title: Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.
abstract: Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. bcarlezon@mclean.harvard.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krystal
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D050882:CREB-Binding Protein / Q000235:genetics; D004195:Disease Models, Animal; D004399:Dynorphins / Q000502:physiology* / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000502:physiology; D012201:Reward; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000150:complications / Q000503:physiopathology; D057170:Translational Research, Biomedical
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D004399:Dynorphins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
keywords: anxiety; anxiety disorders; mood disorders; pharmacotherapy; substance use disorders; treatment