Researchers are hailing ketamine as the most significant new development in psychiatry given its high efficacy for treating major depression. Recent evidence has shown that in addition to depression, ketamine may also be a promising treatment for obsessive-compulsive disorder, post-traumatic stress disorder, and a number of other treatment-refractory neuropsychiatric disorders. In a recent paper published in Drug Discovery Today, researchers explore ketamine’s role in revolutionizing new mental health treatments and discuss how this drug’s mechanism of action has led to an influx of new research and studies on depression treatment.

Ketamine was approved by the US Food and Drug Administration (FDA) in 1970 as an anesthetic and safe alternative to phencyclidine. The therapeutic benefits of ketamine as an antidepressant were explored years later because of a stigma on from its widespread recreational use during the late 1960s and 1970s, and this agent was initially only administered intravenously.

In 2000, researchers found that ketamine had strong, fast-acting, and long-term effects in depression. In a randomized, placebo-controlled, crossover design study, patients with depression received 0.5 mg/kg of ketamine or saline on the first day of testing. Treatments were switched 1 week later. Researchers found that the antidepressant effects of ketamine began within 4 hours, peaked at 72 hours, and lasted for 1 to 2 weeks thereafter.1 In a 2006 study, this finding was replicated in an independent group of 18 patients with major depressive disorder who were resistant to other treatments. Compared with participants who received placebo, those who received ketamine showed significant improvement in symptoms within 110 minutes, with 35% maintaining significant response for at least 1 week.2

In subsequent years, results from a number of placebo-controlled studies revealed that ketamine is largely effective and long-acting in treatment of bipolar disorder and treatment-resistant major depressive disorder and produces antisuicidal and anti-anhedonic effects in mood disorders.

Many of today’s depression treatments are monoaminergic-based, including monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. These treatments have been proven effective for a large number of patients. However, a significant subset of patients with major depressive disorder do not respond to these agents.1 When compared with ketamine, these agents have a delayed onset of action that can take up to several weeks — increasing the risk for organ failure and suicide in this subset.

A single dose of ketamine is shown to produce rapid and robust effects within hours to days of administration. This agent is also shown to rapidly reduce suicidal ideation, fatigue, and anhedonia, and improve circadian rhythm and sleep patterns in major depressive disorder.1 Researchers point out that these symptoms are synonymous across several psychiatric disorders but remain inadequately treated by monoaminergic-based agents.

The notable differences between ketamine and standard antidepressants have spurred researchers to develop new ketamine treatments that are less invasive than those involving intravenous administration. In March 2019, the FDA approved an intranasal version of ketamine called esketamine for adults with treatment-resistant depression.

Researchers say that ketamine’s mechanism of action in the context of clinical antidepressant efficacy is only partially clear. At present, researchers understand that ketamine’s mechanism of action goes beyond modulating the neurotransmission of glutamate and includes direct and indirect high affinity antagonistic binding properties at the N-methyl-D-aspartate receptor, as well as a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput modulation.1 Researchers have also noted that ketamine is a weak agonist at the mu, delta, and kappa opioid receptors.1

Other mechanisms that may contribute to ketamine’s efficacy for depression treatment include agonism at the dopamine receptor, antagonism at the M1–3 muscarinic receptors, and inhibition of the reuptake of serotonin, dopamine, and norepinephrine.1

Researchers are continuing to investigate ketamine’s underlying mechanism of action so they can progress with identifying and developing new agents that work similarly and that offer fewer side effects, as well as prolonged therapeutic effects.

Ketamine has influenced researchers to place more focus on the glutamatergic system when developing new therapies, since it is thought that rapid-acting antidepressants may trigger neurobiological events deeply rooted in the rapid reconfiguration of limbic circuitries.1 In addition to intranasal esketamine, other examples of rapid-acting glutamatergic agents that show promising results are nitrous oxide and sarcosine.

Nitrous oxide has been used as an anesthetic for more than 150 years and offers many of the same mechanisms as ketamine. Results from a 2015 study revealed that patients with treatment-resistant depression who received nitrous oxide experienced significant improvement in symptoms at 2 hours and 24 hours compared with placebo. Symptoms that showed the largest changes in improvement were depressed mood, guilt, suicidal ideation, and psychic anxiety.3 Additional trials are being conducted to determine the safety, efficacy, and optimal dosing of nitrous oxide for depression.

Sarcosine is an amino acid that functions as a glycine transporter-1 inhibitor and has co-agonistic properties at the N-methyl-D-aspartate receptor. Results from clinical trials have shown that sarcosine is a promising treatment for major depressive disorder and produces no adverse events. However, compared with ketamine, sarcosine does not produce the same rapid-acting effects within the same amount of time.1 Studies are currently underway to replicate the effects of both nitrous oxide and sarcosine in depression.

Ketamine has been found to enhance the transmission of gamma-aminobutyric acid (GABA) to reduce depression. Shortly after approving intranasal esketamine, the FDA approved an agent called brexanolone that acts as a positive allosteric modulator of GABA receptors. Brexanolone is currently being used to treat postpartum depression since this therapy produces rapid- and long-acting antidepressant effects similar to that produced by ketamine. The exact mechanism of action of brexanolone remains unclear, though researchers theorize that it binds to synaptic and extrasynaptic GABA receptors to increase functionality. Brexanolone is still being tested in clinical trials, since this agent has been associated with serious adverse events including syncope, altered state of consciousness, suicidal ideation, and intentional overdose.1

Related Articles

Buprenorphine, an opioidergic agent currently used to treat opioid use disorder, is also being studied for treatment of depression. Opioidergic agents were once used to treat melancholia during the 1950s before less addictive therapies became available and are shown to have a wide variety of actions in the brain that reduce depression. Studies evaluating the effects of buprenorphine by itself and combined with other agents on depression have produced promising results, though the FDA has stated it needs additional clinical data before this agent can be used to treat major depressive disorder.

Given what studies have since revealed about the efficacy of ketamine in depression, many researchers are reconsidering the potential benefits of banned or scheduled drugs for psychiatric patients.

Psychoactive drugs being reevaluated include lysergic acid diethylamide (LSD), 3,4-methylenedioxy-methamphetamine, and psilocybin. Researchers are determining whether microdosing these substances could produce therapeutic benefits without harmful side effects or abuse. Results from a 2011 study revealed that psilocybin was successful at significantly reducing symptoms of depression for up to 6 months in patients treated for advanced-stage cancer.1 In a 2015 study that examined the effects of LSD in patients with life-threatening diseases who were experiencing anxiety, LSD was safe, well-tolerated, and effective at reducing psychiatric symptoms.1

Researchers say that the recent FDA approval of intranasal ketamine represents a major breakthrough in psychiatry and that advances in ketamine or ketamine-like treatments may greatly improve the quality of life for patients with depression who do not respond to current treatments. Studies conducted on ketamine have paved the way for research evaluating novel approaches for the prevention and treatment of depression.

Disclosure: One author is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation, among others. Please see original reference for a full list of authors’ disclosures.

References

1. Kraus C, Wasserman D, Henter ID, Acevedo-Diaz E, Kadriu B, Zarate CA Jr. The influence of ketamine on drug discovery in depression [published online August 2, 2019]. Drug Discov Today. doi: 10.1016/j.drudis.2019.07.007

2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64.

3. Nagele P, Duma A, Kopec M, et al. Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biol Psychiatry. 2015;78(1):10-18.