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TMS for Treatment-Resistant Depression

By December 7, 2023No Comments
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Transcranial magnetic stimulation (TMS) is a therapeutic technique that can help people with a type of depression called treatment-resistant depression.

When people with depression seek professional help and support, they’re often at the end of a process that takes years. By the end, we mean they’ve tried, on their own, to manage the uncomfortable and disruptive mental health symptoms they experience, but without success. Therefore, the beginning of treatment marks the end of trying to do it themselves, and recognizing two things:

  1. Treatment works
  2. You have to seek treatment to get treatment

However, we have to qualify that first point: for people diagnosed with clinical depression, traditional treatment – unfortunately – does not always work. For an individual who spends years managing symptoms on their own, then finally seeks professional support, this can be devastating. The one thing they thought might help improve their depressive symptoms – treatment – does not help them at all.

In fact, evidence shows that among people diagnosed with major depressive disorder (MDD), over thirty percent do not respond to traditional treatment, which typically consists of antidepressant medication and talk therapy, a.k.a. psychotherapy. When a person with MDD does not respond favorably to at least two attempts at traditional therapy with antidepressants and psychotherapy, they receive a diagnosis of treatment-resistant depression, or TRD. Therefore, the thirty percent we refer to above have TRD.

Statistics on depression in the U.S. and the world:

  • 280 million worldwide people have clinical depression
  • 21 million adults age 18+ in the U.S. have clinical depression

When we apply what we know about TRD, those figures tell us the following:

  • 84 million people in the world have treatment-resistant depression
  • 3 million adults in the U.S. have treatment-resistant depression

That information begs an important question:

How do we help the millions of people in the U.S. and around the world with TRD?

A study published in December, 2022 offers insight on how a new treatment – transcranial magnetic stimulation (TMS) – might offer symptom relief when traditional therapies prove ineffective.

What is Transcranial Magnetic Stimulation (TMS)?

Transcranial magnetic stimulation (TMS) is a technique that uses targeted electromagnetic pulses, aimed at specific brain areas, in order to stimulate those brain areas and relieve the symptoms of various mental health diagnoses. A TMS machine is similar to an MRI machine in that it delivers noninvasive electromagnetic pulses to specific areas of the body – in this case, the brain – but it’s different in that it’s a much smaller machine, and treatment is delivered through a coil placed directly on the scalp.

Evidence shows that for people with TRD – meaning people diagnosed with MDD who don’t experience relief with typical treatment – TMS treatment can reduce symptoms in over fifty percent of patients, and lead to remission in around one third of patients.

By our calculations, that means that close to three million people in the U.S. can benefit from TMS treatment, and over 40 million people worldwide can benefit from TMS treatment. That’s good news for people with TRD. In even better news, a recent study called “Differential Symptom Cluster Responses to Repetitive Transcranial Magnetic Stimulation Treatment In Depression” presents data on how providers can improve the manner in which they diagnose and treat TRD.

TMS for Treatment-Resistant Depression

The research we cite above shows TMS can help relieve symptoms in people with treatment-resistant depression when other approaches to treatment fail. Additional research shows that the way we diagnose people for TRD may need improvement. Current diagnostic models use questionnaires that deliver a single score to detect the presence of depression, but experts in depression and depression assessment believe that another approach – using symptom clusters – might offer greater diagnostic clarity and specificity.

Therefore, the research team hypothesized they could combine a symptom cluster model with TMS treatment to help clinicians better support people with TRD. In their words:

“The knowledge of how rTMS treatment can differentially impact distinct symptom clusters in depression could eventually facilitate personalized delivery of rTMS based on an individual’s presenting symptoms.”

To test their hypothesis, they created two objectives:

  1. Whether a standard depression measure can be represented using a four symptom cluster model
  2. Whether these symptom clusters had a differential response to TMS treatment

Traditional Diagnosis for Depression May Be Incomplete

The traditional method for assessing the presence or remission of depressive symptoms – and diagnosing depression – is by taking the sum of a score of questions on depression measurement tools known as a psychometric scales. The most common assessments of this type are the Beck Depression Inventory (BDI-2) and the  Hamilton Depression Rating Scale (HAMD). These two assessments, and others like it, are effective in identifying the presence and severity of depression, and have been used by clinicians for decades to diagnose depression in adolescents and adults.

However, in recent years, critics have noted that depression may be more accurately conceptualized as a condition with a series of symptom clusters. This idea is known as multidimensionality, and researchers categorize these clusters of symptoms into several distinct symptom dimensions. The idea is that identifying the relative presence and severity of symptoms by dimension or cluster can add detail and nuance to the diagnostic process. This level of diagnostic detail can then help providers target depression treatment to prioritize the symptom dimensions or clusters that cause the most significant distress and disruption.

How New Metrics Can Help Diagnosing Depression

It’s not that the depression metrics we’ve used for decades aren’t good or don’t work, it’s that they were developed decades ago. We have a clearer understanding of depressive diagnoses than when they were originally created, and with what we know now, we know they can be better. The more we know about depression in an individual based on their initial diagnosis the better we can help them. This new approach builds on the tools we’ve had for years, but improves upon them, with the ultimate goal of improving treatment outcomes for all people with depression.

In this study, researchers grouped symptoms identified on the Hamilton Depression Rating Scale (HAMD) into two types: mood symptoms clusters and anxiety symptoms clusters. Previous research identified these two clusters and found TMS treatment had a differential impact on the symptom clusters: treatment improved depressive cluster symptoms more effectively than it improved anxiety cluster symptoms.

That brings us to the second research objective: testing the effect of TMS on symptom clusters.

Only one previous study examined the differential effect of TMS treatment with regards to the symptom cluster model derived from the HAMD assessment. Therefore, researchers formed a simple goal to reach their second objective: confirm or refute the previous research that showed TMS treatment improves depressive symptoms clusters compared to anxiety symptom clusters.

Targeted TMS, Treatment-Resistant Depression, and Symptom Clusters: How the Study Worked

Researchers obtained data from two multi-center randomized controlled trials of TMS for treatment-resistant depression. In these trials, clinicians delivered pulses to the left dorsolateral prefrontal cortex (DLPFC) of participants with treatment-resistant depression (TRD). The two trials involved a total of 596 individuals diagnosed with TRD in Canada.

Here are the details on those two studies:

  • First trial:
    • The THREE-D study collected records on outcomes for people with TRD from Sept 2013 to Oct 2016
  • Second trial:
    • The CARTBIND study collected records on outcomes for people with TRD from Apr 2016 to Feb 2018

In addition, all participants in the new study:

  • Had a history of at least two (2) inadequate/unsatisfactory responses to treatment with traditional antidepressants
  • Were currently taking at least one traditional antidepressant, as required for approval for TMS treatment

The symptoms clusters researchers created for this model included:

  1. Mood symptoms
  2. Anxiety symptoms
  3. Insomnia symptoms
  4. Somatic – i.e., physical – symptoms

The study gets interesting at this point, because when the researchers applied this symptom cluster model to the HAMD questionnaires, they found the model fit in theory, but did not fit when analyzing real data from real patient. However, when they altered the model to a two-cluster model by allocating specific insomnia-related symptoms and specific somatic symptoms to either the mood cluster or anxiety cluster, they found the model fit very well, and offered important diagnostic insight into the character of each TRD diagnosis.

That’s an insight into the scientific research process, and shows this research team allowed data to drive their conclusions, which is essential: when the data do not fit, scientists either adjust or alter their hypothesis. That’s how good science works, and that’s exactly what this team did.

Targeted TMS, Treatment-Resistant Depression, and Symptom Clusters: The Results

In this study, researchers wanted to find out if a symptom cluster model could help diagnostic clarity in patients with treatment-resistant depression. They accomplished that, and altered their model from a four-cluster model to a two-cluster model. The original model included clusters for mood, anxiety, insomnia, and somatic symptoms, while the adjusted model included clusters for mood and anxiety, both with subsets, or subclusters, for insomnia-related and somatic symptoms.

They designed the second part of the study to identify which cluster of symptoms improved most after targeted TMS treatment: mood cluster symptoms or anxiety cluster symptoms.

Targeted TMS: Impact on Mood and Anxiety Symptom Clusters

Mood symptoms:

  • Overall mood: TMS significantly reduced mood symptoms in both the THREE-D and CARTBIND datasets
  • Mood, insomnia cluster: TMS significantly reduced mood-related insomnia symptoms in both datasets
  • Mood, somatic cluster: TMS significantly reduced mood-related somatic symptoms in both datasets

Anxiety Symptoms:

  • Overall anxiety: TMS did not significantly reduce anxiety symptoms in the THREE-D and CARTBIND datasets
  • Anxiety, insomnia subset: TMS mildly reduced insomnia-related anxiety symptoms in both datasets
  • Anxiety, somatic subset: TMS mildly reduced somatic-related anxiety symptoms in the THREE-D and CARTBIND datasets

These results are important. This is the first study that showed two things. First, people with TRD present with distinct symptom clusters, as opposed to one system cluster under the general category of depression. Second, in people with TRD who engage in targeted TMS, different symptom clusters respond differently to treatment.

How This Data Helps Us Support People With Treatment-Resistant Depression

We’ll start with the diagnostic component of this study. This helps because it will enable us to further clarify the contours of each individual case of depression, and tailor treatment accordingly.

We hear it and say it all the time: there are as many paths to healing from depression as there are paths to developing depression.

This cluster approach to diagnosing depression makes the healing part of that statement more real. If we can identify a more detailed symptom profile for each individual, we may be able to create treatment programs that are more specific and customized than those we create now, with the current standard metrics.

Next, we’ll address the therapeutic component of this study. According to Dr. Tyler Caster, the lead researcher for this study:

“As TMS has the ability to focally stimulate neural regions, it may be possible to regulate specific neural circuits such that targeting distinct symptom clusters may now be possible in a way that cannot be done with medication.”

Completing this study was the first step in this process. The results showed that TMS targeted at the left dorsolateral prefrontal cortex (DLPFC) reduced symptoms in the mood symptom cluster and the insomnia and mood subclusters of the mood symptom cluster. Meaning that it is, indeed, possible to use targeted TMS to relieve specific symptoms clusters in people with TRD.

That’s the start of a potentially game-changing development in treating TRD. Again, we’ll quote the lead author of this study, interviewed in the magazine Nature: Mental Health

“Our long-term goal is to determine whether it may be possible to personalize TMS treatment based on an individual’s presenting symptoms. Ultimately, the hope is to conduct a trial that compares outcomes of the ‘personalized’ approach with the standard treatment approach to determine whether it improves outcomes for patients.”

That’s a long-term goal which, if achieved, can help us deliver targeted support to patients diagnosed with TRD. If we can use TMS for TRD in this manner, we can not only offer hope – big picture – for people with TRD, but also streamline the treatment process, and deliver symptom relief more effectively and more quickly than ever before.

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