Treatment-Resistant Depression: When Antidepressants Aren't Enough, There Are Still Options

Understanding treatment resistance, looking at the bigger picture, and exploring newer approaches to depression care.

Have you tried one antidepressant after another and still find yourself struggling with depression? Maybe one medication helped a little but never quite got you back to feeling like yourself. Maybe the side effects were hard to live with, or you have reached the point where you wonder whether anything will actually work.

If this sounds familiar, you're not alone. As a board-certified psychiatric nurse practitioner (PMHNP-BC) in Brea, I often meet people who have spent years trying different medications with limited success. One of the first things I want them to understand is this: not responding to past treatment doesn't mean your depression is untreatable. Sometimes it means we need to step back, look at the bigger picture, reconsider what has been tried, and explore a different approach. Our understanding of depression keeps growing, and so do our treatment options.

What is treatment-resistant depression?

Treatment-resistant depression, often called TRD, generally means depression that hasn't improved enough after at least two different antidepressants, each tried at an appropriate dose and for an adequate length of time [1]. An antidepressant usually needs several weeks at a therapeutic dose before we can fairly judge whether it's working, although every person responds differently.

It's also important to know that treatment resistance isn't a permanent label. It doesn't mean your depression can't improve, that you've run out of options, or that you did something wrong. It tells us that the treatments tried so far haven't brought enough relief, and that it may be time to rethink the approach. If you are earlier in that process, this article on the first eight weeks of depression treatment explains how I judge whether a medication is working.

Sometimes we need to look beyond the medication

When someone comes to me after several medications haven't helped, I don't automatically assume another prescription is the answer. First, I want to understand why the earlier treatments may not have worked. Was each medication given a fair trial? Was the dose right? Did side effects get in the way of taking it consistently? Could another psychiatric or medical condition be adding to the symptoms? GeneSight testing can sometimes help explain why certain medications haven't agreed with you.

Just as important, are we addressing the other things that shape mental health? Depression is complex. Medication can be incredibly helpful, but our emotional and physical well-being depend on many connected factors:

• Sleep: Poor sleep, chronic insomnia, or conditions such as sleep apnea can strongly affect mood and recovery.
• Nutrition: A balanced diet, and correcting any nutritional deficiencies we find, supports both physical and mental health.
• Physical activity: Regular exercise has proven benefits for depression and can work alongside other treatments.
• Psychotherapy: Working through trauma, relationships, stress, negative thought patterns, and emotional experiences can be a key part of recovery. You can read more about psychotherapy at Peaceful Presence.
• Medical conditions: Thyroid disorders, chronic illness, the effects of other medications, and other medical factors can contribute to depressive symptoms.
• Supplements and integrative approaches: Certain supplements may make sense in selected situations. The evidence varies, so I review each one for safety and interactions first. My integrative wellness page explains how I approach this.
• Gut health: Research continues to explore the connection between the gut and the brain. It's a promising field, but we are still learning how those findings translate into reliable depression treatments.

I believe psychiatric care should consider the whole person, not just the symptoms or the prescriptions. That doesn't mean replacing evidence-based treatment with supplements or lifestyle changes. It means understanding how different approaches can work together as part of one individualized plan.

And sometimes, even after we address all of these, depression still persists. That's when other treatments may be worth exploring.

A different approach: interventional psychiatry

One of the most promising developments in mental health care is the growing use of interventional treatments. Unlike traditional antidepressants, these treatments affect brain function through different pathways. Two important options are transcranial magnetic stimulation (TMS) and ketamine-based treatments, including Spravato (esketamine).

These approaches have expanded our ability to help people whose depression hasn't responded well enough to conventional treatment. They aren't necessarily replacements for medication, psychotherapy, or healthy habits. Instead, they offer additional ways to treat depression, often alongside the rest of your care.

What is TMS?

Transcranial magnetic stimulation, or TMS, is a noninvasive treatment that uses magnetic pulses to stimulate areas of the brain involved in mood regulation [2]. Unlike a medication, TMS doesn't travel through your whole body. It delivers focused stimulation to specific brain regions and influences the networks involved in emotional regulation.

One interesting part of TMS is its connection to neuroplasticity, the brain's ability to adapt and change over time. Depression isn't simply a matter of too little serotonin or an imbalance of one brain chemical. It involves complex interactions between brain circuits, neurotransmitters, physical health, and life experiences. TMS offers a way to influence some of those brain networks directly.

The FDA first cleared TMS for depression in 2008, and it has since become an established option, especially for people who haven't improved enough on antidepressant medication [3]. Its uses have also grown. Depending on the device, FDA-cleared uses now include obsessive-compulsive disorder (OCD), smoking cessation, and certain types of migraine [3], and research continues into other psychiatric and neurological conditions. You can learn more on my TMS therapy page.

TMS technology keeps advancing

One of the exciting things about TMS is how much the technology has changed. Traditionally, TMS meant daily sessions with about 20 to 40 minutes of active stimulation, usually five days a week for six weeks or longer [5]. Today, some protocols use stimulation sessions as short as about three minutes [4]. Different TMS machines can use different coil designs, stimulation patterns, brain targets, and protocols. Researchers are also studying accelerated approaches, where several treatments are given in a single day, which may shorten the overall course for the right patients.

Shorter sessions don't automatically mean better results or fewer visits. How well a treatment works, and whether it fits you, depends on the specific protocol and on you as a person. Still, these advances are encouraging, because they give us more flexibility to tailor treatment.

What does a TMS session feel like?

You sit comfortably in a chair while a magnetic coil is placed against your head. You stay awake and alert the whole time. There is no anesthesia or sedation, and most people go right back to their usual activities afterward, including driving. People often describe the sensation as a light tapping on the scalp.

TMS is generally well tolerated. Temporary headaches or scalp discomfort are among the most common side effects, and they often ease as treatment goes on [2]. A seizure is a rare but serious risk [2]. That's why a thorough medical and psychiatric evaluation comes before any treatment, including a review of your seizure history, medications, and other health factors.

How soon can you notice improvement with TMS?

This is one of the most common questions I hear, and the honest answer is that everyone responds differently. Some people notice subtle changes after their first or second session, like feeling a little lighter, calmer, or more motivated. For many others, improvement builds gradually over several weeks. The timing depends on the person and on the protocol.

An early change can be encouraging, but it doesn't predict the final outcome. In the same way, not noticing much in the first few sessions doesn't mean treatment won't work. What matters is how you progress over the whole course, not how you feel after one session. I also look beyond symptoms alone. Sometimes real progress starts with better sleep, more motivation, or getting back to activities that used to feel overwhelming.

Understanding ketamine and Spravato

Ketamine has been used in medicine for decades, mainly in anesthesia and pain management. It sometimes gets attention because of recreational misuse, but it has a long, well-established history of legitimate medical use. More recently, researchers found that ketamine can relieve depression through a different mechanism than traditional antidepressants. Most antidepressants act on brain chemicals such as serotonin or norepinephrine. Ketamine acts mainly on the brain's glutamate system, which is involved in communication between nerve cells, learning, and neuroplasticity. That has opened a promising new path for treating depression.

Ketamine is sometimes given by IV infusion for depression in certain clinics, but in the United States that use is off-label, meaning it is not FDA-approved for depression.

Spravato is related to ketamine, but it is a distinct treatment. Spravato is the brand name for esketamine, one of the two mirror-image forms that make up the ketamine molecule. It is a nasal spray used only under medical supervision. The FDA approved Spravato in 2019 for adults with treatment-resistant depression, taken with an oral antidepressant. It is also approved for depressive symptoms in certain adults with major depressive disorder who have acute suicidal thoughts or behavior, again alongside an oral antidepressant [7]. In January 2025, the FDA also approved Spravato on its own for adults with treatment-resistant depression, without an oral antidepressant [6].

Unlike IV ketamine for depression, Spravato has specific FDA-approved psychiatric uses, and health insurance may cover it when eligibility requirements are met. You can learn more on my Spravato treatment page.

What does a Spravato visit look like?

A Spravato visit is different from a typical medication appointment. You give yourself the nasal spray in a certified treatment setting, with a healthcare professional supervising. Afterward, you stay in the office for at least two hours so the team can monitor how you respond [7].

During that time, some people feel a temporary sense of disconnection from their surroundings, changes in perception, dizziness, nausea, or drowsiness [7]. Blood pressure can go up for a short time, so staff check your blood pressure, breathing, oxygen level, and other safety signs throughout the visit [7].

Something I care about a lot is making that time comfortable and supportive. The goal isn't just to give a medication and watch the clock. I believe the treatment experience should be intentional and calming. You should have a comfortable space to rest, listen to music if you like, and know that trained staff are right there if you need them.

Some people also benefit from psychotherapy alongside their treatment, to work through emotional experiences, behavior patterns, relationships, or underlying stress. Therapy isn't required for every Spravato patient, but it can be a valuable part of complete psychiatric care.

You will need someone to drive you home after each visit. You should not drive until the next day, after a restful night's sleep [7].

How soon does Spravato work?

One reason Spravato has drawn so much interest is that some people feel better fairly quickly. In clinical research, some patients saw improvement in depressive symptoms as early as 24 hours after treatment [6]. Not everyone improves that fast, though. Some people need repeated treatments over several weeks before they notice a real change.

Treatment usually starts with two visits a week for the first four weeks. After that, visits become less frequent, based on how you respond and on your treatment plan [7]. As with TMS, we track your symptoms and how you're doing day to day throughout your care.

TMS or Spravato: which is right for you?

Both treatments approach depression differently, and neither one is automatically the better choice. TMS is noninvasive, and you can usually drive yourself home and go straight back to your day. Spravato is a medication with a longer monitoring period, and you need a ride home afterward.

Your medical history, past treatments, personal preferences, schedule, and insurance coverage all help decide which option fits. Some people try TMS and later consider Spravato, or the other way around. In selected situations, both may be part of a coordinated plan, although the evidence for combining them is still developing. The goal isn't to choose the newest or most advanced treatment. It's to find what makes sense for you.

TMS and Spravato treatments take place at my 2812 E Imperial Hwy office in Brea.

Will insurance cover these treatments?

Many commercial insurance plans cover TMS and Spravato when specific medical-necessity requirements are met [5]. Those requirements can include records of past antidepressant trials, your treatment history, how severe your symptoms are, and past psychotherapy. Coverage also varies by diagnosis, treatment protocol, insurance company, and individual plan.

An important part of the evaluation is reviewing your treatment history and pulling together the documentation needed to explore coverage. It helps a lot to bring a list of every antidepressant you remember trying, with a rough dose and how long you took it. It doesn't need to be perfect.

Measuring progress: more than a depression score

Before treatment starts, I want to understand how depression is affecting your life. We may use a validated questionnaire such as the PHQ-9 (Patient Health Questionnaire-9) to set a baseline and track changes over time.

But I also want to know how you're functioning. Are you sleeping better? Do you have more energy? Is it easier to get out of bed in the morning? Are you reconnecting with family, enjoying activities again, or feeling more engaged at work? These are the signs of real recovery. The goal isn't just a lower number on a questionnaire. It's helping you get your quality of life back, and your ability to take part in the things that matter to you.

Frequently asked questions

Is TMS painful?

Most people describe it as a tapping feeling on the scalp. It can feel uncomfortable during the first few sessions, and the settings can be adjusted. Headaches are the most common side effect, and they tend to fade as treatment continues [2].

Can I stay on my antidepressant?

Often, yes. Many people keep their current antidepressant during TMS, and Spravato can be used with an oral antidepressant or, since 2025, on its own [6]. Please don't stop any medication on your own. If a change makes sense, I'll help you do it gradually and safely.

Is Spravato the same as ketamine?

No. Esketamine is closely related to ketamine, but Spravato is a separate, FDA-approved medication with a set dose. It is given only in a certified setting, with at least two hours of monitoring after each dose [7].

Taking the next step

If you've tried more than one medication and you're still struggling, it may be time to rethink your treatment plan. That doesn't necessarily mean you need TMS or Spravato. Sometimes the next step is reviewing past medication trials, treating an underlying medical condition, starting psychotherapy, or improving sleep, nutrition, or other contributing factors. For others, an interventional treatment may offer a real chance at meaningful improvement.

At Peaceful Presence Mental Health, my approach is to understand the whole person, review what has already been tried, and work together on an individualized, evidence-based treatment plan.

Treatment-resistant depression doesn't mean you've reached the end of the road. Sometimes it means it's time to explore a different path.

If you'd like to find out whether TMS, Spravato, or another approach may be right for you, use the contact form to schedule a psychiatric evaluation, and tell me a little about what you've tried so far. You can also see everything the practice offers on the services page. If anxiety is part of the picture too, this article on anxiety may help in the meantime.

References

1. Psychiatric News. When Is Depression "Treatment Resistant"? American Psychiatric Association, 2017. https://psychnews.psychiatryonline.org/doi/10.1176/appi.pn.2017.pp1b2
2. National Institute of Mental Health. Sarah H. Lisanby on Transcranial Magnetic Stimulation: Safety and Risk, 2020. https://www.nimh.nih.gov/news/media/2020/sarah-h-lisanby-transcranial-magnetic-stimulation-safety-and-risk
3. Cohen SL, Bikson M, Badran BW, George MS. A visual and narrative timeline of US FDA milestones for Transcranial Magnetic Stimulation (TMS) devices. Brain Stimulation, 2022;15(1):73-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864803/
4. BrainsWay. What Mental Health Conditions Is Deep TMS FDA-Cleared To Treat? https://www.brainsway.com/professionals-faqs/what-mental-health-conditions-is-deep-tms-fda-cleared-to-treat/
5. Psychiatric News. Guidance on Navigating Insurance Plans for TMS-Eligible Patients. American Psychiatric Association, 2021. https://psychnews.psychiatryonline.org/doi/10.1176/appi.pn.2021.10.36
6. Healio. FDA approves Spravato as monotherapy for adults with major depressive disorder, January 22, 2025. https://www.healio.com/news/psychiatry/20250122/fda-approves-spravato-as-monotherapy-for-adults-with-major-depressive-disorder
7. U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray, Prescribing Information, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s019lbl.pdf

This article is for educational purposes and is not individualized medical advice. Treatment decisions require a clinical evaluation. If you are in an immediate mental health crisis or are in danger of harming yourself, call 911, go to the nearest emergency department, or call or text 988 for crisis support.