A Word to the Wise about Ketamine

Major depressive disorder (MDD), also known simply as depression, and its impact on functioning and well-being has been compared to that of other chronic medical conditions such as diabetes. The World Health Organization estimates depression as the fourth highest burden of disease in the world1 .

Sri 1

Figure 1: Proposed neurobiological model of depression2

Prolonged stress and depression alter prefrontal glutamate release and reduce glutamate uptake, leading to increased extracellular glutamate and excitotoxicity3. High levels of extracellular glutamate precipitates neuronal atrophy through dendritic retraction4, reduced dendritic arborization5, and reduced synaptic strength. An example of the effect of prolonged stress on dendritic arborization and length in rats is shown on the right (Fig. 1).

Research on antidepressants has achieved little success in developing fundamentally novel antidepressant mechanisms, leaving psychiatrists with relatively few pharmacologic options. Several antidepressants that are currently in use are mainly targeting the monoaminergic system where substantial numbers of patients are failing to achieve a sustained remission6. Moreover, conventional antidepressants are only beneficial when prescribed over a long- term period. It is clear that we are in urgent need to find a rapidly acting antidepressant with robust efficacy in patients who are resistant to traditional antidepressants.

Sri 2Ketamine is a drug used illicitly as a hallucinogen and was first tested in humans in 1964. It was approved 1970 in the USA as a surgical anaesthesia that was used in Vietnam War due to its safety7. Ketamine can be a prototype for the new generation of antidepressants by showing good efficacy in patients who are refractory to the existing treatments. Low dosages of ketamine reduce depression symptoms within 4 hours of intravenous administration in severely treatment-resistant depressed patients8.

Ketamine exhibits promising antidepressant effects even in patients with bipolar disorder and patients with severe symptoms that did not respond to ECT9. A critical obstacle to the broader study and implementation of ketamine treatment for depression is the lack of clarity as to how to sustain its antidepressant effects. Pilot studies suggest that ketamine may be sustained by repeated intermittent administration with persistence of the antidepressant effects for longer periods in some patients10.

Briefly, ketamine works by enhancing synaptic plasticity (mechanism through which neural circuits regulate their excitability and connectivity) through regulating AMPA and NMDA receptors.

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Figure 2: Prefrontal synaptic connectivity during normal mood, depression, and after remission (Abbreviations: ⦿, activate; ∅, block; , decrease; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; GABA, γ-aminobutyric acid; mTORC1, mammalian target of rapamycin complex 1.)

There have been some clinical trials where ketamine shows acute efficacy 11 in treating TRD (treatment resistant depression) , bipolar depression12 and major depressive disorder with suicidal ideation13, but the number of subjects in these trials ranges from 20 to 57 patients. Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System (FAERS) revealed that patients who received ketamine had a significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain14.

It is encouraging that FAERS makes a case for study of ketamine as a psychiatric drug but there are financial and ethical obstacles for a larger scale clinical trial to validate further the safety and efficacy of Ketamine. To date, Ketamine is not only the most extensively studied NMDA antagonist, with 12 published randomized clinical trials, but is the only NMDA antagonist to date consistently demonstrating antidepressant efficacy across multiple trials15

While Ketamine efficacy and safety are under caution, forthcoming ketamine research should continue to examine three major concerns: 1) elucidating ketamine’s mechanism of action; 2) understanding the administration profile necessary to provide a sustained therapeutic benefit; and 3) examining ketamine’s safety profile, particularly with repeated and likely low-dose administration. Knowing Ketamine can be a drug of abuse, it is difficult to argue its future as a potential drug to treat depression.

Blog written by Srini Natarajan


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