A Deficit in Peripheral Serotonin Levels in Major Depressive Disorder but Not in Chronic Widespread Pain E ´ milie Paul-Savoie, MSc,* Ste´phane Potvin, PhD,*w Kathya Daigle, BSc,* Edith Normand, MSc,* Jean-Franc¸ois Corbin, MD,z Rene ´ Gagnon, PhD,y and Serge Marchand, PhD* Objectives: It has been proposed that serotonin dysfunctions underlie the pathophysiology of various mood disorders (including major depressive disorder, MDD) and chronic pain conditions characterized by deficient pain inhibition, such as fibromyalgia (FM). There is reliable data showing that serotonin disturbances are involved in the pathophysiology of MDD. However, in the case of FM, results published so far are less consistent. Therefore, the current cross-sectional study sought to measure plasma serotonin levels in FM patients, MDD patients, and healthy controls (HC). Methods: Twenty-nine FM patients, 17 MDD patients, and 57 HC were recruited who did not differ in terms of age, sex, and the presence or absence of a regular menstrual cycle. Plasma samples were analysed with mass spectrometry. Results: Serotonin levels were decreased in MDD patients, relative to FM patients and HC. Post hoc analyses showed that serotonin levels were decreased in FM patients taking antidepressants, relative to HC, but not in drug-free FM patients. Moreover, serotonin levels were negatively correlated with mood symptoms across groups. Discussion: Our results further confirm that MDD is associated with decreased serotonin levels, but that serotonin levels are not altered in FM per se, and suggest that 5-Hydroxytryptamine is related to mood symptoms in these patient groups. Our results also suggest that the taking of antidepressant is a major confound to consider when studying serotonin functioning in FM. The long- term use of antidepressants in FM may lead to serotonin depletion. Conversely, serotonin depletion may be before the taking of antidepressants in FM. Key Words: serotonin, major depressive disorder, fibromyalgia, thermal pain (Clin J Pain 2011;27:529–534) G iven that serotonin [5-Hydroxytryptamine (5-HT)] plays a critical role in limbic pathways related to mood regulation and in descending pain pathways related to pain inhibition, 1 it has been proposed that serotoninergic dysfunctions underlie the pathophysiology of various mood disorders (including major depressive disorder, MDD) 2–4 and chronic pain conditions characterized by a deficit in pain inhibition, such as fibromyalgia (FM). 5,6 On the basis of criteria from the American College of Rheumatology, FM is defined by widespread musculoskeletal pain for more than 3 months and the presence of Z11 of 18 tender points, 7 all in the absence of a demonstrable peripheral nociceptive cause. FM is also characterized by muscle stiffness, persisting fatigue, sleep disturbance, and mood symptoms. In particular, there is strong evidence that FM is associated with a 2-fold to 7-fold increase in the likelihood of haing comorbid mood disorders, 8,9 as confirmed by meta-analysis. 10 Evidence from decades of animal research, pharma- cological trials using selective serotonin reuptake inhibitors, and genetic and brain imaging studies of the 5-HT receptors or transporters, all point toward a critical role of 5-HT in the pathophysiology of MDD. 2–4 However, the evidence for an involvement of serotoninergic neurotransmission in the pathophysiology of FM is weaker than evidence relating abnormal 5-HT functioning to MDD. Pain is a dynamic phenomenon resulting from the activity of both endogenous pain excitatory and inhibitory systems, including diffuse noxious inhibitory controls (DNIC). The DNIC theory postulates that a nociceptive stimulation will cancel out another nociceptive stimulation if it occurs on a body surface distanced from the pain surface (eg, “pain inhibits pain” phenomenon). 11,12 In animals, numerous studies showed that the DNIC trigger 5-HT release from neurons in the raphe nuclei (medulla), which dampen nociceptive afferents at the spinal cord dorsal horn. 11–14 DNIC cause a diffuse reduction of pain perception throughout the body. In humans, a lack of pain inhibition may favor the development of chronic pain conditions, including FM. Indeed, using the spatial summation proce- dure, 15 Julien et al 16 found a deficit in pain inhibition [eg, inhibitory conditioned pain modulation(CPM)] in FM patients, but not in low-back pain patients. Given the role of 5-HT in pain inhibition and the deficit of pain inhibition in FM, altered 5-HT functioning would be expected. Indeed, FM has been associated, with relative consistency, with decreased levels of peripheral and cerebrospinal tryptophan (5-HT precursor), 5-HT, and 5-hydroxyindoleacetic acid (5-HT metabolite). 6,17–20 In addition, controlled clinical trials showed the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of FM, but treatment effects were estimated to be rather small. 21,22 Lastly, preliminary results from genetic studies showed an association between FM syndrome and functional polymorphisms of genes coding for the 5-HT transporter and 5-HT 2A receptor, 23,24 but some groups failed to replicate these findings. 25,26 Copyright r 2011 by Lippincott Williams & Wilkins Received for publication January 20, 2010; revised October 21, 2010; accepted December 30, 2010. From the Departments of *Neurosurgery; yPediatry; zHoˆpital Hoˆtel- Dieu, Department of Psychiatry, Faculty of Medicine, University of Sherbrooke, Sherbrooke; and wCentre de recherche Fernand- Seguin, Department of Psychiatry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. Dr Marchand is a supported member of the Centre de recherche clinique E ´ tienne-Le Bel du Centre Hospitalier Universitaire de Sherbrooke. Dr Potvin is holder of a Junior 1 researcher scholar- ship from the Quebec Health Research Funds. Dr Marchand holds grants from the CIHR. Reprints: Serge Marchand, PhD, Universite´ de Sherbrooke, Faculte´ de me´ decine, Axe Douleur CRC-CHUS, 3001, 12e avenue nord, Sher- brooke, Canada, J1H 5N4 (e-mail: serge.marchand@usherbrooke.ca). ORIGINAL ARTICLE Clin J Pain  Volume 27, Number 6, July/August 2011 www.clinicalpain.com | 529