Ketamine and Esketamine in Depression – A Synopsis on Efficacy and Mechanism of Action

THE ADVENT OF KETAMINE

Ketamine is a useful antidepressant that has been shown to act rapidly and effectively even in treatment-resistant depression (TRD). This is particularly relevant in individuals with bipolar disorder (BD), post-traumatic stress disorder (PTSD) and acute suicidal ideation (SI). However, ketamine is limited by its adverse side effects, abuse potential and sensory dissociation.

Ketamine’s antidepressant mode of action remains unclear but it has been shown to have a high affinity for the NMDA glutamate receptor and is considered to be a NMDA antagonist.

This receptor is important for long-term potentiation—strengthening of synaptic connections between neurons—and is critical in the formation of associative memories

New research published in Nature in May 2016 suggests that ketamine may not purely mediate its antidepressant activity through NMDA receptor inhibition as previously thought. [1]

WHO AND WHAT WAS STUDIED?

Ketamine is an arylcyclohexylamine which is related to phencyclidine. In a mouse model of depression, Zanos and colleagues compared the effects of two structural forms of ketamine, (S)- and (R)-ketamine, against a known NMDA receptor antagonist called MK-801.

The researchers predicted greater efficiency of (S)-ketamine as it is a 3-4 fold more potent inhibitor of the NMDA receptor. Ketamine has a short half-life of 1-2 hours. Its antidepressant effect, however, peaks about 3 days after administration.

Esketamine (S-ketamine), the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor than the R-enantiomer and has been developed as an intranasal formulation for therapy in treatment-resistant depression (TRD).

Ketamine has previously been shown to have different potencies in males and females, and so this sex-dependent difference was investigated through the analysis of ketamine metabolite profiles. Metabolites that were different in males and females were then analysed for possible antidepressant effects.

WHAT WERE THE FINDINGS?

By comparing (S)- and (R)-ketamine in a mouse model of depression, the researchers found that while the (S)-ketamine is more potent at inhibiting NMDA receptors, it was less effective in reducing depression-like behaviours than (R)-ketamine. In contrast, the NMDA receptor antagonist MK-801 was surprisingly shown to have no antidepressant-like effects.

Analysis of ketamine metabolites showed that a compound called hydroxynorketamine (HNK) was three times higher in female mice. This finding suggests that the sex-dependent difference in antidepressant potencies was possibly due to the elevated levels of HNK. This was then proven by blocking the metabolism of ketamine to HNK, which then prevented the antidepressant-like effect of ketamine.

Further analysis of HNK showed it to have specific antidepressant-like effects similar to ketamine; however, unlike ketamine, it did not inhibit NMDA receptors.

Instead, HNK was shown to activate another glutamate receptor called the AMPA receptor. By experimentally blocking the AMPA receptor, the researchers confirmed that they could prevent the antidepressant-like effects of HNK.

WHAT DOES THE STUDY REALLY TELL US?

In a mouse model of depression, it was a ketamine metabolite called HNK that was shown to have potent antidepressant activity.

Crucially, it was shown that HNK neither binds to nor inhibits the NMDA glutamate receptor and instead activates another neural receptor called AMPA.

This data, therefore, suggests an NMDA receptor inhibition-independent mechanism for the antidepressant effects of ketamine.

This ketamine metabolite does not have any ketamine-related side effects and together is evidence of a favourable new approach to the development of rapid and effective antidepressants.

BIG PICTURE

Currently prescribed antidepressant treatments only alleviate depressive symptoms in about half of all patients.

Ketamine is an attractive therapeutic with multiple clinical trials suggesting that even a single sub-anaesthetic dose of intravenous ketamine results in a 50-75% response rate in TRD.

In a recent meta-analysis of seven double-blind, randomised, placebo-controlled trials, ketamine was shown to significantly reduce depression severity from days 1-7 in patients with MDD and days 1-4 in patients with BD. Symptom relief has been reported as early as 2 hours and lasting up to 2 weeks in these patients. [2]

In another systematic review of the literature, a single dose of ketamine decreased both depression and SI in patients with MDD. [3]

Given that SI is a leading cause of death among those clinically diagnosed with MDD, the anti-suicidal properties of ketamine underscores the need for further investigation into its mode of action, which may help further the development of more specific treatments.

WHAT SHOULD I KNOW?

There is a growing body of research that supports the use of ketamine as a rapid-acting antidepressant for the treatment of TRD.

Although ketamine is a potent inhibitor of the NMDA receptor, it has been shown that a metabolite of ketamine also has specific antidepressant activity.

Although the biological mechanism is unclear, this ketamine metabolite does not have the same cognitive or motor side effects as ketamine.

IMPORTANT POINTS ABOUT KETAMINE

1. The antidepressant effects of Ketamine have been attributed to its effects as an NMDA blocker, but additional mechanisms linked to glutamate receptors (e.g. AMPA) may play a role as shown in the above study.
2. As an NMDAR antagonist, ketamine blocks postsynaptic NMDA receptors located on glutamatergic neurons in the cortex. It deactivates the eukaryotic Elongation Factor-2 (eEF2) kinase, which subsequently releases the inhibition of BDNF translation, resulting in increased BDNF levels. [Aleksandrova et al, 2017]
3. In addition, ketamine is hypothesised to block NMDA receptors on GABA interneurons, releasing the inhibition of glutamate release. This activates AMPA receptors on glutamatergic cells and subsequently increases BDNF and glutamate in the cortex increasing synaptic efficacy. This may explain the rapid antidepressant effect of ketamine. [Aleksandrova et al, 2017]
4. Evidence suggests that ketamine is a promising rapid-acting anti-depressant, but the response is short-lived. [4]
5. It is a partial agonist at opiate mu-receptors which have pain-relieving properties and reverses tolerance to opioids.
6. Ketamine may interact with the sigma receptors decreasing central sensitization, wind-up phenomenon (development of ongoing, worsening or chronic pain), and pain memory.
7. Ketamine has additional cholinergic, aminergic, and opioid properties which appear to play both a positive and negative modulatory role in both sedation and analgesia.
8. The longest treatment follow up period was 5 weeks where 9/48 treatment-refractory depression patients in the Ketamine arm had sustained response at 5 weeks compared with 0/25 in the placebo (midazolam) arm after a single ketamine infusion. [5]
9. Ketamine has abuse potential, and hence the potential benefits of the drug need to be weighed up against the risk of dependence and neuropsychiatric side effects.

Important Points about Esketamine: 

1. In March 2019, the FDA approved esketamine nasal spray for the treatment of major depression. A 2018 RCT showed that intranasal esketamine administered at doses of 28, 56, and 84 mg appeared to be efficacious in treating TRD [6]. Improvement in depressive symptoms despite reduced dosing frequency, persisted for up to 2 months after cessation of esketamine dosing. The evidence in support of esketamine’s effectiveness derives primarily from two positive phase 3 trials.
2. The most common side effects experienced by patients treated with Esketamine (Spravato) in the clinical trials were disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.

According to the FDA:

Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment. Because of safey concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient. [7]

Read the article on Psychopharmacology, Side Effects and Clinical Application of Esketamine. 

Esketamine thus appears to be a helpful option in treatment-resistant depression however, the rapid action needs to be weighed up against the side effects and abuse potential in managing TRD.

So, where are we? Intranasal esketamine represents an easier method of administration than intravenous administration of ketamine. Do we have clear evidence of efficacy? Maybe? How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear. If patients lose response, should we increase the frequency of administration? This could be problematic. Can coming off the drug be problematic? Data suggest that it could be an issue. Taken together, there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice. Only time will tell how useful it will be. Still, the agent could be helpful to many patients with refractory depression, and efforts to develop rapidly acting agents for severely depressed patients need to be applauded. [Schatzberg, 2019]

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