Ketamine as a Rapid-Acting Antidepressant: Promising Clinical and Basic Research

Suicidal ideation and attempts are a common medical emergency, accounting for about 650,000 adult evaluations per year in emergency settings (1). Depressive disorders are a major driving force behind this, but first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), can take months to work, making them of limited use in acutely suicidal patients. Potentially safe and fast-acting interventions would be invaluable in acute situations until standard antidepressants have time to take effect.

Ketamine, best known as an N-methyl-d-aspartate receptor (NMDAR) antagonist commonly used as an anesthetic, has recently drawn attention for possibly filling the role. At lower doses it exhibits strong antidepressant effects in many patients, and it acts on the order of minutes. Despite these promising effects, its use as an antidepressant has been controversial, as ketamine is also a Schedule III controlled substance that is used recreationally for its dissociative and hallucinogenic effects. Furthermore, the full mechanism of action regarding its antidepressant effects has long remained unclear.

In the present article, we review research surrounding ketamine's potential as a fast-acting antidepressant from a “two-pronged” approach: first, summarizing established and new knowledge on its mechanism of action and second, reviewing clinical research addressing its potential to quickly reduce depression and suicidality.

Mechanism of Action

Ketamine is a chiral compound that operates broadly, having effects on mu, kappa, and delta opioid receptors, as well as dopamine D₂ receptors and the reuptake of serotonin, dopamine, and norepinephrine (2). However, ketamine is best known as an antagonist of the NMDAR, a glutamatergic receptor that allows an influx of cations across neuronal cell membranes (2).

It is ketamine's antagonism of NMDAR that is thought to account for its analgesic and anesthetic effects, with (S)-ketamine binding with greater affinity to NMDAR (2, 3). Until recently, its NMDAR antagonism was thought to account for most of its antidepressant effects as well (4). This hypothesis places ketamine in sharp contrast with traditional antidepressants, whose mechanisms of action generally involve monoamine neurotransmitters (e.g., serotonin or norepinephrine). Despite such putative explanations, limitations of the NMDAR antagonism hypothesis (such as observed antidepressant effects of agents that act as NMDAR agonists, as well as known NMDAR antagonists that lack antidepressant effects) (4) have led to calls for alternative explanations of its mechanism (5, 6).

A recent study published in Nature has addressed this call, concluding that the most relevant mechanism of action for ketamine's antidepressant effects is actually due to one of ketamine's metabolites: [2R,6R]-hydroxynorketamine (HNK), a metabolite formed from (R)-ketamine (7). The investigators demonstrated in mice that [2R,6R]-HNK has significantly stronger antidepressant effects than ketamine itself, as well as its enantiomer [2S,6S]-HNK, which only produced effects at much higher doses. This finding was surprising, as (R,S)-norketamine was thought to be the only active metabolite of ketamine (3, 8, 9).

The investigators also showed via mice models that HNK acts not at the NMDA receptors, like ketamine, but rather via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), in a sustained, excitatory mechanism (7). This non-NMDA-type ionotropic transmembrane glutamate receptor is thought to play a role in plasticity and synaptic transmission, which are key in sustained anti-depressive effects (7, 10, 11). Blockage of this pathway through administration of AMPAR antagonist NBQX showed a loss of antidepressant effects in mice brains upon dosage of ketamine or HNK.

Additionally, it was observed that [2R,6R]-HNK appeared to lack many of the undesirable side effects of ketamine; specifically, mice did not self-administer [2R,6R]-HNK, suggesting lower potential for abuse or addiction (7). Furthermore, [2R,6R]-HNK showed fewer signs of dissociative effects, such as changes in motor coordination and sensory processing (7). This suggests that [2R,6R]-HNK may operate independently of mechanisms that are otherwise active with ketamine. Despite the promise of this recent study, replication in human cells is missing and required for true disease-specific conclusions.

Clinical Research

While standard antidepressants like SSRIs and SNRIs are effective in reducing depression and suicidal ideation, they take weeks to become effective, leaving patients vulnerable to suicidal ideation or behavior. In fact, the first week after standard antidepressant initiation may be a time of increased suicidality, underscoring the importance of a medication that decreases self-harming behaviors in early stages (12). Ketamine has increasingly attracted interest for potentially filling this role since 2000, when the first randomized controlled trial (RCT) of ketamine as an antidepressant was found to produce significant and rapid improvements of mood lasting 1–2 weeks post-infusion (13).

In a recent meta-analysis of seven RCTs involving 183 patients with major depressive episodes, the effects of ketamine were assessed with respect to clinical response and remission. Clinical remission was defined as a Hamilton Depression Rating Scale (HAM-D) score <7 or a Montgomery-Åsberg Depression Rating Scale (MADRS) score <10. Clinical response was defined as a ≥50% decrease in these scores post-treatment. For clinical remission, pooled odds ratio (OR) and number needed to treat (NNT) were calculated after 24 hours (OR=7.06, 95% confidence interval [CI]=2.50–19.95; NNT=5), 3 days (OR=3.86, 95% CI=1.53–9.74; NNT=6), and 7 days (OR=4.00, 95% CI=1.52–10.51; NNT=6). For clinical response, OR and NNT were also calculated at 24 hours (OR=9.10, 95% CI=4.28–19.34; NNT=3), 3 days (OR=6.77, 95% CI=3.40–13.50; NNT=3), and 7 days (OR=4.87, 95% CI=2.24–10.55; NNT=4) (14). Significantly, adverse events were limited to two patients, one with refractory hypertension and another with hypotension and bradycardia. Other, similar meta-analyses have also concluded that ketamine is fast-acting, effective, and generally well-tolerated (6, 15).

While the literature on ketamine's potential as an antidepressant is growing, there is now research examining ketamine's anti-suicidal properties specifically. One of the first group of investigators to assess ketamine's anti-suicidal properties found that in 33 subjects with major depressive disorder, intravenous ketamine reduced suicidal ideation in all four measures used (HAM-D, MADRS, the Scale for Suicide Ideation, and the Beck Depression Inventory). These reductions were significant (p<0.001 for all measures) up to 230 minutes post-infusion, the latest measurement taken, suggesting significant promise for reducing suicidal ideation acutely (16). Limitations of this work, however, include small sample size and open-label administration, accounting for possible bias. Additionally, the 230-minute time point may only be capturing the expected highs and lows of suicidal thoughts.

In an RCT comparing intravenous ketamine to midazolam placebo in patients with treatment-resistant major depression, suicidality assessment in patients 24 hours post-infusion showed that ketamine significantly reduced suicidal ideation in comparison to midazolam (17). These changes, however, were mediated by reduction in non-suicidal depressive symptoms, raising the question of whether ketamine's effect on reducing suicidal ideation is merely a byproduct of its antidepressant actions.

Ketamine's antidepressant effects, however, are relatively short-lived, with one infusion generally lasting around 1 week (18). Consequently, research has begun to examine the safety and efficacy of repeated infusions. In one study, Murrough et al. (19) gave 24 patients with treatment-resistant depression intravenous ketamine thrice weekly over a 12-day period, up to six times. Responders (defined as a ≥50% improvement in MADRS) deviated from non-responders by 4 hours post-first treatment (mean MADRS score: 10.35 compared with 19.0, p=0.013), and the deviation increased by 24 hours (8.35 compared with 18.8, p=0.002). Overall, 70.8% of patients responded to treatment. Of patients who responded, the median time to relapse was 18 days after last infusion (defined as <50% improvement in MADRS compared to baseline, for two consecutive visits). Four patients remained relapse-free until 83 days later, the last day assessed (19). Thus, there is initial evidence to suggest that repeated infusions may be a safe and effective way to extend the protective effects of ketamine in acute settings.

Conclusions

In 2014, Thomas Insel, former Director of the National Institute of Mental Health, declared that ketamine might be “the most important breakthrough in antidepressant treatment in decades” (20). Since then, research has largely substantiated this enthusiasm. Most meta-analyses and reviews published within the last 2 years have found ketamine to be fast-acting, effective, and well-tolerated, although the duration of its effects is somewhat limiting (14, 18). Furthermore, recent research from basic science has finally shed light on what is likely the primary mechanism of action of ketamine's antidepressant properties—its metabolism to [2R,6R]-HNK, with subsequent activation of AMPA receptors (7).

Limitations

There remains much to learn before ketamine can be approved for treatment of suicidal ideation. Ketamine's known effects include both stimulant and opiate-like properties, both of which are known to transiently improve mood but are limited by the possibility of misuse and physiological dependence (5, 21). Furthermore, while adverse events in clinical trials have been rare, the long-term effects of repeated administration are relatively unknown (4).

Perhaps the significance of ketamine research to date has been the discovery of its metabolite, HNK, which may provide a mechanism for the treatment of depressive-like behaviors in mice. This could prove to anchor our quest for safe, efficacious, and rapidly acting therapies for the treatment of human depression and suicidal ideation.

Key Points/Clinical Pearls