abstract = "A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this.",

author = "Sameer Jauhar and Danilo Arnone and Baldwin, {David S.} and Michael Bloomfield and Michael Browning and Cleare, {Anthony j.} and Phillip Corlett and Deakin, {J. F. william} and David Erritzoe and Cynthia Fu and Paolo Fusar-Poli and Goodwin, {Guy m.} and Joseph Hayes and Robert Howard and Howes, {Oliver D.} and Juruena, {Mario f.} and Lam, {Raymond w.} and Lawrie, {Stephen m.} and Hamish Mcallister-Williams and Steven Marwaha and David Matuskey and Mccutcheon, {Robert A.} and Nutt, {David J.} and Carmine Pariante and Toby Pillinger and Rajiv Radhakrishnan and James Rucker and Sudhakar Selvaraj and Paul Stokes and Rachel Upthegrove and Nefize Yalin and Lakshmi Yatham and Young, {Allan H.} and Roland Zahn and Cowen, {Philip J.}",

note = "Funding Information: SJ, AJC, MFJ, PS, NY, AHY and RZ acknowledge this paper represents independent research part funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. MBrowning is supported by the Oxford Health NIHR Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. ODH is funded by Medical Research Council-UK (no. MC_A656_5QD30_2135), Maudsley Charity (no. 666), and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the author(s) and not necessarily those of H Lundbeck A/s, the NHS/NIHR or the Department of Health. CF is supported by the Rosetrees Trust 20212104. SS has received grants/research support from NIMH R21(1R21MH119441 – 01A1), NICHD (1R21HD106779 − 01A1) and SAMHSA (FG000470-01). The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or SAMHSA. RU reports grant funding from Medical Research Council (MR/S037675/1), National Institute for Health Research: Health Technology Assessment (NIHR 127700) and speaker fees from Sunovion, Springer Heathcare and Vitaris outside the submitted work. RU holds unpaid officership with the British Association for Pharmacology- Honorary General Secretary 2021-2024 and is Deputy Editor, The British Journal of Psychiatry. PJC is funded as a Clinical Scientist by the Medical Research Council. Funding Information: SJ has received honoraria for educational talks given on antipsychotics for Janssen, Lundbeck and Sunovian. He has given an educational talk for Boehringer Ingelheim on causes of schizophrenia. He has received honoraria as an adviser for LB pharmaceuticals Inc. in regard to antipsychotic medication. He is a Council Member for the British Association for Psychopharmacology and sat as a panel member for the Wellcome Trust. DSB is President of the British Association for Psychopharmacology (unpaid), Editor of Human Psychopharmacology (editors fee), Medical Patron of Anxiety UK (unpaid), consultancy to Idorsia (July 2020, unpaid: not relevant to consideration of subject matter of paper). MBrowning has received travel expenses from Lundbeck for attending conferences, and has acted as a consultant for J&J, Novartis, P1vital Ltd and CHDR. He owns shares in P1vtial Products Ltd. AJC is President of The International Society for Affective Disorders (unpaid) and in the last three years has received honoraria for educational activities and/or consulting from Janssen, COMPASS Pathways and Medscape, and research grant support from the Medical Research Council (UK), Wellcome Trust (UK), the National Institute for Health Research (UK) and Protexin Probiotics International Ltd. PC is co-founder of Tetricus Labs (unrelated to this work). DE has received funding from NIHR and is scientific advisor for Mydecine, Entheon Biomedical, Clerkenwell Health, Smallpharma Ltd and Field Trip Health Ltd. PFP has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, Mindstrong, Proxymm Science, outside the current study. GMG is a NIHR Emeritus Senior Investigator and Chief Medical Officer at Compass pathways, holds shares in Compass pathways, P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, Ocean Neuroscience, P1Vital, Servier. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ODH is a part-time employee and stock holder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. ODH has a patent for the use of dopaminergic imaging. MFJ has within the last 3 years received honoraria for lectures or consulting from Janssen, Lundbeck, EMS and Daiichi-Sankyo. MFJ has received funding from the Wellcome Innovator scheme “The first in-human, randomised, double-blinded, placebo-controlled study to investigate the safety and tolerability, PK and PD of oral ketamine in HV. RL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, CAN-BIND Solutions, Carnot, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer/Viatris, Sanofi, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. RAM has received honoraria from Otsuka and Janssen. DJN reports speaking honoraria for Lundbeck and Otsuka. RHM-W has received fees from American Center for Psychiatry & Neurology United Arab Emirates, British Association for Psychopharmacology, European College of Neuropsychopharmacology, International Society for Affective Disorders, Janssen, LivaNova, Lundbeck, My Tomorrows, OCM Comunicaziona s.n.c., Pfizer, Qatar International Mental Health Conference, Sunovion, Syntropharma, UK Medical Research Council and Wiley; grant support from National Institute for Health Research Efficacy and Mechanism Evaluation Panel and Health Technology Assessment Panel; and non-financial support from COMPASS Pathways and Magstim. CP has received research funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2, as part of the EU-PEARL project. This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and EFPIA. CP is also funded by a Senior Investigator award from the National Institute for Health Research (NIHR); the Medical Research Council (grants MR/L014815/1, MR/J002739/1 and MR/N029488/1); the European Commission (EARLYCAUSE grant SC1-BHC-01-2019); the NARSAD; the Psychiatry Research Trust; and the Wellcome Trust (SHAPER, Scaling-up Health-Arts Programme to scale up arts interventions, grant 219425/Z/19/Z). Less than 10% of his support in the last 10 years derives from commercial collaborations, including consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and V{\"a}rde Partners, and a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer{\textquoteright}s Disease (NIMA) Consortium (104025), which was also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. TP has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, Schwabe Pharma, and Recordati. JR is an honorary consultant psychiatrist at The South London & Maudsley NHS Foundation Trust, a consultant psychiatrist at Sapphire Medical Clinics and an NIHR Clinician Scientist Fellow at the Centre for Affective Disorders at King{\textquoteright}s College London. JR{\textquoteright}s salary is funded by a fellowship (CS-2017-17-007) from the National Institute for Health Research (NIHR). JR leads the Psychedelic Trials Group with Professor Allan Young at King{\textquoteright}s College London. King{\textquoteright}s College London receives grant funding from COMPASS Pathways PLC and Beckley PsyTech to undertake phase 1 and phase 2 trials with psychedelic compounds. COMPASS Pathways PLC has paid for JR to attend trial related meetings and conferences to present the results of research using psilocybin. No funder had influence over the content of this article. JR has undertaken paid consultancy work for Beckley PsyTech and Clerkenwell Health. Payments for consultancy work are received and managed by King{\textquoteright}s College London. JR does not benefit personally. JR has no shareholdings in pharmaceutical companies. Over the past 3 years, RR has received research support from GW Pharmaceuticals (now Jazz Pharmaceuticals) and Neurocrine Biosciences. The research support is unrelated to the subject matter in this article. SS is currently a full-time employee of Intra-Cellular Therapies, Inc. SS has received honoraria from the British Medical Journal Publishing Group, has received research support from Flow Neuroscience and is a study or sub-investigator of clinical trials supported by Compass pathways, Relmada, LivaNova, and Janssen. PS reports non-financial support from Janssen Research and Development LLC, personal fees and non-financial support from Frontiers in Psychiatry, personal fees from Allergan, a grant from H Lundbeck, grants and non-financial support from Corcept Therapeutics, outside the submitted work. NY has worked as a researcher in clinical studies conducted together with Jannsen Cliag, Corcept Therapeutics and COMPASS Pathways in the last 5 years. LNY has been on speaker or advisory boards for, or has received research grants from, Abbvie, Alkermes, Allergan, Otsuka, Sumitomo Dainippon Pharma, GlaxoSmithKline, Intracellular Therapies, Merck, Sanofi, and Sunovion in the last 3 years. AHY is Editor of Journal of Psychopharmacology and Deputy Editor, BJPsych Open, Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis, Neurocentrx Principal Investigator in the Restore-Life VNS registry study funded by LivaNova. Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.” Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants” Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)” UK Chief Investigator for Novartis MDD study MIJ821A12201. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK) EU Horizon 2020. No shareholdings in pharmaceutical companies. RZ is a private healthcare provider, has received honoraria for talks by Janssen & Lundbeck, is a co-I on a Livanova-funded neurostimulation study, is affiliated with the D{\textquoteright}Or Institute for Research and Education, and has collaborated with digital health companies EMIS PLC and Depsee Ltd, Alloc Modulo. All other authors declare no competing interests.",

year = "2023",

month = jun,

day = "16",

doi = "10.1038/s41380-023-02095-y",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature [academic journals on nature.com]",

}

Jauhar, S , Arnone, D, Baldwin, DS, Bloomfield, M, Browning, M, Cleare, AJ, Corlett, P, Deakin, JFW, Erritzoe, D, Fu, C , Fusar-Poli, P, Goodwin, GM, Hayes, J, Howard, R , Howes, OD , Juruena, MF, Lam, RW, Lawrie, SM, Mcallister-Williams, H, Marwaha, S, Matuskey, D, Mccutcheon, RA, Nutt, DJ, Pariante, C , Pillinger, T, Radhakrishnan, R, Rucker, J, Selvaraj, S, Stokes, P, Upthegrove, R, Yalin, N, Yatham, L, Young, AH , Zahn, R & Cowen, PJ 2023, 'A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression', Molecular Psychiatry. https://doi.org/10.1038/s41380-023-02095-y

TY - JOUR

T1 - A leaky umbrella has little value

T2 - evidence clearly indicates the serotonin system is implicated in depression

AU - Jauhar, Sameer

AU - Arnone, Danilo

AU - Baldwin, David S.

AU - Bloomfield, Michael

AU - Browning, Michael

AU - Cleare, Anthony j.

AU - Corlett, Phillip

AU - Deakin, J. F. william

AU - Erritzoe, David

AU - Fu, Cynthia

AU - Fusar-Poli, Paolo

AU - Goodwin, Guy m.

AU - Hayes, Joseph

AU - Howard, Robert

AU - Howes, Oliver D.

AU - Juruena, Mario f.

AU - Lam, Raymond w.

AU - Lawrie, Stephen m.

AU - Mcallister-Williams, Hamish

AU - Marwaha, Steven

AU - Matuskey, David

AU - Mccutcheon, Robert A.

AU - Nutt, David J.

AU - Pariante, Carmine

AU - Pillinger, Toby

AU - Radhakrishnan, Rajiv

AU - Rucker, James

AU - Selvaraj, Sudhakar

AU - Stokes, Paul

AU - Upthegrove, Rachel

AU - Yalin, Nefize

AU - Yatham, Lakshmi

AU - Young, Allan H.

AU - Zahn, Roland

AU - Cowen, Philip J.

N1 - Funding Information: SJ, AJC, MFJ, PS, NY, AHY and RZ acknowledge this paper represents independent research part funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. MBrowning is supported by the Oxford Health NIHR Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. ODH is funded by Medical Research Council-UK (no. MC_A656_5QD30_2135), Maudsley Charity (no. 666), and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of H Lundbeck A/s, the NHS/NIHR or the Department of Health. CF is supported by the Rosetrees Trust 20212104. SS has received grants/research support from NIMH R21(1R21MH119441 – 01A1), NICHD (1R21HD106779 − 01A1) and SAMHSA (FG000470-01). The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or SAMHSA. RU reports grant funding from Medical Research Council (MR/S037675/1), National Institute for Health Research: Health Technology Assessment (NIHR 127700) and speaker fees from Sunovion, Springer Heathcare and Vitaris outside the submitted work. RU holds unpaid officership with the British Association for Pharmacology- Honorary General Secretary 2021-2024 and is Deputy Editor, The British Journal of Psychiatry. PJC is funded as a Clinical Scientist by the Medical Research Council. Funding Information: SJ has received honoraria for educational talks given on antipsychotics for Janssen, Lundbeck and Sunovian. He has given an educational talk for Boehringer Ingelheim on causes of schizophrenia. He has received honoraria as an adviser for LB pharmaceuticals Inc. in regard to antipsychotic medication. He is a Council Member for the British Association for Psychopharmacology and sat as a panel member for the Wellcome Trust. DSB is President of the British Association for Psychopharmacology (unpaid), Editor of Human Psychopharmacology (editors fee), Medical Patron of Anxiety UK (unpaid), consultancy to Idorsia (July 2020, unpaid: not relevant to consideration of subject matter of paper). MBrowning has received travel expenses from Lundbeck for attending conferences, and has acted as a consultant for J&J, Novartis, P1vital Ltd and CHDR. He owns shares in P1vtial Products Ltd. AJC is President of The International Society for Affective Disorders (unpaid) and in the last three years has received honoraria for educational activities and/or consulting from Janssen, COMPASS Pathways and Medscape, and research grant support from the Medical Research Council (UK), Wellcome Trust (UK), the National Institute for Health Research (UK) and Protexin Probiotics International Ltd. PC is co-founder of Tetricus Labs (unrelated to this work). DE has received funding from NIHR and is scientific advisor for Mydecine, Entheon Biomedical, Clerkenwell Health, Smallpharma Ltd and Field Trip Health Ltd. PFP has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, Mindstrong, Proxymm Science, outside the current study. GMG is a NIHR Emeritus Senior Investigator and Chief Medical Officer at Compass pathways, holds shares in Compass pathways, P1vital and P1Vital products and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, Compass pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, Ocean Neuroscience, P1Vital, Servier. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ODH is a part-time employee and stock holder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. ODH has a patent for the use of dopaminergic imaging. MFJ has within the last 3 years received honoraria for lectures or consulting from Janssen, Lundbeck, EMS and Daiichi-Sankyo. MFJ has received funding from the Wellcome Innovator scheme “The first in-human, randomised, double-blinded, placebo-controlled study to investigate the safety and tolerability, PK and PD of oral ketamine in HV. RL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, CAN-BIND Solutions, Carnot, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, Michael Smith Foundation for Health Research, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer/Viatris, Sanofi, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. RAM has received honoraria from Otsuka and Janssen. DJN reports speaking honoraria for Lundbeck and Otsuka. RHM-W has received fees from American Center for Psychiatry & Neurology United Arab Emirates, British Association for Psychopharmacology, European College of Neuropsychopharmacology, International Society for Affective Disorders, Janssen, LivaNova, Lundbeck, My Tomorrows, OCM Comunicaziona s.n.c., Pfizer, Qatar International Mental Health Conference, Sunovion, Syntropharma, UK Medical Research Council and Wiley; grant support from National Institute for Health Research Efficacy and Mechanism Evaluation Panel and Health Technology Assessment Panel; and non-financial support from COMPASS Pathways and Magstim. CP has received research funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2, as part of the EU-PEARL project. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. CP is also funded by a Senior Investigator award from the National Institute for Health Research (NIHR); the Medical Research Council (grants MR/L014815/1, MR/J002739/1 and MR/N029488/1); the European Commission (EARLYCAUSE grant SC1-BHC-01-2019); the NARSAD; the Psychiatry Research Trust; and the Wellcome Trust (SHAPER, Scaling-up Health-Arts Programme to scale up arts interventions, grant 219425/Z/19/Z). Less than 10% of his support in the last 10 years derives from commercial collaborations, including consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and Värde Partners, and a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium (104025), which was also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. TP has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, Schwabe Pharma, and Recordati. JR is an honorary consultant psychiatrist at The South London & Maudsley NHS Foundation Trust, a consultant psychiatrist at Sapphire Medical Clinics and an NIHR Clinician Scientist Fellow at the Centre for Affective Disorders at King’s College London. JR’s salary is funded by a fellowship (CS-2017-17-007) from the National Institute for Health Research (NIHR). JR leads the Psychedelic Trials Group with Professor Allan Young at King’s College London. King’s College London receives grant funding from COMPASS Pathways PLC and Beckley PsyTech to undertake phase 1 and phase 2 trials with psychedelic compounds. COMPASS Pathways PLC has paid for JR to attend trial related meetings and conferences to present the results of research using psilocybin. No funder had influence over the content of this article. JR has undertaken paid consultancy work for Beckley PsyTech and Clerkenwell Health. Payments for consultancy work are received and managed by King’s College London. JR does not benefit personally. JR has no shareholdings in pharmaceutical companies. Over the past 3 years, RR has received research support from GW Pharmaceuticals (now Jazz Pharmaceuticals) and Neurocrine Biosciences. The research support is unrelated to the subject matter in this article. SS is currently a full-time employee of Intra-Cellular Therapies, Inc. SS has received honoraria from the British Medical Journal Publishing Group, has received research support from Flow Neuroscience and is a study or sub-investigator of clinical trials supported by Compass pathways, Relmada, LivaNova, and Janssen. PS reports non-financial support from Janssen Research and Development LLC, personal fees and non-financial support from Frontiers in Psychiatry, personal fees from Allergan, a grant from H Lundbeck, grants and non-financial support from Corcept Therapeutics, outside the submitted work. NY has worked as a researcher in clinical studies conducted together with Jannsen Cliag, Corcept Therapeutics and COMPASS Pathways in the last 5 years. LNY has been on speaker or advisory boards for, or has received research grants from, Abbvie, Alkermes, Allergan, Otsuka, Sumitomo Dainippon Pharma, GlaxoSmithKline, Intracellular Therapies, Merck, Sanofi, and Sunovion in the last 3 years. AHY is Editor of Journal of Psychopharmacology and Deputy Editor, BJPsych Open, Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis, Neurocentrx Principal Investigator in the Restore-Life VNS registry study funded by LivaNova. Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.” Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants” Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)” UK Chief Investigator for Novartis MDD study MIJ821A12201. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK) EU Horizon 2020. No shareholdings in pharmaceutical companies. RZ is a private healthcare provider, has received honoraria for talks by Janssen & Lundbeck, is a co-I on a Livanova-funded neurostimulation study, is affiliated with the D’Or Institute for Research and Education, and has collaborated with digital health companies EMIS PLC and Depsee Ltd, Alloc Modulo. All other authors declare no competing interests.

PY - 2023/6/16

Y1 - 2023/6/16

N2 - A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this.

AB - A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this.

UR - http://www.scopus.com/inward/record.url?scp=85161821564&partnerID=8YFLogxK

U2 - 10.1038/s41380-023-02095-y

DO - 10.1038/s41380-023-02095-y

M3 - Comment/debate

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression

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