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Ketamine Therapy for Depression: A Psychiatrist's Comprehensive Guide

By Ryan S. Sultan, MD
Assistant Professor of Clinical Psychiatry, Columbia University Irving Medical Center
Board-Certified in Adult Psychiatry and Child & Adolescent Psychiatry
March 29, 2026

What Is Ketamine and Why Is It Used for Depression?

Ketamine was developed in 1962 as an anesthetic and has been used safely in surgical and emergency settings for over 60 years. It is on the World Health Organization's List of Essential Medicines. Starting in the late 1990s and early 2000s, researchers -- most notably John Krystal and his colleagues at Yale University -- discovered that subanesthetic doses of ketamine produced rapid, robust antidepressant effects in patients with treatment-resistant depression.

This discovery was groundbreaking for several reasons. First, ketamine works fast -- within hours rather than weeks. For patients in the depths of severe depression, including those with active suicidal ideation, the speed of response can be life-saving. Second, ketamine works through an entirely different mechanism than any existing antidepressant, opening up a new therapeutic avenue for the approximately one-third of depressed patients who do not respond to standard treatments.

My personal connection to ketamine research runs deep. During my training at Emory University, I co-authored a 2014 paper published in Psychosomatics examining the use of ketamine in combination with electroconvulsive therapy (ECT), working with Patricio Riva-Posse and colleagues in the Department of Psychiatry. Later, during my research training at Yale, I had the privilege of working under John Krystal -- the psychiatrist whose pioneering 2000 study in Archives of General Psychiatry first demonstrated ketamine's antidepressant properties in humans and who has been at the forefront of glutamate-based treatments for depression ever since. These experiences gave me firsthand exposure to the science behind ketamine therapy and the rigor needed to administer it responsibly.

How Ketamine Works: Mechanism of Action

Understanding why ketamine works requires understanding what goes wrong in the depressed brain at the synaptic level.

The Problem: Synaptic Damage from Chronic Stress

Chronic stress and depression cause measurable structural changes in the brain. The prefrontal cortex and hippocampus -- regions critical for mood regulation, decision-making, and memory -- show reduced volume, decreased dendritic branching, and loss of synaptic connections. In other words, depression is not just a "chemical imbalance" -- it involves actual damage to neural circuits.

This synaptic damage is driven in part by elevated cortisol (the stress hormone), which reduces levels of brain-derived neurotrophic factor (BDNF) -- a protein essential for maintaining and growing synaptic connections. Traditional antidepressants (SSRIs, SNRIs) gradually increase BDNF over weeks, which is one reason they take so long to work.

The Solution: Rapid Synaptogenesis

Ketamine takes a different route entirely. Here is the cascade of events:

1. NMDA receptor blockade: Ketamine blocks N-methyl-D-aspartate (NMDA) receptors on inhibitory interneurons. This paradoxically leads to a surge of glutamate -- the brain's primary excitatory neurotransmitter -- in the prefrontal cortex.
2. AMPA receptor activation: The released glutamate preferentially activates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are critical for synaptic plasticity.
3. BDNF release: AMPA receptor activation triggers the release of BDNF from neurons.
4. mTOR pathway activation: BDNF activates the mechanistic target of rapamycin (mTOR) signaling pathway, a master regulator of protein synthesis and cell growth.
5. Rapid synaptogenesis: Within hours, new synaptic connections begin forming -- essentially reversing the synaptic damage caused by chronic stress and depression.

This mechanism explains both why ketamine works so quickly (synaptogenesis begins within hours) and why its effects are transient (the new synapses need repeated stimulation to become permanent, which is why maintenance treatments are necessary).

Beyond NMDA: Other Mechanisms

Research increasingly suggests ketamine's antidepressant effects involve additional mechanisms beyond NMDA receptor blockade:

• Opioid system modulation: Some studies suggest ketamine's antidepressant effects are partially mediated by the opioid system, though this remains controversial. A Stanford study found that naltrexone (an opioid blocker) attenuated ketamine's antidepressant effects in some patients.
• Anti-inflammatory effects: Ketamine reduces neuroinflammation, which is increasingly recognized as a contributor to depression.
• Default mode network modulation: Ketamine appears to disrupt the default mode network (DMN), the brain circuitry associated with rumination and self-referential thinking -- hallmarks of depression.
• HPA axis effects: Ketamine may help normalize the dysregulated hypothalamic-pituitary-adrenal axis that drives chronic stress responses in depression.

IV Ketamine vs. Esketamine (Spravato): Key Differences

There are two primary forms of ketamine used for depression, and understanding the differences is important for informed treatment decisions.

Which is better? The honest answer is that we do not have definitive head-to-head comparison data. IV ketamine has a larger body of clinical evidence and allows more precise dosing. Esketamine has the advantage of FDA approval (which affects insurance coverage and provides a standardized protocol) and does not require IV access. Some clinicians prefer IV ketamine because the racemic mixture (containing both S and R enantiomers) may have therapeutic advantages -- there is emerging evidence that R-ketamine may have antidepressant properties with fewer dissociative side effects.

Who Is a Candidate for Ketamine Therapy?

Strongest indications:

• Treatment-resistant depression (failed 2 or more adequate antidepressant trials)
• Severe depression with acute suicidal ideation requiring rapid intervention
• Major depressive disorder that has not responded to medication and psychotherapy
• Bipolar depression that has not responded to mood stabilizers and other treatments (used with caution)

Relative contraindications:

• Uncontrolled hypertension (ketamine raises blood pressure)
• Active substance use disorder (risk of misuse; may be appropriate if substance use is in remission)
• History of psychotic disorders (schizophrenia, schizoaffective disorder) -- ketamine can worsen psychotic symptoms
• Unstable cardiovascular disease (aneurysm, recent MI)
• Increased intracranial pressure
• Pregnancy
• Active mania

Important caveat: Ketamine is generally not a first-line treatment for depression. The current standard of care calls for trying SSRIs, SNRIs, or other established antidepressants first, combined with psychotherapy. Ketamine is most appropriate when these approaches have been tried and have failed. Using ketamine as a first-line treatment exposes patients to unnecessary risks and costs when simpler, well-established treatments might work.

What to Expect During Ketamine Treatment

Before Treatment

A thorough psychiatric evaluation is essential before starting ketamine therapy. This should include a complete diagnostic assessment (to confirm treatment-resistant depression and rule out contraindications), review of all previous medication trials, medical history review (particularly cardiovascular health and substance use history), baseline vital signs and labs, and informed consent discussion covering benefits, risks, alternatives, and realistic expectations.

During an IV Ketamine Infusion

A typical IV ketamine session involves arriving at the clinical setting, having vital signs checked (blood pressure, heart rate, oxygen saturation), having an IV placed, and receiving the infusion over approximately 40 minutes at a dose of 0.5 mg/kg. During the infusion, patients commonly experience dissociation (feeling detached from body or surroundings), visual or perceptual disturbances (lights may appear brighter, surfaces may appear to shift), a sensation of floating or warmth, altered sense of time, and mild nausea. These effects are transient and typically resolve within 30-60 minutes after the infusion ends. Blood pressure is monitored throughout, as ketamine can cause a temporary 15-25% increase.

After Treatment

Patients are monitored for 1-2 hours after the infusion until dissociative effects resolve and vital signs normalize. Patients must not drive for the remainder of the day and should arrange transportation in advance. Many patients report feeling a "lifting" of depression within hours of the first infusion, though the full effect often develops over the initial series of treatments.

Typical Treatment Protocol

Induction phase: 6 infusions over 2-3 weeks (typically Monday/Wednesday/Friday schedule). This loading period allows the neuroplastic effects to accumulate and is when most patients experience the greatest improvement.

Maintenance phase: After the initial series, patients who respond typically need periodic booster infusions to maintain the antidepressant effect. The frequency varies -- some patients need boosters every 2-4 weeks, others every 2-3 months. The optimal maintenance schedule is individualized based on symptom recurrence.

The Evidence Base for Ketamine in Depression

The evidence supporting ketamine's antidepressant efficacy is substantial and growing.

Key findings from the research literature:

• A landmark 2006 study by Zarate et al. in Archives of General Psychiatry demonstrated that a single IV ketamine infusion produced rapid antidepressant effects within 2 hours in patients with treatment-resistant depression, with 71% of patients responding and 29% achieving remission at 24 hours.
• A 2015 meta-analysis by Newport et al. found that ketamine produced a large antidepressant effect (Cohen's d = 0.99) compared to active placebo controls.
• Multiple studies have demonstrated ketamine's rapid anti-suicidal effects, with reduction in suicidal ideation within hours -- a critically important finding given the limited rapid-acting options for acute suicidality.
• The SUSTAIN-1 and SUSTAIN-2 trials for esketamine demonstrated maintenance of antidepressant response with continued treatment, leading to FDA approval.
• Real-world effectiveness data from large clinical practices suggests response rates of 60-70% in treatment-resistant depression, with remission rates of 30-40%.

Limitations of the evidence:

• Blinding is difficult because ketamine's dissociative effects make it obvious to patients (and sometimes clinicians) who received ketamine vs. placebo.
• Most studies have relatively short follow-up periods. Long-term outcomes with maintenance ketamine treatment need more study.
• Optimal dosing, frequency, and duration of treatment are not fully established.
• Long-term safety with repeated dosing over years needs more data.

Risks, Side Effects, and Safety Concerns

Acute Side Effects

The most common acute side effects are dissociation, dizziness, nausea, elevated blood pressure, headache, and perceptual disturbances. These are transient and typically resolve within 1-2 hours. They are dose-dependent and can be managed by adjusting the infusion rate or pre-treating with ondansetron (for nausea) or adjusting the dose.

Longer-Term Concerns

Urinary tract toxicity: Chronic ketamine use (particularly at high recreational doses) is associated with interstitial cystitis -- inflammation and scarring of the bladder. This has been documented primarily in recreational users consuming grams of ketamine daily. At therapeutic doses (0.5 mg/kg once or twice weekly), this risk appears to be low, but urinary symptoms should be monitored.

Cognitive effects: Chronic recreational ketamine use is associated with cognitive impairment, particularly in memory and executive function. At therapeutic doses, the evidence is more reassuring -- most studies show no significant cognitive decline with treatment-frequency dosing, and some show cognitive improvement as depression lifts.

Dependence and misuse: Ketamine has abuse potential and is a Schedule III controlled substance. While physical dependence at therapeutic doses is uncommon, psychological dependence can develop. This is why medical supervision, structured protocols, and careful patient selection are essential. Patients with active substance use disorders require particularly careful evaluation.

Cardiovascular effects: Ketamine transiently increases blood pressure and heart rate. This is generally well-tolerated in healthy patients but requires monitoring. Patients with uncontrolled hypertension or cardiovascular disease may not be candidates.

Why a Psychiatrist Should Supervise Ketamine Treatment

The proliferation of "ketamine clinics" operated by non-psychiatrists -- including anesthesiologists, nurse practitioners, and even non-medical providers -- raises serious safety concerns. Ketamine therapy for depression requires more than just administering a medication. It requires accurate psychiatric diagnosis (is this truly treatment-resistant depression, or has it been misdiagnosed?), comprehensive evaluation for contraindications (psychotic disorders, substance use disorders, cardiovascular disease), expertise in managing psychiatric medications (ketamine interacts with and may require adjustments to concurrent psychiatric medications), the ability to manage psychiatric emergencies (severe dissociation, panic, suicidal ideation, psychotic symptoms), longitudinal psychiatric care (ketamine is one component of a comprehensive treatment plan, not a standalone solution), and understanding of the neuroscience underlying both depression and ketamine's mechanism of action.

A responsible ketamine provider should be asking: What other treatments have been tried? Are there co-occurring conditions? What is the long-term treatment plan? How will we monitor for relapse? What therapy is happening alongside the ketamine? If these questions are not being asked, the provider may be offering a procedure rather than comprehensive psychiatric care.

My Approach to Depression Treatment

At Integrative Psych in Chelsea, Manhattan, I approach treatment-resistant depression with the same rigor I bring to my research at Columbia University. This means thorough diagnostic evaluation, systematic medication trials, integration of psychotherapy, and careful consideration of newer treatments including ketamine when appropriate.

My training under John Krystal at Yale -- the researcher who has done more than perhaps anyone else to advance our understanding of glutamate-based treatments for depression -- and my early research on ketamine with ECT at Emory with Patricio Riva-Posse have given me a deep understanding of both the promise and the limitations of ketamine therapy. I can help patients determine whether ketamine is appropriate for their specific situation, coordinate treatment if it is, and ensure it is part of a comprehensive, evidence-based treatment plan.

For patients who are not candidates for ketamine or who prefer other approaches, I offer expert management of traditional antidepressants, augmentation strategies, treatment for co-occurring conditions (ADHD, anxiety, substance use), and coordination with therapists for CBT, DBT, and other evidence-based psychotherapies.

Further Reading

• Depression Treatment with Dr. Sultan
• Collaborators: John Krystal, Patricio Riva-Posse
• Psychiatric Medication Management
• Bipolar Disorder Treatment