Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis.
Depression is a widespread and serious disorder that afflicts an estimated 13.1 to 14.2 million adults in the United States each year. Even more compellingly, the lifetime prevalence rate of depression in the US has recently been estimated to include 16.2% of adults (21% women, 13% men), or >32.6 million people. There are multiple putative "causes" of depression, with approximately one-third of an individual's propensity for unipolar depression due to genetic vulnerability, while the remaining two-thirds is due to environmental factors. Although the selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to mainly act by selectively binding to the serotonin (5-HT) transporter to block reuptake of 5-HT from the synapse into the presynaptic nerve terminal, thereby increasing synaptic serotonin concentrations, some of the SSRIs also exhibit other neuropharmacologic effects. One such example is the high affinity for paroxetine in blocking norepinephrine reuptake. Another is the inhibition of dopamine reuptake by sertraline. In depression, hyperactivity of corticotropin-releasing factor (CRF)--producing neurons contribute to the well-characterized hypothalamic-pituitary-adrenal axis hyperactivity of depression. Increased activity of extrahypothalamic CRF circuits are believed to contribute to several depressive symptoms. Treatment and certain SSRIs have been shown to reduce the activity of CRF neurons and may contribute to their therapeutic action. Each SSRI apparently has its own unique pharmacologic properties that likely underlie their observed differences in clinical use.
Nemeroff
Charles B
CB
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA. cnemero@emory.edu
Owens
Michael J
MJ
D000679:Amygdala / Q000187:drug effects; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000187:drug effects; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D011795:Surveys and Questionnaires
D002352:Carrier Proteins; D004298:Dopamine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D018019:Receptors, Corticotropin-Releasing Hormone; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human; C493232:Slc6a4 protein, rat