The Opioid System in Depression

Luke A Jelen; James M Stone; Allan H Young; Mitul A Mehta

doi:10.1016/j.neubiorev.2022.104800

The Opioid System in Depression

Luke A Jelen, James M Stone, Allan H Young, Mitul A Mehta

University of Sussex

Research output: Contribution to journal › Review article › peer-review

25 Citations (Scopus)

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Abstract

Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.

Original language	English
Article number	104800
Pages (from-to)	104800
Journal	Neuroscience and Biobehavioral Reviews
Volume	140
Early online date	29 Jul 2022
DOIs	https://doi.org/10.1016/j.neubiorev.2022.104800
Publication status	Published - Sept 2022

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10.1016/j.neubiorev.2022.104800

Jelen_2022_Opioid_system_depressionFinal published version, 972 KBLicence: CC BY

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title = "The Opioid System in Depression",

abstract = "Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.",

author = "Jelen, {Luke A} and Stone, {James M} and Young, {Allan H} and Mehta, {Mitul A}",

note = "Funding Information: This report represents independent research funded by 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 authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Luke Jelen: Employed by King's College London. Dr Luke A Jelen is supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/T028084/1).Allan Young: Employed by King's College London; Honorary Consultant SLaM (NHS UK). 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). No shareholdings in pharmaceutical companies.Mitul Mehta: Employed by King's College London. Grant funding (past 3 years): Takeda, Johnson & Johnson, Lundbeck, WellcomeTrust (212952/Z/18/Z; 200102/Z/15/Z), MRC (MR/R005931/1; MR/R005885/1; MR/S003444/1), NIHR (CRF-2016-10023). Funding Information: Luke Jelen: Employed by King{\textquoteright}s College London. Dr Luke A Jelen is supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/T028084/1). Funding Information: This report represents independent research funded by 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 authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: Dr Luke Jelen: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr James Stone: Dr Stone reported grants from Protexin Probiotics International, personal fees from Janssen, and grants from Takeda. Professor Allan Young: Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis. Consultant to Johnson & Johnson. Consultant to Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova. 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). No shareholdings in pharmaceutical companies. Professor Mitul Mehta: Has acted as a Consultant for Lundbeck and Neurocrine. Funding Information: Allan Young: Employed by King{\textquoteright}s College London; Honorary Consultant SLaM (NHS UK). 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). No shareholdings in pharmaceutical companies. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = sep,

doi = "10.1016/j.neubiorev.2022.104800",

language = "English",

volume = "140",

pages = "104800",

journal = "Neuroscience and Biobehavioral Reviews",

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TY - JOUR

T1 - The Opioid System in Depression

AU - Jelen, Luke A

AU - Stone, James M

AU - Young, Allan H

AU - Mehta, Mitul A

N1 - Funding Information: This report represents independent research funded by 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 authors and not necessarily those of the NHS, the NIHR, or the Department of Health.Luke Jelen: Employed by King's College London. Dr Luke A Jelen is supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/T028084/1).Allan Young: Employed by King's College London; Honorary Consultant SLaM (NHS UK). 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). No shareholdings in pharmaceutical companies.Mitul Mehta: Employed by King's College London. Grant funding (past 3 years): Takeda, Johnson & Johnson, Lundbeck, WellcomeTrust (212952/Z/18/Z; 200102/Z/15/Z), MRC (MR/R005931/1; MR/R005885/1; MR/S003444/1), NIHR (CRF-2016-10023). Funding Information: Luke Jelen: Employed by King’s College London. Dr Luke A Jelen is supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/T028084/1). Funding Information: This report represents independent research funded by 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 authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: Dr Luke Jelen: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr James Stone: Dr Stone reported grants from Protexin Probiotics International, personal fees from Janssen, and grants from Takeda. Professor Allan Young: Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis. Consultant to Johnson & Johnson. Consultant to Livanova. Received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova. 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). No shareholdings in pharmaceutical companies. Professor Mitul Mehta: Has acted as a Consultant for Lundbeck and Neurocrine. Funding Information: Allan Young: Employed by King’s College London; Honorary Consultant SLaM (NHS UK). 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). No shareholdings in pharmaceutical companies. Publisher Copyright: © 2022 The Authors

PY - 2022/9

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N2 - Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.

AB - Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.

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DO - 10.1016/j.neubiorev.2022.104800

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SP - 104800

JO - Neuroscience and Biobehavioral Reviews

JF - Neuroscience and Biobehavioral Reviews

M1 - 104800

ER -

The Opioid System in Depression

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