By Madison Avenue TMS & Psychiatry - Published on October 17, 2025

Last updated on October 24, 2025

What is Treatment-Resistant Depression?

Depression is tough. It can affect your mood, sleep, appetite, and thinking, draining your interest from things you once enjoyed. And unfortunately, some types are tougher than others.

When depressive symptoms haven’t improved or returned after a regimen of at least two different antidepressant medications, along with psychotherapy, that’s called treatment-resistant depression, or TRD. It’s one type of major depressive disorder, and it affects an estimated 30% of people who’ve been diagnosed with clinical depression and have tried medication.

Symptoms of TRD are the same as for other major depressive disorders, but they typically last longer, are more severe, and may be accompanied by anxiety and thoughts of suicide. There may also be physical symptoms, such as frequent headaches or chronic pain.

“I had struggled with treatment-resistant major depression since early childhood and had tried numerous antidepressants, as well as years of talk therapy and cognitive behavioral therapy, but nothing worked,” said Monica, whom we recently profiled on this blog. 

“For me, depression manifested as a constant background despair. I was only able to feel sad or anxious, which made it very difficult for me to connect with the people around me.” 

Ties to Chronic Stress

Researchers don’t know what causes treatment-resistant depression, but they have identified several possible contributors, including biological factors, genetics, physical health comorbidities, neurochemical imbalances, and structural changes in the brain. 

In addition, psychological factors including chronic stress can contribute to treatment resistance. The release of stress hormones like cortisol keeps the body’s stress-response system in a state of extended alert, leading to inflammation and hormonal imbalances that worsen depression. That diminishes the brain’s resilience ability over time, making it more resistant to treatments.

How is TRD Treated?

Fortunately, a diagnosis of TRD isn’t the end of the line. There are other ways that show promise for restoring normal brain function and alleviating symptoms of depression. 

Managing Stress

For starters, your physician will carefully review your medication regimen to determine whether it was sufficient or whether more time — or better adherence — is needed to draw any conclusions. Your physician may also need to determine whether adjustments are needed to the dosage, medication, or combination of medications. 

He or she may also recommend adding psychotherapy — or finding ways to manage stress, such as: 

• Getting regular exercise
• Getting adequate sleep
• Meditating or finding other ways to relax, such as yoga
• Learning to say no to additional tasks or responsibilities when you’re too busy
• Avoiding alcohol or drugs

Clinical Treatments for TRD

If medication and psychotherapy aren’t doing it, there are other, newer treatment options you may want to consider. We offer both of the following at Madison Avenue TMS & Psychiatry and have found encouraging results with many patients.

Transcranial Magnetic Stimulation (TMS)

First approved to treat depression by the FDA in 2008, TMS is used specifically for patients with treatment-resistant depression, among other disorders. It involves the use of a head-mounted coil that sends subtle magnetic currents through the scalp and skull to stimulate underactive neurons that cause imbalances in brain chemistry. 

This treatment regimen typically takes place over nine weeks to allow the TMS to change the way neurons communicate with each other, helping the patient form new behavior patterns, regulate emotions, and overcome depression.

Studies suggest that up to 70% of patients report significant alleviation of symptoms following TMS and that those treated with it were two to four times more likely to achieve remission from depression symptoms than people who used antidepressants alone.

Spravato (esketamine)

More recently, we have started offering Spravato, approved by the FDA for treatment-resistant depression and depressive symptoms with suicidal thoughts or behaviors, not as a first-line treatment.

Spravato is a nasal spray and derivative of ketamine that must be administered in a clinical setting and under the supervision of a healthcare professional for safety and support. It targets glutamate, a neurotransmitter associated with mood regulation, and treatment is administered according to a structured schedule. Some patients report feeling results within hours of their initial dosage. 

To qualify, you’ll first need a comprehensive psychiatric evaluation.

Other treatment methods

The following options are not offered by Madison Avenue TMS & Psychiatry, though we can discuss whether they may be appropriate with patients. 

• Electroconvulsive therapy, or ECT, which involves passing a mild electric current through your brain, causing a short seizure to stimulate nerve cells and induce mood-enhancing brain changes
• Antipsychotics, which the FDA has approved for use in conjunction with an antidepressant
• Monoamine oxidase inhibitors, a type of antidepressant sometimes used after more traditional versions have failed

How We Can Help

If you suffer from TRD, don’t give up hope: Madison Avenue TMS & Psychiatry is here to help. Our compassionate clinicians and staff are here to listen to your concerns, learn about your experiences and struggles, and recommend a path to recovery. We recognize that there are no one-size-fits-all solutions and that individual treatments will vary.

Call us at 212-731-2033 to schedule a consultation at our Midtown Manhattan office today.

If you or someone you love is thinking about suicide:

• Call 988 – the Suicide and Crisis Lifeline (24/7)
• If in immediate danger, call 911 or go to the ER

Madison Avenue TMS & Psychiatry