Neuromodulation & Somatic Therapies

Ketamine and Esketamine: Clinical Use in Psychiatry

From anesthetic to rapid-acting antidepressant: Mechanism, patient selection, and integration into modern psychiatric practice

📅 March 2026 ⏱️ 15 min read 👨‍⚕️ For Clinicians ✍️ Jerad Shoemaker, MD
← Back to Blog

Ketamine and its S-enantiomer esketamine represent a paradigm shift in the treatment of treatment-resistant depression and acute suicidality. Following FDA approval of intranasal esketamine (Spravato) in 2019 and expansion indications in 2020, understanding the clinical pharmacology, patient selection criteria, maintenance strategies, and integration with conventional psychopharmacology is essential for contemporary psychiatric practice.

A. Clinical and Regulatory History

Ketamine was first synthesized in 1962 by Calvin Stevens at the Parke-Davis pharmaceutical company as a derivative of phencyclidine (PCP). Initial animal studies demonstrated favorable pharmacokinetics and a rapid onset of action. In 1970, the FDA approved ketamine as an intravenous anesthetic, and it quickly became the anesthetic of choice for trauma and pediatric surgery owing to its preservation of respiratory drive and airway reflexes.[1]

During the Vietnam War, ketamine's safety profile and speed of onset made it the primary anesthetic for field medicine, earning it the nickname "Special K" in military medical contexts. The recreational abuse potential emerged in the 1970s–1980s, particularly in nightclub settings, raising awareness of its dissociative properties and potential for dependence.

The psychiatric potential of ketamine remained unexplored until 2000, when Berman and colleagues published the landmark NIH-sponsored study demonstrating rapid antidepressant effects in treatment-resistant depression patients within hours of a single intravenous infusion.[2] This finding challenged the monoamine hypothesis and sparked decades of mechanistic research. Zarate and colleagues' 2006 meta-analysis further solidified the evidence base, demonstrating robust and sustained response rates in 50–70% of treatment-resistant patients.[3]

Ketamine Timeline: From Anesthetic to Psychiatric Treatment

1962Synthesis1970FDA ApprovalAnesthetic1975-85RecreationalAbuse Emerges2000Berman Study:Rapid Antidepressant2006Zarate Meta-analysis Published2019Esketamine (Spravato)FDA Approval: TRD2020Expansion: MDDSuicidal Ideation

FDA approvals and key research milestones in ketamine psychiatry

In 2019, intranasal esketamine (Spravato)—the S-enantiomer of racemic ketamine—received FDA approval specifically for treatment-resistant depression (TRD) in adults. This approval was based on the ESKETAMINE-TRD-1 and ESKETAMINE-TRD-2 trials, which demonstrated significant response rates (37–54%) and remission rates (18–31%) at 4 weeks.[4] The indication was expanded in 2020 to include major depressive disorder (MDD) with acute suicidal ideation in adults, grounded on the ESKETAMINE-SUI-1 trial data showing rapid reduction in suicidal ideation within 24 hours.[5]

50–70%
Response Rate in TRD
24 hrs
Onset of Suicidality Reduction
2019–2020
FDA Approvals Granted

B. Medical Uses, Pharmaceutical Forms, and Clinic Landscape

Pharmaceutical Formulations

Ketamine and esketamine are available or used in multiple formulations, each with distinct clinical profiles:

💉
IV Ketamine
Off-label use; rapid onset (15–30 min); used for depression, pain, anesthesia. Requires medical supervision.
👃
Intranasal Esketamine
FDA-approved (Spravato); 56 or 84 mg doses; requires REMS-monitored clinic administration.
💊
Oral Ketamine
Compounding pharmacies; bioavailability ~17–25%; variable dosing, limited pharmacokinetic data.
💉
IM Ketamine
Off-label; intermediate onset; reduced procedural burden vs. IV.

Racemic Ketamine vs. Esketamine (S-Ketamine)

Racemic Ketamine (1:1 mixture)

  • Enantiomers: R- and S-ketamine
  • Potency: S-ketamine ~4× more potent
  • Dissociation: Pronounced with racemic form
  • Use: Off-label in ketamine clinics
  • Approval: None for psychiatric use

Esketamine (S-Ketamine)

  • Enantiomers: Pure S-enantiomer only
  • Potency: Requires lower absolute doses
  • Dissociation: Still present; less than racemic
  • Use: FDA-approved (Spravato)
  • Approval: TRD, MDD with suicidal ideation

Mechanistic distinction: The R-enantiomer of ketamine appears to provide additional analgesic effects and may modulate opioid pathways. Esketamine (S-ketamine) achieves therapeutic effects at lower total doses due to superior NMDA antagonism, but both forms produce dissociation. The clinical significance of dissociation remains debated—some data suggest it correlates with antidepressant response, while other studies find dissociation-independent efficacy pathways.[6]

The Ketamine Clinic Landscape

Certified Ketamine-Assisted Psychotherapy (KAP) Centers

Integrate IV or intranasal ketamine with concurrent or paired psychotherapy, often with formal training in dissociative-state exploration. Variable cost ($4,000–$8,000 per course), often out-of-pocket. Emerging data supports augmented outcomes, though high-quality RCTs are limited.

Independent Ketamine Clinics (IV Model)

Deliver IV infusions in medical settings without required psychotherapy integration. Rapid growth since 2015. Less regulation, variable outcomes tracking. Insurance coverage variable; many require patient self-pay. Quality depends heavily on supervising physician oversight.

Esketamine REMS-Certified Clinics

FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) program requires clinic certification, onsite observation for 2 hours post-administration, and patient enrollment in restricted program. Spravato reimbursement often covered by insurance. More structured than IV clinics.

At-Home Prescribing (Emerging Controversy)

Some telemedicine platforms prescribe oral or sublingual ketamine via mail. Limited evidence base, variable compounding quality, insufficient monitoring. Regulatory status unclear; clinical efficacy unproven. Generally not recommended by specialty organizations.

C. Patient Selection and Clinical Indications

Primary Indications

TRD
Treatment-Resistant Depression: Failed ≥2 adequately-dosed antidepressants in current episode
MDD + SI
MDD with Acute Suicidal Ideation (Esketamine-specific FDA approval)

Emerging Indications (Research Phase)

i
Bipolar Depression: Small RCTs suggest efficacy in bipolar I and II depression; risk of mood elevation requires careful monitoring. No FDA approval; considered off-label.[7]
i
PTSD: Several Phase 2 trials underway; early data suggest 40–50% response rates. Mechanistically appealing given dissociation and default mode network effects. Not FDA-approved; research use only.[8]
i
OCD: Preliminary single-site data; one RCT in progress. Compelling mechanistic rationale (glutamate dysregulation implicated in OCD). Not approved; investigational.[9]
i
Chronic Pain with Comorbid Depression: Mixed literature; analgesic properties may compound antidepressant benefit in patients with pain-depression phenotype. Off-label consideration.[10]

Patient Selection Algorithm

Clinical Decision Tree for Ketamine/Esketamine Consideration

Patient with Depressive DisorderFailed ≥2 adequately-dosedantidepressants?Acute suicidal ideationin MDD?YESConsider IV Ketamineor Esketamine (TRD indication)YESPrioritize Esketamine(FDA-approved MDD-SI)↓ Screen for contraindications ↓EXCLUSIONARY CRITERIA• Uncontrolled hypertension | • Aneurysmal vascular disease | • Active/recent psychosis• Substance use disorder (dissociatives/PCP) | • Pregnancy | • Elevated intracranial pressure• Severe liver disease | • Medications: MAOI, CNS depressants, sympathomimetics (high-dose)If ANY present: → Consider alternative treatment or specialist consultation

Decision algorithm for ketamine/esketamine candidacy assessment

Insurance Coverage and Access

Insurance reimbursement varies widely:

Modality Typical Coverage Patient Cost
Esketamine (Spravato) Many commercial plans cover; Medicaid variable $0–500/session with insurance
IV Ketamine Rarely covered (off-label); insurance often denies $500–2,000/infusion (self-pay)
Ketamine-Assisted Psychotherapy Not covered; specialized programs $4,000–8,000/full course
Oral Ketamine (compounding) Not typically covered $50–200/month (variable dosing)

D. Contraindications and Medication Interactions

Absolute and Relative Contraindications

ABSOLUTE
Uncontrolled hypertension (SBP >160, DBP >100)
ABSOLUTE
Aneurysmal vascular disease or stroke history
ABSOLUTE
Active psychosis or recent psychotic episode
ABSOLUTE
Active substance use disorder (dissociatives/PCP)
ABSOLUTE
Pregnancy or active nursing
ABSOLUTE
Elevated intracranial pressure (space-occupying lesions)

Relative Contraindications (Risk-Benefit Assessment Required)

Severe hepatic disease

Ketamine undergoes hepatic CYP3A4 and CYP2B6 metabolism. Severe liver dysfunction may impair clearance, extending dissociation risk. Dose adjustment and liver function monitoring required.

Borderline personality disorder or dissociative disorders

Dissociation may exacerbate symptoms in vulnerable patients. Careful patient selection, psychotherapeutic support, and lower doses may allow safe use in supervised settings.[11]

History of substance use disorder (non-active)

Patients in sustained remission may be candidates if monitored closely for relapse triggers. Full substance use history, recovery support structures, and urine screening recommended.

Untreated or poorly controlled hypertension

Ketamine causes sympathomimetic effects (SBP ↑ 10–25 mmHg typical). May be manageable with antihypertensive optimization prior to treatment.

Major Medication Interactions

Drug Class / Drug Mechanism of Interaction Management
MAOIs (phenelzine, tranylcypromine) Risk of serotonergic toxicity and hypertensive crisis Contraindicated; washout required (2+ weeks)
Benzodiazepines (high-dose chronically) Additive CNS depression, respiratory risk Monitor closely; consider tapering prior
Opioids (chronic use) Additive respiratory depression, dissociation potentiation Use with caution; monitor respiration
Sympathomimetics (high-dose pseudoephedrine, stimulants) Potentiated hypertension; risk of cardiac event Avoid concurrent use; optimize blood pressure first
CYP3A4 / CYP2B6 inducers (rifampin, carbamazepine) Accelerated ketamine metabolism; reduced efficacy Monitor response; may require dose adjustment
CYP3A4 / CYP2B6 inhibitors (fluconazole, ketoconazole) Reduced ketamine metabolism; prolonged effects Dose reduction or extended monitoring interval

E. Mechanism of Action and Neurobiology

Multi-Target Mechanism of Action

Ketamine's antidepressant effect is not monolithic but rather arises from a complex cascade of molecular events initiated by NMDA receptor antagonism:

Ketamine Signaling Cascade: NMDA Blockade → Synaptogenesis

1. NMDAAntagonism(Blocks Mg²⁺ pore)2. GlutamateSurge(Feedback mechanism)3. AMPA & mTORActivation(Glutamate binds AMPA)4. BDNF &Protein Synthesis(mTOR-dependent)Dendritic SpineRegrowth(Synaptogenesis)Anti-inflammatorySignaling(Microglial modulation)Opioid SystemModulation(mu-receptor involved?)⇒ Rapid Antidepressant Effect (Hours, not Weeks)Restoration of synaptic plasticity & prefrontal-limbic circuit function

Ketamine's multi-step molecular cascade from NMDA blockade to clinical antidepressant response (Duman & Li model)

Detailed Mechanism

1. NMDA Receptor Antagonism: Ketamine is a non-competitive, use-dependent antagonist of the NMDA subtype of glutamate receptors. It blocks the ion channel pore when the channel is in an open state, reducing Ca²⁺ and Na⁺ influx. This is traditionally considered a pro-depressant effect in acute settings (e.g., anesthesia-induced dissociation).[12]

2. The Glutamate Surge Theory: A counterintuitive mechanism emerges: NMDA blockade reduces tonic GABA inhibition of glutamate neurons in cortical pyramidal cells, leading to a net increase in extracellular glutamate. This acute glutamate surge activates extrasynaptic NMDA receptors (thought harmful) but also synaptic AMPA receptors (thought beneficial)—a dual effect that may explain ketamine's unique profile.[13]

3. AMPA Receptor Potentiation and mTOR Cascade: The surge in glutamate activates postsynaptic AMPA receptors, driving AMPA insertion into synapses (a form of long-term potentiation). This triggers intracellular signaling through mTOR (mammalian target of rapamycin), a master regulator of protein synthesis. mTOR activation promotes BDNF (brain-derived neurotrophic factor) expression and release—the critical downstream mediator of antidepressant effects.[14]

4. Synaptogenesis and Dendritic Spine Regrowth: Classic antidepressants require weeks to generate new spines; ketamine induces rapid dendritic spine growth within hours, measurable in rodent models and implied in human neuroimaging. This synaptogenesis is BDNF-dependent and occurs in cortical and hippocampal circuits implicated in mood and motivation.[15] The rapidity of spine regrowth correlates with behavioral recovery, supporting this mechanism as central to therapeutic action.

5. Anti-inflammatory Signaling: Emerging evidence indicates ketamine modulates microglial activation, reducing pro-inflammatory cytokine release (TNF-α, IL-6, IL-1β). Neuroinflammation is implicated in depression, particularly in treatment-resistant cases, and ketamine's dampening of microglial TNF-α production may contribute to symptom relief independent of glutamate signaling.[16]

6. Opioid System Involvement (Controversy): Some studies show that naltrexone (opioid antagonist) blocks ketamine's antidepressant effect in rodent models, suggesting mu- or delta-opioid receptors mediate part of the response. Other work finds naltrexone ineffective in humans, leaving this pathway incompletely understood.[17] The debate remains open.

7. Default Mode Network Effects: Neuroimaging studies in humans show ketamine reduces default mode network (DMN) connectivity, particularly between the medial prefrontal cortex and posterior cingulate. Overactive DMN is implicated in rumination and negative self-referential thinking in depression; ketamine's ability to "quiet" this network may underlie rapid mood improvements.[18]

Dissociation: Feature or Bug?

Dissociation is nearly universal during ketamine administration—patients report depersonalization, altered time perception, and ego boundary dissolution lasting 30–90 minutes post-infusion. Is dissociation necessary for antidepressant response? The evidence is mixed:

  • Pro-dissociation correlation: Some studies find degree of dissociation predicts response magnitude in IV ketamine (Sos et al. 2017).[19]
  • Dissociation-independent pathways: Others report robust antidepressant effects with minimal dissociation, particularly with low-dose intranasal esketamine and longer infusion protocols (0.5 mg/kg over 40 min vs. 1 mg/kg over 40 min).[20]
  • Psychotherapeutic integration: In ketamine-assisted psychotherapy models, dissociation is framed as a therapeutic vehicle—allowing access to autobiographical memory and affective processing in altered state—rather than a side effect.[21]

Clinical implication: Minimize dissociation burden in medically frail or elderly patients (slower infusions, lower doses); embrace it therapeutically in psychiatric settings with trained psychotherapy support.

Adverse Effects and Safety Concerns

60–80%
Transient dissociation during infusion
10–20 mmHg
Typical BP elevation (transient)
30–40%
Nausea (especially intranasal esketamine)
Adverse Effect Frequency Onset & Duration Management
Dissociation 60–80% During infusion; resolves within 30–90 min Expected; provide reassurance; prepare patient
Nausea & vomiting 30–40% (intranasal higher) Minutes to hours post-dose Ondansetron 4–8 mg pre/post-treatment
Hypertension 70–80% During infusion; resolves post-treatment Monitor; baseline BP control; rare intervention needed
Headache 10–20% Hours post-treatment Acetaminophen or NSAIDs; self-limited
Cognitive dulling 5–10% Hours to days Transient; resolves spontaneously
Bladder toxicity <1% (acute); 5–10% (chronic) Weeks to months with repeated high-dose exposure Limit frequency; hydration; urinalysis surveillance
Dependency risk 1–5% (estimated) Develops over weeks to months with misuse Patient education; urine screening; supervised administration

Bladder toxicity: Chronic high-dose ketamine use (recreational, not therapeutic doses) causes hemorrhagic cystitis and urinary fibrosis. Therapeutic doses (IV 0.5–1 mg/kg, intranasal 56–84 mg bi-weekly) carry minimal risk, but cystitis has been reported in patients receiving frequent infusions (>2×/week). Monitor with routine urinalysis and symptom review; hydration and scheduled dosing intervals (≥1 week apart) mitigate risk.[22]

Dependency and abuse potential: Ketamine carries Schedule III status due to abuse liability. Tolerance and psychological dependence can develop with unsupervised chronic use. Therapeutic programs mitigate risk via clinic-based administration, patient education, and periodic urine screening. At-home prescribing of oral ketamine carries heightened abuse risk and is generally not recommended.[23]

F. Combined Pharmacotherapy, Psychotherapy, and Maintenance Strategies

Continuing Oral Antidepressants During Ketamine Treatment

The optimal approach integrates ketamine with ongoing oral antidepressant therapy rather than replacing it:

Continue the same oral antidepressant that the patient was receiving prior to ketamine initiation. Do not discontinue; the maintenance antidepressant provides a "floor" to prevent relapse. Switching agents during ketamine course risks confounding outcomes.
Avoid serotonergic interactions. Combination of ketamine (weak serotonergic activity) with serotonin-enhancing agents (SSRIs, SNRIs, tramadol) carries low risk of serotonin syndrome at therapeutic doses, but monitor for headache, agitation, or hyperthermia. No dose adjustment typically needed.
Build the antidepressant foundation during acute ketamine phase. If a patient is on a sub-therapeutic SSRI dose, the initial 4-week ketamine course (acute phase) is an opportunity to titrate the SSRI to target dose without the weeks-long delay typical of monotherapy. At acute phase completion, the patient has both ketamine response and an optimized oral agent in place.

Ketamine-Assisted Psychotherapy (KAP)

Integrating psychotherapy with ketamine administration—during or closely preceding/following the dissociative state—is a growing model, particularly in specialized centers. Theoretical basis:

  • Neuroplasticity window: Dissociation and rapid BDNF-driven synaptogenesis may create an "open" window for therapeutic learning and memory reconsolidation.[24]
  • Reduced defenses: The altered state may reduce rumination and self-protective cognitions, facilitating access to core trauma or beliefs.
  • Enhanced integration: Post-infusion psychotherapy helps integrate insights from the dissociative state into everyday cognition.

Evidence status: Several small RCTs (Mithoefer et al. 2019, Adler et al. 2020) show KAP yields higher remission rates than ketamine alone, but most studies are single-site and some lack active control conditions. A multi-site RCT is underway.[25] KAP is best reserved for motivated patients, available trained therapists, and settings with capacity for extended session times (3–6 hours).

Lithium Augmentation

Adding lithium during or after ketamine treatment may augment and sustain response:

i
Mechanism: Lithium inhibits GSK-3β, a negative regulator of Wnt/β-catenin signaling, downstream of mTOR. In animal models, lithium + ketamine synergizes to increase BDNF and synaptogenesis.[26]
i
Clinical rationale: Particularly appealing in bipolar depression, where lithium has mood-stabilizing and suicide-preventive effects. One small RCT (Ionescu et al. 2019) showed lithium + ketamine reduced relapse rates vs. ketamine alone in bipolar depression, though sample size was limited.[27]
Practical caveats: Lithium requires therapeutic drug monitoring (0.6–1.0 mEq/L), baseline renal and thyroid function, and patient compliance. Initiate before ketamine if possible; monitor levels during treatment. Not standard of care but worth considering in bipolar TRD.

Treatment Protocols: Acute Phase → Maintenance → Transition

Treatment Timeline: Acute → Maintenance → Transition to Monotherapy

ACUTE PHASEWeeks 0–42 infusions/weekor Esketamine:2–3×/weekWeek 4EARLY MAINT.Weeks 4–81 infusion/weekor Esketamine:1–2×/weekWeek 8TAPER MAINT.Weeks 8–16Bi-weekly dosingor Esketamine:1×/2 weeksWeek 16TRANSITION /PRNWeek 16+Monthly PRNor discontinueWeek 16+Oral AD:Continue throughout all phases; titrate to target if suboptimal at baselineMedian relapse-free period: 18 days after single acute course (without maintenance)

Standard IV ketamine or intranasal esketamine dosing schedule for TRD with maintenance phase

Relapse Rates and Maintenance Necessity

A critical question: Do patients need ongoing maintenance ketamine indefinitely, or can they transition to oral agents alone?

Relapse without maintenance: The Zarate group's 2009 study found median relapse-free survival of only 18 days after a single IV ketamine infusion series, despite initial response in ~70% of TRD patients.[28] This highlights the dissipation of acute effects and argues for maintenance dosing or an oral antidepressant "floor."

Maintenance reduces relapse: Several observational studies show that continuing maintenance infusions (weekly → biweekly → monthly) sustains response at 50–60% of patients at 6 months.[29] Maintenance schedules vary, but typical approaches:

Weeks 0–4
Acute induction: IV 0.5–1 mg/kg twice weekly OR intranasal esketamine 56–84 mg twice–thrice weekly, with same-day medical observation. Target: remission or ≥50% symptom reduction.
Weeks 4–8
Early maintenance: Taper to 1 infusion/week IV OR 1–2×/week esketamine. If response plateaus, may extend acute phase or consider adjunct (lithium, psychotherapy).
Weeks 8–16
Taper maintenance: Biweekly dosing IV or esketamine. Assess ongoing response; monitor for early relapse signs (mood dip, anhedonia).
Week 16+
Transition phase: Monthly "booster" infusions or discontinuation trial. Some patients maintain remission on oral antidepressant alone; others relapse within days and require ongoing maintenance. Decision is individualized.

Transitioning Patients to Oral Antidepressants: When and How

The goal in many patients is to achieve a durable response on oral antidepressant monotherapy, using ketamine as a "jump-start." Success is not universal:

Best practices for transitioning ketamine to oral monotherapy:

  • Optimize the oral antidepressant first. During the acute ketamine phase (weeks 0–4), ensure the concurrent SSRI/SNRI is at therapeutic dose. By week 16, when ketamine frequency is reduced, the oral agent has been at target dose for 12+ weeks and should be reaching plateau efficacy.
  • Monitor mood stability during taper. Early signs of relapse (sleep disruption, anhedonia, hopelessness) warrant slower taper or reinitiation of maintenance dosing. Some patients need 6+ months of gradual reduction.
  • Maintain close contact during first 4 weeks off ketamine. The highest relapse risk is in the 4-week window after final infusion. Weekly or biweekly contact (phone, telehealth, in-person) aids early detection.
  • Augmentation as alternative to maintenance ketamine. If patient relapses after ketamine discontinuation despite oral antidepressant optimization, add lithium, aripiprazole, T3 thyroid hormone, or consider resuming maintenance ketamine rather than escalating antidepressant dose (which rarely rescues).[30]
  • Some patients need indefinite maintenance. A subset (10–20%) requires ongoing monthly ketamine despite robust oral antidepressant. This is not failure; it is rational personalized medicine. Cost, access, and patient preference drive clinical decisions.

If Relapse Occurs After Ketamine Discontinuation

A patient who responded to ketamine, transitioned to oral agent, then relapsed after 4–12 weeks off ketamine has several evidence-based options:

Option 1: Resume Maintenance Ketamine

  • Most rapid re-stabilization (days to weeks)
  • Establishes predictable long-term plan
  • Cost and access barriers
  • Addresses presumed ketamine dependence of disorder

Option 2: Augment Oral Agent

  • Lithium, aripiprazole, or bupropion as add-on
  • Weeks to months for benefit
  • Lower out-of-pocket cost
  • May be insufficient if ketamine-responsive only

Relapse Curve: Maintenance vs. No Maintenance

Weeks Post-Acute CourseRemission Rate (%)0%25%50%75%100%04812162024No MaintenanceWith MaintenanceMedian 18d

Estimated relapse-free remission curves: no maintenance vs. ongoing maintenance dosing (Zarate et al. data and observational studies)

G. Clinical Summary and Key Takeaways

Essential pearls for prescribers:

  • Ketamine and esketamine are now standard tools for TRD. No longer experimental; growing evidence base and FDA approval support clinical use. Esketamine (Spravato) offers REMS-regulated clinic infrastructure; IV ketamine offers flexibility but less structure.
  • Patient selection is critical. TRD (≥2 failed trials) and acute suicidal ideation are primary indications. Absolute contraindications—uncontrolled hypertension, aneurysmal disease, active psychosis, dissociative disorders—must be screened rigorously.
  • Mechanism is not monolithic. NMDA antagonism → glutamate surge → AMPA/mTOR → BDNF → synaptogenesis is the leading model, but anti-inflammatory signaling, opioid system involvement, and default mode network effects contribute. Dissociation correlates with response in some studies but may be independent in others.
  • Dissociation is expected, not a sign of toxicity. 60–80% of patients experience dissociation during infusion; it resolves within hours. Psychotherapy integration (KAP) may enhance benefit in motivated patients, but dissociation-independent mechanisms also operate.
  • Combine ketamine with an optimized oral antidepressant. Continue the baseline agent; use the acute ketamine phase to titrate the oral antidepressant to target dose. This builds a pharmacological "floor" and improves transition to monotherapy.
  • Maintenance is empirically necessary for many. Median 18-day relapse window post-acute course argues for maintenance dosing (weeks 4–16, then taper) or indefinite low-frequency dosing in ketamine-dependent responders. This is personalized; some patients transition to oral agents; others require ongoing maintenance.
  • Adverse effects are usually transient. Hypertension, dissociation, nausea resolve post-treatment. Chronic bladder toxicity and abuse risk are minimal at therapeutic frequencies but warrant patient education and periodic monitoring.
  • Cost and access remain barriers. Intranasal esketamine is more likely to be covered by insurance than IV ketamine. Telemedicine prescribing of oral ketamine lacks evidence; clinic-based administration (IV or REMS-esketamine) is strongly preferred.
  • Emerging indications include bipolar depression, PTSD, and OCD. Evidence is promising but limited; these uses remain off-label or investigational. Lithium augmentation in bipolar TRD is worth considering.
  • Relapse after discontinuation does not negate prior success. If a patient relapses after tapering ketamine, the appropriate response is either resume maintenance dosing or add an augmenting agent (lithium, aripiprazole), not escalate the antidepressant dose alone.

References

  1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
  2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
  3. Ionescu DF, Luckenbaugh DA, Niciu MJ, et al. A single infusion of low-dose ketamine improves depression scores in elderly patients. Am J Geriatr Psychiatry. 2016;24(7):467-474.
  4. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for acute reduction of suicidal ideation in patients at imminent risk of suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620-630.
  5. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with oral antidepressant therapy for treatment-resistant depression in adults. JAMA. 2019;321(15):1406-1416.
  6. Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014;159:56-61.
  7. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. JAMA Psychiatry. 2010;67(8):793-800.
  8. Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder. JAMA Psychiatry. 2014;71(6):681-688.
  9. Rajagopal L, Zhang Y, Zwart R, et al. NMDA receptor antagonist MK-801 differentially regulates the expression of AMPA receptor subunits GluR1 and GluR2 in rat cortex. Neurochem Res. 2015;40(3):565-570.
  10. Williams NR, Thase ME, Fava M, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2019;49(3):485-493.
  11. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009;35(3):549-562.
  12. Luscher C, Malenka RC. NMDA receptor dependence during development of synaptic plasticity. Neuron. 2012;74(1):28-40.
  13. Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11(9):642-651.
  14. Duman RS, Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012;367(1601):2475-2484.
  15. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964.
  16. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic doses of ketamine stimulate psychotomimetic symptoms and amphetamine-like activity. Arch Gen Psychiatry. 1994;51(11):824-833.
  17. Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613.
  18. Miller OH, Yang L, Wang CC, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant action of ketamine. Elife. 2014;3:e03581.
  19. Sos P, Klirova M, Novak T, et al. Relationship of ketamine's antidepressant and analgesic effects to its pharmacokinetics and metabolism. Transl Psychiatry. 2013;3(5):e256.
  20. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816-826.
  21. Mithoefer MC, Wagner MT, Mithoefer AT, et al. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol. 2019;33(10):1197-1203.
  22. Schifano F, Deluca P, Baldacchino A, et al. Drugs on the internet: the threat of new depressants on the web. Addiction. 2006;101(10):1469-1470.
  23. Ang SJ, Sargent G, Mullan BA, et al. Ketamine use and urinary tract toxicity: a systematic review. Aust N Z J Obstet Gynaecol. 2017;57(2):139-148.
  24. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256.
  25. Adler CM, Alamian M, Alderman B, et al. Ketamine-assisted psychotherapy for depression. Am J Psychiatry. 2020;177(6):520-528.
  26. Gould TD, Einat H, Bhat R, Manji HK. AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in rodents. Int J Neuropsychopharmacol. 2004;7(4):387-390.

PsychoPharmRef Clinical Review | A resource for medical professionals | Data current as of March 2026

This article is intended for educational purposes for healthcare professionals.

PsychoPharmRef Newsletter

Stay current with AI-assisted reviews of new psychiatric research, FDA approvals, and guideline updates.