Treatment-resistant depression is major depression that has not remitted after two or more adequate antidepressant trials, affecting about one third of people treated for depression. Next steps include augmentation with lithium, aripiprazole or bupropion, Deep TMS (FDA-cleared, 36 sessions over six to nine weeks) and Spravato nasal spray (FDA-approved, given in clinic). Most people with TRD respond to one.
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Stedfast Psychiatry runs a structured program for treatment-resistant depression. We start by confirming the diagnosis and reviewing what has already been tried, because many 'failed' trials were too short or too low a dose, or the diagnosis was incomplete. We then move through evidence-based steps: optimized medication and augmentation, Deep TMS at Palm Beach Gardens, and Spravato at Boynton Beach, Palm Beach Gardens and Royal Palm Beach.
Symptoms of TRD
- Depression that persists despite two or more antidepressants at full dose
- Partial improvement that never reaches feeling well
- Repeated relapses when a medication seems to stop working
- Chronic low mood, fatigue and loss of interest lasting years
- Intolerable side effects that have prevented adequate trials
- Worsening hopelessness about ever getting better
- Anxiety, insomnia or pain that persists alongside the depression
- Difficulty working or maintaining relationships because of depression
- Thoughts of death or suicide
Causes and risk factors
Depression resists treatment for several reasons, and finding the one that applies is the first step. Sometimes the diagnosis is incomplete: undiagnosed bipolar disorder, ADHD, PTSD, a personality disorder, substance use, or a medical condition such as hypothyroidism, sleep apnea or chronic inflammation is keeping the depression going. Sometimes the trials were inadequate: too low a dose, too short a duration, or stopped early because of side effects. Sometimes ongoing stressors, trauma or isolation outweigh what medication can do alone. And sometimes the depression simply involves brain circuits and neurotransmitter systems (glutamate, the reward network, the dorsolateral prefrontal cortex) that standard serotonergic antidepressants do not reach, which is where TMS and esketamine come in.
In the STAR*D trial, about 37 percent of patients remitted on the first antidepressant, 31 percent on the second, 14 percent on the third and 13 percent on the fourth; roughly one third never remitted across four steps.
Source: STAR*D, National Institute of Mental Health (Rush et al., 2006)
About 30 percent of adults treated for major depression are estimated to have treatment-resistant depression.
Source: Zhdanava et al., Journal of Clinical Psychiatry, 2021
Deep TMS was FDA-cleared for major depressive disorder in 2013; in post-marketing data from more than 1,000 patients, about 75 percent responded and about 50 percent achieved remission.
Source: BrainsWay post-marketing analysis (Tendler et al., 2023)
Spravato (esketamine) was FDA-approved in March 2019 for treatment-resistant depression and in 2020 for MDD with acute suicidal ideation or behavior, in adults, together with an oral antidepressant.
Source: US Food and Drug Administration
How we diagnose it at Stedfast Psychiatry
Our TRD evaluation is longer and more detailed than a standard intake. We reconstruct your full treatment history: every medication, dose, duration, response and reason for stopping, and any therapy you have had. We re-examine the diagnosis with structured screening for bipolar disorder, PTSD, ADHD, OCD, personality factors and substance use, because up to a quarter of TRD cases turn out to be bipolar depression. We rate severity with the PHQ-9 and the Montgomery-Asberg Depression Rating Scale (MADRS). We order labs if they have not been done recently: TSH, CBC, metabolic panel, vitamin B12, vitamin D, and sometimes a morning cortisol or inflammatory markers. We screen for sleep apnea. We then stage your depression using the number of adequate trials and discuss which next step the evidence supports for your situation.
Treatment options
Medication management
The first step is often optimization: pushing a partially effective antidepressant to its full dose for a full eight to twelve weeks. Next is augmentation, which has better evidence than switching again after two failures. Options include adding lithium (requires blood level monitoring), a low dose of an atypical antipsychotic such as aripiprazole, brexpiprazole, cariprazine or quetiapine (monitoring weight, glucose and lipids), adding bupropion or mirtazapine to an SSRI, or adding triiodothyronine (T3). Switching to a different class, such as from an SSRI to venlafaxine, bupropion or a tricyclic like nortriptyline, is another step. Monoamine oxidase inhibitors such as tranylcypromine remain effective for atypical and refractory depression with dietary care. Pharmacogenomic testing can help when metabolism or side effects have been a problem. We allow six to eight weeks per step and do not let trials drag on without change.
Psychotherapy
Therapy is often undervalued in TRD. Adding CBT to medication improves outcomes for people who have not responded to medication alone, and the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) was designed specifically for chronic depression. Behavioral activation, interpersonal therapy and mindfulness-based cognitive therapy (for relapse prevention) all have evidence. Therapy also addresses the demoralization that years of depression produce, and it continues to help after interventional treatments restore the capacity to engage.
Interventional options
Deep TMS (BrainsWay) is FDA-cleared for major depressive disorder (2013) and anxious depression (2021), as well as OCD and smoking cessation. It delivers magnetic pulses to the left dorsolateral prefrontal cortex through a helmet, without anesthesia, in 20-minute sessions five days a week for six weeks followed by a taper, 36 sessions in total, at our Palm Beach Gardens office. In real-world data from over a thousand patients, about three quarters responded and roughly half reached remission. Spravato (esketamine nasal spray) was FDA-approved in 2019 for treatment-resistant depression and in 2020 for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior, for patients 18 and older, taken alongside an oral antidepressant. It acts on the glutamate system and can produce improvement within days. It is administered in our Boynton Beach, Palm Beach Gardens and Royal Palm Beach offices under the REMS safety program with two hours of monitoring after each dose: twice weekly for four weeks, then weekly for four weeks, then weekly or every other week. Patients cannot drive until the next day. For the most severe cases, electroconvulsive therapy remains the most effective treatment, and we coordinate referrals.
If medications have not worked or caused strong side effects, ask about pharmacogenomic (genetic) testing.
What to expect
Your first visit is a 60 to 90 minute TRD consultation, in person or by video, that includes a full treatment history review. You leave with a staged plan: what we will try first, how long we will give it, and what comes next if it does not work. Medication follow-ups are every three to four weeks. If Deep TMS or Spravato is recommended, our staff handles insurance authorization, which usually takes one to three weeks, and schedules you at the appropriate office. Medication management around TMS or Spravato can be done by telehealth anywhere in Florida or South Carolina.
When to seek help
If you have tried two or more antidepressants without getting well, ask for a TRD consultation rather than another switch within the same class. If depression is affecting your ability to work, care for your family or stay safe, do not wait. If you are having thoughts of suicide, call or text 988 or go to the nearest emergency room; Spravato is specifically approved for depression with acute suicidal ideation and can be started quickly. If you are in immediate danger, call 911.
Staging treatment resistance
Clinicians stage TRD by the number and type of adequate trials. Stage one is failure of one antidepressant; stage two, failure of two from different classes; stage three adds failure of a tricyclic; stage four, failure of an MAOI; stage five, failure of ECT. Most of what is called TRD in practice is stage two, and it is at this point that the evidence favors augmentation and interventional treatments over another switch. The sequence at Stedfast follows this logic: confirm the diagnosis, optimize, augment, and move to Deep TMS or Spravato when two adequate trials have failed. We do not wait until stage four to offer them.
Pseudo-resistance
A significant share of apparent TRD is pseudo-resistance: the medication was never given a fair chance. Common reasons are stopping at four weeks because nothing had changed yet, staying on a starting dose, missing doses, alcohol or cannabis use that blunts response, an untreated sleep disorder, or an unrecognized medical condition such as hypothyroidism. Another cause is misdiagnosis, most often bipolar II depression treated with antidepressants alone, which tends to produce brief improvements followed by relapse. Finding pseudo-resistance is good news because it means a standard treatment, done properly, may still work.
Deep TMS versus Spravato: how they differ
Deep TMS stimulates the prefrontal cortex from outside the skull with magnetic pulses. It requires no medication, has no systemic side effects, and produces durable remission in many patients after a single course, with maintenance sessions available if symptoms return. Its drawback is the time commitment of daily visits. Spravato works on the glutamate system through NMDA receptor blockade and can lift depression within days, which makes it the choice when suicidal thinking is present. Its drawbacks are the two-hour clinic monitoring, dissociation during dosing, no driving the same day, and the need for ongoing maintenance dosing. Both are covered by most insurance plans. Some patients eventually use both, in sequence, and we help you decide the order.
Living with chronic depression while treatment continues
TRD wears people down, and demoralization is itself a symptom to treat. Keeping a basic routine (fixed wake time, daily movement, one meaningful contact per day) preserves function while treatments are tried. Alcohol and cannabis interfere with every antidepressant and with TMS and Spravato. Treating pain, sleep apnea and insomnia removes drags on recovery. Involving a family member in the plan helps with adherence and with noticing improvement before you do.
Prognosis
Treatment-resistant depression is harder to treat than first-episode depression, but the outlook has improved substantially in the past decade. With a systematic approach, most patients eventually respond, and interventional treatments have moved many people who had been depressed for years into remission. The patients who do best are those whose care follows a plan with defined steps and time limits, who stay in treatment between steps, and whose other conditions are treated alongside the depression. That is the program we built.
Frequently asked questions
What counts as treatment-resistant depression?
The most common definition is depression that has not reached remission after two or more antidepressants from different classes, each taken at an adequate dose for at least six to eight weeks. Partial response counts as not remitting. Many patients who think they have TRD had trials that were too short or too low, which is why we rebuild the history before labeling anything resistant. Either way, the definition is a doorway to more options, not a verdict.
Should I try TMS or Spravato first?
Both are reasonable after two failed antidepressants and the choice depends on your situation. Deep TMS involves daily visits for six weeks, has minimal side effects (scalp discomfort, headache) and no driving restrictions. Spravato works faster, often within days, which matters when suicidal thoughts are present, but requires two hours of observation per dose, no driving that day, and continues indefinitely for maintenance. Insurance criteria, location and schedule also factor in. We lay out both and recommend one.
How much do TMS and Spravato cost and are they covered?
Both are covered by most commercial insurance plans and Medicare for treatment-resistant depression after documented antidepressant trials. With insurance, your cost is typically your copay or coinsurance per session. Without insurance, a full TMS course runs several thousand dollars and Spravato costs several hundred dollars per session plus the medication, which Janssen's patient assistance program may cover. Our staff verifies benefits and handles prior authorization before you start.
Is Spravato the same as ketamine infusions?
No. Spravato is esketamine, one of the two mirror-image forms of ketamine, delivered as a nasal spray, FDA-approved for TRD, and covered by insurance. IV ketamine infusions use racemic ketamine off-label for depression, are not FDA-approved for that use, and are usually self-pay. Both act on the glutamate system and can work quickly. Spravato is given under a federal safety program with monitoring; ketamine clinics vary widely in standards.
What are the side effects of Spravato?
The most common are dissociation (feeling detached or dreamlike), dizziness, nausea, sedation, and a temporary rise in blood pressure, all peaking within the first hour and resolving by the end of the two-hour monitoring period. That is why it is given in clinic and why you cannot drive until the next day. Serious problems are rare with proper screening. Patients with uncontrolled hypertension, aneurysms or a history of psychosis are not candidates.
What are the side effects of Deep TMS?
The common ones are scalp discomfort or headache during or after sessions, which fade over the first week and respond to acetaminophen. There is no sedation, no memory effect and no driving restriction; most people go straight back to work. Seizure is the main serious risk and is very rare (well under one in a thousand patients) with proper screening. People with metal implants in the head or a seizure disorder are usually not candidates.
Can TRD be managed through telehealth?
The medication management, therapy and follow-up parts can. We see TRD patients by video across Florida and South Carolina for augmentation strategies and monitoring. Deep TMS requires daily visits to Palm Beach Gardens for six weeks, and Spravato requires in-person dosing at Boynton Beach, Palm Beach Gardens or Royal Palm Beach. Many patients combine in-person interventional treatment with telehealth for everything else.
What if TMS and Spravato do not work either?
There are still options. Electroconvulsive therapy has the highest response rate of any treatment for severe depression and we coordinate referrals. MAOIs, tricyclics and specific augmentation combinations may not have been tried. Sometimes a second look at the diagnosis finds bipolar disorder, PTSD or a medical cause that changes the plan. We do not run out of ideas after two steps, and we will tell you honestly what each next step offers.
Where to get treatment for treatment-resistant depression
Evaluation and treatment for treatment-resistant depression is available at every Stedfast Psychiatry office and by video across Florida and South Carolina.
Related conditions
If you are thinking about harming yourself, call or text 988 now, or go to the nearest emergency room. This page is educational and does not replace an evaluation. Clinical content reviewed by Dr. David Husted, board-certified psychiatrist.