Across our APA offices in California, many patients with treatment-resistant depression (TRD) are hearing about ketamine and wondering: What’s the difference between IV ketamine and intranasal esketamine SPRAVATO? Which is safer? Which is actually FDA-approved for depression?
This article is a psychiatry guide to esketamine vs ketamine, covering mechanisms, FDA approvals, REMS requirements, APA clinics workflow, side effects, how these treatments fit with your existing medications, and who typically qualifies.
1. Mechanisms and formulations: how esketamine and ketamine work
Both ketamine and esketamine treatment act primarily as NMDA receptor antagonists, affecting the glutamate system and downstream synaptic plasticity. They are Schedule III controlled substances.
IV ketamine is the racemic mixture (R- and S-enantiomers) and is FDA-approved only as an anesthetic, not for any psychiatric indication.
Esketamine is the S-enantiomer formulated as an intranasal spray SPRAVATO and is FDA-approved for:
Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior
The FDA expanded approval so that esketamine treatment can also be used as monotherapy in certain TRD situations, giving psychiatrists more flexibility beyond the strict, must combine with an oral antidepressant only.
2. Regulatory status: FDA approval vs. off-label use
This is one of the biggest differences in the esketamine vs ketamine discussion.
Esketamine (SPRAVATO®) – FDA-approved for depression
Clearly defined indications, dosing, and safety requirements in the official FDA label and REMS program.
Must be administered in a certified healthcare setting, like Advanced Psychiatry Associates, with post-dose observation and documentation.
IV ketamine – off-label for depression
Ketamine is not FDA-approved for any psychiatric disorder; its approval is for anesthesia
Use for depression is off-label, guided by clinical studies and expert consensus rather than a formal psychiatric indication.
The FDA has specifically warned about risks of compounded ketamine products (including some nasal or oral formulations) used for psychiatric conditions, emphasizing that these compounded drugs are not FDA-approved and may pose safety/quality risks.
At Advanced Psychiatry Associates in California, we focus on FDA-approved intranasal esketamine, delivered under REMS, rather than office-based IV ketamine infusions.
3. REMS requirements & clinic workflow (Esketamine)
Because esketamine treatment can cause sedation, dissociation, and transient increases in blood pressure, the FDA requires a REMS, Risk Evaluation and Mitigation Strategy program.
A typical visit to APA California offices looks like this:
Pre-dose check
Confirm indications (TRD or MDD with suicidality).
Review current medications and recent response.
Measure blood pressure and pulse.
Confirm you have no driving planned after treatment.
Dosing
You self-administer esketamine nasal spray under supervision.
Dose is determined by protocol, clinical response, and tolerability.
Observation
Vitals monitored.
Staff assess for dissociation, sedation, nausea, and overall clinical status.
You may rest quietly; no procedures requiring coordination or concentration.
Discharge
You leave Advanced Psychiatry Associates clinics only when deemed clinically stable.
You must have a ride home and avoid driving, operating machinery, or high-risk activities for the rest of the day
This structured environment and standardized monitoring are key advantages of esketamine compared to many IV ketamine settings, which can be more variable in protocols, observation standards, and coverage.
4. Efficacy: what the data show
Both ketamine and esketamine act rapidly in many patients with treatment-resistant depression, often within hours to days.
Esketamine Treatment has multiple randomized controlled trials and long-term continuation data in TRD, supporting its approval as an add-on and now also as monotherapy in specific adult TRD populations.
IV ketamine has strong evidence from clinical trials as well, but remains off-label; major guidelines and consensus statements emphasize the need for careful patient selection and standardized protocols because of safety and misuse concerns.
From a psychiatric practice standpoint, esketamine’s formal approval, defined dosing, and REMS framework give it a clearer role in a structured treatment-resistant depression algorithm than IV ketamine.
5. Side effects & safety monitoring
Esketamine (intranasal)
Commonly monitored effects include:
Dissociation and perceptual changes
Sedation or feeling “out of it” temporarily
Dizziness, nausea, or vomiting
Transient blood pressure increases
These are usually time-limited and managed in-clinic, with vitals and clinical status documented before discharge.
IV ketamine
Reported issues in studies and reviews include:
Dissociation and psychotomimetic symptoms, often more pronounced at anesthetic-range doses
Acute hypertension and tachycardia
Cognitive and memory changes with repeated high-dose or long-term exposure
Potential for misuse, dependence, and bladder/urinary tract problems seen in chronic high-dose recreational use
The American Society of Anesthesiologists (ASA) and FDA have highlighted concerns about ketamine for mental health being provided outside structured medical frameworks, especially when compounded or delivered remotely.
6. Integration with ongoing medications
Esketamine is typically used for treatment-resistant depression, meaning a person has not responded to two or more adequate antidepressant trials.
At Advanced Psychiatry Associates clinics across California:
We review your entire medication history (antidepressants, mood stabilizers, antipsychotics, anxiolytics, and medical medications).
Esketamine is often used in combination with an oral antidepressant, though recent FDA updates allow monotherapy in specific TRD contexts; in practice, we individualize based on prior intolerance and current regimen.
Dosing and frequency are adjusted based on clinical response, side effects, and vitals, within label and REMS requirements.
For IV ketamine, integration with ongoing meds is less standardized because its use is off-label, and protocols vary widely between clinics.
7. Who qualifies — and who may not
Typical esketamine candidates
Adults with treatment-resistant depression (TRD) who have not responded to at least two adequate antidepressant trials
Adults with MDD and acute suicidal ideation or behavior, when a rapid reduction in depressive symptoms is needed under close monitoring
Able to attend in-clinic sessions on a scheduled basis and arrange transportation home after each dose
Important cautions and contraindications
Based on labeling and expert reviews, esketamine may not be appropriate in cases such as:
Uncontrolled hypertension or significant cardiovascular/aneurysm history
History of intracerebral hemorrhage
Severe hepatic impairment
Certain aneurysmal or vascular malformations
Significant current substance use disorder where dissociative agents pose a high misuse risk
Pregnancy or breastfeeding (risk–benefit discussion required)
Every patient at APA clinics receives an individual risk–benefit assessment before esketamine treatment is recommended.
Next step: Find out if you’re an esketamine candidate
If you’ve already tried several antidepressants and still don’t feel like yourself, we can evaluate whether FDA-approved esketamine, within a structured, medically monitored program, fits your situation.
Resources
Esketamine Is The Psychiatric Protocol for Treatment-Resistant Depression
The Advanced Psychiatric Algorithm for APA Treatment-Resistant Depression
What to Expect For Transcranial Magnetic Stimulation (TMS) at APA
