Depressive symptomatology presents across numerous neuropsychiatric, neurological, neurodevelopmental, and general medical conditions. For example, many adolescents and adults with Autism Spectrum Disorder, older adults with Neurodegenerative disorders including Alzheimer’s, those with chronic pain syndromes, and those who suffer a concussion or mild traumatic brain injury all show symptoms of depression. Patients with depressive symptoms associated with these conditions are often not diagnosed with MDD (the diagnostic criteria indicate that the symptoms should not be attributable to the physiological effects of a substance or to another medical condition). So, often treatment for depressive symptoms associated with these disorders are considered “off-label”. Thus, a logical question is whether a specific treatment that has been shown to be effective in those with MDD would likely alleviate depressive symptoms in these other disorders. It’s complicated and the short answer is, “maybe”, but in most cases we don’t know yet. In this month’s blog I will flesh out both sides of the argument.
I’ll start with the positive. Though everyone would like to believe that they are special and that their situation is totally unique, unless there is reason to believe otherwise, I would that one should be able to expect that the same networks still underlie the same functions and that treatments targeting those networks may still have therapeutic effects. This is the basis for NIMH’s recent shift toward “Research Domain Criteria” (RDoC), where biomarkers and treatments are based on symptom domains rather than DSM or IDC diagnostic codes. Under the RDoC research framework a number of specific networks have been implicated in specific behavioral domains, see https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/constructs/rdoc-matrix.shtml.
As it relates to TMS the same protocol that is effective for MDD may still modulate the same brain network in presumably the same way for people with depressive symptoms manifesting from different originating mechanisms. As I have mentioned in previous blogs, the brain and its response to TMS is agnostic to the diagnostic code given to that person’s condition (based on behavioral symptom presentation). A second argument for at least trying the standard TMS depressive treatments in these populations is the finding that TMS to the dorsolateral prefrontal cortex (DLPFC), when effective, modulates a similar network as ECT and cognitive behavioral therapy for depression. Response to any of these treatments seems to modulate DLPFC cortical and subcortical connections. Thus, if this network is impacted by any of these disorders, modulation of the functional connectivity of this network may alleviate some of the depressive symptoms. And at the very least, TMS’s safety profile makes trying TMS as a secondary treatment if/when medication and/or psychotherapy is not an option or not effective a reasonable possibility.
Now for the counter argument. As we know, depression is not just one thing. Although most brains and brain networks generally function similarly, and respond to TMS similarly, each disorder (and to be more specific each individual with each disorder) has its own unique pathogenic mechanisms that may contribute to the mechanisms underlying presentation of symptoms and impact the brain’s response to TMS. For example, for those with neurodegenerative disorders, the disease affects both the responsivity and connectivity of the cortex that you are attempting to modulate. Thus, you have forces working against you that need to be considered. You may need to stimulate at a higher intensity or for a longer time or apply additional sessions. In this population, the location of stimulation may be the same, but other aspects of the protocol may need to be adjusted. Other disorders may require different locations for stimulation such as ASD or TBI where the brain has been — over the course of development or due to an injury — wired up differently.
We must remember that the brain is plastic and when faced with injury or illness, it may rewire itself in a way that may be generally adaptive, but not necessarily consistent with standard expectations. The truth is that everyone’s brain constantly adapts and adjusts its connectivity and network functioning based on changing biological and environmental forces, so-called developmental and experience-based plasticity. The response of the brain to a given intervention (TMS or otherwise) therefore may differ depending on the baseline state of the brain at the time the intervention is presented. There have been tens (if not hundreds) of thousands of healthy adults and MDD patients who have received the “standard” TMS protocols such that we have an expectation of what we should see in treated individuals. However, if /when we do not see the expected response in a patient with depressive symptoms associated with other neuropsychiatric, neurological, neurodevelopmental, or general medical conditions, we may need to adjust our parameters given what we think we know about the pathophysiology of the co-occurring disorder.
To this end, there are a number of ongoing studies aiming to identify “biotypes” that may predict what treatment would be most effective for a given individual with a given disorder or symptom. If we can reliably identify these biotypes, we can streamline the process and provide the “best” therapeutic option (TMS or otherwise) for a given patient with less guessing. As with Cancer and Heart Disease, the hope is that if we can identify biotypes for depression and other neuropsychological disorders, we can develop more effective treatments. For those interested in biotypes and transdiagnostic symptom domains as they relate to depression and associated symptoms, some good recent papers include:
Full disclosure, however, this is a burgeoning field with a lot of interest and excitement. Though the above cited literature comes from reputable sources, findings should be interpreted with caution as most of these studies still require replication and validation prior to broad clinical application. That being said, we have the tools and techniques available. If I was a betting woman, I would bet that in the next decade we will have a way to predict who will respond best to which drug, which psychotherapy, which neurostimulation protocol, and/or other interventions. Stay tuned! As new studies are published, I am always happy to share the links to those papers.