Drug: Ketamina y esketamina

What It Is

Ketamine is an anesthetic first approved in the 1970s that lifts mood quickly at doses well below the ones used for surgery. It acts on the NMDA glutamate receptor and produces dissociation. Its antidepressant effect arrives within hours, where a standard antidepressant takes weeks.

Two forms are used for depression. Esketamine is the S-enantiomer, one of the two mirror-image halves of the ketamine molecule, made into a nasal spray and FDA-approved for treatment-resistant depression. Racemic ketamine, the original 1-to-1 mixture of both halves, is given as an intravenous infusion off-label for the same purpose. Both are delivered in a supervised clinic.

What It Does

In the phase 3 trial behind the approval, patients with treatment-resistant depression switched to esketamine nasal spray plus a newly started oral antidepressant. By day 28 their depression scores fell 4.0 points further than the group given a placebo spray plus a new antidepressant, on the 0-to-60 MADRS scale. The control group got a real antidepressant, not a sugar pill, so the 4.0-point gap survives a harder test.

Intravenous racemic ketamine shows the same effect, and faster. A meta-analysis of randomized placebo-controlled trials found a single infusion raised the odds of remission roughly sevenfold at 24 hours, with a number needed to treat of about 5. It also produced a large drop in depression scores within a day.

A separate meta-analysis in treatment-resistant depression traced the timing. The effect was strong within 4 hours, peaked at 24 hours, and was still present, though smaller, at 7 days. Repeated infusions extended it.

In the relapse-prevention trial behind the approval, patients reached stable remission on esketamine and then kept taking it. They relapsed far less often than the group moved to a placebo spray: 26.7% versus 45.3%, a 51% lower risk of relapse.

The Research & Studies

Everything here is based on the research we have collected and checked, sorted into groups and ordered with the strongest evidence first. Click any claim to open the studies behind it.

Mood & stress

El aerosol nasal de esketamina más un nuevo antidepresivo oral alivió la depresión resistente al tratamiento 4.0 puntos más que el antidepresivo solo para el día 28Moderate

In plain terms

Añadir el aerosol nasal de esketamina a un antidepresivo recién iniciado alivió la depresión resistente al tratamiento más que el antidepresivo solo después de cuatro semanas.

In detail

El ensayo de fase 3 TRANSFORM-2 (Popova et al., Am J Psychiatry 2019) asignó aleatoriamente a 227 adultos con depresión resistente al tratamiento, definida como falta de respuesta a al menos dos antidepresivos en el episodio actual, a aerosol nasal de esketamina más un antidepresivo oral recién iniciado o a un antidepresivo recién iniciado más un aerosol nasal placebo. El criterio de valoración primario, el cambio en la puntuación MADRS desde el inicio hasta el día 28, favoreció a la esketamina en 4.0 puntos (IC del 95 %: -7.31 a -0.64). La disociación, las náuseas, el vértigo, la disgeusia y el mareo fueron más comunes con la esketamina y generalmente aparecieron poco después de la administración y se resolvieron en aproximadamente 1.5 horas.

The study · 1

Popova et al., efficacy and safety of flexibly dosed esketamine nasal spray in treatment-resistant depression · Am J Psychiatry 2019;176:428-438

Una única infusión intravenosa de ketamina elevó las probabilidades de remisión aproximadamente siete veces a las 24 horas en un metaanálisis de ensayos aleatorizadosModerate

In plain terms

Al combinar los ensayos controlados, una única dosis de ketamina intravenosa mejoró bruscamente la depresión en un día, mucho más rápido que un antidepresivo estándar.

In detail

McGirr et al. (Psychol Med 2015) combinaron siete ensayos controlados aleatorizados intravenosos y uno intranasal (73 sujetos en brazos paralelos y 110 en diseños cruzados; 149 con trastorno depresivo mayor y 34 con trastorno bipolar). Frente a controles con solución salina o midazolam, la ketamina elevó la remisión a las 24 horas (RP 7.06; NNT 5), a los 3 días (RP 3.86) y a los 7 días (RP 4.00), con una diferencia de medias estandarizada de 0.90 a las 24 horas y una mayor eficacia en la depresión unipolar (DME 1.07) que en la bipolar (0.68). Se produjeron efectos psicotomiméticos transitorios, pero ninguna psicosis persistente ni viraje afectivo.

The study · 1

McGirr et al., systematic review and meta-analysis of ketamine in the rapid treatment of major depressive episodes · Psychol Med 2015;45:693-704

El efecto antidepresivo de una única infusión de ketamina alcanza su punto máximo a las 24 horas y disminuye a los 7 días, y las infusiones repetidas lo prolonganModerate

In plain terms

El impulso de una infusión de ketamina es más fuerte a un día y comienza a desvanecerse en una semana, por lo que se administra como una serie de infusiones, no una sola vez.

In detail

Marcantoni et al. (J Affect Disord 2020) sintetizaron 28 estudios en 35 publicaciones sobre ketamina intravenosa subanestésica en la depresión resistente al tratamiento, examinando los resultados a las 4 horas, 24 horas y 7 días. Un efecto fuerte de la ketamina apareció dentro de las 4 horas y alcanzó su punto máximo a las 24 horas; permaneció presente pero disminuido a los 7 días. Múltiples infusiones produjeron un efecto potenciado y prolongado. Los autores señalaron que la seguridad y eficacia a largo plazo del uso prolongado de ketamina todavía están por establecerse.

The study · 1

Marcantoni et al., meta-analysis of intravenous ketamine infusion for treatment resistant depression · J Affect Disord 2020;277:831-841

Una única dosis de ketamina intravenosa redujo la ideación suicida en un día, con el efecto manteniéndose hasta una semanaModerate

In plain terms

En ensayos combinados, una dosis de ketamina intravenosa redujo los pensamientos suicidas en un día, y la caída duró hasta aproximadamente una semana.

In detail

Wilkinson et al. (Am J Psychiatry 2018) obtuvieron datos de participantes individuales de 10 de los 11 ensayos identificados que usaron solución salina o midazolam como control, analizando a los 167 participantes que tenían ideación suicida al inicio. La ketamina redujo la ideación suicida en un día tanto en medidas calificadas por el clínico como en autoinformes, con tamaños del efecto de d de Cohen de 0.48 a 0.85 sostenidos hasta una semana, y el beneficio se mantuvo tras ajustar por los cambios en la gravedad de la depresión.

The study · 1

Wilkinson et al., effect of a single dose of intravenous ketamine on suicidal ideation, an individual participant data meta-analysis · Am J Psychiatry 2018;175:150-158

Continuar con la esketamina tras la remisión redujo la tasa de recaída aproximadamente a la mitad, por lo que el beneficio depende de la dosificación continuadaModerate

In plain terms

Las personas que siguieron tomando esketamina después de mejorar se mantuvieron bien con mucha más frecuencia que quienes la suspendieron, lo que demuestra que el beneficio debe mantenerse.

In detail

Daly et al. (JAMA Psychiatry 2019) incluyeron a 705 adultos con depresión resistente al tratamiento; 297 que alcanzaron una remisión estable o una respuesta estable tras una fase de inducción y optimización con esketamina más un antidepresivo oral fueron asignados aleatoriamente a continuar con la esketamina o pasar a un aerosol nasal de placebo, manteniendo el antidepresivo oral en ambos grupos. Entre los 176 pacientes en remisión estable, la recaída se produjo en el 26.7 % con esketamina continuada frente al 45.3 % con placebo (P de log-rank = 0.003, NNT 6); entre los que respondían de forma estable, 25.8 % frente a 57.6 % (NNT 4).

The study · 1

Daly et al., efficacy of esketamine nasal spray for relapse prevention in treatment-resistant depression · JAMA Psychiatry 2019;76:893-903

La esketamina mejoró los síntomas depresivos a las 4 y 24 horas en pacientes con riesgo inminente de suicidio, pero la separación del placebo había desaparecido para el día 25Emerging

In plain terms

Añadir esketamina a la atención estándar ayudó a pacientes deprimidos con alto riesgo de suicidio en cuestión de horas, pero su ventaja frente al placebo se había desvanecido hacia las tres semanas y media.

In detail

Canuso et al. (Am J Psychiatry 2018) asignaron aleatoriamente a 68 participantes con riesgo inminente de suicidio a esketamina 84 mg o placebo dos veces por semana durante cuatro semanas, junto con un tratamiento estándar integral. El criterio de valoración primario, el cambio en la MADRS a las 4 horas, favoreció a la esketamina (tamaño del efecto de 0.61), al igual que el momento de las 24 horas (0.65), pero no el día 25 (0.35). El ítem de pensamientos suicidas de la MADRS mejoró solo a las 4 horas, y el juicio global del clínico sobre el riesgo de suicidio no difirió significativamente entre grupos en ningún momento.

The study · 1

Canuso et al., intranasal esketamine for rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide · Am J Psychiatry 2018;175:620-630

How it works

La ketamina actúa bloqueando el receptor de glutamato NMDA y aumentando las conexiones entre las neuronas, un mecanismo distinto al de los antidepresivos basados en serotoninaModerate · mixed

In plain terms

La ketamina bloquea un receptor de glutamato y fortalece rápidamente las conexiones entre las células cerebrales, lo que constituye una vía diferente para mejorar el estado de ánimo respecto a la que siguen los antidepresivos basados en serotonina.

In detail

Según la revisión de Zanos y Gould (Mol Psychiatry 2018), la acción antidepresiva de la ketamina comienza con el antagonismo del receptor NMDA, que produce un aumento del glutamato y una señalización posterior que incrementa la sinaptogénesis en los circuitos reguladores del estado de ánimo a lo largo de horas. La revisión también señala que varios mecanismos, incluidas las acciones de los metabolitos de la ketamina, siguen bajo investigación, por lo que la explicación de cómo la farmacología aguda produce un cambio duradero del estado de ánimo no está completamente resuelta.

The study · 1

Zanos and Gould, mechanisms of ketamine action as an antidepressant · Mol Psychiatry 2018;23:801-811

How It Works

Ketamine works by blocking the NMDA glutamate receptor, and that single action starts a cascade the older antidepressants never trigger. Standard drugs raise serotonin or noradrenaline and take weeks to change mood. Ketamine instead produces a rapid surge of glutamate signaling and, over the hours that follow, an increase in the connections between neurons in mood-regulating circuits. This is a different mechanism from the serotonin 5-HT2A receptor the classic psychedelics act on, which is why ketamine is grouped with the dissociatives instead of psilocybin.

What Happens Across a Course of Treatment

1The single dose

Ketamine blocks NMDA receptors and triggers a brief rise in glutamate signaling. During the dose the person experiences dissociation, a sense of detachment from the body and surroundings. Blood pressure and heart rate rise transiently, and there is sometimes nausea. These acute effects are why the dose is given in a clinic with monitoring, and they settle within hours.

2The hours after

Over the hours following the dose, mood often lifts and suicidal thoughts often ease, faster than any standard antidepressant acts. The proposed mechanism is a short window of new synaptic connections in mood-regulating circuits, driven by the glutamate surge the block sets off. Mechanism alone does not establish clinical benefit, and the size of the lasting effect is still being worked out.

3Days to weeks, and maintenance

The effect of a single dose fades within days to weeks. This is why intravenous ketamine is given as a series of infusions and esketamine as an induction course followed by maintenance dosing. The benefit lasts only while dosing continues; a single dose does not reset the depression.

The Legal Position

In law, ketamine splits into its two forms, and the two are treated very differently in the United States:

• Racemic ketamine is a Schedule III controlled substance, FDA-approved as an anesthetic. Its use for depression is off-label, given as an intravenous infusion in a clinic. Off-label prescribing of an approved drug is legal and common, but it stops short of a formal approval for depression.
• Esketamine nasal spray is approved for treatment-resistant depression and, separately, for depressive symptoms with suicidal thoughts. It is dispensed only through a restricted program in certified healthcare settings, where the patient is monitored for about two hours after each dose.
• Neither is available by ordinary prescription to take at home, and both are given under supervision because of the acute dissociation and blood-pressure rise.

Both forms are legitimate, regulated treatments, reachable through a psychiatrist or a certified clinic, and the risks attach mainly to frequent, high-dose, or unsupervised use.

The Chinese Medicine View

Chinese medicine has a long-standing frame for altered states of mind, and it leans toward caution. The Heart is said to house the Shen, the spirit or consciousness, and clear thought, steady emotion, and restful sleep are read as signs of a settled Shen. A mind flooded, disoriented, or thrown into fear or agitation is described as a disturbance of the Shen. The classical tradition treats such disturbance as something to calm and anchor. The bias of the medicine is toward grounding: settling the Shen and harmonizing the Heart and Liver. A scattered mind is rooted back in the body through stillness, breath, and regular life.

In this frame, ketamine's dissociation reads as a deliberate loosening of the Shen from its anchor. The tradition would approach that with care, especially in someone already depleted, agitated, or unsettled, and most of all outside a calm, supervised setting. In the tradition's own terms, this matches what the trials show: a strong effect, a short-lived one, tied to setting and supervision. The wider preventive tradition of Yang Sheng, nourishing life, puts self-directed daily practices first and treats potent, mind-altering interventions as a last, carefully-set step.

Cautions For This Practice

Extra restraint

Everything to be aware of is here, in one place. This practice suits most healthy people; a few situations call for real care.

El uso frecuente de ketamina a dosis altas puede causar cistitis ulcerosa grave, una lesión vesical dolorosa y a veces duradera

Shahani et al. (Urology 2007) describieron a nueve consumidores diarios de ketamina con disuria intensa, frecuencia urinaria, urgencia y hematuria macroscópica. Los urocultivos fueron estériles; la TC mostró un engrosamiento marcado de la pared vesical, capacidad reducida y trabeculación perivesicular; la cistoscopia mostró cistitis ulcerosa grave, y las biopsias mostraron denudación epitelial e inflamación. La suspensión de la ketamina, junto con pentosano polisulfato, produjo cierto alivio sintomático. Informes posteriores confirmaron el síndrome y su dependencia de la dosis y la frecuencia.Shahani et al., ketamine-associated ulcerative cystitis, a new clinical entity

The acute effects need supervision

Every dose causes dissociation. It also raises blood pressure and heart rate briefly, and can bring nausea, vertigo, or an altered sense of taste. These are the reason the treatment is given in a clinic with monitoring. Anyone with uncontrolled high blood pressure, unstable heart disease, or an aneurysm is at higher risk from the blood-pressure rise and should raise it with the prescribing clinician.

Bladder and urinary toxicity with frequent high-dose use

Frequent, high-dose ketamine, the pattern in heavy recreational use, can cause a severe bladder-wall inflammation called ketamine cystitis. Symptoms are painful, frequent, urgent urination and blood in the urine; in the worst cases the bladder damage lasts. This risk rises with dose and frequency. It is one of the strongest reasons the treatment is dose-controlled and supervised, and one of the clearest harms of unsupervised use.

Abuse and dependence potential

Ketamine carries potential for misuse and psychological dependence. That is why it is a controlled substance and why clinic use is monitored. A history of substance use disorder is a reason for particular care. Separately, the long-term safety of extended maintenance is not yet fully mapped.

Who should be especially careful

A personal or family history of psychosis is an important reason for caution, because dissociatives can worsen psychotic symptoms. Pregnancy, uncontrolled hypertension, and active substance use disorder all change whether and how the treatment should be used. There is no dosing or sourcing here; the pathway that has been studied is a dose-controlled, supervised one.

Ketamine and esketamine are real, clinically used treatments for depression. The antidepressant effect is fast and repeatable. The risk turns on the setting: it is far lower in a dose-controlled, supervised course than in frequent, unsupervised high-dose use. For anything touching your own care, work with a qualified clinician.

Common Questions

Does ketamine work for depression?

Yes. But it is studied mainly in treatment-resistant depression, so it is a later-line option, used after other antidepressants have failed.

What is the difference between ketamine and esketamine?

The difference that matters is regulatory. Esketamine has the FDA label and a defined dosing program; intravenous ketamine has the larger body of trial evidence for a rapid effect.

Does it help with suicidal thoughts?

Yes, fast and for a limited window. An individual-participant meta-analysis found a single dose of intravenous ketamine cut suicidal thinking within one day. The moderate-to-large effect held for up to a week and ran partly separate from the change in overall mood. An esketamine trial in people at imminent suicide risk showed clear improvement at 4 and 24 hours, but the separation was no longer significant by day 25. The effect is rapid but time-limited, which is why it runs alongside continuing care.

Is ketamine safe, and is it addictive?

The risks are real and rise with dose and frequency. The heavy recreational pattern, high doses taken often and unsupervised, is where the serious bladder damage and the dependence concentrate. The clinic version uses controlled doses on a set schedule, so the same molecule carries far less of that risk. Whether it is "safe" depends almost entirely on which of those two settings you mean.

Go Deeper

• Psychedelics in mental health: the wider field, where ketamine sits beside psilocybin for depression and MDMA-assisted therapy for post-traumatic stress. The blinding problem and the law are laid out there.
• Depression: what actually helps: the full range of treatments for depression, and where a fast-acting option like ketamine sits among the ones with a longer track record.