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Review
. 2022 Sep:140:104800.
doi: 10.1016/j.neubiorev.2022.104800. Epub 2022 Jul 30.

The opioid system in depression

Luke A Jelen  1 , James M Stone  2 , Allan H Young  3 , Mitul A Mehta  4
Affiliations
Review

The opioid system in depression

Luke A Jelen et al. Neurosci Biobehav Rev. 2022 Sep.

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.

Keywords: Delta opioid receptor (DOR); Depression; Kappa opioid receptor (KOR); Mu opioid receptor (MOR); Nociceptin opioid receptor (NOP); Opioid system.

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Conflict of interest statement

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.

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