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August 11, 2022

FAQ: Dr. Robert A. Millet on Treatment Resistant Depression

by Robert Millet, MD, DLFAPA

If you’ve been treated for depression, but you’re not experiencing improvement in your symptoms, you may have treatment-resistant depression. Medication or counseling often relieves depression symptoms for most, but not always for all. If you have treatment-resistant depression, your symptoms may improve for a short period of time and then return, or they may not improve at all.

If your depression symptoms are continuing despite the standard treatments, know there are treatment options for treatment-resistant depression. Dr. Robert Millet, MD, leads Avance Psychiatry’s Treatment Resistant Disorders and Interventional Psychiatry Group. He has over 25 years of clinical experience and specializes in treatment resistant disorders, with a particular interest in treatment resistant depression.

Dr. Millet has answered the most Frequently Asked Questions about treatment resistant depression below.


What is treatment resistant depression (TRD)?

About 30% of the 15 million Americans with major depressive disorder (MDD) are not responding adequately to their current antidepressants. The problem is compounded by the fact that multiple, repeated antidepressant trials offer little additional benefit. When patients fail two trials of standard antidepressant therapy, the chances of remission with the third antidepressant are less than 15% and less than 5% with the fourth (1). For Americans with unresolved symptoms of depression, earlier and better interventions are needed.


What are the treatment options for TRD?

Until recently, there were only a few choices if standard antidepressants did not work: augmentation with atypical antipsychotics, transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT). For many patients, logistical factors, time commitments and the risk of permanent side effects made these treatments unappealing. Recently, ketamine (2,3) and esketamine (marketed as Spravato®) have become alternatives to TMS, ECT and adjunctive antipsychotic medications. Ketamine is not approved by the FDA but has been shown in studies to be effective in TRD, Bipolar Depression, PTSD, OCD, chronic pain, and opioid dependence. Spravato® is FDA-approved for use in depression.


What is Spravato®?

Spravato® is esketamine, an isomer of ketamine, and it is used to treat major depression. It is the more potent isomer of ketamine, which allows it to be delivered effectively and comfortably by nasal spray. Spravato® was approved by the FDA in 2019 as it was shown in clinical trials to be safe and effective in patients with treatment resistant depression (4).


What does Spravato® treat?

Spravato® is FDA approved for treatment resistant depression in adults in conjunction with another antidepressant. Treatment resistant depression is now defined as depression that does not respond to adequate trials of two antidepressants. Spravato® has been recently approved for use in adults with major depressive disorder who have suicidal ideation. These patients do not have to fail adequate trials of two antidepressants – they can proceed directly to Spravato® treatment.


How does Spravato® work?

Like many antidepressants, we don’t know the exact mechanism of action. We do know Spravato® interacts with the NMDA receptor, a subtype of glutamate receptor. This is different from most of the current antidepressants, which interact with receptors involved with norepinephrine, serotonin, and dopamine.


What makes Spravato® different?

Spravato® targets the NMDA receptor system, and in clinical trials, 70% of patients with TRD responded (2). Many of these patients failed 3-5 antidepressants and had suicidal ideation as one of their depressive symptoms. Clinically, there are three main advantages to Spravato® treatment: it works when other antidepressants do not, it works quickly (in days to weeks instead of months), and there are virtually no medication side effects between treatments.


Can patients have other diagnoses in addition to major depressive disorder (MDD) and still receive Spravato®?

Yes. It is not uncommon for patients with MDD to have other conditions like anxiety disorders, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) or a history of alcohol or other substance abuse. These patients can still receive Spravato®.


Is Spravato® covered by insurance?

Yes, Spravato® is covered by most major insurance plans. Coverage and copay costs can be determined before patients receive their first treatment. The current out-of-pocket cost ranges from $0 to $225 per treatment. There are programs sponsored by the maker of Spravato® to help with high copays.


Why do patients need to go to a certified treatment center?

Spravato® treatment centers work with pharmacies certified to dispense Spravato®. The Avance Care pharmacy is experienced in submitting and processing the insurance authorization forms needed for Spravato® treatment. Spravato® treatment is part of an FDA REMS. (Risk Mitigation and Evaluation Strategy) to manage and monitor the patients who receive Spravato®. Patients can experience sedation, dissociation, and increased blood pressure during the 2-hour in office treatment. The side effects require a 2-hour monitoring period in the office, and patients cannot drive until the day after treatment


Who provides Spravato treatment at Avance Care?

Avance Psychiatry has recruited Robert A. Millet, MD, a psychiatrist who specializes in treatment resistant disorders and treatment resistant depression, to the Brier Creek office. Dr. Millet was one of the first physicians in the U.S. to use Spravato and has delivered over 6,500 Spravato treatments.


Can patients refer themselves to Dr. Millet for treatment?

Yes. This can be done through the Avance Care website or by calling the clinic at 984.263.0846. The first visit will be a consultation to determine if Spravato® is the best medication for a patient’s depression and what other options may be available if Spravato® is not the best choice.


Who will provide routine mental health care for patients while they receive Spravato® treatments?

Patients should follow up with their regular provider to prescribe all medications except Spravato®.


How often are the treatments and when will patients know if they will respond?

Treatments are twice a week for the first month, and then once a week for the second month. Most patients see results within the first four treatments (two weeks of treatment). Almost all patients who are responders will notice results within the first eight treatments (four weeks of treatment).


Who do I contact about treatment and insurance coverage questions?

The Avance Psychiatry Clinic is available to help patients Monday through Friday from 8AM to 5PM.

Patients should call 984.263.0846 and ask to schedule a Spravato® consult with Dr. Millet.

New consults are usually seen within 1-2 weeks, and treatment usually starts the week after the initial consultation.



1. Rush AJ et al. Am J Psychiatry. 2006;163(11):1905-1917.

2. Mischel NA, Kritzer MD, Patkar AA, Masand PS, Szabo ST.J Clin Psychopharmacol. 2019 Nov/Dec;39(6):665 672.

3.Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU.Expert Rev Neurother. 2015;15(9):1015-29

4. Popova V et al. Am J Psychiatry. 2019;176(6):428-438.

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