Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression.
Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term morbidity during treatment of depression. Increasing evidence supports an association between depressive illness and disturbances in brain glutamate activity, nitric oxide synthesis, and gamma-amino butyric acid. Animal models also confirm that suppression of glutamate N-methyl-D-aspartate receptor activity or inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of gamma-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide. These stress-induced structural changes can be reversed by antidepressant treatment. In patients with depression, antidepressant withdrawal after chronic administration is associated with a stress response as well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal evokes a behavioral stress response that is associated with increased hippocampal N-methyl-D-aspartate receptor density, with both responses dependent on N-methyl-D-aspartate receptor activation. Drawing from both clinical and preclinical studies, this article proposes a preliminary molecular perspective and hypothesis on the neuronal implications of adherence to and discontinuation of antidepressant medication.
Harvey
Brian H
BH
Division of Pharmacology, School of Pharmacy, Potchefstroom University for Christian Higher Education, Potchefstroom, South Africa.
McEwen
Bruce S
BS
Stein
Dan J
DJ
D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000737:chemistry; D002908:Chronic Disease; D003863:Depression / Q000188:drug therapy / Q000453:epidemiology / Q000209:etiology*; D004195:Disease Models, Animal; D006801:Humans; D008137:Longitudinal Studies; D009446:Neurobiology; D019636:Neurodegenerative Diseases; D009473:Neuronal Plasticity / Q000187:drug effects; D017063:Outcome Assessment, Health Care; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D000928:Antidepressive Agents