title: Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited.
abstract: BACKGROUND
  Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues.
  
  
  METHODS
  The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels.
  
  
  CONCLUSIONS
  In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: 'the monoamine hypothesis revisited' to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression.
authors.affiliation: Utrecht University, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Division of Pharmacology, Universiteitsweg, The Netherlands. j.prins1@uu.nl
authors.forename: Jolanda
authors.initials: J
authors.lastname: Prins
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: S Mechiel
authors.initials: SM
authors.lastname: Korte
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D014179:Neurotransmitter Uptake Inhibitors