Atypical antipsychotics are first-line drugs for schizophrenia and bipolar disorder. Although bradycardia associated with these medications is rare, previous studies have shown that several atypical antipsychotics cause bradycardia [1-4]. Lurasidone is an atypical antipsychotic. It has potent binding affinity for D2, 5-hydroxytryptamine (HT) 2A and 5-HT7 receptors; moderate affinity for 5-HT1A, α-2A and α-2C receptors. The tolerability profile of lurasidone is noteworthy in terms of a good weight and metabolic profile and no cardiovascular adverse effects such as bradycardia, orthostatic hypotension or prolongation of the QTc interval [5,6]. It is now generally accepted that lurasidone has the minimal side effects on the cardiovascular system. However, we describe a patient with bipolar disorder who developed sinus bradycardia after combination treatment with lurasidone. Since no case of lurasidone-induced sinus bradycardia has been so far documented, this report is about the patient who developed this complication.

Written informed consent was obtained from the patient for the publication of this report.

A 46-year-old female with bipolar disorder presented with euphoria, irritability, insomnia and hyperactivity under drug treatment with “lithium 600 mg/day, valproate 2,000 mg/day and risperidone 6 mg/day”. Two weeks later, the patient was started on 1,200 mg/day of lithium, but she showed no improvement. Therefore, she was admitted to the hospital for therapy after another two weeks. The lithium concentration was 0.54 mmol/L (reference range: 0−1.2 mmol/L) at the time of admission. Of note, the patient had no history of cardiovascular disease. How-ever, she was previously diagnosed with type 2 diabetes and had been taking “metformin 1,500 mg/day, acarbose 300 mg/day” for blood glucose control. On admission, the patient's cardiovascular physical examination revealed no abnormalities with heart rate (HR) fluctuating at 75−100 beats/min and blood pressure (BP) at 100−105/ 65−70 mmHg. In addition, a full examination of the patient showed no abnormalities in routine blood, biochemistry, thyroid function or cardiac ultrasound examinations, except for an increase in HbA1c (8.30%). To reduce the meta-bolic effects of the psychotropic drugs, the dose of valproate was reduced to 1,500 mg/day, risperidone was discontinued, and lurasidone was added for treatment. After the patient received lurasidone 80 mg/day for 5 days, her HR gradually decreased, with an HR of ≤ 55 beats per minute (beats/min) for most of the day (BP fluctuated at 92−100/61−65 mmHg). As the baseline HR of the patient fluctuated at 75−100 beats/min, and there was no previous history or underlying cause of bradycardia, we suspected medication was the cause of her sinus bradycardia, particularly lurasidone, which had been administered for the first time. After 1 week of closing observation, HR was similar to the previous measurement, and 24-hour dynamic electrocardiography (DCG) showed a mean HR of 55 beats/min (Fig. 1). Other examinations showed a lithium concentration of 0.74−0.91 mmol/L and a valproate concentration of 72.25−86.69 µg/ml (reference range: 50−100 µg/ml). A decision was made to discontinue lurasi-done. After discontinuing lurasidone for 5 days, the patient's HR returned to normal (no other medication was adjusted). Since the patient did not agree to a retrial of lurasidone by slow dose titration, no rechallenge was attempted after the withdrawal of lurasidone. No similar discomfort was reported at the 6-month follow-up visit, electrocardiogram (ECG) showed a mean HR of 90 beats/min (Fig. 2). Unfortunately, the patient refused to have a DCG because she thought her sinus bradycardia had recovered.

This case shows that the bipolar disorder patient’s sinus bradycardia started with lurasidone and disappeared with lurasidone discontinuation. No other psychotropic medication was adjusted during this period. The association of sinus bradycardia and lurasidone was “probable” based on the Naranjo adverse drug reaction (ADR) probability scale (Supplementary Table 1; available online) [7], although bradycardia was not documented in the lurasidone package insert and has not been documented previously.

Sinus bradycardia has long been defined as a sinus rhythm of less than 60 beats/min in adult. However, 15% of healthy Asian population has an HR below 60 beats/min, with a prevalence of 18% in men and 9% in women [8]. Bradycardia is typically asymptomatic. However, some sinus bradycardia can lead to serious complications such as syncope and new-onset or deterioration of previous heart failure [9]. In addition, the mortality rate doubles when the heart rate is below 50 beats/min compared to 60−100 beats/min [10]. As a result, attention should be paid to sinus bradycardia in clinical practice. In psychiatry, antipsychotic medications such amisulpride, aripiprazole, ziprasidone, and risperidone are frequently a cause of bradycardia in psychiatry [1-4]. It is challenging to recognize antipsychotic-induced sinus bradycardia since it lacks specific symptoms. None of the patients reported in these cases had a history of cardiovascular disease, despite some research suggesting that the risk of bradycardia increases with the severity of the cardiovascular disease [10]. The patient in this case experienced sinus bradycardia after the addition of lurasidone. Similar to previous cases, she had no specific symptoms and was only discovered when the ECG was completed. This suggests that an ECG should be performed routinely on antipsychotic- using individuals, especially when a new antipsychotic is prescribed.

Previously reported atypical antipsychotics that cause bradycardia are known to activate 5-HT1A receptors either directly or indirectly. Similar to these antipsychotics, lurasidone has partial agonist activity at the serotonin 5-HT1A receptor [6]. Previous studies have shown that signalling through the 5-HT receptor is associated with vagal-mediated bradycardia [11], as reflected in the pharmacological mechanism of lurasidone [6]. Animal studies have shown that 5-HT1A receptor activation in the ventral lateral medulla, vomeronasal nucleus and dorsal motor nucleus of the vagus nucleus induces bradycardia [12, 13]. However, data on 5-HT1A activation and bradycardia in humans are limited. Only one study from 1996 suggested that central 5-HT1A receptors in humans might not be associated with modulating the excitability of cardiac vagal motor neurons in the Bezold-Jarisch reflex [14]. Other studies on the associations between 5-HT and bradycardia have shown inconsistent results with 5-HT2A. Although most studies point to a reduction in bradycardia with 5-HT2A antagonists [15], bradycardia was found to be exacerbated in a rat study [16]. However, 5-HT7 receptor antagonists do not appear to improve bradycardia [17]. Although 5-HT antagonism has been proposed as a potential cause of antipsychotic-induced sinus bradycardia [1-4], we consider other biological factors may have a greater influence in this situation, including pharmacokinetic factors and genetic vulnerability [18].

Unlike lurasidone, lithium may be more likely to cause sinus bradycardia, especially at concentrations of lithium toxicity [19,20]. Studies have shown that the incidence of cardiotoxicity in lithium toxicity is approximately 5.7% [21]. Potential causes include a decreased spontaneous rate of depolarization of the sinus node and decreased conduction velocity in the atrioventricular and intraven-tricular conduction system induced by lithium [22]. How-ever, we did not consider that the adverse effects of lithium carbonate were the most likely cause of the sinus bradycardia reported in this patient, and the reasons are as follows: First, no drug interactions when lurasidone in combination with lithium [23]. Second, two follow-up studies showed that lurasidone combined with lithium or valproate was safe [24,25]. Third, the patient had been taking 1,200 mg/day lithium prior to admission and did not have the usual gastrointestinal adverse effects. Fourth, lithium concentrations were within normal limits after lurasidone administration and discontinuation. Finally, after the discontinuation of lurasidone, the patient recovered from sinus bradycardia without an adjustment of the lithium dose. Therefore, we considered that the interaction between lithium and lurasidone is the secondary possibility for sinus bradycardia in this patient.

There are no controlled studies addressing the guidelines for the management of drug induced bradycardia and the indications for pacing. The first recommendation for drug-induced sinus bradycardia is to discontinue the suspected drug [9]. When the medication cannot be stopped, symptomatic treatment with drugs such as atropine and isoproterenol or pacemaker implantation may be considered [9,18]. In addition, observation therapy may be considered in patients with clinically insignificant or benign asymptomatic bradycardia without important hemodynamic changes or other clinical consequences [9]. Previously reported antipsychotic-induced bradycardia resolved after discontinuation of the medication without the need for additional medication or pacemaker installation [1-4]. In addition, these patients had no residual symptoms after discontinuation of the drug. Similar to previous cases, the patient in our case recovered by discontinuing the suspected drug and did not experience any further sinus bradycardia at the 6-month follow-up. This suggests that, if the medicine is rapidly stopped, the prognosis for antipsychotic-induced sinus bradycardia is ex-cellent. Therefore, psychiatrists may first consider discon-tinuing the suspected medication when they meet antipsychotic-induced sinus bradycardia.

The absence of rechallenge to reconfirm was the main limitation of this report. Therefore, more case studies would be needed in the future to completely rule out the possibility of transient factors other than drugs.

In conclusion, this case highlights the importance of considering bradycardia as a potential side effect when starting lurasidone therapy, although bradycardia induced by lurasidone is rare and not symptomatic. Identifying populations at risk for lurasidone induced sinus bradycardia will help in the promotion of lurasidone therapy. In addition, further studies should explore the underlying mechanisms of sinus bradycardia induced by lurasidone.

We acknowledge the Affiliated Brain Hospital of Guangzhou Medical University and all staff that involved in patient treatment.

No potential conflict of interest relevant to this article was reported.

None.

Describing the case: Qijie Kuang. Funding: Yingjun Zheng. Writing—original draf & editingt: Qijie Kuang. Writing—scientific & language editing: Sumiao Zhou, Shenglin She. All authors read and approved the final manuscript.