Severe bradycardia triggered by repetitive transcranial magnetic stimulation in a patient with major depressive disorder and premature ventricular contractions: a case report

Abstract

Background

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD) with a low incidence of adverse effects. However, bradycardia is not commonly recognized as an adverse effect of rTMS. In this case report, we present the first documented instance of a patient with MDD and premature ventricular contractions (PVCs) who developed severe bradycardia following rTMS treatment.

Case presentation

We report the case of a 46-year-old Chinese woman with a 7-year history of MDD and a 6-year history of PVCs. She had been taking paroxetine, tandospirone citrate, and metoprolol long-term without experiencing bradycardia. After initiating rTMS treatment, she developed severe bradycardia. Even after discontinuing metoprolol, the severe bradycardia persisted for several days. Notably, the severe bradycardia disappeared one day after pausing rTMS therapy. When rTMS was resumed, the bradycardia reoccurred and subsequently resolved again upon pausing the rTMS treatment.

Conclusion

The influence of rTMS on heart rate (HR) is likely mediated through the autonomic nervous system (ANS). Currently, severe arrhythmias are not widely recognized as adverse effects of rTMS. While the exact mechanisms by which rTMS affects the cardiovascular system remain unclear, this case underscores the necessity for caution when using rTMS to treat psychiatric patients with arrhythmias.

Background

Major depressive disorder (MDD), characterized by a persistent low mood or loss of interest, is a prevalent and debilitating illness [1]. The 12-month prevalence of MDD is approximately 6% [2], significantly impacting psychosocial functioning and diminishing overall quality of life [2, 3]. By 2030, it is projected to become the leading cause of global disease burden [2]. The pathophysiology of MDD remains elusive, and its clinical manifestations are complex and varied. Additionally, nearly two-thirds of individuals with MDD also present with clinical anxiety [2]. Despite the availability of various treatments, there are currently no specific cures. The first-line treatments for MDD include pharmacotherapy, psychotherapy, or a combination of both, which have proven to be effective [2]. However, at least 30% of patients with depression do not respond to two or more adequate doses and duration of antidepressant treatments, even when adhering to the prescribed regimen [4].

Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention for patients with MDD who have not achieved satisfactory outcomes from pharmacological and psychotherapeutic treatments [3,4,5]. As a non-invasive therapy, rTMS is recognized for its high safety profile and tolerability [3]. The most prevalent adverse effect of rTMS is scalp discomfort or pain during the treatment, affecting approximately 40% of patients. This is followed by headaches, reported by 20–30% of patients post-treatment, and fatigue, which affects about 15–20% of patients [3]. Adverse reactions to rTMS are generally mild and transient, with the incidence of serious adverse reactions, such as seizures, being exceedingly low [3]. For individuals without known risk factors, the incidence of seizures during TMS treatment is less than 1 in 60,000 sessions (< 0.02 per 1,000 sessions) [6]. Notably, bradycardia is not typically considered an adverse effect of rTMS. Previous studies have demonstrated that rTMS can induce temporary reductions in heart rate (HR); however, no instances of serious arrhythmias resulting from rTMS have been documented.

In this case report, we present the first documented instance of a patient with MDD and Premature Ventricular Contractions (PVCs) who developed severe bradycardia (HR < 50 per minute) following rTMS treatment. This insight could enhance our understanding of the potential adverse effects associated with rTMS treatment and provide valuable information for optimizing rTMS protocols.

Case presentation

The patient is a 46-year-old Chinese woman. Seven years ago, following a period of psychological stress, she gradually developed low mood and decreased interest, accompanied by feelings of hopelessness, helplessness, and worthlessness. She was diagnosed with moderate MDD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [7]. During this period, the patient was administered escitalopram at a maximum dosage of 20 mg/day and zolpidem at 10 mg/night; however, the patient did not respond to this treatment regimen. Six years ago, the patient experienced episodes of palpitations and chest tightness. After an electrocardiogram (ECG) at the hospital, she was diagnosed with PVCs and began taking metoprolol at 47.5 mg once daily. Subsequently, her psychiatric medication regimen was changed to escitalopram at 20 mg/day and mirtazapine at 15 mg every night, but her response to this treatment was still poor. She actively engaged in psychotherapy and switched to agomelatine at 25 mg/day; however, her depressive symptoms did not improve. Three years ago, her depressive symptoms remained severe, and she developed anxiety and worry. Her Zung Self-Rating Depression Scale (SDS) score was 72, indicating severe depression [8]. Additionally, her Self-Rating Anxiety Scale (SAS) score was 55, suggesting mild anxiety [9]. She was diagnosed with severe MDD based on DSM-5 criteria [7]. Under medical supervision, she started long-term treatment with paroxetine (40 mg/day), tandospirone citrate (45 mg/day), and metoprolol (47.5 mg/day), which helped control her depressive symptoms. Her HR and BP remained within normal ranges, and during this period, she did not report any palpitations or chest tightness. One month before admission, the patient experienced significant psychological stress, leading to a worsening of her depressive symptoms. She primarily presented with low mood, decreased interest, reduced activity, anxiety, and nervousness. Three weeks before admission, a follow-up 24-hour Holter monitor indicated that the patient still had PVCs, and she continued metoprolol (47.5 mg/day) as part of her cardiology treatment.

The patient was admitted with a diagnosis of severe MDD and PVCs. Upon admission, the patient’s HR was measured at 79 beats per minute (bpm), and her blood pressure (BP) was 103/86 mmHg. Following admission, her complete blood count, liver function tests, renal function tests, electrolyte panel, thyroid function tests, coagulation profile, cardiac enzyme markers, and routine urinalysis and stool examination were all within normal limits. ECG, electroencephalogram, chest CT and head magnetic resonance imaging (MRI) revealed no abnormalities. Additionally, echocardiography indicated a slightly enlarged left heart with left ventricular systolic function at the lower limit of the normal range. Physical examination revealed no abnormalities. Furthermore, the patient has no family history of psychiatric or neurological disorders. During her hospital stay, her vital signs remained stable, with HR and BP within normal ranges. The patient’s prior medication regimen demonstrated a positive response and good tolerance to paroxetine, tandospirone citrate, and metoprolol. Consequently, upon admission, her treatment was continued with paroxetine (40 mg/day), tandospirone citrate (45 mg/day), and metoprolol (47.5 mg/day).

The patient had shown limited response to pharmacological treatment and had no prior exposure to rTMS therapy. Following confirmation of the absence of contraindications, rTMS was initiated on the fourth day of hospitalization and administered once daily thereafter. The treatment was delivered using an RT-100 magnetic stimulator (Sichuan Junjian Wanfeng Medical Equipment Co., Ltd., Sichuan, China). The motor threshold was defined as the minimum TMS intensity required to elicit a resting motor evoked potential in the contralateral abductor pollicis brevis muscle. Based on the concept of frontal asymmetry in cortical activity in depression, the primary rTMS targets for treating depression include low-frequency (LF) stimulation of the right dorsolateral prefrontal cortex (DLPFC) and high-frequency (HF) stimulation of the left DLPFC (L-DLPFC) [10], both of which have demonstrated antidepressant efficacy [11]. Among these, HF stimulation of the L-DLPFC is the most widely adopted; however, no stimulation site has demonstrated unequivocal or universal efficacy, reinforcing the importance of individualized treatment protocols [12]. Given the patient’s pronounced anxiety symptoms requiring targeted intervention, we selected the right DLPFC (R-DLPFC) as the stimulation site. This decision was supported by evidence suggesting that right-sided stimulation is particularly effective for anxiety [13, 14], and that LF-rTMS may offer better tolerability than HF-rTMS [11]. The therapy was administered daily at 2 p.m., targeting the R-DLPFC with a stimulation frequency of 1 Hz, 100% motor threshold intensity, and a duration of 30 min per session. Each session delivered 1800 pulses without intermissions. The treatment was conducted by professional medical personnel. During the initial rTMS session, the patient reported mild dizziness. At the end of the session, her BP was 98/68 mmHg, and her HR was 58 bpm. Subsequent HR monitoring throughout the day revealed persistently low HR levels (52–58 bpm). To ensure cardiovascular safety, we adjusted the dosage of metoprolol and maintained HR monitoring.

After the second rTMS treatment, the patient reported experiencing severe dizziness during the session. Clinical assessment revealed a HR of 34 bpm, BP of 127/104 mmHg, blood glucose level of 5.8 mmol/L, and an ECG indicating bradycardia accompanied by arrhythmia. After a period of quiet rest, her dizziness resolved spontaneously, and she was able to ambulate without difficulty. For safety reasons, metoprolol was discontinued, and we instituted close monitoring of her HR, BP, blood glucose, and fingertip oxygen saturation. Subsequent HR monitoring demonstrated persistently low values following each rTMS session, with multiple measurements on treatment days consistently registering below 45 bpm (HR monitoring refer to Table 1). Systolic blood pressure (SBP) ranged from 101 to 117 mmHg, while diastolic blood pressure (DBP) fluctuated between 63 and 108 mmHg. Both blood glucose levels (5.6–5.9 mmol/L) and blood oxygen saturation (97–98%) remained within normal limits. ECG results indicated bradycardia and frequent PVCs. To further evaluate the patient’s condition, a 24-hour Holter ECG and cardiac MRI were scheduled on the day of the fourth rTMS session.

The 24-hour Holter ECG revealed bradycardia with frequent PVCs, and an average HR of 66 bpm. The lowest HR, recorded between 14:00 and 15:00, was 39 bpm. Cardiac MRI indicated mild left ventricular enlargement. Compared to the patient’s 24-hour Holter report from three weeks prior, which showed PVCs 5,115 times/24 hours, 30 pairs of PVCs/24 hours, and 4 episodes of ventricular bigeminy/24 hours. The current report indicated 21,800 PVCs /24 hours, 171 pairs of PVCs/24 hours, and 20,934 episodes of ventricular bigeminy/24 hours, with increased heart rate variability (HRV) indices. A consultation with a cardiologist specializing in arrhythmias concluded that the etiology of the patient’s severe arrhythmias during hospitalization remains undetermined.

Over the subsequent five days, the patient continued her existing psychiatric medication regimen of paroxetine (40 mg/day) and tandospirone citrate (45 mg/day), without receiving rTMS treatment. During this period, her HR gradually increased to 80–100 bpm, and her BP fluctuated within the normal range. The patient did not report any symptoms of palpitations, headaches, or other discomfort. Given the observed improvement in her depressive symptoms, both the patient and her family expressed a strong desire to resume rTMS treatment. After a five-day hiatus, rTMS was reintroduced with identical parameters.

Upon resumption of rTMS therapy, the patient’s HR significantly decreased to 36 bpm within 4 h. On the same day, her BP and random blood glucose levels remained within the normal range. The following morning, the patient’s HR was recorded at 52 bpm, accompanied by intermittent episodes of dizziness. Due to her physical discomfort, she was unable to undergo the rTMS treatment for that day. Consequently, we suspended the rTMS session. Through close monitoring, her HR gradually returned to normal, reaching 64 bpm by the afternoon. On the subsequent day, multiple HR measurements indicated that her HR remained within the normal range, and she did not experience any dizziness or other discomfort. To evaluate the association between the patient’s severe bradycardia and rTMS, the Naranjo Causality Scale was employed, yielding a score of 9 points, which indicated a definitive causal relationship between rTMS and severe bradycardia [15]. Following extensive communication with the patient and her family, it was decided to terminate rTMS therapy. Throughout this period, continuous monitoring of the patient’s HR and BP was maintained to ensure her safety. Subsequently, the patient did not undergo further rTMS treatment, and no additional episodes of bradycardia were observed.

Table 1 HR monitoring at various time intervals Post-rTMS treatment sessions

Discussion

The pathophysiology of arrhythmias is not entirely understood, but an imbalance in autonomic nervous system (ANS) activity is considered a significant contributing factor [16]. The ANS comprises the sympathetic and parasympathetic (vagal) branches, with increased vagal activity leading to bradycardia. Severe bradycardia can result in cerebral hypoperfusion, dizziness, fatigue, dyspnea, heart failure, cardiac arrest, and even death. HRV analysis provides crucial insights into autonomic function [17]. Although arrhythmias, such as PVCs, and depression are generally regarded as conditions affecting the heart and brain, respectively, they often co-occur and are linked by a bidirectional causal relationship [18, 19]. Within this complex and reciprocal heart-brain interaction, the ANS serves as a critical mediator [18]. As a essential component of the heart-brain axis (HBA) [20], the ANS plays a fundamental role in the pathophysiology of common psychological disorders [21]. The severity of depression is positively correlated with HR and negatively correlated with HRV [22, 23].

Our patient with MDD also has comorbid arrhythmia, which is not uncommon in individuals with depression [18]. She has been on long-term medication with paroxetine, tandospirone citrate, and metoprolol. Notably, the patient has been on these medications for the past three years, undergoing regular cardiology evaluations, with no complaints of bradycardia during this time. Interestingly, without any changes in the medication regimen, the patient developed severe bradycardia after the addition of rTMS therapy. Even when metoprolol was paused, there was no increase in HR, and severe bradycardia persisted during rTMS therapy. It is notable that the severe bradycardia resolved spontaneously on two separate occasions after pausing rTMS treatment for one day. Importantly, an evaluation using the Naranjo Causality Scale (score of 9) indicated a definitive causal relationship between rTMS and severe bradycardia [15].

Similar to the phenomenon observed in this case report, previous research have demonstrated that rTMS treatment can induce a decrease in HR [24, 25]. Among the current rTMS treatment targets, the DLPFC is recognized for producing the most significant decrease in HR [25,26,27]. The mechanism by which rTMS treatment reduces HR is not yet fully understood. This effect may be attributed to the overlap between the depression-related brain networks and the HBA. DLPFC, subgenual anterior cingulate cortex (sgACC), and vagus nerve (VN) are crucial anatomical structures within the HBA [26]. The antidepressant effect of DLPFC-rTMS may be attributed to transsynaptic activation of sgACC and inhibition of limbic regions (such as amygdala and thalamus), thereby mediating VN drive [25, 26]. By modulating the network connectivity and neural regulation of these brain regions, rTMS stimulation influences changes in HR mediated through the VN [28].

In contrast to the phenomenon observed in this case, the reduction in HR caused by rTMS is believed to be transient and mild, which is considered beneficial for normalizing ANS physiological markers [26]. Previous studies have utilized HR as a functional outcome measure to determine the optimal stimulation target in the DLPFC [29]. However, the aforementioned conclusions are typically drawn from studies on healthy individuals and patients with depression not complicated by somatic diseases. The presence of PVCs in this patient indicates a potential dysfunction of the ANS. ANS deficiencies and myocardial electrical instability may result in the heart’s abnormal sensitivity to rTMS stimulation, leading to excessive vagal nerve excitation and exacerbation of arrhythmias.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), offers superior cardiovascular safety compared to tricyclic antidepressants (TCAs) and has minimal effects on HR and BP [30, 31]. Tandospirone citrate, a non-benzodiazepine anxiolytic and partial agonist of the 5-HT1A receptor, is used to treat anxiety symptoms [32]. It exhibits a synergistic effect with SSRIs and can be an effective augmentation strategy in antidepressant treatment [33]. Tandospirone does not significantly alter HR, and its combination with SSRIs is considered safe [34]. Metoprolol, a widely utilized cardioselective β-blocker, is effective in treating arrhythmias. It is estimated that approximately 70% of metoprolol metabolism in the body is mediated by the CYP2D6 enzyme [35]. Paroxetine and other SSRIs can inhibit the activity of CYP2D6, thereby affecting the metabolism of metoprolol and resulting in a prolonged reduction in HR [35]. Furthermore, paroxetine can enhance synaptic serotonin concentrations, thereby exerting a subtle influence on ANS [36]. Although these medications do not typically induce significant cardiovascular adverse effects, the possibility of severe bradycardia resulting from the combination of these drugs and rTMS cannot be excluded.

In this case report, despite the significant increase in PVCs, the patient’s HR remained low. While ANS disorders such as arrhythmias are not contraindications for rTMS treatment, this suggests that caution should be exercised when administering rTMS to patients with psychiatric conditions and pathological arrhythmias. Currently, there are no studies elucidating the mechanisms underlying HR changes during rTMS treatment. There is a lack of prospective studies, and existing research is limited by small sample sizes [27]. Moreover, cardiovascular indicators are often measured during rTMS treatment mainly for assessing its safety rather than investigating its relationship with ANS function [27]. Therefore, future large-scale studies are warranted to elucidate the association between rTMS parameters/targets and ANS responses while further exploring the intricate brain-heart relationship for optimizing rTMS protocols.

Conclusion

rTMS treatment can affect the ANS and may lead to severe arrhythmias in patients with pre-existing ANS dysfunction. Therefore, administering rTMS treatment to patients necessitates meticulous consideration of their medical history and concurrent cardiovascular medications. Furthermore, it is imperative to document the patient’s baseline cardiovascular parameters, including HR and BP, at the initiation of rTMS therapy and to monitor these parameters during treatment. Although the mechanisms underlying the cardiovascular effects of rTMS remain unclear, this case highlights the potential for severe adverse reactions during rTMS treatment, enriches the clinical guidelines for rTMS, and underscores the necessity for caution when treating psychiatric patients with arrhythmias using rTMS.