Endocannabinoid concentrations in major depression: effects of childhood maltreatment and relation to hippocampal volume

Raegan Mazurka¹, Kate L Harkness^{2

3}, Stefanie Hassel^{4

5

6}, Niclas Stensson^{7

8}, Nikita Nogovitsyn^{9

10}, Jordan Poppenk^{2

11

12}, Jane A Foster¹³, Scott D Squires¹¹, Jessie Rowe², Roumen V Milev^{2

3}, Katherine E Wynne-Edwards¹⁴, Gustavo Turecki¹⁵, Stephen C Strother^{16

17

18}, Stephen R Arnott¹⁹, Raymond W Lam²⁰, Susan Rotzinger⁹, Sidney H Kennedy^{10

21}, Benicio N Frey^{9

22}, Leah M Mayo^{23

24

25

26}

Affiliations

¹ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. r.mazurka@dal.ca.
² Department of Psychology, Queen's University, Kingston, ON, Canada.
³ Department of Psychiatry, Queen's University, Providence Care Hospital, Kingston, ON, Canada.
⁴ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁵ Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
⁶ Mathison Centre for Mental Health Reseach and Education, University of Calgary, Calgary, AB, Canada.
⁷ Pain and Rehabilitation Centre, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
⁸ Occupational and Environmental Medicine Centre, Department of Health, Medicine and Caring Sciences, Unit of Clinical Medicine, Linköping University, Linköping, Sweden.
⁹ Mood Disorders Treatment and Research Centre, St. Joseph's Healthcare, Hamilton, ON, Canada.
¹⁰ Centre for Depression and Suicide Studies, St. Michael's Hospital, Toronto, ON, Canada.
¹¹ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
¹² School of Computing, Queen's University, Kingston, ON, Canada.
¹³ Center for Depression Research and Clinical Care, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁴ Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada.
¹⁵ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.
¹⁶ Rotman Research Institute, Baycrest, Toronto, ON, Canada.
¹⁷ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
¹⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁹ Indoc Systems, Toronto, ON, Canada.
²⁰ Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
²¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
²² Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
²³ Department of Psychiatry, University of Calgary, Calgary, AB, Canada. leah.mayo@ucalgary.ca.
²⁴ Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. leah.mayo@ucalgary.ca.
²⁵ Mathison Centre for Mental Health Reseach and Education, University of Calgary, Calgary, AB, Canada. leah.mayo@ucalgary.ca.
²⁶ Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden. leah.mayo@ucalgary.ca.

PMID: 39394160
PMCID: PMC11470058
DOI: 10.1038/s41398-024-03151-z

Endocannabinoid concentrations in major depression: effects of childhood maltreatment and relation to hippocampal volume

Raegan Mazurka et al. Transl Psychiatry. 2024.

. 2024 Oct 12;14(1):431.

doi: 10.1038/s41398-024-03151-z.

Authors

Affiliations

¹ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada. r.mazurka@dal.ca.
² Department of Psychology, Queen's University, Kingston, ON, Canada.
³ Department of Psychiatry, Queen's University, Providence Care Hospital, Kingston, ON, Canada.
⁴ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁵ Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
⁶ Mathison Centre for Mental Health Reseach and Education, University of Calgary, Calgary, AB, Canada.
⁷ Pain and Rehabilitation Centre, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
⁸ Occupational and Environmental Medicine Centre, Department of Health, Medicine and Caring Sciences, Unit of Clinical Medicine, Linköping University, Linköping, Sweden.
⁹ Mood Disorders Treatment and Research Centre, St. Joseph's Healthcare, Hamilton, ON, Canada.
¹⁰ Centre for Depression and Suicide Studies, St. Michael's Hospital, Toronto, ON, Canada.
¹¹ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
¹² School of Computing, Queen's University, Kingston, ON, Canada.
¹³ Center for Depression Research and Clinical Care, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁴ Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada.
¹⁵ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.
¹⁶ Rotman Research Institute, Baycrest, Toronto, ON, Canada.
¹⁷ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
¹⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁹ Indoc Systems, Toronto, ON, Canada.
²⁰ Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
²¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
²² Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
²³ Department of Psychiatry, University of Calgary, Calgary, AB, Canada. leah.mayo@ucalgary.ca.
²⁴ Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. leah.mayo@ucalgary.ca.
²⁵ Mathison Centre for Mental Health Reseach and Education, University of Calgary, Calgary, AB, Canada. leah.mayo@ucalgary.ca.
²⁶ Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden. leah.mayo@ucalgary.ca.

PMID: 39394160
PMCID: PMC11470058
DOI: 10.1038/s41398-024-03151-z

Abstract

Evidence from preclinical animal models suggests that the stress-buffering function of the endocannabinoid (eCB) system may help protect against stress-related reductions in hippocampal volume, as is documented in major depressive disorder (MDD). However, stress exposure may also lead to dysregulation of this system. Thus, pathways from marked stress histories, such as childhood maltreatment (CM), to smaller hippocampal volumes and MDD in humans may depend on dysregulated versus intact eCB functioning. We examined whether the relation between MDD and peripheral eCB concentrations would vary as a function of CM history. Further, we examined whether eCBs moderate the relation of CM/MDD and hippocampal volume. Ninety-one adults with MDD and 62 healthy comparison participants (HCs) were recruited for a study from the Canadian Biomarker Integration Network in Depression program (CAN-BIND-04). The eCBs, anandamide (AEA) and 2-arachidonylglycerol (2-AG), were assessed from blood plasma. Severe CM history was assessed retrospectively via contextual interview. MDD was associated with eCBs, though not all associations were moderated by CM or in the direction expected. Specifically, MDD was associated with higher AEA compared to HCs regardless of CM history, a difference that could be attributed to psychotropic medications. MDD was also associated with higher 2-AG, but only for participants with CM. Consistent with hypotheses, we found lower left hippocampal volume in participants with versus without CM, but only for those with lower AEA, and not moderate or high AEA. Our study presents the first evidence in humans implicating eCBs in stress-related mechanisms involving reduced hippocampal volume in MDD.

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Conflict of interest statement

RM, KLH, NN, SH, NS, JP, SS, JR, KEW, GT, BNF reported no relevant conflict of interests. LMM is a paid consultant for Synendos Therapeutics for work unrelated to the current manuscript. RVM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes for Health Research, Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute and Ontario Mental Health Foundation. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes for Health Research, Canadian Network for Mood and Anxiety Treatments, Carnot, CB Solutions, Genome BC, Janssen, Lundbeck, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Shanghai Mental Health Center, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. SCS received funding from the Ontario Brain Institute and Canadian Institutes for Health Research (MOP137097) for neuroimaging analysis in CAN-BIND, and SCS is a Senior Scientific Advisor and co-owner of ADMdx, Inc., a neuroimaging consulting company. SRA has carried out consultancy work for Indoc Research. SR holds a patent “Teneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Inventors: David Lovejoy, R.B. Chewpoy, Dalia Barsyte, Susan Rotzinger.” SHK has received research funding or honoraria from the following sources: Abbott, Alkermes, Abbvie, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen and holds stock in Field Trip Health. JAF has served on the Scientific Advisory Board for MRM Health NL and has received consulting/speaker fees from Alphasights, Novozymes, Klaire Labs, Takeda Canada, Rothman, Benson, Hedges Inc., and WebMD.

Figures

**Fig. 1. Endocannabinoid concentrations as a function of MDD and severe CM status.**
AEA concentrations were higher among participants with a major depressive disorder (MDD) versus healthy comparison participants (A). However, these results may be explained by psychotropic medication use among MDD participants (see in-text). 2-AG concentrations were higher among MDD participants, but only for those with versus without a history of severe childhood maltreatment (CM) (B). *p < 0.05.

**Fig. 2. Relation of severe CM and AEA to left hippocampal volume.**
Hippocampal volume was smaller in participants with a history of severe childhood maltreatment (CM) compared to those without severe CM, but only among participants with low AEA, and not moderate or high AEA. Note. Low, mod, and high values represent +/− 1.5 standard deviations of the mean AEA values. *p < 0.05.

See this image and copyright information in PMC

References

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Endocannabinoid concentrations in major depression: effects of childhood maltreatment and relation to hippocampal volume

Affiliations

Endocannabinoid concentrations in major depression: effects of childhood maltreatment and relation to hippocampal volume

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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Full Text Sources