Referrals for ketamine therapy tend to arrive in two very different ways: (1) as a well-considered clinical escalation after multiple prior steps, or (2) as a last-ditch request from a patient who is exhausted and searching for anything that might help. This guide is designed for the first scenario, and to help with the second.
The goal of this article is to help providers decide when a referral makes clinical sense, what information helps the consult go well, and how to coordinate care responsibly when it does. National guidance consistently frames ketamine and esketamine as options after several adequate pharmacologic trials, with attention to risk, setting, and monitoring.
Practical “When to Refer” Thresholds
Treatment-Resistant Depression (TRD)
A reasonable referral threshold is an adult with major depressive disorder (MDD) who has not responded adequately to multiple evidence-based treatments and remains significantly impaired. Ketamine and esketamine are most often discussed in the context of TRD, with guideline summaries emphasizing use after multiple failed medication attempts.
Signals a referral may be appropriate
- Persistent moderate-to-severe symptoms despite multiple adequate antidepressant trials (with documentation).
- Functional impairment that is not improving (work, caregiving, basic self-care).
- Intolerable side effects or contraindications to additional medication strategies, where alternatives are limited.
- A pattern of partial response then relapse, despite reasonable adherence and follow-up.
Severe, Persistent, or Recurrent Depression
Guideline summaries (including U.S. Department of Veterans Affairs/Department of Defense [VA/DoD] clinical practice guidelines and secondary sources) note ketamine or esketamine as potential augmentation options, while also emphasizing limitations in evidence quality and the need for careful patient selection.
Signals a referral may be appropriate:
- Ongoing moderate-to-severe symptoms despite a partially effective antidepressant regimen.
- Recurrent depressive episodes with significant functional disruption.
- Clinical consideration of augmentation strategies after first-line options (e.g., optimization, psychotherapy, standard augmenting agents) have been explored.
- Escalating severity, including increased hopelessness or decline in functioning, despite active treatment.
Complex Pain with Meaningful Comorbid Mood Symptoms
Referral may be appropriate when pain is complex, refractory, and clearly intertwined with mood symptoms, sleep disturbance, and functional decline—especially when standard pain and mental health treatments have not been sufficient. (This does not imply “pain is psychological.” Rather, it acknowledges the overlap between neural circuitry, stress physiology, mood regulation, and functional impairment.) Pain-focused ketamine infusion guidance exists, including consensus recommendations, contraindications, and monitoring expectations.
Signals a referral may be appropriate:
- Chronic pain that remains functionally disabling despite multidisciplinary treatment.
- Co-occurring depression or anxiety that amplifies pain-related impairment.
- Centralized pain features (e.g., sleep disruption, fatigue, cognitive fog) alongside mood symptoms.
- Repeated treatment failures in both pain-directed and mood-directed care.
What to Send With the Referral (for a better consult)
Minimum helpful referral packet
- Current problem list and diagnoses (primary psychiatric and/or pain diagnoses).
- Medication history with dose, duration, and response (include adverse effects).
- Relevant psychotherapy history (type, duration, response).
- Substance use history and any SUD treatment history (current and remote).
- Suicide risk context (current ideation, attempts, protective factors, supports).
- Recent vitals and medical comorbidities, especially cardiovascular history.
- For pain: pain diagnosis, prior interventions, opioid history, functional status, and prior specialty notes.
Nice-to-have
- Most recent PHQ-9 / GAD-7 / PCL-5 (or your preferred, validated tools).
- Sleep assessment (insomnia pattern, OSA risk, CPAP adherence if applicable).
- Any history of psychosis, bipolar disorder, dissociation, or mania/hypomania.
- Recent labs or relevant medical workup when clinically indicated.
“Red Flags” That Should Trigger Extra Coordination Before Referral
These are not automatic disqualifiers, but they should slow the process down and prompt shared decision-making.
Higher-risk psychiatric context
- Current uncontrolled psychosis or mania/hypomania concerns.
- Significant dissociative disorder symptoms that are destabilizing.
- Active, untreated substance use disorder, especially if safety and misuse risk are not well contained.
Higher-risk medical context
- Poorly controlled cardiovascular disease or unstable physiology (risk depends on protocol, setting, and monitoring).
- Complex respiratory risk, particularly if there are concerns for sedation-related hypoventilation (monitoring expectations matter here).
Important setting warning (especially relevant to patient questions)
The FDA has specifically cautioned against compounded ketamine products for psychiatric indications and highlighted serious risks when used without onsite monitoring.
This matters because some patients will ask about at-home routes they found online. A provider referral can be a stabilizing force: “If you pursue this, do it in a medically supervised setting with appropriate screening and monitoring.”
How to Talk to Patients
A simple framing that works
- “This is one option we consider when standard treatments have not been enough.”
- “It requires medical screening and monitoring during visits, because side effects can include dissociation, blood pressure changes, and sedation.”
- “If it is not a fit, we will tell you directly and discuss next-step options.”
Expectation-setting (what patients often misunderstand)
- Response can be rapid for some, but durability varies and maintenance planning matters.
- It is not “one and done,” and it is not primarily a talk-therapy substitute.
- Safety is not optional, and setting and monitoring are part of the treatment.
Good Collaboration Looks Like:
Before starting
- Clarify management plan for baseline psychiatric meds during induction and maintenance.
- Align on how symptom monitoring will be tracked (tools, cadence, who receives results).
- For pain patients, clarify how analgesic regimens will be handled to avoid destabilizing changes mid-series.
During treatment
- Agree on what constitutes a “pause and reassess” signal (worsening suicidality, emergent mania, misuse concerns, significant medical adverse events).
After a series
- Decide what “success” means in advance (symptom reduction, function, return to work, sleep stability).
- Plan maintenance only if benefits are clear and risks remain acceptable.
References
1.American Academy of Family Physicians (AAFP). “Management of Major Depression: Guidelines From the VA/DoD.” (2023).
2.Swainson J, et al. “CANMAT Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder.” Can J Psychiatry. (2021).
3.McIntyre RS, et al. “Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression.” Am J Psychiatry. (2021).
4. CADTH / NCBI Bookshelf. “Ketamine for Adults With Treatment-Resistant Depression or PTSD.” (2024).
5. Cohen SP, et al. “Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain.” (ASRA/AAPM/ASA). Reg Anesth Pain Med. (2018).
6.SPRAVATO® (esketamine) Prescribing Information. Janssen.
7. FDA. “FDA warns about compounded ketamine for psychiatric disorders.” (Oct 10, 2023).
