ASCERTAIN-TRD · Is TMS right for me?

So You Failed an Antidepressant. Now What?

An actionable summary of ASCERTAIN-TRD, a 2024 study that compared three common next steps for depression that hasn't improved with medication.

Written by Kevin P. Muthu, MD
Reviewed November 2026 · 7 minute read

About 1 in 5 American adults will have major depression at some point in their lives.² For many of them, antidepressant medication has been life-changing.

But we also know, from the landmark STAR*D study, that the first antidepressant a person tries leads to full remission in only about 30% of people.³ That leaves roughly 70% of patients who did everything right. They pushed past the stigma to get diagnosed. They put up with side effects like nausea, headaches, and sometimes weight gain or sexual problems. They took their medication at a proper dose for 4 to 6 weeks or longer. And they still didn't get the relief they were hoping for.

So what are the options when that first hope doesn't work out? The researchers behind the ASCERTAIN-TRD trial set out to answer exactly that question.¹

What the study did

The study included 278 adults whose depression had not improved after at least two antidepressants taken at an adequate dose for long enough, and who were still struggling on their current antidepressant. Doctors call this treatment-resistant depression.

Each person was randomly placed into one of three groups:

• Add TMS: they kept their current antidepressant and added transcranial magnetic stimulation (TMS), a non-invasive treatment that uses magnetic pulses to stimulate brain areas involved in mood.
• Add aripiprazole: they kept their current antidepressant and added aripiprazole (Abilify), an antipsychotic medication commonly used to boost antidepressants.
• Switch medications: they stopped their current antidepressant and switched to an SNRI, either venlafaxine (Effexor XR) or duloxetine (Cymbalta).

Over 8 weeks, trained raters tracked each person's depression using the MADRS, a standard clinician-rated depression scale. The study compared TMS against switching, and aripiprazole against switching. It did not compare TMS directly against aripiprazole.

What the study found

Adding TMS produced the biggest improvement. On average, people who added TMS saw their depression scores fall about 30% more than people who switched to an SNRI: a drop of about 17 points on the MADRS, compared with about 13 points. This was the study's main measure, and the difference was statistically significant.¹

More people in the TMS group also had a meaningful response, meaning their symptoms were cut at least in half: 52% with TMS, compared with 36% after switching. That is about 16 more people out of every 100. Because this study compared two treatments against switching, it used a stricter bar for statistical certainty than usual, and this particular difference fell just short of that bar. It points in the same direction as the main result, but it's a supporting finding rather than a proven one.¹

Adding aripiprazole did not beat switching on the main measures. It was not significantly better than switching to an SNRI on the clinician-rated depression score, response, or remission. People taking aripiprazole did rate their own symptoms and quality of life somewhat better than those who switched.^1,8

The bottom line: If two antidepressants haven't worked and you're still struggling, adding TMS gave people in this study the strongest improvement in depression compared with switching to another medication.

Why side effects matter in this decision

Effectiveness is only half the picture. The medications in this study come with side effects worth knowing about before you choose.

SNRIs like venlafaxine can raise blood pressure, so they need to be used carefully, or not at all, in people with high blood pressure or heart conditions. They can also cause sexual side effects, including lower sex drive in anyone and ejaculation problems or erectile difficulties in men.⁶ Stopping venlafaxine can bring on withdrawal symptoms such as dizziness, nausea, vomiting, "brain zap" sensations, ringing in the ears, anxiety, agitation, irritability, insomnia, headaches, and rarely seizures.⁶ A 2025 analysis in Molecular Psychiatry found that about 43% of people who stop an antidepressant experience some withdrawal symptoms.⁴

Aripiprazole works on the brain's dopamine system, which can lead to a different set of problems:⁷

• Akathisia: a relentless inner restlessness that can make it hard to sit still.
• Impulse-control problems: such as compulsive gambling or other compulsive urges.
• Metabolic changes: weight gain and increases in blood sugar and cholesterol.
• Neuroleptic malignant syndrome: a rare but potentially life-threatening reaction that can occur with any antipsychotic.
• Tardive dyskinesia: with longer-term use, which is often needed when aripiprazole is used for depression, there is a risk of involuntary movements of the tongue, jaw, and face. Because we rely on facial expressions to connect with each other, this can lead to embarrassment and social isolation, which can make depression harder to escape.

What about seizures?

Seizures are rare with all three treatments, but they are a common worry with TMS, so it helps to see the numbers side by side.

Across more than half a million TMS sessions, the seizure rate was about 0.003% per session, or roughly 3 in every 100,000 sessions.⁵ For a full course of TMS with a figure-8 coil, the most widely used type of TMS coil, the cumulative risk was about 0.014% per patient, or roughly 1 in 7,000.⁵

By comparison, FDA prescribing information reports seizures in 0.26% of people taking venlafaxine (about 1 in 385)⁶ and 0.1% of people taking aripiprazole (about 1 in 1,000).⁷

What to make of these results

If you've tried two antidepressants without enough relief, this study suggests that adding TMS gives you a strong chance of meaningful improvement, more than switching to an SNRI on the study's main measure. It also lets you avoid many of the medication side effects described above, such as blood pressure changes, sexual side effects, weight and metabolic changes, movement problems, and withdrawal symptoms.

Medication is still the right choice for many people, and every treatment decision depends on your own history, health, and goals. But this is information you deserve to have before making your next treatment decision together with your doctor.

This article is for general education and is not a substitute for individualized medical advice. Results vary from person to person. MUTHU Brain Medicine does not provide emergency services. If you are in crisis, call 911 or call or text 988 to reach the Suicide & Crisis Lifeline.