Treatment-Resistant Depression: When Antidepressants Don't Work

What lies behind depression that doesn’t respond to medication—and what should everyone know about TMS for depression available in Portugal?

Taking antidepressants for months and feeling no difference. Switching medications, adjusting doses, waiting. Still feeling no difference. This is the reality for one in three people diagnosed with major depression in Portugal. It’s not a lack of effort. It’s not a lack of willpower. It’s biology. In fact, it has a clinical name: treatment-resistant depression (TRD). For this group, TMS for depression has become one of the most solid solutions that contemporary psychiatry has to offer.

A meta-analysis published in 2026 in Clinical Medicine & Research (Huang et al.), which analyzed more than 1,300 patients across 12 controlled studies, confirmed that TMS for depression produces statistically significant improvements in key clinical measures. At The Clinic of Change in Lisbon, we work every day with people who come to us after having gone down that path—and who have found in TMS treatment for depression a solution that medication could not provide.

What, exactly, is treatment-resistant depression?

From a clinical standpoint, depression is considered treatment-resistant when a person does not respond adequately after taking two or more different antidepressants at the correct dosage and for an adequate duration. It is estimated that between 30% and 40% of people with major depression fall into this category. Furthermore, the consequences go far beyond the persistence of symptoms: increased risk of social isolation, inability to work, and, in the most severe cases, suicidal ideation.

Depression or burnout: how can you tell the difference?

It’s one of the most frequently asked questions—and most searched terms in Portugal. Burnout and depression share symptoms such as fatigue, lack of motivation, and difficulty concentrating, but they have different causes and treatments. Burnout is typically associated with work overload and improves with rest and a change of environment. Major depression is a mood disorder with a neurobiological basis: it persists regardless of the context, affects sleep, appetite, and the ability to feel pleasure, and does not improve with rest.

Therefore, this distinction is clinically important because the treatment differs. TMS for depression targets specific neural circuits that are impaired in major depression—and that may remain intact in burnout. A psychiatric evaluation is the only reliable way to distinguish between the two conditions and determine the appropriate treatment.

Why doesn't medication work in every case?

Antidepressants act on neurotransmitters—serotonin, norepinephrine, and dopamine. For many people, this is enough. However, for others, the problem lies elsewhere: in neural circuits that do not respond to the drug’s effects, in areas of the cerebral cortex that remain underactive even with appropriate medication.

This is precisely where TMS treatment for depression differs. Instead of acting systemically via the bloodstream, it targets the left dorsolateral prefrontal cortex—which is consistently underactive in major depression—with precise magnetic pulses. As Garnaat et al. (Brown University, 2019) explain, TMS induces focal neuronal depolarization and promotes neuroplasticity, modifying dysfunctional circuits in a way that psychotropic medications cannot achieve.

What does the research say about the effectiveness of TMS for depression?

In fact, the data have been consistent for more than two decades. Response rates between 50 and 60 percent, remission rates between 30 and 40 percent—in patients for whom medication had already failed. The landmark study by O’Reardon et al. (Biological Psychiatry, 2007), the first large-scale controlled trial of TMS for depression, involved 301 patients randomized to active TMS or sham stimulation, in daily sessions over four to six weeks. Active TMS outperformed sham on the MADRS, HAMD17, and HAMD24 scales, with remission rates approximately double and a dropout rate of only 4.5%. This study formed the basis for FDA approval in 2008.

In 2018, the THREE-D study (Blumberger et al., The Lancet) demonstrated that the iTBS protocol—with sessions lasting just 3 minutes—is clinically equivalent to the conventional 37-minute protocol. In 2025, Croarkin et al. published the most comprehensive results involving adolescents and young adults: approximately 70% reported clinically significant improvement, with less than 1% reporting worsening.

How much does TMS treatment for depression cost in Portugal?

It’s one of the most frequently asked questions—and it deserves a straightforward answer. A full course of treatment for depression typically involves about 30 sessions over six weeks. Full programs are available under specific conditions.

As for health insurance: some plans already cover TMS for treatment-resistant depression. Coverage varies by insurer, so our team can help clarify this before you begin. Compared to years of doctor visits, hospital stays, and medications that yield no results, TMS treatment for depression in Lisbon is often a more effective option—both financially and in terms of the patient’s well-being.

TMS in combination with medication: antagonism or synergy?

Do I have to stop taking antidepressants to undergo TMS for depression? The answer, in most cases, is no. The review by Garnaat et al. indicates that TMS can be added to a stable medication regimen with superior results—except in cases where certain medications (such as high-dose benzodiazepines) may interfere with the response. In any case, the decision always rests with the psychiatrist, following an individual assessment.

When to seek specialized help

Seek professional help if:

• You have been diagnosed with major depression and have not responded adequately to two or more antidepressants;
• You suspect you may have treatment-resistant depression and want to find out if TMS for depression is right for you;
• You are confusing depression with burnout and would like a separate clinical evaluation;
• Would you like to know which clinics in Portugal offer TMS for depression under psychiatric supervision?
• Do you have questions about the cost of TMS for depression in Lisbon and your insurance coverage?

Treatment is available for treatment-resistant depression. The first step is a consultation with a specialist psychiatrist.

How can The Clinic of Change help?

At The Clinic of Change in Lisbon, we offer outpatient TMS treatment for depression, under the continuous supervision of a psychiatrist and a multidisciplinary team. The evaluation consultation is a mandatory first step: it reviews your medical history, previous treatments, and eligibility. Only then does the treatment protocol begin—30 sessions over six weeks, with integrated psychological support whenever indicated. No waiting list.

Schedule your appointment.

Because treatment-resistant depression isn’t the end of the road—it’s the beginning of a different path.

Sources:

Huang, M. et al. (2026). Effects of TMS on Patients with Major Depressive Disorder. Clinical Medicine & Research, 24(1), 35–41.

Garnaat, S. L. et al. (2019). Updates on TMS Therapy for Major Depressive Disorder. Psychiatric Clinics of North America, 41(3), 419–431.

O’Reardon, J. P. et al. (2007). Efficacy and Safety of TMS in the Acute Treatment of Major Depressive Disorder. Biological Psychiatry, 62(11), 1208–1216.

Blumberger, D. M. et al. (2018). Effectiveness of theta burst versus high-frequency rTMS (THREE-D). The Lancet, 391(10131), 1683–1692.

Croarkin, P. E. et al. (2025). The Effectiveness of TMS in Adolescents and Young Adults With Major Depressive Disorder. Journal of the American Academy of Child & Adolescent Psychiatry.

NICE IPG542 (2015). Repetitive TMS for depression. nice.org.uk

This article is for informational purposes only and is not a substitute for a personalized medical consultation. Please contact us.