Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with b...

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Veröffentlicht in:	Psychiatry and clinical neurosciences Jg. 73; H. 10; S. 613 - 627
1. Verfasser:	Hashimoto, Kenji
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Melbourne John Wiley & Sons Australia, Ltd 01.10.2019 Wiley Subscription Services, Inc
Schlagworte:	(R)‐ketamine (or arketamine), (S)‐ketamine (or esketamine), (S)‐norketamine Animal models Animals Antagonists Antidepressants Antidepressive Agents - administration & dosage Antidepressive Agents - history Antidepressive Agents - pharmacology Bipolar disorder Bipolar Disorder - drug therapy Calcium Calcium channels (voltage-gated) Depressive Disorder, Major - physiopathology Enantiomers Excitatory Amino Acid Antagonists - administration & dosage Excitatory Amino Acid Antagonists - history Excitatory Amino Acid Antagonists - pharmacology Glutamic acid receptors gut microbiota History, 20th Century History, 21st Century Humans Ketamine Ketamine - administration & dosage Ketamine - analogs & derivatives Ketamine - history Ketamine - pharmacology Mental depression Mental disorders Metabolites N-Methyl-D-aspartic acid receptors Patients PCN Frontier Review PCN Frontier Reviews Potassium channels (inwardly-rectifying) Potassium channels (voltage-gated) Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors γ-Aminobutyric acid A receptors (R)-ketamine (or arketamine), (S)-ketamine (or esketamine), (S)-norketamine gut microbiota
ISSN:	1323-1316, 1440-1819, 1440-1819
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Zusammenfassung:	Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)‐ketamine (or arketamine) and (S)‐ketamine (or esketamine). Because (S)‐ketamine has higher affinity for NMDAR than (R)‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects than (S)‐ketamine in animal models of depression and that (R)‐ketamine has less detrimental side‐effects than (R,S)‐ketamine or (S)‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABAA] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23
ISSN:	1323-1316 1440-1819 1440-1819
DOI:	10.1111/pcn.12902