High-frequency Repetitive Transcranial Magnetic Stimulation Targeting Left Dorsolateral Prefrontal Cortex for Depression Ameliorates Insomnia yet Triggers Excessive Daytime Sleepiness: A Catch-22 Situation

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is effective and safe for the treatment of depression. We observed improvement in insomnia along with symptoms of depression following high-frequency rTMS over the left dorsolateral prefrontal cortex in a patient with treatment-resistant depression, which progressed to excessive daytime sleepiness during the treatment sessions. Causality assessment suggested a probable association of rTMS with excessive sleepiness. The implications of the effect of rTMS on sleep are discussed.

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved intervention for treatment-resistant depression, and it shows favorable results in achieving response and remission. ¹ Due to the accumulating evidence base for rTMS in depression, it was recommended as a first choice following one antidepressant failure in the recent Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for depression. ² TMS is tolerated by most patients without many adverse effects. Most reported adverse effects are minor including headache, local pain and discomfort, muscle twitches, and tingling sensation, which are self-limited, and often well tolerated. ³ The most important severe adverse effect is seizures, but the incidence is very low, with only 41 reports until 2020. ⁴ There are no reports of rTMS significantly affecting sleep except for a few reports of insomnia. ³ We describe a patient who not only had improvement of insomnia but also developed excessive daytime sleepiness (EDS) following high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) for the management of treatment-resistant depression.

Case Report

Mr R, a 56-year-old man with a history of recurrent depressive disorder for the past 6 years, presented in the ninth episode characterized by sad mood, anhedonia, anergia, insomnia, anxiety, irritability, and fleeting auditory hallucinations. He had comorbid hypothyroidism, ischemic heart disease, dyslipidemia, bronchial asthma, intervertebral disc prolapse, benign prostatic hypertrophy, and three cerebrovascular accidents previously. He underwent a permanent dual-chamber demand pacemaker installation 4 years ago due to sick sinus syndrome. There was no history of any substance use. He did not hold a regular occupation during this period. He had failed to respond to adequate trials of paroxetine, desvenlafaxine, sertraline, and augmentation with lithium in the past, but had responded well to electroconvulsive therapy in the previous episode. ⁵ So, for the current episode, he was suggested ECT; however, he preferred rTMS because of logistical reasons. He was on a stable dose of 200 mg sertraline, 20 mg aripiprazole, 100 mg quetiapine, and 6 mg melatonin per day (no change in the past 4 weeks before rTMS). While on these medications, his insomnia subscore in HDRS-17 was 4 (out of 6). The patient’s medical regimen included thyroxine 100 µg, atorvastatin/aspirin 10/75 mg, dabigatran 150 mg, pregabalin/methylcobalamin 75 mg/750 µg, metoprolol 25 mg, and furosemide 40 mg daily, and there were no recent modifications to these medications. A cardiological evaluation was done for fitness to undergo rTMS because of the pacemaker.

He received 10-Hz rTMS at 120% resting motor threshold over the left DLPFC, a standard treatment protocol for treatment-resistant depression, ⁶ using Magventure-MagProX100 with a figure-of-eight coil. The protocol had 75 trains, each lasting for 4 s and an inter-train interval of 11 s with 3,000 pulses per session. We planned to administer five sessions daily per week in the acute treatment phase on an outpatient basis. All the medications were continued in the same dose during the rTMS treatment. At baseline, his Hamilton Depression Rating Scale (HDRS-17) and Hamilton Anxiety Rating Scale (HARS) scores were 20 and 23, respectively. The insomnia subscore on HDRS-17 was 4 (2 for early insomnia and 2 for middle insomnia). The side effects were monitored after each session using the TMS side-effect questionnaire. ⁷ From the third session onward, the patient experienced excessive daytime sleepiness (EDS) that affected his functioning. At the end of five sessions, his insomnia subscore on HDRS-17 reduced to 1, but EDS persisted. Quetiapine was decreased to 50 mg initially and stopped at the end of ten sessions due to persistent EDS. His insomnia subscore in HDRS-17 was 0 at the end of ten sessions. As he continued to have the EDS, melatonin was also discontinued at the end of 15 sessions. Even after stopping both these medications, he continued to have EDS (score on Epworth Sleepiness Scale, ⁸ ESS was 10 out of 24) at the end of 15 sessions. As he achieved remission of depressive symptoms at the end of 15 sessions (HDRS score 5), we reduced the rTMS sessions to three per week for the next 2 weeks, and then two per week for another 2 weeks (as continuation phase rTMS to sustain the improvement). While tapering rTMS sessions, EDS improved as shown by the reduction in ESS scores to zero (Figure 1). He tolerated rTMS sessions well and had minor discomfort related to local muscle twitching of the left eyebrows and left face during the sessions. The application of Naranjo algorithm ⁹ for causality assessment resulted in a score of 7, indicating a probable association between rTMS and EDS (Supplementary Table 1).

Figure 1.

Changes in Rating Scale Scores Over Time.

Discussion

Our patient had insomnia at the baseline (as part of depression) while on a stable dose of medications for the past 4 weeks and developed EDS after starting rTMS that persisted even after the discontinuation of sedating medications, which suggests a possibility of rTMS-induced effects on sleep. There was not only improvement in insomnia with rTMS but possibly it overcorrected to produce EDS. Although there was no recorded baseline ESS score available, there were no reported complaints of EDS prior to the administration of rTMS. While the patient’s concurrent medical conditions could potentially contribute to EDS, it is noteworthy that EDS was noticed post-rTMS treatment and was not present before the intervention. Furthermore, the patient remained on a stable dosage of medications prescribed for the comorbid medical conditions, and there were no documented reports of exacerbation or deterioration in any other symptoms during this period. The ESS score decreased to 0 on tapering off of rTMS, indicating a possible dose-response relationship in rTMS-induced sleepiness. Previous reports also found that rTMS treatment improves insomnia associated with depression. ¹⁰ Hines et al. ¹¹ found an improvement in total rapid eye movement sleep after a course of TMS, regardless of improvements in depression; however, total sleep time improved only in the TMS responders subgroup. Similarly, other studies have noted the positive effects of 10-Hz rTMS on sleep when applied over left DLPFC for the treatment of depression, and the improvement was possibly independent of mood changes.^12,13 However, some studies (e.g., Rosenquist et al. ¹⁴ ) found no specific effect of TMS on sleep, and the authors concluded that TMS is an “arousal-neutral antidepressant.”

The combined effect of rTMS and psychotropic medications is not extensively studied. In individuals with depressive disorder, a study indicated that sertraline can increase cortical excitability without affecting inhibitory GABA_B neurotransmission, whereas antipsychotics such as quetiapine reduce cortical excitability by modulating inhibitory GABA_B neurotransmission. ¹⁵ Pu et al. ¹⁶ documented their findings on the combination of HF-rTMS with agomelatine, a structural analog of melatonin that exerts a potent agonist effect on melatonin MT₁ and MT₂ receptors, in patients with depressive disorder. They observed an improvement in sleep quality compared to sham rTMS.

The mechanism of action of TMS for improving insomnia in persons with depression is not known. ¹³ It has been suggested that the local decrease in alpha activity during REM sleep after rTMS treatment could be a possible marker of upregulation of cortical activity induced by rTMS and of clinical outcome, consistent with the left frontal hypoactivation theory of depression. ¹⁷ Also, high-frequency rTMS to the left DLPFC has been shown to increase slow-wave activity, ¹⁸ and transiently modulate nocturnal sleep spindle activity, ¹⁹ potentially reflecting neuroplasticity induced by rTMS. TMS has also been used for the treatment of both sleep disorders insomnia and hypersomnia; there is a possibility that rTMS corrects the putative imbalance between cortical excitatory and inhibitory activity associated with insomnia. ²⁰ Most studies targeting insomnia have used low-frequency stimulation, with only a few used high-frequency stimulation. This suggests considerable heterogeneity in the effects of rTMS on insomnia. ¹⁰ At the same time, there are studies that examined the effect of rTMS in improving hypersomnia and EDS. One study of high-frequency rTMS of left DLPFC in depressed adolescents found improvement in hypersomnia, but not in insomnia. ¹² Another study examined the effects of low-frequency rTMS over the right DLPFC among patients with Parkinson’s disease and found significant improvement in EDS in the active intervention group. ²¹

In conclusion, rTMS over the left DLPFC could have an effect on sleep independent of the improvement in mood, although these effects need further study. The beneficial effect of HF-rTMS on insomnia might extend beyond correcting insomnia to trigger increased sleepiness, as shown in this case. An understanding of the rTMS parameters that could have a facilitatory effect on sleep will enable us to administer a “pro-sleep rTMS” as an antidepressant in those with depression and also design rTMS-based interventions for sleep disorders.

Supplemental Material

The supplemental material for this article is available online.