Episode

"The K-Hole Theory"

K-Hole Theory

When to Consider Ketamine Treatment

Faisal Rafiq MD.

Episode

"The K-Hole Theory"

K-Hole Theory

When to Consider Ketamine Treatment

Faisal Rafiq MD.

Episode

"The K-Hole Theory"

K-Hole Theory

When to Consider Ketamine Treatment

Faisal Rafiq MD.

Comments

Key Outline Points
Spravato (Esketamine) Treatment Criteria & Clinical Uses FDA-Approved (On-Label) Indications Spravato is FDA-approved for use in conjunction with an oral antidepressant in the following situations: Treatment-Resistant Depression (TRD): Defined as failure of at least two different antidepressant medications of adequate dose and duration in the current depressive episode. Patient must be currently experiencing moderate to severe Major Depressive Disorder (MDD). Major Depressive Disorder with Acute Suicidal Ideation or Behavior: Used for rapid reduction of depressive symptoms in patients with active suicidal thoughts or behaviors. Requires concurrent initiation or continuation of oral antidepressant therapy. General Eligibility Criteria To qualify for Spravato treatment, a patient must meet the following: Diagnosis of MDD with TRD or acute suicidality. Failure of at least two oral antidepressants in the current episode (for TRD). 18 years of age or older. No history of psychotic disorders, including schizophrenia. No active substance use disorder, particularly with stimulants or alcohol. No uncontrolled hypertension or cardiovascular instability. Must be able to attend in-clinic administration sessions twice weekly initially. Must be enrolled in the REMS (Risk Evaluation and Mitigation Strategy) program. Must have adequate social or transportation support due to the 2-hour post-administration monitoring requirement. Off-Label Uses (Emerging or Investigational) Spravato and racemic ketamine (IV/IM formulations) are being used or studied off-label in the following conditions: Post-Traumatic Stress Disorder (PTSD): Particularly in complex PTSD or refractory cases. Some evidence for rapid symptom relief in suicidal ideation and dissociative symptoms. Bipolar Depression (with caution): Used cautiously in bipolar depression not responsive to standard treatments. Not for patients with active mania or mixed episodes. Obsessive-Compulsive Disorder (OCD): Under investigation, based on its rapid-acting glutamate modulation. Chronic Suicidality: Beyond MDD context, some clinics utilize Spravato as a maintenance treatment for patients with repeated suicidal crises. Severe Anxiety Disorders (e.g., GAD, Panic Disorder): Anecdotal or emerging evidence for benefit in refractory cases. Substance Use Disorders: Intranasal or IV ketamine is under study for alcohol and cocaine dependence, due to neuroplasticity and craving modulation effects. Pain Management (rare with Spravato, more with IV ketamine): Conditions such as neuropathic pain, CRPS (Complex Regional Pain Syndrome) — usually managed with IV ketamine, not Spravato. Contraindications: History of aneurysmal vascular disease, including intracranial, thoracic, or abdominal aorta, or arteriovenous malformation. History of intracerebral hemorrhage. Uncontrolled hypertension. Pregnancy and breastfeeding (risk not well established). Monitoring Requirements: Vital signs before and after administration. Two-hour observation period post-dose. BP monitoring post-dose due to risk of transient elevation. Assessment for dissociation, sedation, and psychotomimetic effects. Ongoing mood and suicidality monitoring using standardized scales (e.g., PHQ-9, MADRS).
Clinical Considerations Advantages of Spravato: FDA-approved with more structured safety protocols. Easier to administer in psychiatric office settings. Generally more standardized dosing and oversight via REMS. Advantages of IV Ketamine: Greater clinical flexibility and titration precision. May be more cost-effective in some settings. Often perceived to have faster and stronger acute effects (anecdotally). Broader off-label psychiatric uses (e.g., PTSD, bipolar depression, OCD). Summary Spravato is often the first-line esketamine option due to FDA approval and insurance reimbursement, particularly for treatment-resistant depression and suicidal ideation. IV ketamine, while off-label, is widely used in treatment-resistant psychiatric conditions and may offer greater efficacy or flexibility, but with fewer reimbursement pathways.
Spravato (Intranasal Esketamine) vs. IV Ketamine

Category
Spravato (Esketamine)
IV Ketamine (Racemic Ketamine)
Formulation
Esketamine hydrochloride (S-enantiomer)
Racemic ketamine (R- and S-enantiomers)
Route of Administration
Intranasal spray
Intravenous infusion (usually over 40 minutes)
FDA Approval
Yes – for: 
1. Treatment-Resistant Depression (TRD) 
2. MDD with acute suicidal ideation/behavior


No FDA approval for psychiatric use (used off-label)
Controlled Substance Schedule
Schedule III
Schedule III
Mechanism of Action
NMDA receptor antagonist, increases glutamate and synaptic plasticity
Same mechanism, but racemic ketamine may have broader or slightly different receptor profiles
Dosing Protocol
Twice weekly for 4 weeks (Induction), then taper to weekly or biweekly
Typically 0.5 mg/kg over 40 min, 2–3 times per week during induction
Setting
REMS-certified clinic with 2-hour post-dose monitoring
Typically outpatient infusion center or clinic with emergency readiness
Onset of Action
Rapid — typically within hours to 1 day
Also rapid — often within 1–24 hours
Duration of Effect
Short-acting; may require ongoing maintenance dosing
Similar; maintenance often required
Insurance Coverage
Often covered under pharmacy benefit due to FDA approval
Rarely covered for depression; usually out-of-pocket
Cost
Expensive but may be reimbursed; approx. $800+ per session
Typically $400–$800 per infusion session (out-of-pocket)
Efficacy Evidence
Supported by multiple RCTs in TRD and suicidal depression
Robust off-label evidence, including RCTs, for TRD and suicidality
Side Effects
Dissociation, increased BP, nausea, sedation, dizziness
Similar profile; possibly more dissociation and psychotomimetic effects due to higher dosing
Monitoring
BP, mental status, sedation scores, 2-hour observation
BP, cardiac monitoring, dissociation tracking during infusion

Faisal Rafiq MD.