Esketamine

Esketamine is (S)-ketamine, one of the two mirror-image forms that make up racemic ketamine. It has roughly four times the affinity for the NMDA receptor that the R-form has, which makes it about twice as potent as the racemate as an anesthetic and analgesic and allows roughly half the dose for the same effect ^[11].

Its importance is as an antidepressant. A dose-response study established that intranasal esketamine added to an oral antidepressant reduced depressive symptoms in treatment-resistant depression ^[1], and the phase 3 programme followed: a flexible-dose study in adults under 65 met its endpoint ^[2], a fixed-dose study produced a smaller and less consistent separation ^[3], and a study in patients over 65 did not meet its primary endpoint ^[4]. A relapse-prevention trial found that patients who had responded and then continued esketamine relapsed substantially later than those switched to placebo, which is the strongest single result in the programme ^[5]. Separate trials addressed acute suicidality and showed rapid symptom reduction without a demonstrated effect on suicidal ideation itself as a distinct outcome ^[6][7]. A later head-to-head trial against quetiapine, both added to an oral antidepressant, favoured esketamine on remission at week 8 and on remission sustained to week 32 ^[8].

It was approved in the United States in 2019 and is dispensed only through a restricted programme. The reason is not toxicity in the usual sense but the acute effects: sedation, dissociation, dizziness and a transient rise in blood pressure that peaks around 40 minutes after dosing, which is why the two-hour observation exists ^[9].

The acute effects are the safety story, and they are predictable rather than idiosyncratic. Dissociation, sedation, dizziness, nausea and a transient rise in blood pressure that typically peaks around 40 minutes after dosing occur commonly enough that the drug is given only in a certified setting with a two-hour observation period and a driving prohibition for the rest of the day ^[9]. Blood pressure is checked before dosing and again after; uncontrolled hypertension, aneurysmal vascular disease and a history of intracerebral haemorrhage are the situations where that rise stops being merely inconvenient.

Longer-term, the file is reassuring but shorter than the drug's use now is. Open-label follow-up has not shown the ulcerative cystitis that heavy recreational ketamine use causes, and has not shown cognitive decline; that reflects supervised intermittent dosing rather than any property of the enantiomer, and it is a smaller and shorter evidence base than the one behind established antidepressants ^[9]. It carries abuse potential and is a controlled substance. It is used with an oral antidepressant, not instead of one, and it is not a treatment anyone administers to themselves. This entry is educational and is not medical advice.

Ketamine was synthesized in 1962 and marketed as the racemate, an equal mixture of the S and R forms. The enantiomers were separated and studied from the 1980s onward, mostly by anesthesiologists interested in whether the S-form could deliver the same anesthesia with less of the emergence confusion that gave ketamine its reputation. Esketamine was marketed as an anesthetic in parts of Europe under the name Ketanest well before anyone proposed it as an antidepressant ^[11].

The antidepressant programme grew out of the finding, around the turn of the century, that sub-anesthetic racemic ketamine relieved severe depression within hours. Because the racemate was a generic anesthetic with no commercial route to approval, development went to the single enantiomer delivered as a nasal spray. A dose-finding trial reported in 2018 ^[1], the phase 3 studies read out through 2019 ^[2][3][4][5], and the nasal spray was approved in the United States in 2019 for treatment-resistant depression, with the suicidality indication following. Whether the chosen enantiomer was the right one has been questioned throughout, since animal data had suggested advantages for the R-form ^[14]. A head-to-head trial against quetiapine in 2023 gave the approved product its first active comparison ^[8].

Esketamine occupies an unusual position: clinicians who are sceptical of the ketamine clinic industry generally regard the approved nasal spray as the legitimate version of the same idea, because it is the one that went through phase 3 and is given under observation. That respect is not universal. The programme is often criticised for the pattern of its results, since one of three short-term phase 3 trials clearly met its endpoint, the fixed-dose study separated weakly and the trial in older adults did not separate at all, and for comparing against a newly started oral antidepressant rather than against racemic ketamine ^[10].

Among patients the recurring complaints are practical rather than pharmacological: the cost, the requirement to attend a certified site twice weekly at the start, the two hours of observation and the inability to drive afterwards. The recurring surprise is that the dissociation is expected and usually settles within the observation window rather than being a sign something has gone wrong. The comparison people most often want, esketamine against generic intravenous racemic ketamine, has still not been run at the scale that would settle it ^[10].