rTMS for Depression in Autism

(rTMS-MDD Trial)

Overseen By Anjuli G Ner, HBSc

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must not be taking: Benzodiazepines, Anticonvulsants

Disqualifiers: Substance use disorder, Seizures, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 33

Duration: 6 weeks

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The current clinical trial is focused on evaluating the efficacy of rTMS for treatment of depression in youth and young adults (hereafter called transition aged youth, TAY) with autism spectrum disorder (ASD). The motivation to undertake the current efficacy study is driven by: (1) the substantial impact of depression on TAY with ASD (based on prevalence and contribution to disability/impairment); (2) lack of evidence-based treatments for depression in autism (there are no current trials rigorously evaluating any treatment for depression, i.e., psychotherapeutic, pharmacotherapeutic, brain stimulation); (3) rTMS has demonstrated efficacy in non-autistic individuals to improve symptoms of depression and may be better tolerated in youth than medication treatment; (4) a prior pilot rTMS study focused on treatment of executive function deficits in autism indicated that high frequency rTMS delivered using a rigorous randomized control trial (RCT) protocol can be feasibly implemented in TAY with autism, is well tolerated (mild to moderate adverse effects and low drop out), and has the potential to improve symptoms of depression.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have changed your psychotropic medications or increased their dosage in the last 30 days.

Is rTMS safe for humans?

Research shows that rTMS, including theta burst stimulation (TBS), is generally safe for humans, with some studies reporting minor tolerability issues in a small number of participants. ^{1 2 3 4 5}

How is the treatment rTMS for Depression in Autism different from other treatments?

The treatment uses repetitive transcranial magnetic stimulation (rTMS) with a specific pattern called theta burst stimulation (TBS), which targets the brain's prefrontal cortex to help improve depression symptoms. This approach is unique because it uses magnetic fields to stimulate nerve cells, offering a non-invasive alternative to medication and psychotherapy. ^{2 4 5 6 7}

What data supports the effectiveness of the treatment for depression in autism?

Research shows that repetitive transcranial magnetic stimulation (rTMS), including theta burst stimulation (TBS), can help reduce symptoms of major depression. Studies have found that these treatments can be effective when used alongside other therapies, like medication and psychotherapy, for people with depression. ^{2 5 7 8 9}

Who Is on the Research Team?

Stephanie H Ameis, MD, MSC

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for young adults with autism who are also dealing with depression. They should be fluent in English, able to consent, clinically stable without medication changes for a month, and have an IQ of 70 or above. Those who are actively suicidal, pregnant, have seizures history or recent substance abuse can't participate.

Inclusion Criteria

Global Assessment of Function (GAF) scores (≤60) that is sustained over a lead-in period of two weeks AND/OR VABS-III below adequate functioning at baseline assessment.

My mental health treatment hasn't changed in the last 30 days.

Fluent in English

Exclusion Criteria

Significantly debilitating medical or neurologic illness, or acute or unstable medical illnesses as determined by study physician

Metal implants or a pace-maker, claustrophobia that would preclude the MRI scan

Actively suicidal (i.e., suicidal ideation with plan and intent) or high risk for suicide as assessed by a study psychiatrist

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive bilateral theta burst stimulation (BL-TBS) to dorsolateral prefrontal cortex (DLPFC) 5 days per week for 6 weeks

6 weeks

30 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Active Bilateral Theta Burst Stimulation
• Sham Bilateral Theta Burst Stimulation

Trial Overview The study tests rTMS (a type of brain stimulation) to see if it helps improve depression symptoms in autistic youth. Participants will receive either the real rTMS treatment or a sham (fake) version to compare outcomes in a controlled setting.

How Is the Trial Designed?

Group I: Active bilateral theta burst stimulation Active Control 1 Intervention

An X100 stimulator with a B65 A/P type coil (Magventure Inc.) will be used. The coil is positioned under MRI guidance using real-time neuronavigation using Brainsight \[x,y,z= -38, 44, 26(left), +38, 44, 26 (right). BL-TBS will be delivered at 90% RMT, corrected for scalp to cortex distance, to targeted left and right DLPFC sites, differing only in stimulation pattern and total number of pulses (triplet 50 Hz bursts, repeated at 200 msec (i.e., 5 Hz); right DLPFC (continuous TBS, cTBS): 120 seconds uninterrupted bursts (total of 600 pulses); left DLPFC (intermittent TBS, iTBS: 2 seconds on and 8 seconds off; 600 pulses per session; total duration of 3 min 9 seconds/hemisphere).

Group II: Sham bilateral theta burst stimulation Placebo Group 1 Intervention

An X100 stimulator with a B65 A/P type coil (Magventure Inc.) will be used with the active coil facing away from the scalp, for sham stimulation. The coil is positioned under MRI guidance using real-time neuronavigation using Brainsight \[x,y,z= -38, 44, 26(left), +38, 44, 26 (right). To reproduce the nociceptive qualities of the stimulation, the B65-type stimulation coil - sham side - includes a built in electrical stimulator in the coil connector which "fires" a synchronous electrical pulse along with the TMS stimulus through electrodes mounted on the forehead or near the area of stimulation, to generate auditory and somatosensory (vibration) stimuli.

Active Bilateral Theta Burst Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as rTMS for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder

Approved in European Union as rTMS for:

• Major Depressive Disorder

Approved in Canada as rTMS for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Published Research Related to This Trial

In a randomized-controlled trial involving 32 patients with major depression, bilateral theta burst stimulation (TBS) to the dorsolateral prefrontal cortex showed a significant increase in treatment response compared to sham stimulation, with 9 responders in the TBS group versus 4 in the sham group.

The study also indicated a trend towards higher remission rates in the TBS group as measured by the Beck Depression Inventory, suggesting that TBS may enhance the effectiveness of ongoing medication and psychotherapy in treating major depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. Plewnia, C., Pasqualetti, P., Große, S., et al.[2018]

In a randomized controlled trial involving 56 patients with moderate to severe depression, bilateral theta-burst stimulation (TBS) and repetitive transcranial magnetic stimulation (rTMS) did not show significant improvements in depression scores compared to sham treatment.

However, there was a noted tendency for both active treatments to increase the responder rate, particularly for the TBS group, suggesting that further research may be needed to explore its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. Prasser, J., Schecklmann, M., Poeppl, TB., et al.[2015]

Accelerated intermittent theta burst stimulation (TBS) was found to be safe and well tolerated in 12 suicidal therapy-resistant depressed patients, showing a significant decrease in suicidal ideation over time.

However, the reduction in suicidal thoughts was not definitively linked to the active TBS treatment compared to sham stimulation, indicating that further research is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The acute effects of accelerated repetitive Transcranial Magnetic Stimulation on suicide risk in unipolar depression: preliminary results. Desmyter, S., Duprat, R., Baeken, C., et al.[2022]

Intermittent theta-burst stimulation (iTBS) targeting the left visual cortex (VC) was found to be non-inferior to targeting the left dorsolateral prefrontal cortex (DLPFC) in improving depressive symptoms in patients with major depressive disorder (MDD), based on a study of 75 participants over 14 days.

The VC group experienced lower rates of suicidal ideation and fewer adverse events, such as eye discomfort and pain, suggesting that VC-targeted iTBS may be a safer option for treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-inferiority of intermittent theta burst stimulation over the left V1 vs. classical target for depression: A randomized, double-blind trial. Kong, Y., Zhou, J., Zhao, M., et al.[2023]

Continuous theta burst stimulation (cTBS) was found to be safe and well-tolerated in patients with major depressive disorder (MDD) or bipolar depression (BD), with no significant differences in adverse events compared to sham treatment.

However, the meta-analysis of three randomized controlled trials involving 78 participants showed no significant improvement in depression scores or response rates with cTBS compared to sham, indicating that cTBS may not provide a therapeutic advantage for treating major depressive episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. Cai, DB., Qin, XD., Qin, ZJ., et al.[2023]

In a well-designed 8-week randomized, double-blind sham-controlled trial involving 60 participants with autism spectrum disorder (ASD), inhibitory continuous theta burst stimulation (cTBS) did not show superior efficacy compared to sham stimulation in improving clinical or neuropsychological outcomes.

Both the active and sham groups exhibited similar improvements over time, suggesting that previous positive results from open-label trials may be influenced by placebo effects, indicating a need for more rigorous studies on rTMS/TBS in ASD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A lack of efficacy of continuous theta burst stimulation over the left dorsolateral prefrontal cortex in autism: A double blind randomized sham-controlled trial. Ni, HC., Chen, YL., Chao, YP., et al.[2023]

In a pilot study involving 13 adults with autism spectrum disorder (ASD), intermittent theta burst stimulation (iTBS) applied over the bilateral posterior superior temporal sulcus (pSTS) showed significant immediate improvements in parent-rated autistic symptoms after 5 days of treatment.

The effectiveness of iTBS on cognitive flexibility and clinical symptoms was influenced by individual factors such as baseline social-communicative impairment, cognitive performance, and concurrent psychotropic medication use, highlighting the need for personalized approaches in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-day multi-session intermittent theta burst stimulation over bilateral posterior superior temporal sulci in adults with autism-a pilot study. Ni, HC., Lin, HY., Chen, YL., et al.[2022]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

In a study of 54 patients with major depression, the combination of intermittent theta burst stimulation (iTBS) and low-frequency rTMS (LF-rTMS) significantly improved depression and anxiety symptoms more than high-frequency rTMS (HF-rTMS).

The results suggest that iTBS combined with LF-rTMS may be a promising alternative therapy for major depression, offering both efficacy and time-saving benefits compared to traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left intermittent theta burst stimulation combined with right low-frequency rTMS as an additional treatment for major depression: A retrospective study. Mi, Y., Ji, Y., Lou, Z., et al.[2022]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. [2015]

3. Croatia pubmed.ncbi.nlm.nih.gov

The acute effects of accelerated repetitive Transcranial Magnetic Stimulation on suicide risk in unipolar depression: preliminary results. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Non-inferiority of intermittent theta burst stimulation over the left V1 vs. classical target for depression: A randomized, double-blind trial. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

A lack of efficacy of continuous theta burst stimulation over the left dorsolateral prefrontal cortex in autism: A double blind randomized sham-controlled trial. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

5-day multi-session intermittent theta burst stimulation over bilateral posterior superior temporal sulci in adults with autism-a pilot study. [2022]

8. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

9. India pubmed.ncbi.nlm.nih.gov

Left intermittent theta burst stimulation combined with right low-frequency rTMS as an additional treatment for major depression: A retrospective study. [2022]