Esketamine nasal spray (Spravato) is the first novel antidepressant approved (2019) in over three decades. Esketamine is indicated for treatment-resistant depression (TRD) in conjunction with an oral antidepressant. It was developed for commercial purposes because the patent for ketamine was long expired.
As the name would suggest, esketamine is the S-enantiomer of ketamine, which has been increasingly used off-label for TRD. Like racemic ketamine, esketamine is a Schedule III controlled substance.
It is unknown whether the antidepressant action of the S-enantiomer is superior, inferior, or equal to racemic ketamine. The opposite enantiomer, R-ketamine (arketamine) is also under investigation. S-ketamine is more responsible for the anesthetic effect, while R-ketamine is more responsible for hallucinations because it is 3–4 times more potent at blocking NMDA receptors than R-ketamine. S-ketamine appears to be less effective than R-ketamine at reducing depressive symptoms (Stahl, 2015) but may be less likely to cause psychoactive side effects.
The induction phase for Spravato is twice weekly over 4 weeks, then weekly x 4, then every 1–2 weeks for maintenance treatment. It costs about $625 per dose.
Spravato is less convenient than would be expected for a nasal spray. It must be given in the presence of a health care provider and should never be dispensed to the patient for home use. The patient must be observed for 2 hours and cannot drive for the rest of the day. Due to the risk of vomiting, the patient must fast for 2 hours (no fluid for 30 minutes) prior to treatment.
Most of the therapeutic effect of esketamine is apparent by 24 hours after the first dose. Up to 75% of patients experience dissociation with Spravato. None of the clinical trials were controlled for the dramatic “high” esketamine produces. It was well-tolerated, with only 5% of subjects dropping out within one year due to side effects.
Ketamine (Ketalar) is a dissociative anesthetic that has shown rapid efficacy in relieving refractory depression following intravenous infusion. It is not FDA-approved for this indication but is increasingly utilized as an alternative to electroconvulsive therapy (ECT).
Ketamine’s rapid antidepressant effect has been demonstrated by over 20 controlled trials. The effects of ketamine on depression are apparent as early as 40 minutes after infusion and are maintained for at least 2–3 days. Within two hours of ketamine treatment, patients are generally lucid and not sedated. By four hours, there appears to be continued improvement in positive thinking and hopefulness. By one week after a single infusion, depressive symptoms are likely to recur to some extent.
Side effects of ketamine include dissociation, visual hallucinations, sialorrhea (hypersalivation), nausea, vertigo, tachycardia, and elevated blood pressure. Serious risks include increased intracranial and intraocular pressure. Unlike other general anesthetics, ketamine does not suppress respiratory drive, which makes it great for anesthesia in third world countries. However, there is a possibility of laryngospasm [ luh RING go spaz um ], sudden involuntary contraction of vocal cords that can be fatal via suffocation. Catastrophic outcomes are rare when ketamine is used at subanesthetic antidepressant doses, but the patient needs to be monitored with emergency services available.
Ketamine has a black box warning of a 12% risk of emergence reactions (as in emerging from general anesthesia) varying in severity from pleasant dream-like states to hallucinations, or delirium. This may manifest as confusion, excitement, or irrational behavior. The duration of an emergence reaction is usually a few hours, with recurrences up to 24 hours post-op in some cases, but with no residual psychological effects.
The presumed antidepressant mechanism of ketamine is NMDA receptor antagonism, which reduces the activity of glutamate, the brain’s most important excitatory neurotransmitter. The mechanism appears to somehow involve the endogenous opioid system (endorphins). Ketamine is not an opioid, but when naltrexone (opioid antagonist) was administered prior to a ketamine infusion, ketamine was ineffective for depression (Williams NR et al, 2018). Naltrexone does not block the dissociative effect of ketamine. Benzodiazepines and Z-drugs (zolpidem, etc) can attenuate the antidepressant effect of ketamine, so they should be washed out prior to treatment.
Originally synthesized from phencyclidine (PCP, “angel dust”), ketamine is a Schedule III controlled substance with potential for abuse and psychological dependence. Ketamine has a half-life of 10–15 minutes, which is shorter than other dissociatives such as PCP and dextromethorphan. The total dissociative experience should last no longer than 1–2 hours.
Recreational users of “special K” can snort, inject, or take it orally. The desired recreational effects include euphoria, derealization, visual hallucinations, and increasing awareness of sound and color. A bad experience from too much ketamine is referred to as falling into a “K-hole”, where the user feels trapped in a frozen state, as if stuck in a hole peering out, detached from their physical presence. While stuck in a “K-hole”, the user can, for instance, think about moving their arm and then see an arm moving in front of them, but the association between the thought and the movement does not register.
Risks with long-term maintenance treatment of depression with ketamine are unknown. Studies in mice suggest the potential for irreversible cognitive decline with chronic use (Ding et al, 2016).
Dosing: For treatment-resistant depression, the optimal ketamine protocol has not been clearly established. The most common frequency is twice weekly infusions for up to 4 weeks using a relatively low dose of 0.5 mg/kg administered over 40 minutes. Compare this to the anesthetic dose of 1–4.5 mg/kg—also the IV/IM dose used for agitation in the ambulance or emergency department.