Elsevier

Neuropharmacology

Volume 149, 1 May 2019, Pages 212-220
Neuropharmacology

Plasma concentrations of oleoylethanolamide in a primary care sample of depressed patients are increased in those treated with selective serotonin reuptake inhibitor-type antidepressants

https://doi.org/10.1016/j.neuropharm.2019.02.026Get rights and content

Highlights

  • Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with antidepressant activity in preclinical models.

  • Depressed patients recruited at a primary care setting were found to have increased plasma levels of OEA and 2-AG.

  • This was observed only in patients with current antidepressant treatment with selective serotonin reuptake inhibitors (SSRI).

  • The concentrations of OEA correlated with somatic symptoms of depression.

  • A potential role for OEA in the pharmacological actions of SSRI is discussed.

Abstract

Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with multiple physiological roles that has been proposed to have antidepressant-like activity in preclinical models. OEA shares biosynthetic pathways with anandamide (AEA) a transmitter involved in affective disorders and anxiety in humans. However, although the participation of OEA in depression has been proposed, both, the contribution of OEA to the depressive phenotype and the effect of antidepressant therapy on circulating levels of this and related non-cannabinoid acylethanolamides in humans are basically unknown. The main objective of this study is to compare the plasma concentrations of OEA and related acylethanolamides in a sample of primary care patients with depression (n = 69) with those of healthy non-depressed patients (n = 47). At the time of admission to the study, 22 patients were under selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and 47 patients were not receiving any type of intervention. In addition, plasma concentrations of the endocannabinoid 2-AG and two related monoacylglycerols were monitored. Plasma OEA concentrations were found to be elevated in depressed patients and to correlate with somatic symptoms of depression. Plasma concentrations of both, AEA and 2-AG, were found to be elevated also in depressed patients. Further analysis demonstrated that the elevation observed in the plasma concentrations of both, OEA and 2-AG, was associated to SSRI antidepressant therapy at the time of recruitment. Further clinical research is needed to understand whether SSRI-induced elevations in OEA levels contribute to the response to SSRI in depressed patients as described in preclinical models.

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,

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    These authors contributed equally to the present study.

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