Ketamine and Esketamine in Depression
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Direct answer
Ketamine, a subanaesthetic dose given intravenously at 0.5 mg per kilogram over about 40 minutes, produces an antidepressant effect within hours to days in a proportion of patients with treatment-resistant depression, including those with active suicidal ideation — the fastest onset in psychopharmacology, acting through NMDA receptor antagonism that triggers AMPA-receptor-mediated synaptogenesis via brain-derived neurotrophic factor. Esketamine, the S-enantiomer delivered as an intranasal spray (56 mg or 84 mg per session), is approved for treatment-resistant depression and, in some jurisdictions, major depression with acute suicidal ideation — given twice weekly for four weeks, then weekly, under supervision because of dissociation, sedation and blood-pressure rise. In the United States a risk-evaluation programme requires administration in a certified setting with two-hour post-dose monitoring and no self-administration; Indian approval, first granted in 2020, has commonly been positioned as monotherapy for resistant depression, with supervision rules equally strict.
What you must remember
- Mechanism to quote: non-competitive NMDA receptor antagonism, with the downstream signal running through AMPA receptor activation, BDNF release and rapid synaptogenesis in prefrontal circuits — a glutamate story, not a monoamine one, which is why onset is hours rather than weeks.
- IV racemic ketamine: 0.5 mg/kg infused over about 40 minutes; antidepressant response often within 24 hours; effect lasts days to about a week, so repeated dosing is required; best evidence in treatment-resistant depression and for rapid reduction of suicidal ideation.
- Intranasal esketamine dosing ladder: 56 mg or 84 mg per session, twice weekly for weeks 1-4, weekly for weeks 5-8, then weekly or every two weeks for maintenance — one of the few dosing schedules worth memorising verbatim.
- Supervised administration: because of dissociation, sedation and transient hypertension, doses are given in clinic — about two hours of observation, no driving that day, blood pressure checked before and after; home self-administration is prohibited.
- Adverse effects: dissociation and perceptual disturbance during and shortly after dosing, elevated blood pressure (avoid in aneurysmal vascular disease and uncontrolled hypertension), abuse and dependence potential, and with chronic recreational use ulcerative cystitis (ketamine bladder).
- Evidence limits: maintenance benefit depends on continued dosing, relapse follows interruption, and data in adolescents and pregnancy are limited.
- Indian access fact: the regulator approved esketamine nasal spray in 2020, with India reportedly the first country to approve it as monotherapy for resistant depression, per manufacturer announcements — a positioning worth hedging but quotable; IV ketamine remains off-label, cheap and widely used in teaching hospitals.
A treatment-resistant patient's first six weeks
A 42-year-old man with three failed antidepressant trials and current suicidal thinking is referred to a tertiary centre. The team's first discussion is procedural: clinic dosing, blood pressure before and after, two hours of observation, transport arranged because driving is barred that day. His first 84 mg intranasal dose produces twenty minutes of floating dissociation, "strange but not unpleasant"; blood pressure rises 15 mmHg and settles. Over the induction phase — twice weekly for four weeks — his depression rating scores fall substantially by week two, and the suicidal ideation that made him a referral softens within days, the effect that justifies the whole programme.
Weeks five to eight shift to weekly dosing, and his oral antidepressant continues, since most trial evidence supports combination with an oral agent in many jurisdictions. Maintenance follows: weekly or fortnightly dosing, blood pressure surveillance, mood monitoring, and a relapse plan, because stopping esketamine typically means the benefit recedes within weeks.
Where students slip
The mechanism is the most missed mark: ketamine is an NMDA glutamate receptor antagonist, and candidates who answer "dopamine reuptake inhibition" lose the psychiatry question — the follow-through via AMPA and BDNF completes the answer. The second slip is imagining a take-home spray: supervision, dissociation monitoring and the two-hour observation are the safety spine, and stems test exactly that. The third is indication discipline — ketamine is not first-line for new-onset depression; it enters after multiple failures or where suicide risk demands speed, with ECT still the comparator and often the stronger choice in psychosis or food refusal. Know the contraindication pair — uncontrolled hypertension and aneurysmal vascular disease — and the chronic-abuse pair — dependence and ketamine bladder. Indian framing: cost confines esketamine to metropolitan centres, IV ketamine off-label fills the gap in teaching hospitals, and the viva-ready line is that India approved esketamine as monotherapy in 2020 per the manufacturer's announcement — a fact to state with "commonly reported" rather than certainty.
Frequently asked questions
What is the mechanism of ketamine's antidepressant effect?
NMDA receptor antagonism leading to AMPA-receptor activation, BDNF release and rapid synaptogenesis — a glutamatergic pathway producing effects within hours.
What is the standard intravenous antidepressant ketamine dose?
Racemic ketamine 0.5 mg per kilogram infused over about 40 minutes, repeated in series, with benefit assessed over the following days.
How is intranasal esketamine scheduled?
56 mg or 84 mg per session — twice weekly for four weeks, weekly for the next four, then weekly or fortnightly maintenance, always clinic-administered.
Why must esketamine be given under supervision?
Dissociation, sedation and transient blood-pressure elevation occur after each dose, so patients are observed for about two hours and must not drive that day; home self-administration is barred.
Can ketamine or esketamine be used in pregnancy?
They are generally avoided where alternatives exist, since reproductive-safety data are limited; ECT remains the rapid-acting treatment with the best established safety in pregnancy.