This study examined the incidence of clozapine-induced tachycardia in people commencing clozapine through daily monitoring of HR over the first month of clozapine treatment. Almost all our participants (93.5%) had at least one recorded HR > 100 bpm, and two thirds had at least 3 consecutive days with HRs above 100 bpm recorded. In addition, 44 (35.8%) had at least one HR recording exceeding 120 bpm, and about 8% had persistent recordings exceeding 120 bpm. Participants with lower baseline HR had greater increases in HR during clozapine titration, though this did not increase the risk of tachycardia. Neither age, ethnicity nor BMI predicted the risk of tachycardia by day 14 or day 28. Younger age (< 30 years) and female sex increased the risk of tachycardia by day 14, but there was no risk difference by day 28. Cigarette smoking was associated with higher change in HR at day 28, suggesting that smoking may contribute to some of the effect seen.

Tachycardia appeared early in the titration, with a dose response effect at lower clozapine doses that plateaued around 150 mg daily. In total, 59% percent had tachycardia at day 14, but this resolved for some, and by the end of 4 weeks, 44% had tachycardia.

Our findings align with previous research that shows that clozapine-induced tachycardia is common when starting clozapine, and it persists in many patients [5,6,7,8, 20]. Tachycardia has been reported as the third most common adverse drug reaction cited as a reason for clozapine discontinuation (after sedation and neutropenia) [21], but it is often overlooked by treating clinicians [6].

Risk factors previously suggested to increase the likelihood of clozapine-induced tachycardia include younger age, higher clozapine doses and concurrent use of medications with known cardiac effects [6, 7, 10, 11]. The current findings showed a more complex association with clozapine dose with an initial dose-response effect which plateaued at 150 mg. Tachycardia was associated with younger age at day 14; this association was not significant at day 28, although this may have been a question of power. Our findings also identified people who smoked as experiencing a greater increase in their HR in terms of bpm increase. It was also interesting that those with the lowest baseline HRs had the greatest average increases in bpm—this has not been studied before, and it warrants further attention.

There has been little research on clozapine-induced tachycardia. The strengths of this study included the large sample size and sequential daily measuring of HR in a systematic and consistent fashion. We adopted a relatively conservative definition of tachycardia in which participants required persistently elevated HRs > 100 bpm over 3 days to meet the criteria to increase sensitivity and avoid being biased by outlier measurements.

In terms of limitations, data were only collected during the period of hospital admission, with patients with earlier discharge having shorter duration of total data collection. The small number of people on non-standard clozapine titration schedules and on β-blockers meant meaningful analyses by these variables was not possible. We also did not know if patients were being exposed to clozapine for the first time or if they were undergoing a re-trial. Clozapine levels were not routinely collected during the first 2 weeks of titration, and as such we were not able to adequately explore the early relationship between clozapine levels and tachycardia. We did not have information on other medications, aside from medications that regulated HR. The recordings of baseline HR were taken 3 days before starting clozapine during the participant’s hospital admission. Given that they are likely to have been experiencing acute psychosis and associated stress, it is quite possible their HRs were elevated above their normal resting rates. Lastly, this study only considered the first month of clozapine treatment. Further research is required to look at longer term clozapine treatment.

The mechanisms whereby clozapine induces tachycardia appear multifactorial and have not been fully elucidated. Hypotheses include clozapine’s action on the autonomic nervous system, particularly the cholinergic and adrenergic pathways. Muscarinic receptor antagonism may reduce vagal tone, resulting in increased HR. Clozapine may enhance sympathetic activity, leading to elevated levels of norepinephrine and subsequently tachycardia [22]. Moreover, clozapine’s affinity for various receptors, including histamine and serotonin receptors may be contributory to tachycardia through indirect mechanisms involving alterations in neurotransmitter release and modulation of cardiac ion channels. In the longer term, the metabolic side effects of clozapine, such as weight gain and insulin resistance, might also indirectly contribute to cardiovascular issues, including tachycardia [23].

In clinical practice, approaches to monitoring and treating clozapine-induced tachycardia are variable, meaning that it often goes undetected and untreated. Our data show that tachycardia is very common during clozapine initiation, and regular cardiovascular monitoring is recommended, particularly during the early stages of treatment. Given tachycardia > 100 bpm self-resolved in one third of patients by 4 weeks, watchful monitoring may be warranted over the first month of treatment. However, patients with systemic symptoms, including raised BP or persistent tachycardia > 120 bpm may require early treatment. Slower dose titration and adjustment may help mitigate the initial onset of tachycardia [24].

Tachycardia is commonly asymptomatic but may present with shortness of breath, palpitations or chest discomfort. Tachycardia may be an early sign of myocarditis or cardiomyopathy, so serious underlying cardiotoxicity should be ruled out [23]. Persistent tachycardia exceeding 120 bpm or a change in HR of more than 30 bpm from baseline have been identified as risk markers for myocarditis, specifically during clozapine titration [25]. While cardiovascular events, notably myocarditis or cardiomyopathy, require clozapine discontinuation, isolated tachycardia (provided myocarditis is ruled out) should not precipitate discontinuation but rather should be appropriately managed [26].

In terms of pharmacological interventions, a 2016 systematic review found no eligible randomised trials for clozapine-induced tachycardia [23], but some lower quality evidence exists. For example, Stryjer et al. found that β-blockers decreased the mean HR of 20 people with clozapine-associated tachycardia by 16.5 bpm, with 85% no longer meeting criteria for tachycardia [27]. There are further case reports/series of persistent tachycardia being successfully treated with β-blockers [10, 28] and clozapine dose reduction [24, 28].

Despite the limited published evidence, the use of cardiac-specific β-blockers was supported to treat clozapine-induced tachycardia in a Delphi study of international psychosis experts [29]. Cardio-selective β-blockers such as atenolol should be trialled first line, starting at 12.5 mg daily and titrated to the lowest effective dose, up to a maximum of 100 mg daily [3]. Bisoprolol has been recommended over atenolol by some authors, as its higher β-1 selectivity may confer a lower impact on glucose metabolism, making it preferable for patients at risk of diabetes [30].

Ivabradine is a suitable second-line option [31], which can be commenced at 5 mg twice daily and increased to 7.5 mg twice daily after 2–4 weeks if necessary [3]. Ivabradine specifically inhibits the If channel in the sinoatrial node. Unlike β-blockers, ivabradine reduces HR without affecting blood pressure or myocardial contractility, making it a potentially safer option for patients with cardiovascular comorbidities [28]. However, more robust clinical trials are needed to establish its efficacy and safety profile in this context.

Non-pharmacological strategies include ensuring adequate fluid intake, avoiding excessive caffeine or nicotine, and monitoring for other contributing factors such as fever or dehydration. Considering that many people treated with clozapine also suffer from increased cardiovascular risk related to smoking and metabolic side effects [32, 33], it is important to actively manage additional cardiometabolic risks.

Future research should focus on well-designed RCTs to evaluate both pharmacological and non-pharmacological interventions. In addition, exploring genetic and biomarker-based predictors of tachycardia risk could help tailor individualized treatment strategies, improving patient outcomes and minimising adverse effects.