By Kyle Roth, FNP-BC, APRN, MSN, MHA | Roth Family Medicine and Mental Health | Pocatello, Idaho

For years, ketamine was known primarily as an anesthetic and, regrettably, as a drug of misuse. What's happened in psychiatric medicine over the past two decades represents one of the most significant breakthroughs in the treatment of depression in a generation — and for patients in Pocatello and Southeast Idaho who have tried antidepressant after antidepressant without relief, it may be the most important development they've never heard of.

This is a comprehensive, clinically grounded guide to ketamine therapy for treatment-resistant depression (TRD). I'm writing it because my patients deserve to make fully informed decisions — and because there is a significant gap between what the research shows and what most people in our region actually know.

To understand why ketamine is so clinically remarkable, you first need to understand why standard antidepressants often fall short.

SSRIs and SNRIs work by increasing the availability of monoamine neurotransmitters — primarily serotonin, and secondarily norepinephrine. This approach is effective for many patients. But it takes weeks to work, doesn't help everyone, and entirely misses a neurobiological pathway that is increasingly understood to be central to depression: the glutamate system.

Ketamine is an NMDA (N-methyl-D-aspartate) receptor antagonist. At sub-anesthetic doses, it temporarily blocks NMDA receptors, which produces a cascade of downstream effects:

1. Rapid glutamate surge: NMDA blockade causes a burst of glutamate release, which activates AMPA receptors
2. BDNF release: This triggers the release of brain-derived neurotrophic factor (BDNF), a protein critical for neuroplasticity and the formation of new synaptic connections
3. mTOR activation: The mechanistic target of rapamycin (mTOR) pathway is activated, stimulating synaptic protein synthesis
4. Rapid synaptogenesis: New synaptic connections form in the prefrontal cortex — reversing the synaptic atrophy that chronic depression produces

The practical result: ketamine can produce measurable antidepressant effects within hours, compared to the 4–8 weeks required for SSRIs. For patients with severe, treatment-resistant depression — or those with active suicidal ideation — this speed of action is clinically extraordinary.

Ketamine therapy is typically considered when:

• The patient meets criteria for treatment-resistant depression — having failed adequate trials of at least two antidepressants of different classes
• There is active suicidal ideation where rapid intervention is clinically urgent
• Standard antidepressants are contraindicated or poorly tolerated
• The patient has co-occurring anxiety, PTSD, or OCD that hasn't responded to standard treatment
• Functional impairment is severe and ongoing

Contraindications and relative contraindications that require careful evaluation include:

• Active or history of psychotic disorder (schizophrenia, schizoaffective disorder)
• Uncontrolled hypertension — ketamine transiently raises blood pressure and heart rate
• Active substance use disorder, particularly involving dissociatives
• Unstable cardiovascular disease
• Active mania or rapid-cycling bipolar disorder (bipolar depression, treated appropriately, may be a candidate)
• Pregnancy

A thorough pre-treatment evaluation — medical history, current medications, cardiac assessment, and psychiatric assessment — is essential and is standard practice at our clinic.

The most extensively studied formulation. Administered as a slow intravenous infusion, typically over 40–60 minutes at a sub-anesthetic dose (usually 0.5 mg/kg, though this is adjusted based on individual response and tolerability).

Standard protocol for TRD is a series of 6 infusions over 2–3 weeks, followed by maintenance infusions at individually determined intervals.

Advantages:

• Most evidence: hundreds of studies documenting efficacy and safety
• Precise dose control
• Rapid onset (effects often within 24 hours)
• Can be used in patients who cannot use intranasal formulations

Esketamine is the S-enantiomer of ketamine and is FDA-approved specifically for treatment-resistant depression (2019) and for major depressive disorder with acute suicidal ideation (2020). It is the first treatment with a specific FDA indication for TRD.

Administered in a certified healthcare setting with monitoring for at least 2 hours post-dose. Standard protocol is twice-weekly for 4 weeks (induction), then weekly for 4 weeks, then every 1–2 weeks (maintenance).

Advantages:

• FDA-approved specifically for TRD — regulatory clarity
• Insurance coverage more available (still limited; often requires prior authorization)
• Intranasal delivery — no IV required

At Roth Family Medicine and Mental Health, we offer a thorough evaluation to determine which formulation is most appropriate for each patient's clinical situation.

Patients often want to know what to expect perceptually during an infusion. Honest, clear preparation matters enormously — and contributes to therapeutic outcomes.

During a ketamine infusion, patients commonly experience:

• Dissociation: A sense of detachment from the body or surroundings — sometimes described as "floating" or feeling outside oneself
• Altered perception of time: Minutes may feel like hours, or time may seem to stop
• Visual and sensory changes: Colors may appear brighter; patterns or mild visual effects may be noticed with eyes closed
• Emotional experiences: Some patients experience a sense of profound peace; others encounter difficult emotions that surface unexpectedly
• Physical sensations: Mild dizziness, nausea (manageable with pre-treatment antiemetics), tingling, or warmth

The intensity of these experiences varies significantly between patients and across sessions. Most patients describe the experience as manageable and, with preparation and a calm clinical environment, often meaningful.

The set and setting — the patient's mental state going in, and the physical and interpersonal environment of the clinic — meaningfully affect the experience and the therapeutic outcome. This is why the clinical context of ketamine administration matters, not just the molecule.

Ketamine is not simply a chemical reset button. The most durable outcomes occur when ketamine treatment is paired with psychological integration work — processing what came up during the experience, identifying insights, and anchoring new perspectives into behavioral changes.

Integration can take several forms:

• Post-session processing conversations with a trained clinician
• Structured journaling between sessions
• Psychotherapy (CBT, ACT, or trauma-focused modalities) running concurrently with the ketamine series
• Lifestyle restructuring — using the neuroplasticity window that ketamine opens to establish new patterns around sleep, exercise, social connection, and stress management

Research suggests that patients who engage in integration work show better and more durable response than those who receive ketamine in isolation.

The honest answer is: it varies. Response durability after an initial 6-infusion series typically ranges from 2 weeks to several months. A meaningful subset of patients have very durable responses; others require maintenance infusions.

Factors that appear to affect durability include:

• Severity and duration of depression
• Presence of ongoing psychosocial stressors
• Engagement with integration and psychotherapy
• Concurrent antidepressant medication (some evidence suggests combining ketamine with an oral antidepressant improves durability)
• Lifestyle factors (sleep, exercise, inflammation)

For many patients, ketamine is part of a longer-term treatment strategy — using the neuroplasticity window it creates to engage in therapy and lifestyle change that builds resilience over time.

Ketamine has been used safely as an anesthetic for over 50 years. At the sub-anesthetic doses used in psychiatric treatment, the safety profile is well-characterized.

Common, manageable side effects:

• Transient dissociation during infusion (resolves within 1–2 hours)
• Nausea (prevented with pre-treatment antiemetics)
• Transient blood pressure and heart rate elevation
• Headache
• Fatigue after infusion

Serious risks (rare but requiring monitoring):

• Significant blood pressure elevation — reason why cardiac assessment and monitoring is essential
• Emergence of psychotic symptoms in predisposed individuals — reason why screening for psychosis history is critical
• Bladder toxicity — associated with long-term recreational use at high doses; extremely rare at therapeutic doses in clinical protocols

At therapeutic doses in a clinical setting, the risk of ketamine dependency is low. Patients with personal or family history of substance use disorders are screened carefully and may require modified protocols.

Am I a candidate if I only failed one antidepressant? Potentially, depending on the clinical picture. Patients with severe functional impairment, active suicidal ideation, or specific clinical characteristics may be candidates earlier in their treatment course. This is an individualized clinical decision.

Does ketamine work for bipolar depression? Ketamine has been studied in bipolar depression and shows promising results, though the evidence base is smaller than for unipolar TRD. Bipolar status requires careful evaluation and a different clinical approach.

Will I be unconscious during the infusion? No. Sub-anesthetic ketamine does not produce unconsciousness. You will be in an altered but conscious state, able to communicate with clinical staff.

Can I drive after an infusion? No. Patients require a responsible adult driver after each session. We advise against operating any machinery for the remainder of the day.

How do I get started? Contact Roth Family Medicine and Mental Health to schedule a pre-treatment evaluation. We will review your psychiatric history, prior medication trials, medical health, and goals to determine whether ketamine therapy is appropriate and, if so, which protocol is best suited to you.

1. Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354.
2. Murrough JW, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression. Am J Psychiatry. 2013;170(10):1134–1142.
3. Aan Het Rot M, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139–145.
4. Dore J, et al. Ketamine-assisted psychotherapy: Patient demographics, clinical data, and outcomes. J Psychoactive Drugs. 2019;51(2):189–198.
5. Zarate CA Jr, 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.

Medical Disclaimer: This content is for educational purposes only and does not constitute medical advice. Ketamine therapy carries risks and is not appropriate for all patients. Always consult a qualified healthcare provider before pursuing any treatment.

Kyle Roth, FNP-BC, APRN, MSN, MHA | Roth Family Medicine and Mental Health | Pocatello, Idaho | (208)-904-4705 | www.rothfamilymed.com