NMDA Antagonists

Reviewed by the HeyPsych Medical Review Board

Board-certified psychiatrists and mental health professionals

Indications

Primary Indications

Treatment-resistant depressionMajor depressive disorder with acute suicidalityBipolar depression (investigational)PTSD (exploratory)

Mechanism

NMDA antagonists block NMDA receptors, reducing excessive glutamate activity and enhancing synaptic plasticity. Ketamine increases glutamate release and activates AMPA receptors, which may restore neural connectivity impaired in depression.

Protocol

Preparation

Medical evaluation including psychiatric assessment, cardiovascular screening, and baseline labs.

Procedure

IV ketamine: 0.5 mg/kg infused over 40 minutes in monitored setting.
Esketamine: intranasal dosing under supervision, with post-dose monitoring for 2 hours.
Investigational oral or subcutaneous agents administered in trials.

Frequency: Typically 2 sessions/week initially; taper to maintenance as indicated.

Duration: Acute course 4–6 weeks; maintenance may extend months to years.

Total Treatment Time: Variable depending on response and relapse prevention strategy.

Expected Outcomes

Immediate

Rapid reduction in depressive symptoms
Reduction in suicidal ideation

Short Term

Improved mood stability
Improved functioning

Long Term

Potential relapse prevention with maintenance
Durability of response varies

Side Effects

common

Dissociation
Elevated blood pressure
Dizziness
Nausea

uncommon

Perceptual disturbances
Transient anxiety
Headache

rare

Bladder toxicity with long-term misuse
Substance misuse liability

Contraindications

absolute

Active psychotic disorder
Uncontrolled cardiovascular disease
Pregnancy

relative

History of substance use disorder
Severe liver impairment

special considerations

Close monitoring required during and after administration

Research Evidence

studies

Berman RM et al., 'Antidepressant effects of ketamine in depressed patients', Biol Psychiatry (2000).
Wilkinson ST et al., 'The effect of a single dose of intravenous ketamine on suicidal ideation', Depression & Anxiety (2018).
Daly EJ et al., 'Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy for treatment-resistant depression', JAMA Psychiatry (2019).

limitations: Durability of effect remains limited; repeated dosing protocols and long-term outcomes require further study.

Cost Considerations

typical session cost: $400–$800 per ketamine infusion; $600–$900 per esketamine session

total treatment cost: Thousands of dollars per course; ongoing maintenance adds cost

insurance coverage: Esketamine covered by some insurers; ketamine typically out-of-pocket

cost effectiveness: Potentially cost-effective for rapid relief in severe TRD, but high cost limits accessibility

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Integration Support

concurrent therapies

Psychotherapy to support integration
Ongoing antidepressant medication
Lifestyle modification for relapse prevention

lifestyle recommendations

Avoid driving or operating machinery same day
Engage in supportive therapy
Monitor cardiovascular health

References

Berman RM et al., 'Antidepressant effects of ketamine in depressed patients', Biol Psychiatry (2000)Daly EJ et al., 'Efficacy and safety of intranasal esketamine', JAMA Psychiatry (2019)Wilkinson ST et al., 'Effect of IV ketamine on suicidal ideation', Depression & Anxiety (2018)

This treatment information is for educational purposes only. Treatment decisions should be made in consultation with qualified healthcare professionals based on individual circumstances, symptoms, and medical history. Do not attempt treatment without professional guidance.

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