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

Summary & key facts

This paper is a review of ketamine as a fast-acting antidepressant and of other drugs being tested for the same purpose. The author explains why faster treatments are needed, summarizes clinical and animal evidence that ketamine can work quickly in people whose depression did not improve with usual medicines, notes that one form of ketamine was approved as a nasal spray in 2019, and points out that other drug targets and ketamine breakdown products are under study. The review emphasizes promising findings but also that many details still need more research.

Key facts:

• Major depressive disorder is described as one of the most disabling psychiatric illnesses.
• About one third of people with major depressive disorder do not get better from current antidepressant medicines.
• Typical antidepressants often take weeks to months to have a full effect, which creates a need for faster treatments.
• Growing evidence shows that ketamine, which blocks a brain receptor called the NMDA receptor (a protein involved in how nerve cells talk to each other), can produce rapid and sometimes sustained antidepressant effects in people whose depression resisted other treatments.
• Ketamine is a chemical mix of two mirror-image forms called R-ketamine and S-ketamine; the S form was developed into a nasal spray that the US Food and Drug Administration approved in March 2019.
• Laboratory and animal studies suggest that R-ketamine may have stronger and longer-lasting antidepressant effects and fewer harmful side effects than S-ketamine or the mixed form, but that evidence is mainly from preclinical work rather than from people.
• The paper reviews ketamine’s main breakdown products, norketamine and hydroxynorketamine, because they may help explain how ketamine reduces depression symptoms.
• The author also outlines other possible rapid-acting antidepressant approaches being tested, including other NMDA blockers, drugs that affect certain calcium or potassium channels, and drugs that change GABA receptor activity; these are experimental and not yet proven to replace ketamine.
• The review highlights that while ketamine and related compounds look promising, more clinical research is needed to understand how well they work, how long effects last, and their safety compared with current treatments.

Abstract

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 [GABA A ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.

Topics

Neuroscience and Neuropharmacology Research Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Anesthesia Antidepressant Cognition Hippocampus Internal medicine Ketamine Major depressive disorder Medicine NMDA receptor Pharmacology Psychiatry Psychology Receptor Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood