Noninvasive radiosurgery offers major relief for treatment-resistant depression

Key takeaways:

• Thirteen of 14 patients with suicidal thoughts at baseline had no suicidal ideation at the final follow-up.
• Depression scores fell by at least 50% at some point for 11 of 18 evaluable patients.

A noninvasive neurosurgical technique that targets a specific brain pathway with radiation was linked to a marked reduction in major depression symptoms among people with severe, treatment-resistant psychiatric illness, according to study results.

Stereotactic radiosurgical capsulotomy also produced a significant drop in suicidal ideation, based on findings from a prospective observational study presented at the ASTRO Annual Meeting.

“Patients had remarkable, life-changing improvements — and, given the resolution of suicidal ideation, this was a life-saving treatment in many cases,” lead author Mohamed Khattab, MD, radiation oncologist at University of South Florida and Tampa General Hospital, told Healio.

A different approach

About 30% of people with depression have a treatment-resistant form, according to the study background.

That label applies to patients who have not improved adequately after at least two therapies, and this group has high rates of suicidal ideation and suicide attempts, Khattab said.

Available options often have limited benefit and can carry adverse effects.

For example, electroconvulsive therapy can affect memory, ketamine can cause hemodynamic or genitourinary toxicity, and invasive neurosurgical procedures such as radiofrequency ablation capsulotomy may lead to confusion, incontinence, hemorrhage, bleeding, or infection.

SRS capsulotomy is a highly focused form of radiation therapy that does not require an incision.

The procedure, which has mainly been studied for severe treatment-resistant obsessive-compulsive disorder, creates a small lesion in the anterior limb of the internal capsule. Abnormalities in this pathway have been associated with mood and psychiatric disorders.

Because it does not require opening the skull or implanting hardware, SRS capsulotomy offers a way to interrupt a circuit that contributes to persistent severe symptoms — essentially rebalancing reward and grief pathways — while limiting effects on nearby brain tissue, Khattab said.

Khattab was the principal investigator for the study while working at Vanderbilt University Medical Center.

Since 2020, some Vanderbilt patients with treatment-resistant major depression who failed multiple medications and other escalated interventions have been referred for SRS capsulotomy after multidisciplinary review by radiation oncology, psychiatry and neurosurgery. The treatment has been provided per medical judgment and as compassionate care, Khattab said.

Patients could also choose to enroll in a prospective institutional registry.

In a prior report, Khattab and colleagues described three patients, all of whom had reduced or resolved suicidal thoughts without neurologic adverse effects or cognitive decline.

At ASTRO, Khattab presented data from a larger group of 20 patients with treatment-resistant major depressive disorder, with an average illness duration of more than 30 years.

All had received cognitive behavioral therapy and multiple medications without improvement. Some had also failed electroconvulsive therapy (55%) or transcranial magnetic stimulation (35%), and 40% were refractory to ketamine.

Fourteen patients (70%) had active suicidal ideation, and many had attempted suicide multiple times. Another 10 patients (50%) also had obsessive-compulsive disorder.

After outpatient SRS capsulotomy, patients returned for follow-up every 3 months with MRI, including tractography, which creates 3D maps of nerve tracts in the brain, plus clinical examination.

Researchers measured depressive symptoms with the Beck Depression Inventory, OCD symptoms with the Yale-Brown Obsessive Compulsive Scale, and cognition with the Montreal Cognitive Assessment. Suicidal ideation was also monitored.

Impressive findings

Median follow-up was 38.6 months.

At the final follow-up, 13 of the 14 patients who had suicidal thoughts at presentation no longer had suicidal ideation. Khattab called that result striking.

Depression symptoms were assessed in 18 patients.

Beck Depression Inventory scores dropped by a mean of 15.1 points from baseline to final follow-up. Scores fell by 50% or more at some point in 11 patients (61.1%), with nine patients (50%) still meeting that threshold at final follow-up, and 16 patients (88.8%) showing at least some improvement from baseline.

“These results are particularly impressive considering the severity of disease our patients had,” Khattab said. “These numbers are especially high given they had failed so many prior treatments.”

Among the 10 patients who also had OCD, mean Yale-Brown Obsessive Compulsive Scale scores declined by 9.8 points from baseline to last follow-up. Half achieved a reduction of at least 35%, which Khattab described as a very meaningful clinical response.

Benefits appeared within as little as 3 months.

Montreal Cognitive Assessment scores showed no sign of cognitive decline after treatment. In fact, scores for all 20 patients stayed stable or improved from baseline to final follow-up, with a mean change of 2.5 points.

Khattab called that one of the most important findings because any brain procedure raises concerns about cognitive effects.

No serious complications were seen in the cohort.

Four patients (20%) had more tissue change than expected, prompting dose reductions, Khattab said. Two experienced grade 2 symptoms such as headache or dizziness that resolved with standard care, while the other two remained without symptoms.

No participants developed personality changes, weakness, or neurologic deficits.

A highly specialized approach

The researchers noted limitations, including the small sample and single-center design. The absence of a comparison group also means the improvement cannot be proven causal.

“Despite these limitations, this study shows a strong signal for a potential new treatment,” Khattab said. “Our findings indicate that radiosurgery may offer patients the benefit of capsulotomy without invasive surgery. The benefits were durable, and we were very pleased with the safety and tolerability of this approach.”

The team hopes to secure funding for a randomized, sham-controlled trial of SRS capsulotomy. Khattab said he hopes the potential to substantially improve outcomes in a notoriously difficult-to-treat condition will help attract philanthropic support.

“We’re not talking about a small number of people. This is a vast population, and it is sad to think how many people are suffering — not just these individuals, but their families, their friends and their communities,” Khattab said. “The cost burden of psychiatric disease on society — considering both direct and indirect spending — is more than double the cost of all cancer care combined. Having this treatment option could bring huge value, not only to patients but also in the context of public health and socioeconomic impact.”

Khattab said results from a randomized sham-controlled trial could support wider use of SRS capsulotomy, help identify patients most likely to benefit, and guide future comparisons with other treatments.

For now, he said the data suggest that patients with truly refractory disease could be candidates for SRS capsulotomy under compassionate use.

“The typical radiation oncologist should not be doing this,” Khattab said. “This should be delivered in highly specialized programs by people who are well trained and have this unique expertise, and who are very selective in the patients they treat. We want to make sure this treatment is done ethically, appropriately and very cautiously to ensure it is both effective and safe.”

Perspective

SRS for psychiatric conditions such as OCD has shown benefit for patients who do not respond to standard treatment. For example, a meta-analysis by Reyes and colleagues reported a 57% response rate and 37% remission rate with SRS for OCD.

Khattab and colleagues focused specifically on SRS capsulotomy for major depressive disorder. Previous reports have been small. This larger study included 20 patients who had failed several treatments, including ketamine and electroconvulsive therapy.

In these patients, SRS capsulotomy led to significant improvement in Beck Depression Inventory scores. The average change moved from severe depression to mild mood disturbance at peak response and to borderline clinical depression at final follow-up. Researchers also saw improvement in OCD scores among patients with OCD symptoms, and cognitive scores improved as well. This adds another effective option for major depressive disorder.

This treatment should be used with psychiatric support and multidisciplinary discussion after other options are nearly exhausted. Patients also need continued psychiatric follow-up to monitor effectiveness. Stigma remains around brain radiosurgery for psychiatric use because of the historical indiscriminate and imprecise use of lobotomies in the mid-20th century. Modern techniques are far more precise and better studied, so that stigma may gradually lessen.

More evidence is needed to rebuild confidence in surgery for psychiatric indications. SRS capsulotomy may improve quality of life for people with major depressive disorder that has not responded to other treatments.

Disclosures: Chao reports no relevant financial disclosures.

Sources/Disclosures

Source:

Khattab MH, et al. Abstract 183. Presented at: ASTRO Annual Meeting.

Disclosures: Khattab reports prior research funding from Varian Medical Systems and Brainlab; ownership in Radiosurgery Consultants LLC; and service with The Radiosurgery Society’s Functional Radiosurgery Working Group. Please see the study for all other authors’ relevant financial disclosures.

Ask a clinical question and tap into Healio AI's knowledge base.

• PubMed, enrolling/recruiting trials, guidelines
• Clinical Guidance, Healio CME, FDA news
• Healio's exclusive daily news coverage of clinical data