Esketamine and Ketamine in Psychiatry: A Scientific Perspective

Over the last decade, ketamine and its derivative, esketamine, have reshaped conversations around psychiatric treatment. Traditionally used as anesthetics, these compounds are now gaining attention for their rapid antidepressant effects and their potential to address conditions that have long resisted conventional therapies.

From major depressive disorder (MDD) to treatment-resistant depression (TRD), researchers are actively exploring how these agents can help patients where other treatments fall short. This article delves into the science behind ketamine and esketamine, their similarities, differences, clinical applications, safety profiles, and ongoing research.

Understanding Ketamine and Esketamine

Ketamine, first synthesized in the 1960s, has been widely used as a dissociative anesthetic. It exists as a mixture of two mirror-image molecules, or enantiomers:

• R-ketamine
• S-ketamine (esketamine)

Esketamine, the purified S-enantiomer, is marketed under the brand name Spravato and was approved by the U.S. Food and Drug Administration (FDA) in 2019 for treatment-resistant depression.

Key Scientific Differences:

• Ketamine: Administered intravenously, intramuscularly, or orally; commonly used off-label for psychiatric purposes.
• Esketamine: Delivered via a nasal spray and FDA-approved for psychiatric indications, but administered strictly under medical supervision.

Mechanism of Action: A Closer Look

Traditional antidepressants, such as SSRIs and SNRIs, work by increasing levels of serotonin, norepinephrine, and dopamine. However, they often take 4 to 6 weeks to produce noticeable effects and may fail in cases of treatment resistance.

Ketamine and esketamine, by contrast, primarily target the glutamatergic system. They act as NMDA receptor antagonists, triggering a cascade of neural changes:

• Increased Glutamate Levels → Enhances brain signaling pathways.
• BDNF Release → Promotes neuroplasticity and the growth of new neural connections.
• Synaptic Restoration → Repairs disrupted circuits involved in mood regulation.

This unique mechanism explains why many patients report rapid relief within hours, making these agents particularly valuable in acute depressive episodes and suicidal crises.

Clinical Applications in Psychiatry

Research has expanded ketamine and esketamine’s potential role in multiple psychiatric conditions.

Condition	Ketamine	Esketamine
Treatment-Resistant Depression (TRD)	IV ketamine shown to improve symptoms in 50-70% of TRD cases.	FDA-approved for TRD via nasal spray.
Major Depressive Disorder	Rapid onset of antidepressant effects within hours.	Approved as an adjunct to oral antidepressants.
Post-Traumatic Stress Disorder (PTSD)	Promising but still experimental.	Limited data; not FDA-approved.
Anxiety & OCD	Some evidence supports symptom reduction.	Research is ongoing.
Suicidal Ideation	Reduces suicidal thoughts quickly, often within hours.	Approved specifically for acute suicidal risk in MDD.

Regional Availability and Access

Accessibility to safe, evidence-based ketamine care has grown significantly across the U.S. For example, ketamine treatment in Gilbert, Arizona is increasingly available through clinics that follow structured, medically supervised protocols. This ensures patients receive scientifically grounded care while minimizing risks associated with unsupervised use.

Safety Profiles: Ketamine vs. Esketamine

While both compounds are considered generally safe under clinical supervision, understanding their risk profiles is essential.

Short-Term Side Effects

• Common: Dissociation, dizziness, mild hallucinations, elevated heart rate, nausea.
• Duration: Usually subside within 1–2 hours post-treatment.
• Management: Monitored settings ensure quick interventions when necessary.

Long-Term Safety Considerations

• Dependency Risk: Low in medically supervised environments but higher with recreational misuse.
• Cognitive and Bladder Effects: Rare at therapeutic doses but reported with chronic high-frequency use.
• Regulatory Oversight: Esketamine has stricter controls, including REMS (Risk Evaluation and Mitigation Strategy) requirements.
  

Table: Safety Comparison

Aspect	Ketamine	Esketamine
Approval Status	Off-label for psychiatric use	FDA-approved for TRD and suicidal risk
Administration	IV, IM, oral, sublingual	Intranasal only
Monitoring	Recommended but not mandated	Mandatory, under REMS guidelines
Common Side Effects	Dissociation, nausea, dizziness	Similar side effects, generally less intense
Abuse Potential	Moderate if unsupervised	Lower due to restricted distribution

Comparing Efficacy: Research Insights

Several studies highlight ketamine and esketamine’s potential for treatment-resistant depression:

• Intravenous Ketamine Trials: Around 50-70% of participants report significant symptom improvement after just one or two infusions.
• Esketamine Clinical Trials: Demonstrated statistically significant reductions in depressive symptoms when combined with oral antidepressants.
• Suicidality Studies: Both agents show rapid decreases in suicidal ideation, making them particularly valuable in emergency psychiatric care.

Integration With Psychotherapy

Emerging evidence suggests ketamine and esketamine may work best when combined with psychotherapy. The rapid boost in neuroplasticity creates a “window of opportunity” where patients may better respond to interventions such as:

• Cognitive Behavioral Therapy (CBT)
• Eye Movement Desensitization and Reprocessing (EMDR)
• Trauma-Focused Therapies

This integrated approach aligns biological and psychological healing, improving long-term outcomes.

Future Directions in Ketamine and Esketamine Research

Ongoing studies aim to answer critical questions:

• Biomarkers of Response: Predicting which patients benefit most.
• Long-Term Efficacy: Understanding how benefits sustain over months or years.
• New Delivery Methods: Exploring oral, sublingual, and at-home supervised protocols.
• Novel Derivatives: Developing compounds with fewer side effects and reduced abuse potential.

Final Thoughts

Ketamine and esketamine represent a paradigm shift in psychiatric treatment. By working on the glutamatergic system rather than traditional serotonin pathways, they offer rapid, effective relief for patients struggling with treatment-resistant depression and related conditions.

However, these treatments are not first-line options and must be administered in controlled settings with proper monitoring. As research continues, their role in psychiatry will likely expand, shaping a future where mental health care is faster, more precise, and more effective.