Prior to the 1980’s treatment for depression, including lobotomies, ECT, and first generation of antidepressant medications, came with quite serious side effects. Lobotomies may have led to a “calming” effect, but also often caused personality changes, a loss of decision-making ability, poor judgment, and sometimes even death. ECT is arguably, to this day, the most effective antidepressant treatment, but it also comes with memory loss, other cognitive side effects, and still carries a stigma for the way it was practiced early in the 20th century. The first antidepressant medications approved for depression, MAOI and tricyclic medications, were introduced on the market in the 1950’s and 60’s, but also came with quite serious side effects including hypo/hypertension, headache, sleep disturbance, convulsions, and were potentially lethal in overdose or with certain dietary combinations.
Therapeutic options improved greatly in both quantity and quality in the 1980’s and 90’s with the introduction of SSRIs and SNRIs and cognitive-behavioral therapy. The newer generation of drugs had fewer and less serious (though not inconsequential) side-effects. Cognitive-behavioral therapy is quite effective as it actively engages the patient in the therapeutic process and has minimal psychophysiological side-effects as it does not involve any psychoactive substance. More recently, in the early years of the 21st century TMS emerged as an evidence-based therapeutic option for depression. The first rTMS protocol (37 minute 10 Hz left DLPFC stimulation) received FDA clearance in 2008 followed by a shorter duration 10 Hz protocol in 2017 and an even shorter (3 minute) theta burst rTMS protocol in 2018.
Another category of antidepressant treatments that have their own industry involves lifestyle changes. Though this category doesn’t get as much attention by researchers, there is no doubt that lifestyle choices impact depressive symptoms both positively and negatively. There is good evidence to support the physical and mental health benefits of leading a healthy lifestyle including: exercising and sleeping more, increased social interactions, stress reduction, and reducing or eliminating the intake of alcohol and caffeine. That being said, initiating and maintaining these lifestyle changes may not be financially possible, feasible within the patient’s environment, or may be prohibitively burdensome to the patient, especially in a depressed state.
So fast forward to today, 2020, a patient presents with major depressive disorder, you are their clinician. What do you prescribe? Which of the available treatments (or combination of treatments) will lead to the greatest therapeutic benefit, with the lowest patient burden and the fewest potential side-effects? If you prescribe more than one, are there synergistic or contraindicated effects of the combination? If prescribed sequentially, is there a logical order to try various treatments in? Full disclosure, I am not a licensed therapist nor an MD. I am simply a researcher who has been around the experimental therapeutics literature for quite some time and have an in depth understanding of both the relative efficacy and potential side effects of all of the above mentioned treatments. I also recognize that a “one-size fits all” treatment for depression does not exist and many treatments involve a large investment of time, money, or energy which may not be readily available to a patient in a depressed state.
So, let’s compare the various options. Certainly antidepressant medications are quite low on the patient inconvenience scale. Per pill, drugs are readily available, easy to take, and (assuming insurance coverage) are relatively inexpensive. They can be delivered to your door and taken in the comfort of your own home. Alternatively, CBT and rTMS require the patient to leave the house, go to a clinic or therapist’s office for multiple sessions, and engage in social interactions. Additionally, per session, these options are relatively expensive (even with insurance coverage). CBT probably has the best side-effect profile, however, finding a trained therapist who has good rapport with the patient may be difficult. rTMS has side-effects, but they are largely minor and related to the stimulation itself and none are life-threatening and rTMS clinics are becoming increasingly accessible in many parts of the country.
It should be noted that rTMS is only FDA approved for “treatment-resistant” Major Depressive Disorder, meaning that by definition the patient has to have tried and failed at least one antidepressant drug trial. This is not because it was not effective for those who were not treatment-resistant or those who were treatment naïve, but rather that the placebo effect (for sham stimulation) was too large for these groups for the active rTMS to show superiority. Finally, there is currently no way to know a priori what response rate any given participant will have to treatment (though research on predictive biomarkers is actively underway).
Thus, most patients end up starting with a single antidepressant medication (typically an SSRI or SNRI) and CBT (if trained therapists are accessible). If the first-line medication is not effective, patients may find themselves being prescribed alternate or adjunctive medications. However, perhaps the best designed and most robust study to investigate antidepressant sequencing the “Sequenced Treatment Alternatives to Relieve Depression” (Star*D) trial found that each additional antidepressant treatment trial comes with diminishing returns and increased risk of intolerable side effects. Thus, I would argue that as soon as a patient fails their first antidepressant drug trial, that rTMS should be considered. rTMS can be given on top of meds and CBT and therapy. rTMS specifically targets the dorsolateral prefrontal cortex (DLPFC) a region of the brain known to be involved in cognitive control, working memory, and emotion regulation, all skills critical to successful therapy including CBT.
So, given the current state of multiple potentially effective treatments with relatively mild side-effect profiles, all things being equal, the following would be my recommendation. If available, start with CBT therapy and a first-line antidepressant drug first. If the drug is ineffective, or only partially effective, the clinician should know this within 6 weeks. If the depressive symptoms are not fully treated with an adequate dose of the first-line drug treatment, I would not add on additional medications. Instead, I would initiate rTMS while still continuing with CBT therapy. I would continue the medication (unless it was completely ineffective or had intolerable side effects). After 4-6 weeks with rTMS the patient and therapist may find that the three treatment modalities work better together than any one does individually. One caveat to this suggestion is to keep an eye out for medication-rTMS interactions including insomnia, hypermania, and increased seizure risk, though most of these can be minimized by adjusting the rTMS schedule or dose of the medication.
If enough symptom relief is experienced, after the rTMS regimen is completed, patients may require a lower dose of the antidepressant medication long-term or may be able to be safely tapered completely off their antidepressant medication. Lastly, with the relief of depressive symptoms and the strategies learned through CBT, the patient may have enough energy, motivation, and self-determination to begin initiating some of the lifestyle changes mentioned above leading to improved long-term physical and mental health.