For referring clinicians
What you should know before you refer
Written for psychiatrists, psychiatric nurse practitioners, pain physicians and primary care physicians considering a referral for ketamine infusion therapy.
You keep prescribing and ongoing management. We assess, treat, score and report back to you.
What we do
Sub-anesthetic intravenous ketamine for treatment-resistant mood conditions and for chronic neuropathic pain.
Dosing targets a modeled serum concentration rather than fixed weight-based dosing. Patients undergo metabolic and, where indicated, pharmacogenomic assessment before treatment. Infusions are physician-administered with continuous monitoring, one patient at a time.
Ketamine is FDA-approved as an anesthetic. Its use for mood conditions and chronic pain is off-label.
Who to refer
Major depressive disorder without psychotic features, in patients who have had adequate trials of at least two medications from different classes without significant benefit. Patients who have not improved with electroconvulsive therapy or with repetitive transcranial magnetic stimulation are also candidates.
Neuropathic pain not controlled by injections, nerve blocks or prescription analgesics: trigeminal neuralgia, complex regional pain syndrome, phantom limb pain, and postherpetic neuralgia. Also chronic back and neck pain that has stopped responding to other treatment, and fibromyalgia.
We characterize and classify a pain condition before recommending ketamine for it. Where a presentation is primarily nociceptive, or acute on chronic, we will usually tell the patient that this may not be the right treatment and explain why.
Medications that may affect the response
Several medications compete at the NMDA receptor or at D2 and D3 receptors and may limit the clinical effect of ketamine. These include risperidone, olanzapine and lamotrigine. A patient taking one of them would need a downward titration and temporary discontinuation for roughly two weeks before the infusion series and through the course, resuming afterward if clinically indicated.
The role of lamotrigine in particular remains a topic of controversy, and the evidence that it blunts the response to ketamine is mixed rather than settled. Our preference is that patients we accept are not taking lamotrigine at the time of their infusions. That is a decision for the prescribing clinician, and we are glad to work through it with you.
Benzodiazepines deserve particular attention, because they are common and because the effect appears to be dose-related. Concurrent use has been associated with a smaller antidepressant response,1 with a longer time to response and a shorter time to relapse,2 and in one series a daily dose above the equivalent of eight milligrams of oral diazepam predicted a poorer result.3
In our own practice, a daily dose somewhere around the equivalent of eight to ten milligrams of oral diazepam is enough to reduce both the effect of the infusion and how long it lasts. That is a clinical observation rather than a study, and it is not a threshold we can give you with precision. It is usually the first thing worth addressing before a course, and it is a conversation we would rather have with you than with the patient alone.
Naltrexone and other agents acting at opioid receptors, and anything that alters ketamine metabolism, are reviewed case by case. There are others, and we will discuss them with you and with the patient.
None of this resolves neatly in the abstract, and a particular patient is far easier to think about than a general rule. Call the office and we will set up a time to talk it through — the medication list, whether this person is a reasonable candidate, the timing of a taper, or anything else that would help you decide.
Dr. Grass takes those conversations himself, and a call that ends in do not refer this patient is as useful to us as one that does not.
1. Frye MA, Blier P, Tye SJ. Concomitant benzodiazepine use attenuates ketamine response. J Clin Psychopharmacol. 2015. PMID 25928701.
2. Albott CS, Shiroma PR, Cullen KR, et al. The antidepressant effect of repeat dose intravenous ketamine is delayed by concurrent benzodiazepine use. J Clin Psychiatry. 2017;78(3):e308–e309.
3. Andrashko V, Novak T, Brunovsky M, et al. The antidepressant effect of ketamine is dampened by concomitant benzodiazepine medication. Front Psychiatry. 2020;11:844. PMID 33005153.
What we ask of you
- Retain prescribing and ongoing psychiatric management. We do not take over medication management, and we do not want to.
- Send records and recent labs. We will not treat without them.
- Tell us about suicidal ideation directly. We do treat these patients, but only on your recommendation and in ongoing co-management with you.
What you get back
- A written assessment before treatment, including our view on candidacy — which is sometimes negative.
- Serial symptom scores at defined intervals, sent to you.
- A note after each course, and notification of any adverse event.
What the evidence supports, and what it does not
It is worth being direct with colleagues about where the literature actually sits.
The acute antidepressant effect of ketamine is well replicated. Durability, the optimal maintenance strategy, real-world effectiveness outside trial conditions, and the adequacy of blinding in the trial literature are all genuinely unsettled.
Our own outcome data is a single-site retrospective case series presented at meetings. It is not peer-reviewed work, and we describe it that way. We would rather you referred a patient with an accurate picture than an enthusiastic one.
Our outcome data, with its limitations Safety, risks and limits
Who will be treating your patient
Gerald W. Grass, MD. In medicine since 1983 and working with ketamine since 1985. Formerly Assistant Professor of Anesthesiology and Pain Medicine at Yale University School of Medicine and Director of the Yale Pain Medicine Fellowship Program, and Chief of Pain Medicine at VA Connecticut.
Principal investigator on a VA Connecticut study of NMDA antagonists, including ketamine, with an enhanced multimodal infusion technique in intractable neuropathic pain syndromes, 2010–2013. The RESTORE protocol came out of that work.
He starts the IV, runs the infusion, and remains with the patient until it ends and through the early part of recovery.
Two bodies of work are registered with the United States Copyright Office: Ketamine Infusion Center Standards — Guidelines for Ketamine Infusion Therapy in Non-Hospital Facilities (TXu002183277, December 2019), and the clinician training course (TXu002192721, December 2019). The course has run quarterly since 2016: six modules and forty-six sections, combining classroom instruction with supervised clinical training in a working infusion suite.
For a referring clinician the relevance is practical. The protocol your patient will receive is written down and is taught to other physicians, so you can ask exactly what will be done and get the same answer every time.
To discuss a patient
Dr. Grass will speak with you personally before a referral
Tell us what the patient has already had and we will tell you honestly whether this is likely to help, including when the answer is no.
The RESTORE method Fees Our results
RESTORE — ketamine therapy, done precisely.