Combining Pharmacotherapy With Transcranial Magnetic Stimulation in the Treatment of Major Depression

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With Transcranial
Magnetic Stimulation
in the Treatment of
Major Depression

Mehmet E. Dokucu, M.D., Ph.D.
Philip G. Janicak, M.D.

The high prevalence of treatment-resistant depression (TRD) has been an important impetus in the development of transcranial magnetic stimulation (TMS). To adequately demonstrate the efficacy of TMS in treating TRD, the pivotal trials included patients treated with TMS monotherapy or sham TMS. The U.S. Food and Drug Administration (FDA) advises that TMS is for treating patients who have experienced one or more failed antidepressant medication trials and who are not presently undergoing any antidepressant therapy. In clinical practice, however, most patients continue taking their antidepressant and other psychotropic medications while receiving an acute course of TMS. Also, after completion of an acute TMS treatment course, the most common maintenance strategy utilizes antidepressant(s) (with or without reintroduction of TMS with impending relapse). In support of this practice, the consensus review of the Clinical TMS Society states that “TMS therapy can be administered with or without the concomitant administration of antidepressant or other psychotropic medications…. [T]here is currently no evidence of an increased risk of adverse events by combining medications with TMS” (Perera et al. 2016, p. 344). According to a survey of Clinical TMS Society members, the majority of practitioners recommend continuing medications during acute TMS therapy and refraining from medication changes during the acute course (Perera et al. 2016).

The choice of medication to combine with TMS to optimize outcome remains problematic. A large number of preclinical and human studies have attempted to elucidate the pathophysiology of depression, as well as antidepressant medication mechanisms. Far fewer studies have attempted to understand the mechanisms of action of device-based treatments such as electroconvulsive therapy, deep brain stimulation, and TMS. A detailed review of these areas of research is beyond the scope of this chapter. It can, however, be confidently stated that due to the heterogeneity of depressive syndromes and lack of consistent biological markers, there are no depression treatments that are based on well-described disease mechanisms. For example, despite the fact that electroconvulsive therapy is very effective and has been available for over 75 years, its use is affected by problems of access, stigma, and tolerability, and its mechanism of action is still not clearly understood, although promising theories are proposed (Kellner et al. 2012). This lack of understanding of the mechanism of action is also true for other forms of therapeutic neuromodulation, and as a result, it is currently not possible to make precise statements about the interaction between TMS and pharmacotherapy when administered concurrently or sequentially during the treatment of depression.

In this chapter, we review the knowledge base and recommended clinical practices for utilizing TMS in combination with pharmacotherapy for acute treatment, sequentially when transitioning from acute TMS therapy to maintenance medication therapy, and again in combination if TMS reintroduction is needed during the maintenance period.

Augmentation Studies Combining Medication and TMS


Many early TMS studies have essentially been augmentation trials because patients were also taking one or more medications. For example, Conca et al. (1996) administered 10 sessions of low-frequency TMS to 12 patients taking antidepressants and compared the results with those of 12 patients who received only medication. Statistically significant changes in scores on the Hamilton Depression Rating Scale (HDRS) favored TMS augmentation after three sessions of TMS (P<0.003), and changes were even greater after the tenth session (P<0.001). The same research group performed a brief course of 10-day add-on TMS in 12 inpatients and reported that eight subjects (66.7%) responded to the treatment as assessed by HDRS change scores (Conca et al. 2000). They also observed an earlier onset of response in the TMS group (statistical analysis not made available) and proposed that a shorter duration of the index depressive episode may be a positive predictor of treatment response. In a more recent, open-label study, Berlim et al. (2014) used deep TMS as an augmentation to medications. Seventeen outpatients with severe TRD received 4 weeks of daily, high-frequency deep TMS. At week 5, on the basis of HDRS change scores, the remission rate was 41.2% and response rate was 70.6%. For the group receiving TMS, suicidality (P<0.019), anxiety (P<0.0001), and quality-of-life (P<0.028) scores also significantly improved from baseline.

Although TMS has not been approved by the FDA for treating bipolar disorder, many patients are receiving off-label TMS for the depressed phase of the disorder (see Chapter 8, “Transcranial Magnetic Stimulation for the Treatment of Other Mood Disorders”). An add-on safety and feasibility trial (N=19) with deep TMS in patients with bipolar depression found a significant decrease from baseline HDRS scores (P<0.001) and good tolerability (Harel et al. 2011).

Carpenter et al. (2012) reported the results of a large open-label, naturalistic, acute trial to inform clinicians using TMS in routine practice settings. Forty-two mostly private clinical centers participated. The primary outcome measure was the Clinical Global Impression—Severity of Illness Scale (CGI-S) change score, and the secondary outcomes were change scores on the Inventory of Depressive Symptomatology—Self Report (IDS-SR) and the 9-item Patient Health Questionnaire (PHQ-9). Nearly all patients continued taking their current psychiatric medications. On the basis of the CGI-S change scores at the end of acute TMS therapy, more than half of the patients met response criteria and approximately one-third achieved remission. Notably, there was no increase in adverse effects.

Su et al. (2005) studied 30 Chinese patients with TRD in a sham-controlled, double-blind, randomized trial in which a 10-session TMS course was added to ongoing medications. Ten participants were assigned to each of three groups, which were assigned to receive either 20-Hz TMS, 5-Hz TMS, or sham TMS. As indicated by HDRS change scores, response rates for patients in the two active TMS arms were superior to those for patients receiving the sham procedure (P<0.01; Su et al. 2005).

An ongoing 8-week, multicenter, randomized open-label study titled Augmentation versus Switch: Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With Treatment Resistant Depression (ASCERTAIN-TRD;, identifier #NCT02977299) will attempt to evaluate TMS versus aripiprazole as augmentation strategies with venlafaxine as the primary treatment. The three open-label arms will consist of 1) aripiprazole augmentation (a 5-mg/day starting dose with a 15-mg/day maximum), 2) TMS augmentation, and 3) switching to venlafaxine extended-release. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) change score, and an important secondary outcome will be the Quality of Life Enjoyment and Satisfaction Questionnaire—Short Form (Q-LES-Q-SF) change score.


A meta-analysis of sham-controlled clinical trials considered response in patients with TRD using TMS as an augmentation to medication (Liu et al. 2014). Seven randomized trials met the investigators’ inclusion criteria, with a total sample size of 279 (171 active TMS patients and 108 sham TMS patients). The response rate was 46.6% for active TMS versus 22.1% for sham TMS (odds ratio=5.12; 95% confidence interval=2.11–12.45; z=3.60; P<0.0003). The change in baseline HDRS scores also suggested that active TMS was superior to the sham procedure (a small difference of 0.86; P<0.00001). The small number of studies and subgroup heterogeneity, however, tempered the authors’ conclusions. The results of an earlier meta-analysis (Berlim et al. 2013), which included six studies (N=392), were consistent with these results. Berlim and colleagues commented that high-frequency TMS may also accelerate time to antidepressant response.


The pivotal monotherapy TMS trial that led to FDA clearance of the first device for treatment of unipolar major depression included a 6-month durability-of-effect phase. During this period, TMS could be reintroduced as an augmentation to maintenance antidepressant monotherapy. Eighty-four percent (32/38) of patients with predefined worsening of depression for 2 consecutive weeks benefited from reintroduction of TMS (requiring an average of ~14 sessions), with no increase in adverse events (Janicak et al. 2010; O’Reardon et al. 2007).

Phase III of the randomized sham-controlled National Institute of Mental Health–sponsored optimization of TMS (OPT-TMS) study involved medicated and unmedicated patients who achieved remission after Phases I and II of the study. Although participants were followed for 6 months, only the 3-month analysis was performed because of attrition. Approximately half of the patients who achieved remission were taking medication, typically venlafaxine or nortriptyline combined with lithium or lamotrigine. Medicated and unmedicated patient groups did not show any significant difference in clinical outcome at the 3-month follow-up. Fifty-eight percent of the participants were still in remission at 3 months, and 13.5% of the patients had relapsed. Average time to relapse was 7.2 weeks (Mantovani et al. 2012).

The largest maintenance study to date extended to 12 months and included 275 patients with TRD at the end of the acute phase, summarized in “Acute Studies” earlier in this section (Carpenter et al. 2012; Dunner et al. 2014). At the end of the study, 120 patients achieved response or remission and were offered maintenance medication or naturalistic follow-up with the choice of reintroduction of TMS therapy if symptoms worsened. Sixty-two percent of the participants maintained at least response status throughout the 52-week follow-up. Dunner and colleagues concluded that TMS can achieve durability of benefit in a statistically significant (P<0.0001) and clinically meaningful way. Of note, 32.5% required a mean number of 16.2 sessions of reintroduction TMS within 1 month of initiating their maintenance phase. Similar to the acute-phase naturalistic study, almost all patients were taking concomitant medications, and the median number of medications was one for remitters and two for the rest of the cohort. No meaningful associations were reported with medication use characteristics and categorical outcomes.

Clinical Considerations When Combining TMS With Medications


During the initial TMS consultation, the clinician should obtain a comprehensive history of antidepressant medications. Although cumbersome to use, the Antidepressant Treatment History Form (ATHF) is one tool that can help gather this information (Sackeim 2001). Although this history is taken primarily to establish the level of treatment resistance, the data can also help inform pharmacotherapy treatment decisions while TMS therapy is in progress. All concomitant psychotropic medications should be carefully categorized as partially helpful or not helpful. Medications that are not at least partially helpful should be sequentially tapered and stopped. Medications that are contributing to adverse effects (e.g., weight gain) and have not been helpful should be tapered first. Ideally, a patient’s medication regimen should be stable for at least 2–4 weeks prior to starting TMS; this preparation allows the physician to specifically assess the adverse effects and response to TMS.

Obtaining a list of all current medications, their dosages, and their duration of treatment is critical to understanding and minimizing the risk of seizures. In addition, some medications (e.g., benzodiazepines, high-dose anticonvulsants) may diminish the efficacy of TMS therapy by increasing the activation thresholds of the neuronal circuits (Li et al. 2004). Finally, if patients should report adverse effects that do not commonly occur during TMS, full knowledge of current medications and their timeline may help identify the source more accurately.


Some patients would like to discontinue their current psychiatric medications when they present for a consultation session and will seek the opinion of the TMS clinician. The most common reasons for this desire for discontinuation are medication-related adverse events and a lack of confidence in the effectiveness of one or more medications. Importantly, patients may minimize symptomatic improvements when they initially start the medication. Without a detailed understanding of current medications and the temporal relationship with any changes in symptoms, the TMS clinician cannot formulate an opinion. Furthermore, if the TMS clinician is not the patient’s primary mental health care provider, direct communication with that provider is essential in formulating a plan about any medication changes that may enhance the efficacy of TMS, decrease the risk for adverse events, or both. Reviewing records and communicating with the patient’s primary treatment team and family can help clarify whether certain medications are partially effective. The fact that patients may not see their primary psychiatric providers during the TMS course increases the importance of the TMS clinician being familiar with the medication regimen and response history.


Table 4–1 lists the most recent Safety of TMS Consensus Group guidelines for medications that may worsen the seizure risk associated with TMS treatment (Rossi et al. 2009). Although many antidepressants can lower seizure threshold, bupropion carries a more prominent warning regarding its seizure-inducing potential. Hence, we will review it in more detail.

Bupropion, compared with other medications, has lower risks of sexual dysfunction and weight gain and therefore is commonly prescribed as a monotherapy or augmenting agent for patients being treated for depression. This agent, however, carries an increased seizure risk in special populations (i.e., those with eating disorders or those with prior seizure history) and also may alter the motor threshold (Mufti et al. 2010). At times, TMS candidates and their referring clinicians may ask whether it is safe to continue bupropion during TMS therapy. In regard to this issue, one systematic literature review (Dobek et al. 2015) identified 25 TMS-induced seizures between 1980 and 2015, none of which were related to taking bupropion. One patient whose TMS-induced seizure was reported to the FDA was concomitantly taking bupropion, sertraline, and amphetamine. Dobek and colleagues, however, stated that rarely occurring seizures during TMS did not point to a specific antidepressant such as bupropion. Janicak et al. (2008) reported on 34 patients who were taking bupropion and underwent more than 1,000 TMS treatments without a seizure event.


The patient is a 27-year-old resident physician who presented for TMS therapy to manage his 4-month treatment-resistant major depressive episode and comorbid migraines. A comprehensive medication history was obtained, and the patient’s primary psychiatrist was contacted for verification. He was taking bupropion extended-release 450 mg/day, which was initiated after his poor tolerance of two selective serotonin reuptake inhibitors and one serotonin-norepinephrine reuptake inhibitor because of sexual dysfunction and increased appetite and associated weight gain. The bupropion daily dose was titrated from 150 mg to 450 mg because of gradual but small improvement of his depressive symptoms. Even at 450 mg, however, he continued to experience functional impairment as well as dose-related worsening of his migraines. He began undergoing left dorsolateral prefrontal cortex high-frequency (10 Hz) TMS therapy, and over the course of 2 weeks, his bupropion was tapered to 150 mg, with complete resolution of his migraines. He continued TMS for another 4 weeks, ultimately achieving complete remission of depressive symptoms, with a final IDS-SR score of 6 (down from a baseline score of 53). Furthermore, the patient experienced no significant adverse effects with the combination of bupropion and TMS.

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Mar 17, 2020 | Posted by in PSYCHIATRY | Comments Off on Combining Pharmacotherapy With Transcranial Magnetic Stimulation in the Treatment of Major Depression
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