title: The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse.
abstract: A decreased level of brain 5-hydroxytryptamine (5-HT) has been theorized to be a core pathogenic factor in depression for half a century. The theory arose from clinical observations that drugs enhancing extracellular levels of 5-HT (5-HT(Ext)) have antidepressant effects in many patients. However, whether such drugs indeed correct a primary deficit remains unresolved. Still, a number of anomalies in putative biomarkers of central 5-HT function have been repeatedly reported in depression patients over the past 40 years, collectively indicating that 5-HT deficiency could be present in depression, particularly in severely ill and/or suicidal patients. This body of literature on putative 5-HT biomarker anomalies and depression has recently been corroborated by data demonstrating that such anomalies indeed occur consequent to severely reduced 5-HT(Ext) levels in a mouse model of naturalistic 5-HT deficiency, the tryptophan hydroxylase 2 His(439) knockin (Tph2KI) mouse. In this review, we will critically assess the evidence for 5-HT deficiency in depression and the possible role of polymorphisms in the Tph2 gene as a causal factor in 5-HT deficiency, the latter investigated from a clinical as well as preclinical angle.
authors: Department of Cell Biology, Duke University Medical Center, , Durham, NC 27710, USA. jacob.jacobsen@dm.duke.edu
authors: Jacob P R
authors: JP
authors: Jacobsen
authors: Ivan O
authors: IO
authors: Medvedev
authors: Marc G
authors: MG
authors: Caron
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D055879:Gene Knock-In Techniques; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D011110:Polymorphism, Genetic; D012701:Serotonin / Q000172:deficiency*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D013405:Suicide / Q000523:psychology; D009435:Synaptic Transmission; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D001120:Arginine; D015415:Biomarkers; D006639:Histidine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C487802:Tph2 protein, mouse