Safe Management of a Bipolar Depressed Patient With Prefrontal Repetitive Transcranial Magnetic Stimulation (rTMS) Over 7 Years and > 2 Million Stimuli

Dear Editor:

Daily left prefrontal rTMS is being increasingly used for the acute treatment of unipolar and bipolar depression, with acute remission rates in open label studies ranging from 30–60% (1, 2). The treatment also appears to have reasonable 6 and 12-month durability (3, 4). However, some patients require periodic maintenance treatments in order to not relapse back into a complete episode (5). There is much discussion but little data concerning the safety of long-term maintenance TMS, or how much exposure to TMS an individual can have over a lifetime (6). We present the case of a young woman who may have the highest TMS exposure to date (7 years, 2 million stimuli), who is largely depression free without safety issues.

Mrs. Z is a 33-year-old Caucasian woman and the product of a normal birth and delivery. Her depression began at age 13,for which she received counseling. At age 15, she began a long series of medication trials for depression, starting with fluoxetine 20mg/day for 6 months, without full relief of her depression and with side effects. She continued to try several medications over the next few years, included lithium, aripiprazole, olanzapine, risperidone, bupropion, sertraline, and duloxetine, with only partial response and then intolerance to side effects. At age 18, (1998), the patient experienced her first hypomanic episode, with symptoms of increased talkativeness, pressured speech, flight of ideas, irritable mood, decreased need for sleep, increased excitability, and psychomotor agitation. Consequently, she was diagnosed with Bipolar Affective Disorder NOS according to DSM-IV. A few weeks later, hypomania gave way once more to depressive symptoms, which at this time included sadness, anhedonia, anxious, irritable, and difficulty sleeping. She ruminated on death and had thoughts of suicide, though she never made a suicide attempt. Mrs. Z was hospitalized and had a course of 9 treatments with right unilateral electroconvulsive therapy (ECT), with only a partial response. By age 19, she had developed tolerance to antidepressant medications. As TMS was not FDA approved in the US at that time she traveled to Chicago to receive TMS (left prefrontal, twice daily, 14 days) and remitted. She quickly relapsed however when she returned to Charleston, despite aggressive polypharmacy, including levomefolic acid 15 mg, lisdexamfetamine 30 mg, gabapentin 600 mg BID, levothyroxine 224 mcg, zolpidem10 mg, diazepam 5 mg, vilazodone 40 mg, and lamotrigine 400 mg. She was enrolled as a nursing student but could not complete her courses due to her illness. She also received another course of TMS in Atlanta, with a good response to an acute course of 14 treatments, followed by a relapse about two months after returning to Charleston.

In 2007, at age 27, Mrs. Z enrolled in an open-label TMS trial at MUSC and remitted (7). The patient had an initial course of 40 consecutive daily sessions (over 8 weeks) of high-frequency (10 Hz) rTMS at 120% motor threshold (MT). Each session consisted of 8000 pulses, with 5s-trains and an inter-train interval of 10s. Stimulation was delivered over the left dorsolateral prefrontal cortex (DLPFC), defined as the site 6 cm anterior-in the same parasagittal plane-to the optimal scalp location of the thumb cortical representation. Depressive symptoms were greatly improved after this induction phase, as indicated by clinical observations and a decrease (49 to 10) in Mrs. Z’s the self-reported twenty one-item Beck Depression Inventory-II (BDI-II) score. While at baseline, she scored 49, considered ‘severe depression’ (maximum severity score: 63), after five TMS sessions, the score dropped to 35, to 23 after ten sessions, and continued to drop during the eight weeks of treatment that followed (49 to 13, 12, 10 after 5, 6,7,8 weeks). The patient also used a computer version visual analog scale (VAS) before and after rTMS to self-report, on a range of 0 to 100, the following indicators: happy, irritable, angry, excited, confused, calm, sad, anxious, nervous, bored, relaxed, tired, distracted, pain, and discomfort. After the eight-week acute open-label treatment, she received maintenance treatment and was transitioned by a taper phase of seven sessions over 3 weeks (three sessions in week 1, two sessions in week 2 and 3), using the same stimulation parameters (8000 pulses) provided during acute treatment. Thereafter, the schedule was one session per week for 2 weeks, and one session per 2 weeks. She continued with TMS treatments, trying to increase the time between TMS treatments and minimize the number of maintenance treatments needed. (see Figure 1) Figure 1 displays the number of maintenance TMS treatments needed over the past 7 years, without a full relapse. She has averaged needing one treatment about every 2 weeks.

Figure 1 –

This is a timeline of the patient’s treatments for depression, focusing on the number of TMS sessions and the BDI-II score. Note that in 2011 she travelled out of the US and did not have TMS for several months. Her mood suffered but she did not fully relapse.

The treatment frequency of TMS sessions was determined according to her depressive symptoms. In addition, some maintenance session parameters were modified with different pulses per session. She received 6000 pulses per session in some treatments. In other treatment sessions, the dosage of TMS was increased back to 8000 pulses per session, correlating with increases in depressive symptoms. Ms. Z had 337 TMS sessions total within six and half years, for a total number of 2,425,200 pulses (an average of 7,196 pulses per session). To monitor symptoms, BDI-II was administered periodically. Symptom changes as monitored by VAS data, also indicate treatment efficacy. The 255 usable VAS data were collected before and after TMS sessions. These results show that TMS significantly reduced irritability, anger, confusion, anxiety, and distractibility, while it significantly increased calmness and relaxation. Also noted was an increase in discomfort and pain after each treatment, likely related to a side effect of TMS. Additionally, rTMS tended to increase happiness and decrease sadness. She then began a series of maintenance TMS. Mrs. Z’s depression remained in remission with rTMS in conjunction with antidepressants (lamotrigine 600 mg/day, duloxetine 60 mg, lithium 450 mg, aripiprazole 30 mg, Ativan 1 mg). She also took Synthroid 100mcg for hypothyroidism, having been diagnosed with thyroid cancer and undergoing thyroidectomy in 2007. With continued remission due to TMS and aggressive medications, she has been able to resume her life and graduate from nursing school, obtain a nurse practitioner degree, get married, and lead a local dance company.

With this exposure to TMS we have been diligent with respect to safety. Prior to beginning rTMS, the patient’s neurological examination was normal and has remained normal. Serial MRI scans have remained normal. Her BDI-II score at the last TMS visit was 10.

Maintenance TMS appears to be possible in those patients with recurrent mood disorders who are not able to stay well with medications alone. This amount of TMS appears to be safe, at least in this one case. Further research on the total life exposure to TMS is needed.