Medically reviewed by Barbra Scheirer,
PMHNP
Last reviewed: [September 29, 2026]
If antidepressants haven’t worked, talk to a psychiatrist about adjusting your medication, adding an augmenting drug, trying therapy, TMS, or esketamine (Spravato).
Taking an antidepressant every day and still feeling flat, exhausted or hopeless is discouraging. Many people in that spot assume they are doing something wrong, or that nothing will help. Neither is true. If you are searching for what to do for treatment resistant depression, the most useful first step is knowing that this is a recognized clinical situation with several evidence-based next steps. This guide explains what it means, why medications sometimes fall short, and the options a psychiatric provider may discuss with you.
What Is Treatment-Resistant Depression?
A Clinical Definition
Treatment-resistant depression (TRD) is generally diagnosed when major depression has not improved enough after at least two different antidepressants, each taken at an adequate dose for an adequate length of time, usually six to eight weeks. Researchers often point to the large STAR*D study, in which about a third of participants did not reach remission even after several sequential treatment steps.
It Is Not a Personal Failure
TRD describes how the illness responds to a particular treatment, not how hard you have tried. Brain chemistry, genetics, other health conditions and life stress all play a part. It also does not mean you are out of options.
Signs Your Depression May Be Treatment-Resistant
Symptoms That Linger Despite Treatment
You may want to raise the question if, after two medication trials, you still notice:
- Persistent low mood, or feeling numb most days
- Poor sleep, low energy or trouble concentrating
- Loss of interest in things you once enjoyed
- Only a partial improvement that stalls
- Symptoms that return after an initial good response
When to Seek a Second Look
Only a clinician can diagnose TRD, so this list is a prompt to book an appointment, not a self-test. If you have thoughts of harming yourself, call or text 988 right away.
Why Antidepressants Sometimes Don’t Work
Treatment Factors
Sometimes the plan needs adjusting rather than abandoning. The dose may be too low, the trial too short, or side effects may have led to missed doses. Some people also metabolize medications differently, which changes how much of the drug reaches the brain. Chronic stress, poor sleep and isolation can keep symptoms going too, which is one reason medication is rarely the only lever.
Other Conditions That Get in the Way
Depression rarely travels alone. Untreated anxiety, ADHD, trauma, bipolar disorder, sleep apnea, thyroid problems, and alcohol or substance use can all blunt a response. A person whose depression is really the low phase of bipolar disorder, for example, can worsen on a standard antidepressant. That is why re-evaluating the diagnosis matters as much as changing the prescription.
What to Do Next: Your Treatment Options
Once the basics have been checked, several paths are open. Your provider will match them to your history, health and preferences.
Adjusting or Switching Medication
The simplest step is often changing the dose or moving to a different class, for instance from an SSRI to an SNRI or bupropion. Someone who felt only jittery on one SSRI may do better on a different drug, or on a lower starting dose raised gradually. A structured trial of four to eight weeks gives a fair read on whether the new plan is working.
Adding Medication (Augmentation)
If a medication helps partially, adding a second one can close the gap. Common augmenting options include certain atypical antipsychotics, lithium, thyroid hormone and bupropion. Each carries its own monitoring needs, such as blood tests or metabolic checks, so this is done under close supervision.
Psychotherapy
Medication and therapy work through different routes, and combining them often outperforms either alone. Cognitive behavioral therapy and behavioral activation target the thinking patterns and inactivity that keep depression going, while interpersonal therapy focuses on relationships and life transitions. Someone who has withdrawn from friends, for example, might start with small, scheduled activities. Expect to commit to several weeks of regular sessions.
TMS Therapy
Transcranial magnetic stimulation uses magnetic pulses to stimulate mood-related areas of the brain. It is non-invasive, needs no anesthesia, and is FDA-cleared for adults whose depression has not responded to antidepressants. A typical course is daily sessions, five days a week, for roughly four to six weeks. Side effects are usually mild, such as scalp discomfort or headache. For severe or persistent cases, electroconvulsive therapy remains another well-studied option your psychiatrist may raise.
Ketamine or Spravato
Esketamine (Spravato) is a nasal spray approved by the FDA for treatment-resistant depression. It is taken in a certified healthcare setting, with monitoring for about two hours afterward because it can cause dizziness, sedation or raised blood pressure. Intravenous ketamine is used off-label and is less standardized. Both are typically considered when other options have not helped enough, and both require a medical screening first.
How a Psychiatric Evaluation Can Help
A Fresh Look at the Whole Picture
A psychiatric evaluation reviews your symptoms, medical history, past medications and current stressors together. It can uncover a missed diagnosis, a medication interaction, or a physical contributor such as a vitamin or thyroid issue that no one has checked. Providers often use short questionnaires, like the PHQ-9, to measure severity and track progress over time.
A Plan Built Around You
Rather than repeating what has already failed, the goal is a sequenced plan with clear checkpoints, so you know what comes next if the current step falls short.
What to Expect at Your First Visit
Before the Appointment
Bring a list of every antidepressant you have tried, with doses, how long you took them, and why you stopped. Note your current symptoms, sleep, appetite and side effects, plus any other medications and supplements.
During the Visit
Expect questions about your mood, safety, family history, substance use and daily functioning. You will leave with a clearer picture of what is going on and a proposed plan, which may include a medication change, a referral for therapy, or a discussion of options such as TMS or esketamine and where to access them.
Talk to a Psychiatrist About What’s Next
Treatment-resistant depression is difficult, but it is treatable, and a stalled first or second medication is a reason to change the plan, not to give up hope. At Mighty Mental Health, we are a psychiatry and medication management office in Las Vegas and Summerlin, NV, offering telehealth visits and in-office consultations. Our Psychiatric Nurse Practitioner, Barbra Scheirer, offers comprehensive care treatment plans for what to do for treatment resistant depression, which may include prescribing medication or recommending therapy as part of a well-rounded approach. We accept Nevada Medicaid, CareSource, Silver Summit, Health Plan of Nevada, Molina and Anthem. Contact us today at 702-479-1600 or through our contact form.
Frequently Asked Questions
How do I know if I have treatment-resistant depression?
Only a licensed clinician can diagnose it. Typically it means your symptoms have not improved enough after two antidepressants taken at proper doses for long enough. A psychiatric evaluation can confirm this and rule out other causes.
What is the next step if antidepressants aren’t working?
Book an evaluation before changing anything yourself. Your provider may adjust the dose, switch medications, add an augmenting drug, recommend therapy, or discuss TMS or esketamine.
How long does it take to see results?
It varies. Medication changes usually need four to eight weeks, therapy several weeks of regular sessions, and TMS often shows gains within a few weeks of daily treatment. Esketamine can work sooner for some people, though response differs.
Can I keep taking my medication during other treatments?
Often yes, and many treatments are designed to work alongside medication. Esketamine, for example, is commonly paired with an oral antidepressant. Never stop or change a dose on your own, since stopping suddenly can cause withdrawal symptoms or a relapse.
References
- Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry, 2006.
- U.S. Food and Drug Administration. Spravato (esketamine) prescribing information.
- U.S. Food and Drug Administration. Transcranial magnetic stimulation device clearance for major depressive disorder.
- National Institute of Mental Health. Major Depression overview.
Written by Mighty Mental Health Editorial Team
Clinically reviewed by:
Barbra Scheirer, APRN, PMHNP-BC
The Mighty Mental Health Editorial Team develops and maintains educational content focused on psychiatry, mental health treatment, and medication management. Our articles are created to reflect evidence-based practice, current clinical standards, and a patient-centered approach to behavioral health care. Each piece is clinically reviewed by Barbra Scheirer, APRN, PMHNP-BC, to help ensure the information we publish is accurate, clear, relevant, and aligned with accepted standards in psychiatric evaluation, diagnosis, treatment planning, and medication management.
At Mighty Mental Health, we are committed to publishing trustworthy mental health information that supports informed decision-making for individuals and families seeking care. Our content is designed to make complex topics more understandable while maintaining a high standard of medical accuracy and professional integrity. Through clinical oversight, editorial review, and a focus on compassionate, evidence-based psychiatric care, we strive to provide reliable educational resources for those exploring mental health concerns, treatment options, and ongoing wellness support.