Clinical Applications and
More than 15 million people in the United States have some form of depression (Substance Abuse and Mental Health Services Administration 2016). Less than half ever seek treatment (Pratt and Brody 2014), and 75% of those who do are managed by their primary care physician (Goldman et al. 1999). Of those who are treated, only about half receive adequate treatment (Katon et al. 1992), and far fewer receive optimal treatment. Even with optimal treatment, however, full recovery from depression is surprisingly difficult to achieve considering that there are more than 30 antidepressant medications approved by the U.S. Food and Drug Administration (FDA), as well as several evidence-based psychotherapies and augmentation agents.
The largest and most important study to date of antidepressant efficacy is the National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (Rush 2007). This seminaturalistic study took 7 years to complete and involved 4,040 patients at 23 psychiatric and 18 primary care “real-world” settings. An important finding was that only 35% of properly treated patients achieved remission with the first antidepressant (i.e., citalopram) prescribed. The likelihood of achieving remission decreased steadily with each subsequent treatment failure, so that after a patient experienced three failed trials of antidepressants, the likelihood of achieving remission with additional medication trials was only about 10% (Warden et al. 2007). Despite aggressive treatment, up to 30% of patients remain symptomatic. These are patients with treatment-resistant depression.
Defining Treatment-Resistant Depression
Treatment-resistant depression (TRD) is an ambiguous term for which there is no universally agreed-upon definition; various criteria have been proposed. Table 2–1 lists common definitions of TRD. In this book, we consider TRD as the failure to achieve remission after two adequate antidepressant treatment courses with evidence-based doses and durations.
Selecting Patients for TMS
It is difficult to specify the “ideal patient” for transcranial magnetic stimulation (TMS). Response to TMS is not reliably predicted by any identified biological markers or clinical factors, such as age, sex, duration of illness, or symptom severity (Lisanby et al. 2009), and the only firm contraindication to TMS is the presence of a ferromagnetically sensitive foreign object in the head area (see Chapter 3, “Risk Management Issues in Transcranial Magnetic Stimulation for Treatment of Major Depression”).
According to FDA product labeling, TMS may be considered for a patient who does not respond to any number of antidepressant treatment courses. TMS should be considered for all patients with TRD and not as a treatment of last resort, because it is likely to be more effective when administered earlier in the course of illness before more severe treatment resistance emerges. Table 2–2 lists key clinical factors to keep in mind when considering TMS as an option for TRD.
Posttreatment decrease in a depression rating scale score of less than 50% from pretreatment baseline
Posttreatment depression rating scale score remains higher than an established cutoff value after a specified length of treatment
Failure to achieve remission after one, two, or three adequate treatment courses
Evidence of clinical response but failure to regain functional performance
Some combination of the above
Source. Adapted from Greden JF, Riba MB, McInnis MG, Sen S: “Treatment Resistant Depression,” in Treatment Resistant Depression: A Roadmap for Effective Care. Edited by Greden JF, Riba MB, McInnis MG. Washington, DC, American Psychiatric Publishing, 2011, p. 3. Copyright ©2011 American Psychiatric Publishing. Used with permission.
The patient is a 26-year-old single woman who was studying abroad. She had an episode of depression 6 years earlier, but she was in remission taking fluoxetine 20 mg/day until she became symptomatic approximately 3 months before returning to the United States for a brief family visit. She contacted her former psychiatrist, who referred her for TMS evaluation. Her Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR) score of 14 showed the presence of moderate symptoms, with prolonged sleep latency, sleep fragmentation, decreased energy, and low self-esteem. She was deemed to be an appropriate candidate for TMS but was scheduled to resume her studies only 4 weeks after she was seen in consultation. Thirty left-sided high-frequency (10 Hz) dorsolateral prefrontal cortex (DLPFC) TMS treatments were administered over the course of 4 weeks, with two treatments per day administered on several days. Upon completion of treatment, her QIDS-SR score of 4 indicated that she was in remission. She was advised to continue taking fluoxetine and resumed her studies without interruption.
In the pivotal study leading to FDA clearance of TMS, patients met diagnostic criteria for recurrent, unipolar, nonpsychotic major depressive disorder (O’Reardon et al. 2007). They also demonstrated the following demographic and clinical features:
Table 2–2. Clinical factors to consider when recommending transcranial magnetic stimulation (TMS)
Recurrent depressive illness (unipolar or bipolar)
Current FDA label is for unipolar depression only.
Duration of illness
No defined limitations
Duration <3 years may predict better response.
Level of treatment resistance
At least one trial at or above minimum dose and duration in the current episode
FDA label states any number of treatment failures.
Moderate to severe
For example, patient has a PHQ-9 score >10.
No defined limitations
Current FDA label is for patients ages 22–70 years.
No difference in efficacy
No defined limitations
Patients must be ambulatory and able to cooperate.
No ferromagnetic object within 30 cm of coil
Implanted medical devices
TMS has been safely administered to patients with pacemakers, implantable cardioverter defibrillators, vagus nerve stimulators, and/or deep brain stimulation electrodes.
Optimize anticonvulsant; consider low-frequency TMS.
TMS has been safely administered to patients who were pregnant or breastfeeding.
Monitor for emergence of mania or suicidal ideation.
Note. FDA=U.S. Food and Drug Administration; PHQ-9=9-item Patient Health Questionnaire.
Moderate to severe treatment resistance
Patients experienced between one and four failed research-grade antidepressant medication trials (mean=1.6) in the current episode and received from 1 to as many as 23 trials in total (i.e., adequate and inadequate) to validate the presence of true pharmacological resistance.
There was no limit to the total number of lifetime treatment attempts.
Moderate to severe symptoms
Nearly 50% of patients were unemployed because of their depression.
Nearly 30% of patients were receiving disability payments because of their depression.
Recurrent course of illness
Over 95% of patients had experienced prior episodes.
The average age was about 48 years, reflecting a population that was about 10 years older than a first-episode patient population.
These characteristics describe a patient population with a significant degree of treatment resistance. For patients whose depression has not responded to standard first- and second-line treatments, further antidepressant medication treatment would likely involve the use of older medications such as tricyclic antidepressants and monoamine oxidase inhibitors in addition to augmentation strategies such as lithium, thyroid hormone, or second-generation antipsychotics. The risk of discontinuation of antidepressant medication treatment because of side effects increases dramatically, as demonstrated in the STAR*D study, in which the likelihood of discontinuation tripled after one treatment failure and quintupled after three treatment failures (Rush 2007). For such a patient population, electroconvulsive therapy (ECT) would often be the next step, but TMS now offers a well-tolerated alternative for some of these patients (see Chapter 7, “Transcranial Magnetic Stimulation and Other Neuromodulation Therapies”).
The patient is a 63-year-old woman with a long history of major depression who remained symptomatic despite ongoing treatment. The current episode began 4 years earlier when she moved from the small town where she grew up to a major metropolitan area. At the time of evaluation, she was taking venlafaxine extended-release 150 mg/day, lithium carbonate 600 mg twice daily, and quetiapine 200 mg every night. Previous antidepressant medications in the current episode included once a day dosages of fluoxetine 40 mg, sertraline 150 mg, and citalopram 40 mg. All medication trials lasted at least 8 weeks. Her treatment also included trials of psychotherapy and various augmentation agents.
Her mother committed suicide when the patient was age 9, and the patient’s first episode of depression at age 14 involved a suicide attempt by drug overdose. She was hospitalized three times, and a course of ECT when she was in her mid-50s was clinically effective but caused persistent memory deficits. Despite having had brief periods of relative well-being, she never achieved full or sustained remission.
Her score on the 9-item Patient Health Questionnaire (PHQ-9) at the time of evaluation was 26, indicating the presence of severe depression with persistent suicidal thoughts but without specific intent or plan. Her score on the Generalized Anxiety Disorder 7-item scale (GAD-7) was 21, indicating the presence of severe anxiety. She was unable to drive, was housebound, had lost contact with nearly all her friends, and had given up her usual activities. Medical problems included obesity, hyperlipidemia, and chronic obstructive pulmonary disease.
The patient received a total of 36 TMS treatments using 10-Hz, left-sided DLPFC stimulation. Evidence of improvement did not appear until relatively late in her treatment course, but at the conclusion of treatment her PHQ-9 and GAD-7 scores had decreased to zero and her symptoms were in remission. Her response was confirmed by her family and primary psychiatrist, whom she had seen prior to TMS treatment. She continued under the care of her primary psychiatrist and continued taking venlafaxine, but lithium and quetiapine were gradually discontinued. Six months after completing her course of TMS, the patient remained in remission. In addition, she lost 25 pounds, resumed an active social life, was driving again, and returned to her usual interests.