Ketamine as a Rapid Onset Antidepressant

The discovery of the ketamine as a rapid onset antidepressant and further exploration into processes involved could significantly impact treatment for patients as well as public health worldwide.

Ketamine and The Next Generation of Antidepressants with a Rapid Onset of Action

The article below is part of Frshmind’s “Psychedelic Science Snapshot Series” where Frshminds reviews the latest in psychedelic research.

Original authors: Rodrigo Machado-Vieira, Giácomo Salvadore, Nancy DiazGranados, and Carlos A Zarate Jr
Summarized by: Emily Fewster

Glutamate and Major Depressive Disorder

Major depressive disorder (MDD) is a debilitating disorder that affects more than 264 million people, and is even considered the leading cause of disability worldwide (World Health Organization, 2020). Despite its prevalence, issues concerning the effectiveness of conventional treatments have arisen. For example, in the largest open-label study evaluating conventional therapies for MDD, less than one-third of patients receiving standard antidepressants experienced remission after four months of treatment (Trivedi et al., 2006). As well as the issue of efficacy, the delayed onset of therapeutic effects allows for high rates of mortality and morbidity to be present during this latency period, which is associated with a worse long-term prognosis (Machado-Vieira, Salvadore, Luckenbaugh, Manji, & Zarate, 2008). There’s a clear need for alternative treatments for MDD, specifically a drug like ketamine, a rapid onset antidepressant.

Glutamate is an important and powerful excitatory neurotransmitter in the human brain, meaning it increases the likelihood of neurons firing. It activates diverse groups of receptors, one of these groups, called ionotropic glutamate receptors, include NMDA receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and kainate (KA) receptors. When activated, these ion channels open and allow ionic an influx to the cell, which then activates intracellular signaling cascades. The AMPA receptors mediate this rapid excitation at most of the synapses, are responsible for the early synaptic response to glutamate, and at mature synapses, AMPA receptors are frequently co-expressed with NMDA receptors where together they contribute to synaptic plasticity processes involved in learning, memory, and neuroprotection (Malinow & Malenka, 2002).

Alterations in the glutamatergic system have been observed in the central nervous system (CNS, CSF, and brain tissue) as well as the periphery in subjects with MDD (Sanacora et al., 2008). In fact, many studies support a critical role for the glutamatergic system in the pathophysiology of MDD, as it is believed to be a key target in mood regulation (Maeng & Zarate, 2007; Sanacora et al., 2008; Zarate, Quiroz, Payne, & Manji, 2002). Similarly, post-mortem and genetic studies support the role of glutamatergic system dysfunction in MDD, showing increased levels of glutamate and decreased levels of AMPA receptor subunits have been found in the prefrontal cortex of individuals with MDD (Beneyto & Meador-Woodruff, 2006; Hashimoto, Sawa, & Iyo, 2007; Scarr, Pavey, Sundram, MacKinnon, & Dean, 2003). Further, reduced NMDA receptor binding and subunit expression have also been found in the temporal and two frontal brain regions of subjects with MDD (Choudary et al., 2005; Nudmamud-Thanoi & Reynolds, 2004). Early reports also describe the action of antidepressants on glutamatergic receptors and the antidepressant-like effects of NMDA antagonists in animal models (Manji et al., 2003). However, for unclear reasons, exploration of glutamate in mood disorders remained stagnant until recently.

How Does Ketamine Work?

Ketamine (dl2-(o-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride) is an NMDA antagonist (Harrison & Simmonds, 1985) and a derivative of PCP. Its primary method of action is blocking the NMDA receptor at the PCP site within the ionotropic channel. Simultaneously, it induces a substantial presynaptic release of glutamate by increasing the firing rate of glutamatergic neurons. (Moghaddam, Adams, Verma, & Daly, 1997). This increase in glutamate release then favors AMPA receptors over NMDA receptors because the latter are blocked by ketamine, causing a greater throughput through the former and AMPA mediated synapse strengthening. Interestingly, chronic treatment with standard antidepressants has also been shown to enhance AMPA receptor surface levels (Du et al., 2004; Du et al., 2007). Taken together, these findings suggest that the strengthening of synapses mediated by AMPA may be involved in the early antidepressant effects seen with ketamine, while intracellular signaling cascades that activate AMPA receptors from monoaminergic regulation modulate the long-term antidepressant effects of standard antidepressants.

Treating Patients with Ketamine

Due to previously mentioned discoveries, ketamine has been explored in humans for the treatment of MDD. One double-blind placebo-controlled study found that a single intravenous subanesthetic dose of ketamine induced a fast (within two hours) and relatively sustained antidepressant effect, with no serious adverse effects (Zarate et al., 2006). More than 70% of patients met the criteria for response 24 hours after infusion, and 35% showed a sustained response after one week. To emphasize the relevance of these results, the response rates obtained with ketamine after 24 hours (71%) are comparable to those reported after six to eight weeks of treatment with standard monoaminergic-based antidepressants (65%) (Entsuah, Huang, & Thase, 2001; Thase et al., 2005).

As well, there has been increased interest in the joint study of MDD and risk of alcoholism, as the glutamate system appears to play a major role in both conditions. Phelps et al. (2008) recently assessed antidepressant response in patients with treatment-resistant MDD, and found that subjects with both MDD and a family history of alcohol dependence showed significantly greater improvement in depression rating scales scores after ketamine infusion compared to those who had no family history of alcohol dependence. The precise reasons for these findings are essentially unknown, however emerging data suggests that genetic alterations in NMDA receptor subunits may be associated with increased vulnerability to alcohol dependence due to alterations of the sensitivity of the NMDA complex. Schumann et al. (2008) found evidence of an association between NR2A and alcohol dependence, and alcohol has also been shown to regulate NR2A expression in brain regions associated with addiction-related neurobiological processes (Boyce-Rustav & Holmes, 2006). Since ketamine acts as a partial NR2A antagonist, it is possible that this difference in NR2A sensitivity may explain the greater response to ketamine’s antidepressant effects.

Potential Side Effects of Using Ketamine as a Rapid Onset Antidepressant

However, concerns over misuse and abuse is to be noted, as this is not a new phenomenon in psychiatry and has been seen before with agents such as benzodiazepines and stimulants. Despite ketamine’s safety profile and lack of physical dependence (Britt & McCance-Katz, 2005; Green et al., 1998), an increased tolerance to ketamine’s antidepressant effects might occur after repeated doses, as a recent case report noted that a second infusion of ketamine showed limited effect one month after an initial infusion (Liebrenz et al., 2009). Further, repeated exposure to ketamine increases the risk of psychosis, dissociative episodes, and severe emotional distress (Dillon, Copeland, & Jansen, 2003). It’s also expected that the sedative and psychotomimetic side effects of ketamine will probably continue to limit its clinical use in larger samples.

Yet, the fact remains that monoaminergic antidepressants take weeks to achieve their full effect, leaving patients receiving these medications particularly vulnerable. This, along with low rates of remission and frequent relapses are issues that need to be tackled with the next generation of antidepressants. Ketamine is shown to be a good proof of concept tool to develop biomarkers in order to further our understanding of the neuropsychological mechanisms of depression and what aspects are important in the development of future pharmacological treatments. It demonstrates a consistently reproducible antidepressant effect within a short period of time, showing that a similar agents that can induce rapid and sustained effects after repeated doses is possible. The discovery of the rapid antidepressant effects of ketamine and further exploration into processes involved could significantly impact treatment for patients as well as public health worldwide.

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