The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse

Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2444-59. doi: 10.1098/rstb.2012.0109.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Arginine / genetics
  • Arginine / metabolism
  • Biomarkers / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Depression / drug therapy
  • Depression / genetics
  • Depression / physiopathology*
  • Gene Knock-In Techniques
  • Histidine / genetics
  • Histidine / metabolism
  • Humans
  • Mice
  • Polymorphism, Genetic
  • Serotonin / deficiency*
  • Serotonin Uptake Inhibitors / metabolism
  • Serotonin Uptake Inhibitors / pharmacology
  • Suicide / psychology
  • Synaptic Transmission
  • Tryptophan Hydroxylase / genetics
  • Tryptophan Hydroxylase / metabolism*

Substances

  • Antidepressive Agents
  • Biomarkers
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Histidine
  • Arginine
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase