title: Fatty acid metabolism and its longitudinal relationship with the hypothalamic-pituitary-adrenal axis in major depression: Associations with prospective antidepressant response.
abstract: BACKGROUND
  Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better understand these associations, we might identify novel targets for add-on therapy to increase antidepressant-response, and/or early indicators to improve response prediction.
  
  
  OBJECTIVE
  To determine whether alterations in FA-metabolism, and their relationship with the HPA-axis, are associated with prospective response to the antidepressant paroxetine in MDD.
  
  
  METHODS
  We first compared 70 initially unmedicated MDD-patients with 51 age- and gender-matched controls at study-entry, regarding salivary cortisol and erythrocyte membrane FAs [omega-3 docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), FA-chain length, -unsaturation and -peroxidizability]. Subsequently, we treated patients with 6 weeks 20mg/day selective serotonin reuptake inhibitor paroxetine. After 6 weeks, we continued this treatment in responders (i.e. showing ≥50% decrease in Hamilton depression rating scale-score), and randomized non-responders to a 6-week, double-blind, placebo-controlled dose-escalation up to 50mg/day. We repeated cortisol and FA-measures in patients after 6 and 12 weeks.
  
  
  RESULTS
  Compared to controls, patients showed higher FA-chain length, FA-unsaturation and FA-peroxidation, and more negative relationships of FA-unsaturation and FA-peroxidation with cortisol. Moreover, these negative relationships were associated with paroxetine nonresponse. Nonresponse was also associated with low DHA, which was related to low fatty fish intake. Furthermore, early responders showed initial low FA-chain length, FA-peroxidation and EPA that increased during the study, while non-responders exhibited opposite patterns.
  
  
  CONCLUSIONS
  FA-metabolism alterations, and their relationship with cortisol, are associated with prospective paroxetine response in MDD, and may therefore form an early indicator of treatment effectiveness. Moreover, dietary fatty fish intake may improve antidepressant response through an effect on FA-metabolism.
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands. Electronic address: R.J.Mocking@amc.uva.nl.
authors.forename: Roel J T
authors.initials: RJ
authors.lastname: Mocking
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Hanka F
authors.initials: HF
authors.lastname: Verburg
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Westerink
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Johanna
authors.initials: J
authors.lastname: Assies
authors.affiliation: Laboratory Genetic Metabolic Disease, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Maarten W J
authors.initials: MW
authors.lastname: Koeter
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands; University of Groningen, University Medical Center Groningen, Program for Mood and Anxiety Disorders, Department of Psychiatry, Groningen, The Netherlands.
authors.forename: Henricus G
authors.initials: HG
authors.lastname: Ruhé
authors.affiliation: Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands; Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Aart H
authors.initials: AH
authors.lastname: Schene
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D004281:Docosahexaenoic Acids; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015118:Eicosapentaenoic Acid; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D050356:Lipid Metabolism; D008137:Longitudinal Studies; D008297:Male; D017374:Paroxetine / Q000627:therapeutic use*; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D012463:Saliva / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D004281:Docosahexaenoic Acids; D017374:Paroxetine; D015118:Eicosapentaenoic Acid; D006854:Hydrocortisone
keywords: Cortisol; Docosahexaenoic acid; Eicosapentaenoic acid; Fatty acids; Major depressive disorder; Paroxetine; Prognosis; Serotonin uptake inhibitors; n-3 PUFA