What is Treatment-Resistant Depression?

        Treatment-resistant depression is difficult to define, as it currently has no strict diagnostic criteria. The clinical definition of treatment-resistant depression is depression that has not been alleviated by its prescribed treatments. It is functionally defined by the Food and Drug Administration (FDA) as a case of depression that has not responded to at least one trial of antidepressants. A longitudinal study conducted by the National Institute of Mental Health (NIMH) in 2006 examined multiple sufferers of major depressive disorder and their trials of medication for depression.[1] The study found that, while remission was possible for the study population (and, in fact, achieved by a significant percentage of participants), many other participants in the study opted to withdraw from the study in response to discomfort from their drug regimen. Factors that contribute to resistant depression include an insufficient dosage of depression medication, patient noncompliance, concurrent psychiatric disorders, and early discontinuation of treatment. A major factor in the early discontinuation of antidepressants is how intolerable the side effects of antidepressants can be for a patient experiencing adverse reactions. More appropriate treatment-resistant depression options exist, which don’t require antidepressants; one of which is transcranial magnetic stimulation (TMS).


Diminishing Effect of Multiple Trials of Antidepressants

        In 2006, the National Institute of Mental Health published the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. The goal of the study was to assess the outcomes of depression treatment for a large group of people diagnosed with a major depressive disorder over time.[2] Participants from all over the country were enrolled by their doctors, and they belonged to a wide array of different age groups (18-75 years of age) and socioeconomic positions.

        The methodology of the study sought to assess various treatment-resistant depression options in real-time with participants who were actively seeking treatment for their depression. The first level of treatment was a prescription for a single antidepressant, Celexa (citalopram), for 12 to 14 weeks. If a participant experienced their depressive symptoms in remission after starting the Celexa, they were transitioned out of active participation in the study and observed for a year, for side effects and sustainability of positive benefit. If Celexa was ineffective for patients at this level, they were escalated to level two.

        Level two of the STAR*D trial was meant to augment or modify treatment if the Celexa was unsuccessful or uncomfortable for the patient. They were given an option at this point to continue taking Celexa with an additional drug or discontinue that medication altogether. If they chose to discontinue the Celexa, they were randomly assigned one of the following: Zoloft (an antidepressant belonging to the same group as Celexa), Wellbutrin (an antidepressant of the atypical type) or Effexor (an antidepressant that works with both serotonin and norepinephrine neurotransmitters). If a patient decided to augment the Celexa, they were prescribed Wellbutrin or BuSpar, an anxiolytic that boosts the effectiveness of antidepressants (but is not itself one).

        If a patient did not see improvement in level two, they were escalated to level three. At level three, if a patient decided to switch their medications, they were randomly assigned either Remeron (an atypical antidepressant) or a tricyclic antidepressant (nortriptyline) for up to fourteen weeks. It makes sense that tricyclic antidepressants would be introduced in level three; they are generally prescribed in cases where clinical need decisively outweighs potential risk, due to the intensity of their side effects. If a patient decided to add on a medication, they were prescribed either lithium (a mood stabilizer typically used for the treatment of intense cases of Bipolar I) or triiodothyronine (T3), a thyroid medication that has an off-label capacity to enhance the effects of antidepressant medications.

        If a patient reached level four without any meaningful cessation of depressive symptoms, all preexisting prescribed psychiatric medications were stopped and the patient was prescribed one of two drugs: Parnate, an antidepressant of the MAOI type, or a combination of Effexor and Remeron. Parnate is a monoamine oxidase inhibitor: a particular type of antidepressant that is powerful in its effects, both positive and negative. Particular foods, beverages, and medications are to be avoided when a patient is taking an MAOI and the side effects can be aggressive, even when taken responsibly.

        The objective of the prescribed treatments in STAR*D was for full depression in remission: a complete cessation of depressive symptoms. This is because those who experience depressive symptoms going into full remission are less likely to relapse into another depressive episode or have their symptoms return than those who experience even a statistically meaningful positive response. Results of treatment plans were self-reported. In level one, one-third of patients reached remission (this group was taking just Celexa alone). In level two, 25 percent of patients achieved remission (this level replaced Celexa with another antidepressant or added a supplemental medication to Celexa if the patient so wished). In the level three group, which involved taking lithium or T3, 12 percent to 20 percent of patients saw the cessation of depressive symptoms. This group reported a high negative response rate to the medications in this level, more so with lithium than T3. In level four, 70 percent of participants were symptom-free but were generally more positive about their treatment plan if they had been taking the Effexor and Remeron, as opposed to the MAOI option, which many participants discontinued due to the side effects.

STAR*D Trial Outcomes Graph

        The notability of the study’s findings is twofold: as patients progressed through the levels of the study, the positive results diminished (higher percentages of participants achieved remission earlier in the study) and participant involvement declined, due in no small part to the side effects from increasingly intense drug regimens: 42 percent of remaining study participants withdrew after level 3.


Side Effects Are a Big Problem With Antidepressants

        Side effects of antidepressants play no small part in the difficulties of treating treatment-resistant depression. Patient noncompliance and early discontinuation of treatment can oftentimes be directly linked to difficult-to-tolerate psychiatric medication regimens. The side effects of antidepressants are systemic, meaning they affect the body as a whole (or, at the very least, multiple organ systems). Depression medication side effects are also dependent on the type of medication prescribed. The average depressed person visiting a primary care physician is likely to be prescribed a selective serotonin reuptake inhibitor (SSRI). Some notable brand names for drugs of this class include Celexa, Zoloft, Prozac, and Paxil.

        Common antidepressant side effects of SSRIs include nausea, dry mouth, diarrhea, insomnia, nervousness (agitation or restlessness), and sexual changes (generally marked by reduced desire or interest). In cases where a tricyclic antidepressant (TCAs) like Tofranil or Elavil is prescribed, the side effects change: many report stomach issues like constipation and other systemic effects like increased sweating. TCAs, in general, are prescribed less frequently because of the severity and intensity of their side effects; they are an early class of anti-depression drugs and are usually prescribed after failure to achieve results with SSRIs, which are milder in comparison. The first type of medication for depression was the monoamine oxidase inhibitor (MAOI): they have a history of being very effective but ultimately have been phased out of the average antidepressant regimen because of their tendency to escalate blood pressure. The final group, atypical antidepressants, are drugs that do not fall into any of the aforementioned antidepressant groups but can effectively treat depression. Wellbutrin is a popular antidepressant medication of this type.


TMS is an Appropriate Option for Patients Who Have Not Had Success With Antidepressants

        Transcranial magnetic stimulation (TMS) can be an appropriate solution for patients with severe depressive symptoms who do not tolerate depression medication side effects well. The trade-off between side effects and a positive benefit is generally more favorable than other therapies.

        TMS therapy uses magnets at an intensity similar to an MRI to stimulate a specific area of the brain, the prefrontal cortex. The prefrontal cortex is the area of the brain responsible for higher-order thought and cognition: decision-making, regulating social behavior, and personality expression. TMS therapy aims to alleviate symptoms of depression by targeting this area for stimulation to increase neural activity. After repeated treatments, patients can experience a significant reduction of depressive thoughts and feelings.

        TMS therapy does not require the use of medication for depression to be effective or to bolster its efficacy. This is key for many with resistant depression; generally, patients with this kind of depression are averse, or otherwise uncommitted, to prescription drug regimens. Often the side effects are too unpleasant for the patient to stay committed to the drug regimen, or the patient discontinues their medication on their own because they do not work (a common occurrence for those with resistant depression). TMS therapy itself has few side effects, and they are mild and short-lived. A patient undergoing TMS may complain of scalp discomfort or a headache after a session; both of which can be addressed easily and quickly with over-the-counter medication.

        Studies have shown that TMS therapy works in cases of resistant depression. A 2012 study by Linda Carpenter, MD, of Brown University et al, researched 42 TMS clinics across the United States that had treated 307 outpatients suffering from major depressive disorder (MDD).[3] The study found a response rate of 58 percent and a remission rate of 37 percent. Patients that had participated in the study had undergone an “average of 2.5 antidepressant treatments of adequate dose and duration without satisfactory improvement”. These findings are encouraging to anyone searching for treatment-resistant depression options.

        TMS therapy is effective, while not being difficult to tolerate as a procedure or with regard to its side effects, at treating cases of severe or resistant depression. It does not require the use of antidepressants and is thus a more appropriate option for those who have not had successful or pleasant experiences with medication for depression.


What is treatment resistant depression?

The FDA define treatment resistant depression as cases that have not responded to at least one trial of antidepressants. This includes that sufferers that have opted not to continue die to side effects as well as other factors.

What are the most common side effects of antidepressants?

The most common side effects of antidepressants are insomnia, blurred vision, dry mouth, fatigue, weight gain, nausea, GI distress and sexual dysfunction.

What is TMS?

TMS stands for transcranial magnetic stimulation. It’s a treatment that uses magnets to stimulate the prefrontal cortex to promote brain cell activity to decrease depressive symptoms. It’s a drug free therapy with contraindications so limited that patients require no post-treatment monitoring and are able to drive home straight away.

What are the most common side effects of TMS?

The most common side effects of TMS are scalp discomfort and headache.

All content provided on this blog is for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. If you think you may have a medical emergency, call your doctor or 911 immediately. Reliance on any information provided by the Active Recovery TMS website is solely at your own risk.

Meet Jonathan Horey, MD

Dr. Jonathan Horey became familiar with TMS while training and working at Columbia University in New York City where many of the early and important studies on TMS were conducted. Dr. Horey has since completed more extensive training in TMS and keeps himself up-to-date with the latest research on brain stimulation techniques, including TMS.