Plasma concentrations of oleoylethanolamide in a primary care sample of depressed patients are increased in those treated with selective serotonin reuptake inhibitor-type antidepressants
Introduction
Depression is the fourth-leading cause of disease burden. Some reports have stated that 25% of the population will experience depression symptoms at some point in their lives, being the illness that provokes the second highest level of disability worldwide (Mathers and Loncar, 2006; Richards, 2011). Improving the diagnosis and treatment of depression is a challenge for all mental health care professionals and researchers, given its substantial personal, economic and social costs (Greenberg et al., 2003; Sobocki et al., 2006). Traditionally, pharmacological treatment of depression has been focused on increasing monoamines in different brain areas by using drugs that prevent their reuptake, such as serotonin-selective reuptake inhibitors (SSRIs) or noradrenaline-selective reuptake inhibitors (NSRIs). However, this pharmacological approach is not effective for all patients (Coppola and Mondola, 2014). This issue has led to the search for other pharmacological strategies addressing innovative targets within a broader conceptualization that comprises the body's response to stress (Slavich and Irwin, 2014; Zajkowska et al., 2014). Following this rationale, in the last decade much effort has been developed to study the contribution of the endogenous cannabinoid system (ECS) to the pathogenesis and therapy of stress-associated disorders, including depression (Gorzalka et al., 2008; Hill et al., 2009a,b; Rubino et al., 2015).
The endocannabinoid system (ECS), is an on-demand lipid transmitter-based modulatory system regulating multiple functions in the brain and peripheral tissues (Piomelli, 2003; Mechoulam and Parker, 2013). The ECS includes two main chemical species, acylethanolamides (such as arachidonoylethanolamide [AEA]) and monoacylglycerols (such as 2-arachidonoylglycerol [2-AG]). Both, AEA and 2-AG engage with cannabinoid CB1 and CB2 receptors located in neurons and glial cells to control synaptic transmission in circuits involved in important homeostatic functions including eating, reproduction, social behaviour, playing, learning, memory and stress responses (Mechoulam and Parker, 2013; Wei et al., 2017). In addition to these cannabinoid receptor-signalling lipids, other molecular congeners devoid of cannabimimetic properties have been described. Among them, the satiety factor oleoylethanolamide [OEA]) that exerts its actions through the peroxisome proliferators receptor alpha (Rodríguez de Fonseca et al., 2001; Fu et al., 2003) has gained much relevance for its role in mediating hedonic responses for food and drugs (Tellez et al., 2013; Bilbao et al., 2013, 2016).
Concerning endocannabinoids, both, preclinical and clinical studies have demonstrated a link in between anandamide and 2-AG and affective disorders (Hill et al., 2008; Blankman and Cravatt, 2013; Mechoulam and Parker, 2013; Hillard and Liu, 2014). According to these studies, a decrease in endocannabinoids results in the presence of behaviours that mimic the symptoms of human depression, whereas an increase in extracellular endocannabinoids resulted in antidepressant effect. This finding originated from several studies in animals, that include pharmacological strategies to reduce endocannabinoid degradation using selective blockers of the main endocannabinoid-hydrolizing enzyme fatty acid amide hydrolase (FAAH) (Kathuria et al., 2002; Blankman and Cravatt. 2013; Hillard and Liu, 2014). They were also confirmed in human observations (Hill et al., 2008, 2009a,b). Regarding non-cannabinoid acylethanolamides, such as palmithylethanolamide (PEA) or oleoylethanolamide (OEA), its contribution to human affective disorders is much less known, although there is substantial evidence coming from preclinical experimental reports. Thus, pharmacological administration of OEA was found to display antidepressant activity in animal models of depression (Jin et al., 2015) through the modulation of serotonin/noradrenaline release (Yu et al., 2015). This effect was attributed to the interaction of OEA with peroxisome proliferator-activated receptors-alpha (PPARα) receptors, since it was mimicked by clinically-used PPARα agonists such as fenofibrate (Jiang et al., 2017), potentially by activating central PPARα receptors present in hippocampal cells (Song et al., 2018). In addition, OEA was found to ameliorate depressive symptoms associated to either lipopolysaccharides (LPS) administration (Sayd et al., 2014) or to acute alcohol exposure (Antón et al., 2017), helping to reduce LPS release from the intestine into the circulation by preventing alcohol-inducing damage (Antón et al., 2018). The neurobiological basis of the potential antidepressant actions of OEA also involves both Histamine (Provensi et al., 2014; Costa et al., 2018), and Oxytocin (Gaetani et al., 2010) circuits, which are involved not only in the feeding suppression induced by this acylethanolamide but also in the antidepressant actions of SSRIs, the main class of antidepressants used for the therapeutics of depression (Uvnäs-Moberg et al., 1999; Munari et al., 2015; Scantamburlo et al., 2015).
Given the previous findings, and the lack of studies addressing the effect of SSRI on circulating OEA levels in humans, the main aim of this study was to compare the concentrations of oleoylethanolamide and related congeners in a sample of patients with depression demanding treatment. Patients were recruited in a primary care setting, and the effect of SSRI, the influence of the severity of depression, the type of symptoms (cognitive-affective vs. somatic), age, sex and BMI were analyzed.
Section snippets
Participants and recruitment
Two samples were used in this study. The clinical sample consisted of 69 patients with mild or moderate depression. The participants were recruited in primary care settings by general practitioners from the population of patients who consulted for mood disturbances and who participated in another research project about psychotherapy for depression. The inclusion criteria were the following: a) age between 18 and 65 years; b) depressive symptoms for over two months; c) diagnosis of major
Preliminary analyses
The sociodemographic characteristics of the patient/control groups are presented in Table 1. The results showed that both samples were similar in age, gender and BMI. The analyses also showed statistically significant differences between samples in marital status (p < 0.01), education (p < 0.05) and employment status (p < 0.001). Patients with depression were more often married, had fewer university studies and were more often unemployed than the control group. The results regarding the
Discussion
The present study reveals that depressed patients demanding treatment in primary care settings display alterations in their plasma concentrations of both, endocannabinoids and non-cannabinoid acylethanolamides, including 2-AG and OEA. A remarkable discovery is the association of the elevations of the plasma concentrations of these two mediators in those patients under treatment with SSRI-type antidepressants. The antidepressant-induced rise of both 2-AG and OEA is relevant because these
Conflicts of interest
The authors have no conflict of interest to disclose.
Acknowledgements
The authors would like to thank the general practitioners, nurses and admission desk staff from Colonia Santa Inés/Teatinos, Puerta Blanca and Alameda/Perchel Primary Care Centers for their outstanding participation in this study.
The present study has been supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (ISCIII) and European Regional Development Funds-European Union (ERDF-EU) (Subprograma RETICS Red de Trastornos Adictivos RD12/0028/0001, RD16/0017/0001,
References (49)
- et al.
Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biol. Psychiatry
(2007) - et al.
Is there a role for palmitoylethanolamide in the treatment of depression?
Med. Hypotheses
(2014) - et al.
Histamine-deficient mice do not respond to the antidepressant-like effects of oleoylethanolamide
Neuropharmacology
(2018) - et al.
Regulation of endocannabinoid signaling by stress: implications for stress-related affective disorders
Neurosci. Biobehav. Rev.
(2008) - et al.
The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants
Trends Pharmacol. Sci.
(2009) - et al.
Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress
Psychoneuroendocrinology
(2009) - et al.
Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress
Pharmacol. Biochem. Behav.
(2015) - et al.
Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression
Pharmacol. Res.
(2010) - et al.
Analysis of ECs and related compounds in plasma: artifactual isomerization and ex vivo enzymatic generation of 2-MGs
J. Lipid Res.
(2014) Prevalence and clinical course of depression: a review
Clin. Psychol. Rev.
(2011)
Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: an open trial
Eur. Psychiatry
Endocannabinoid signaling in the control of social behavior
Trends Neurosci.
Involvement of norepinephrine and serotonin system in antidepressant-like effects of oleoylethanolamide in the mice models of behavior despair
Neurosci. Lett.
Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-kB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration
Addict. Biol.
Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide
Br. J. Pharmacol.
Comparison of Beck depression inventories -IA and -II in psychiatric outpatients
J. Pers. Assess.
Oleoylethanolamide dose-dependently attenuates cocaine-induced behaviours through a PPARα receptor-independent mechanism
Addict. Biol.
Role of the satiety factor oleoylethanolamide in alcoholism
Addict. Biol.
Chemical probes of endocannabinoid metabolism
Pharmacol. Rev.
Structured Clinical Interview for DSM-IV Axis I Disorders—Clinician Version (SCID-CV)
Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha
Nature
The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin
J. Neurosci.
The economic burden of depression in the United States: how did it change between 1990 and 2000?
J. Clin. Psychiatr.
Cited by (35)
Endocannabinoids, cortisol, and development of post-traumatic psychopathological trajectories
2023, General Hospital PsychiatryMulti-omics analysis reveals BDE47 induces depression-like behaviors in mice by interfering with the 2-arachidonoyl glycerol-associated microbiota-gut-brain axis
2023, Ecotoxicology and Environmental SafetyEndocannabinoid hydrolases differentially distribute in platelets and red blood cells and are differentially released by thrombin
2023, Prostaglandins and Other Lipid MediatorsDetermination of inflammation-related lipids in depressive rats by on-line supercritical fluid extraction-supercritical fluid chromatography-tandem mass spectrometry
2021, Journal of Pharmaceutical and Biomedical AnalysisCirculating endocannabinoids and prospective risk for depression in trauma-injury survivors
2021, Neurobiology of StressCitation Excerpt :Women with MDD have lower serum 2-AG concentrations compared to non-depressed controls (Hill et al., 2008; Hill et al., 2009) and symptoms of depressed mood are inversely correlated with 2-AG concentration (Hill et al., 2008; Stensson et al., 2018). On the other hand, a recent study found significantly higher circulating concentrations of both AEA and 2-AG in patients with MDD, although the increase in 2-AG did not survive correction for anti-depressant use (Romero-Sanchiz et al., 2019). Other studies have examined associations of acute changes in circulating eCBs with changes in mood using exercise (Heyman et al., 2012; Koltyn et al., 2014) and psychological stress (Dlugos et al., 2012) to provoke acute increases in circulating 2-AG and AEA.
- 1
These authors contributed equally to the present study.