title: Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.
abstract: Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.
authors.affiliation: 1] Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience (Pharmacology and Psychiatry), University of Cadiz, Cadiz, Spain [2] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Perez-Caballero
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Pérez-Egea
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Neuropsychopharmacology and Psychobiology Research Group, Salus Infirmorum Faculty of Nursing, University of Cadiz, Cadiz, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Romero-Grimaldi
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Puigdemont
authors.affiliation: Department of Neurosurgery, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Molet
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Psychiatry, Faculty of Medicine, University Complutense and Instituto de Investigación 12 de octubre, Madrid, Spain.
authors.forename: J-R
authors.initials: JR
authors.lastname: Caso
authors.affiliation: 1] Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience (Pharmacology and Psychiatry), University of Cadiz, Cadiz, Spain [2] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: J-A
authors.initials: JA
authors.lastname: Mico
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Pérez
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Pharmacology, Faculty of Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: J-C
authors.initials: JC
authors.lastname: Leza
authors.affiliation: 1] Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain [2] Neuropsychopharmacology and Psychobiology Research Group, Psychobiology Area, Department of Psychology, University of Cadiz, Cadiz, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Berrocoso
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology*; D002908:Chronic Disease; D046690:Deep Brain Stimulation / Q000009:adverse effects; D003865:Major Depressive Disorder / Q000503:physiopathology* / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D012189:Retrospective Studies; D013315:Stress, Psychological; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005904:Glial Fibrillary Acidic Protein