Ketamine/esketamine for treatment-resistant depression

Ketamine discovery

Like most meaningful discoveries, the road leading to the development of ketamine as a treatment of mood disorders was long and winding, punctuated by dead ends and fueled by serendipity. In 1956, V. Harold Maddox, a chemist at Parke-Davis, created a new chemical process which resulted in the creation of phencyclidine ( ). Initially used as an anesthetic in animals ( ), phencyclidine was later tried in humans ( ). Although it was generally considered a safe anesthetic, it produced a severe emergence delirium in some patients ( ), and later studies raised concerns that the drug could cause psychotomimetic symptoms similar to schizophrenia ( ). As such, phencyclidine was deemed inappropriate for human use, motivating work to identify related compounds that might be more appropriate for clinical applications. One of these compounds, CI-581, a short-acting agent with favorable anesthetic properties, was synthesized by Calvin Stevens in 1962. Considering the compound contained both a ketone and an amine in its structure, it was named ketamine ( ). Domino and Corssen first reported on the use of ketamine in humans in a study conducted on prisoners at the Jackson Prison in Michigan in 1964 ( ), coining the term “dissociative anesthetic,” that remains in use today.

For over 50 years, ketamine has been used as an anesthetic agent. Originally patented for veterinary use in 1963 and receiving a USFDA indication under the name Ketalar for human use as an anesthetic treatment in 1970 ( ), it rapidly became a favored field anesthetic given its sympathomimetic properties and analgesic effects that outlast its anesthetic effect ( ). Ketamine was first placed on the World Health Organizations Essential Medicines List in 1985 related to its ease of use and safety profile that make it especially appealing in underresourced health systems. In recent years, illicit and recreational use of ketamine in some countries has prompted renewed evaluations of ketamine’s role in the worldwide medical system and the possible need for increased levels of control. However, four reviews of the drug over the past 15 years by the World Health Organization (WHO) consistently recommended that ketamine should not be placed under increased international control that could limit access to the drug ( ).

Rationale for use in depression

A series of evolving hypotheses and discoveries inspired the studies that ultimately demonstrated ketamine’s antidepressant properties. To our knowledge, the first reported study of ketamine’s potential use in the treatment of psychiatric illnesses was done in 1973 in Shiraz, Iran. Khorramzadeh and Lotfy treated 100 patients carrying various psychiatric diagnoses with increasing doses of ketamine. Astonishingly, they reported improvement in psychiatric symptoms in 95% of patients treated with 0.4–0.6 mg/kg or slightly higher (0.7–1.0 mg/kg) doses of ketamine ( ). The rationale behind this trial was based primarily on the psychological effects of ketamine and the potential for it to improve the psychodynamic healing process, as the underlying neurobiological effects of ketamine had not even been well understood at this time.

In the early 1990s, Skolnick and colleagues at the NIH explored the effects of N -methyl- d -aspartate (NMDA) glutamate receptor antagonists on the depression-like behaviors caused by inescapable stress in mice ( ). Based on the knowledge that NMDA receptors are required for long-term potentiation (LTP), which is impaired by inescapable stress, and also by the fact that traditional antidepressants are effective in reversing the depressive-like behaviors caused by inescapable stress, they hypothesized that NMDA receptor antagonists could produce similar antidepressant effects in mice. Using standard rodent behavioral assays they were able to successfully demonstrate antidepressant-like effects with a competitive antagonist, a noncompetitive antagonist, and a partial agonist of the NMDA receptor.

Around the time the findings of the NIH lab were being published, evidence demonstrating notable stress-related effects on glutamatergic neurotransmission was mounting. Studies showing acute stress-related increases the extracellular glutamate levels, especially in hippocampus, amygdala and PFC and dramatic alterations in the membrane trafficking of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the prefrontal cortex were increasing interest in the potential role of glutamate in the pathogenesis and pathophysiology of mood disorders ( ). Meanwhile, in the chronic stress setting there was evidence of changes in the regulation of glutamate release in PFC following exposure to chronic stressors. In sum, the emerging series of preclinical studies provided increasing supportive evidence to suggest glutamate’s contribution to pathogenic pathways leading to depression and the potential to target the system in the development of novel treatments for mood disorders. This background paired with the recognition that altered function of cortical circuits, that are predominantly glutamatergic in nature, were critical to the pathogenesis and pathophysiology of mood disorders were specifically cited as the driving impetus ( ) for the seminal study by that first demonstrated the antidepressant effects of ketamine in a small controlled clinical trial.

Since the publication of the initial findings suggesting ketamine possessed rapid and robust antidepressant effects there has been a tremendous amount of reverse “bedside to bench” translation providing more information on its mechanisms of antidepressant action. Multiple new mechanisms of action have been proposed in addition to those hypothesized previously, and it is possible, in fact likely, that several mechanisms uniquely contribute to the overall antidepressant effect. At present, evidence of ketamine’s proximal effect as an NMDA receptor antagonist via binding to its phencyclidine site ( ; ) serving as the initial step in antidepressant process remains best supported by the current evidence. The antagonism of NMDA receptors was originally postulated to protect against the excitotoxic effects of elevated levels of extracellular glutamate levels and the associated downstream consequences. However, it was also noted that selective NMDA receptor antagonism can decrease the firing of the inhibitory GABAergic neurons, resulting in transiently increased levels of glutamate release, at times referred to as a glutamate surge. The increased levels of glutamate released into the synaptic space in turn engage other non-NMDA glutamate receptors such as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Activation of the AMPA receptor is believed to activate several intracellular signaling cascades and eventually facilitate the process of synaptogenesis ( ; ). Other mechanisms such as effects on opioid receptors ( ), immune function ( ; ), and monoaminergic pathways ( ), among others ( ), have also been reported, but have not been as extensively studied. Beyond the more proximal effects of ketamine’s pharmacology there is also great interest in understanding how the effects are transduced through changes in brain circuitry ( ; ). The range of possible critical mechanisms of antidepressant action and the unique properties of the various forms of ketamine should be considered in review of the efficacy data presented below.

The relation of molecular structure and pharmacology to function and response

When considering the data on efficacy presented below it is important to remember ketamine is a chiral molecule comprised of two enantiomers, S-ketamine (esketamine) and R-ketamine (arketamine). The racemic mixture was initially used for clinical purposes and continues to be the most common form used for anesthetic purposes in North America. However, the S-ketamine enantiomer is also commonly used in Europe for anesthesia based on reports suggesting improved tolerance ( ). R-ketamine is not currently approved for clinical use but remains under development for potential use in neuropsychiatric disorders. The specific properties of the individual enantiomers in relation to the clinical benefits and untoward effects associated with the treatment of mood disorders are currently an area of great interest.

Dose