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Clozapine associated cardiotoxicity: Issues, challenges and way forward
Asian Journal of Psychiatry 50 (2020) 101950
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Clozapine associated cardiotoxicity: Issues, challenges and way forward
T
Guna Kanniah*, Shailesh Kumar Waikato Clinical Campus, University of Auckland, New Zealand
A R T I C LE I N FO
A B S T R A C T
Keywords: Clozapine Cardiotoxicity Myocarditis Cardiomypathy Subclinical Cozapine Cardiotoxicity
Objective: To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge. Results: Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Rechallenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5–24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT. Conclusion: Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.
1. Introduction Clozapine is unequivocally deemed as the most effective medicine for treatment refractory schizophrenia (Kane et al., 2000; Rosenheck et al., 1997; Wahlbeck et al., 1999). The superiority of clozapine over other second generation antipsychotics (SGAs) has been established on a number of outcome measures such as response to treatment, medication, adherence to, patient satisfaction (McEvoy et al., 2006) and reduced mortality Tiihonen et al. (2009). Clozapine is, by no means, without its problems- to the extent that it is also seen as the most toxic in its class. Severe adverse effects, notably blood dyscrasia,- neutropenia, agranulocytosis, sedation, hypotension, seizures metabolic syndrome, cardiotoxicity, constipation and hypersalivation have relegated it to third and fourth in line of treatment. Three types of clozapine associated cardiotoxicity (CACT) have been identified in the literature: Clozapine associated Myocarditis (CAM), Clozapine Associated Cardiomyopathy (CAC) and Subclinical Clozapine Associated Cardiotoxicity (SCAC) (Youssef et al., 2016; Chow et al.,
⁎
2014). With prevalence figures of 3.88 % for CAC and 4.65 % for CAM and CAC (Youssef et al., 2016) and reported rates of mortality figures of 10 % CACT is often overlooked in the literature (Topliss et al., 2007; Ronaldson et al., 2015). Myocarditis is defined pathologically as an inflammatory disorder of the myocardium. Heterogeneous symptomatology may make diagnosis difficult and explain the lack of precise data on incidence and prevalence of CAM. The most probable aetiopathological mechanism for CAM is a medicine-induced, acute hypersensitivity (type 1, IgE-mediated) reaction, (Kilian et al. (1999)). Genetic factors, living in areas such as Australia and New Zealand with high ozone concentrations which in turn increases the risk of M2 receptors blockade and cholinergic receptor dysfunction and elemental deficiencies have also been proposed as alternative aetio-pathological models for CAM. There is however no evidence in favour of one of these mechanisms in particular (Datta and Solomon, 2018). Cardiomyopathy is a more chronic disease of myocardial contractile dysfunction (Youssef et al., 2016). The term “subclinical” in SCAC refers to the subclinical asymptomatic episodes of
Corresponding author at: Waikato Hospital, Private bag 3200, Hamilton 3200, New Zealand. E-mail address: [email protected] (G. Kanniah).
https://doi.org/10.1016/j.ajp.2020.101950 Received 18 November 2019; Received in revised form 28 December 2019; Accepted 9 February 2020 1876-2018/ © 2020 Elsevier B.V. All rights reserved.
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•Subclinical LV dysfunction •Benign ECG abnormalities •Asymptomatic mild LV function impairment •Adverse effects on LV function at modest doses •Asymptomatic, dilated cardiomyopathy, •Biventricular dysfunction.
paroxysmal atrial fibrillation or 'silent' AF including benign ECG abnormalities, asymptomatic mild LV function impairment, asymptomatic, dilated cardiomyopathy and biventricular dysfunction (Chow et al., 2014; Thyagarajan et al., 2016). Even asymptomatic mild Left Ventricular (LV) impairment may be associated with metabolic syndrome (including increased triglycerides, low high-density lipoprotein cholesterol (HDL-C), high-sensitivity C reactive protein and BMI), elevated neutrophil count, elevated heart rate, smoking and N-terminal probrain natriuretic peptide thus increasing the risk of mortality and morbidity in SCAC (Chow et al., 2014). SCAC may indeed be a “silent killer”. In a preliminary prospective study of cardiac status of patients with treatment-resistant schizophrenia with no evidence of cardiovascular disease (n = 15; aged 18–55 years), subclinical but substantial decrease in LV functioning occurred in surprisingly high proportions of participants. The finding was based on a number of echocardiographic indices with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index. The changes in these indices were uncorrelated with drug concentrations (Curto et al., 2015). Several reliable laboratory parameters for diagnosing myocarditis and cardiomyopathy exist but clear protocols for monitoring them among patients taking clozapine are lacking. Laboratory tests such as raised peripheral eosinophil counts; C-Reactive Protein (CRP), troponins T and I, creatine kinase-MB (CK-MB), B-type natriuretic peptide (BNP), the N-terminal fragment of pro-BNP (NT-pro-BNP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and ECG help diagnose CAM but are not pathognomic (Rostagno et al., 2011; Ronaldson et al., 2011). CAC, a serious and poorly understood cardiac side effect of clozapine presents with physical signs and symptoms including dyspnoea, tachycardia, palpitations, chest pain and fatigue. These features are also common to heart failure and can be misleading. To make matters worse 40–83 % of reported cases of CAC can be asymptomatic (Curto et al., 2016). Echocardiographic evidence of myocardial dysfunction with an ejection fraction (EF) < 50 % and increased serum concentrations of BNP support the diagnosis of CAC (Curto et al., 2016). SCAC includes the laboratory measures outlined above along with a range of often non-specific symptoms. CAC, CAM and SCAC are often underreported possibly because of the nonspecific nature of presenting signs and symptoms, poorly understood pathophysiological mechanisms and the lack of specificity of diagnostic tests (Rostagno et al., 2011; Curto et al., 2016; Layland et al., 2009). Incidence of early (≤2 months) CAM ranges from < 0.1 to 1.0 % and later (3–12 months) figures for CAC being approximately 10 times less (Curto et al., 2016). SCAC incidence may be higher than CAC and CAM (Thyagarajan et al., 2016; Rostagno et al., 2011; Ronaldson et al., 2011; Curto et al., 2016). Significant geographical variations have also been reported (Ronaldson et al., 2011). In many cases not all the features associated with CACT may manifest with only evidence of reduced LV output after exercise rather than a physiological increase (Chow et al., 2014). By understanding the serious but relatively infrequent full range of clozapine associated cardiotoxicity we can not only manage the side effect better but also have an informed debate about the issue of re-challenging clozapine in a sub group of patient where clozapine had to be discontinued.
2.1. Diagnosing of Clozapine associated myocarditis (CAM) Diagnosing CAM on clinical grounds is challenging. In its non-fulminant form symptomatology of CAM resembles that of clozapine titration. Often the most common clinical features reported in adverse reactions to clozapine (fever, tachycardia, chest pain, dyspnoea, electro- or echocardiographic abnormality, raised levels of troponin, CK, leucocytosis) resemble features of patients presenting with biopsyproven viral myocarditis (abnormal ECG, dyspnoea, palpitations, chest pain, tachycardia, arrhythmia, elevated levels of cardiac biomarkers, influenza-type symptoms, viral prodrome, leucocytosis) (Layland et al., 2009). Given the often confusing clinical picture operationalised diagnostic criteria for CAM and CAC was proposed by Youssef et al. (2016) 2.1.1. Management of Clozapine associated myocarditis (CAM) The management of CAM usually includes empirical and supportive use of medications to improve cardiac functioning and minimise the risk of cardiac failure such as diuretics, beta-blockers, and ACE inhibitors, corticosteroids. Diuretics essentially reduce fluid overload and subsequent progression of cardiac failure (Curto et al., 2016). Betablockers may improve ventricular function, limit further worsening of heart failure, and reduce mortality risks in patients with myocarditis. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are other options that has been utilised to manage cardiac failure (Curto et al., 2016). This undoubtedly involves discontinuing clozapine, being cognisant of the risk of relapse of psychosis and switching to another class of antipsychotic. (Cohen et al., 2015; Pieroni et al., 2004). 2.1.2. Rechallenge with clozapine in Clozapine associated myocarditis CAM The general consensus is against a re-challenge with clozapine in patients who have experienced CAM especially in the presence of convincing evidence of cardiac damage. In some patients a retrial may have to be considered. This should be a last resort and before doing so factors such as the degree of severity of psychosis and its associated disability and risk of suicide, the initial clinical response to clozapine and failure of other medications will need to be considered. Extreme caution will need to be exercised and retrial should only be considered after full clinical resolution of myocarditis and absence of evidence of cardiac impairment, supervised under closely controlled conditions, in hospital settings. It is imperative to restart clozapine, follow the dictum of “start low, go slow” while frequently repeating cardio markers (Kropp et al., 2005; Cook et al., 2015; Munshi et al., 2013; Ittasakul et al. (2016); Ronaldson et al. (2012a)). This option of retrial is not routinely advocated, but may be reserved as last resort for patients with very limited options. 2.2. Diagnosing Clozapine associated cardiomyopathy (CAC)
2. Nature of Clozapine associated Cardiotoxicity (CACT) Symptoms of CAC are similar with those of heart failure that includes dyspnoea, tachycardia, palpitations, chest pain and fatigue but in up to 40–83 % patients may present asymptomatic. (Curto et al., 2016). A definitive diagnosis is based echocardiographic evidence of a reduction of LV ejection fraction (LVEF) < 50 %, increased serum concentrations of BNP, and echocardiographic evidence of myocardial dysfunction (Alawami et al., 2014). The reported mortality is about 12.5–24.0 % which is similar to mortality risks associated with myocarditis (Curto et al., 2016). Similar to CAM, Youssef eta l (2016) have also operationalised diagnostic criteria for CAC
CAC and CAM are rare but potentially life-threatening conditions. CAM often manifests early in the course of treatment ranges (≤2 months) with an incidence of < 0.1 to 1.0 % whereas CAC occurs later (3–12 months) and the incidence is about 10 times less than CAM (Curto et al., 2016). More than 85 % of CAM cases occurring the first 2 months and up to 75 % within 3 weeks(Layland et al., 2009). SCAC is diagnosed using echocardiography and N-terminal pro-B-type natriuretic peptide assay but other parameters may also be helpful (Chow et al., 2014; Layland et al., 2009). 2
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exercised with re-challenging with clozapine in patients with SCAC especially If impaired LV function is identified. An individualised approach will be required for each patient in consultation with treating psychiatrists and cardiologists while re-challenging for SCAC
2.2.1. Management of Clozapine associated cardiomyopathy (CAC) The treatment of CAC warrants suspension of clozapine treatment and is evidenced by improvement in LV dysfunction in most cases. Haemodynamic stabilisation includes, as in the case of myocarditis, management with angiotensin-converting enzyme inhibitors, diuretics, β-blockers and possibly aldosterone antagonists (Kropp et al., 2005).
3. Variations in global prevalence of Clozapine associated cardiotoxicity and its implication for clinical practice
2.2.2. Rechallenge with clozapine in Clozapine associated cardiomyopathy (CAC) This is generally not recommended. In the critical presence of LV dysfunction Clozapine should be suspended and discontinued without further deliberation. There is very limited data on the safety of drug rechallenge in clozapine induced cardiomyopathy. Only three case reports of such patients: one experienced a recurrence of exacerbation of cardiomyopathy (Curto et al., 2016). Thus safety of clozapine rechallenge in CAC is far from established. Re-challenge in the rare instance based on criteria stated for myocarditis, may be considered in carefully selected cases but close monitoring and frequent echocardiography are required (Kropp et al., 2005).
Considerable differences in the prevalence rates of CACT have been reported globally (Ronaldson et al., 2011; Reinders et al., 2004). Ethnogenetic and practice factors may explain such variation (Ronaldson et al., 2015). Predisposing genetic polymorphisms have been identified for several drug hypersensitivity reactions including abacavir (Lucas et al., 2007) Stevens Johnson syndrome with carbamazepine (Chung et al., 2004) severe skin reactions with allopurinol (Hung et al., 2005) and cholestatic hepatitis with flucloxacillin (Daly et al., 2009). With regard to side effects associated with clozapine the role of genetic factors including Human leukocyte antigen (HLA) genes in the causation of neutropaenia has been of considerable interest. The role of genetic factors in the causation of CACT is purely at a speculative level. Even if there was a case for genetic factors to help us understand some of the differences in global prevalence for CACT they may not be hugely helpful for the clinician tasked with the responsibility to reducing the risk of adverse events. Clinical practice factors may be more helpful in this regard. The rate of clozapine titration and co prescribed medications are some of the practice factors that contribute to the variation (de Leon et al. (2015d); Swart et al., 2016). We review such and other practice factors and propose a protocol for monitoring CACT.
2.3. Diagnosing Subclinical Clozapine associated cardiotoxicity (SCAC) In one study (n = 38 patients), subclinical heart dysfunction occurred in one-third of young, previously healthy, clozapine treated patients (Rostagno et al., 2011). NT-pro-BNP values relate inversely with LVEF. At 1 year follow up the whole group did not show significant changes in clinical, ECG and echocardiographic measurement, however a LVEF decrease > 5% was found in 33 % of patients with baseline normal LVEF while LVEF remained below 55 % in 70 % of the patients. None of the subjects with cardiac abnormalities reported clinical symptoms (Rostagno et al., 2006). Two-dimensional (2D) speckle-tracking strain and strain rate measurement by transthoracic echocardiogram (TTE) is considered to be better than traditional parameters such as LVEF in detecting subtle changes in LV function (Chow et al., 2014) By early identification and recognition of signs of SCAC, potential risks can be minimized before significant clinical manifestations and cardiac function impairments manifest.
4. A protocol for monitoring Clozapine associated Cardiotoxicity (CACT) Noting the wide variation in the prevalence figures of CACT (Datta and Solomon, 2018), the clinical determinants (de Leon et al. (2015d); Swart et al., 2016) and its poorly understood aetio-pathological mechanisms it is our recommendation that clinicians may wish to follow a three step process for prevention of CACT: 1. slow titration (Ronaldson et al., 2012b; de Leon et al. (2015d)), 2. close cardiac monitoring and 3. reducing polypharmacy especially of medications that are known to increase risk of cardiotoxicity. These steps will be examined in greater detail below.
2.3.1. Management of Subclinical Clozapine associated cardiotoxicity (SCAC) Chow et al. (2014) found SCAC may be related to the degree of systemic inflammation, low plasma HDL-C and/or higher resting heart rate. In the absence of specific diagnostic markers the authors recommended regular echocardiographic surveillance, clinical evaluation and ECG among patients with SCAC in order to exclude clozapine-induced acute myocarditis and to monitor for long-term cardiomyopathy. Findings consistent with myocarditis (new onset tachycardia with HR > 120 bpm, raised hsCRP, HsTropT, acute deterioration in LVEF and/or systemic symptoms suggestive of myocarditis or cardiac failure) must prompt immediate cardiology review in order to consider clozapine cessation and commencement of cardio-protective drugs such as β blockers and ACE inhibitors. Such monitoring consisting of clinical review, ECG and echocardiograph should be 3 months, 12 months, 2 years, 5 years and 10 years following the start of clozapine to assess for impaired and/or deteriorating cardiac function. Although data from clinical trials are lacking, interventions supportive of cardiac function with medications such as ACE inhibitors or beta blockers may be worth considering in patients with SCAC. This may improve the long-term cardiac outcome as has been reported in other studies of CAC and CAM (Curto et al., 2016; Kropp et al., 2005).
4.1. Slow Titration We recommend starting clozapine therapy: 12.5 mg (half a 25 mg tablet) once or twice daily on the first day, followed by one or two 25 mg tablets on the second day. If well-tolerated, the daily dose increased slowly in increments of 25–50 mg in order to achieve a dose level of up to 300 mg/day within 2–3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50–100 mg at half-weekly or, preferably, weekly intervals. After the two week period (when the risk of CACT potentially reduces), the dosage can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages Tables 1 and 2. 4.2. Close cardiac monitoring Combining recent recommendations we recommend the following protocol for cardiac monitoring (Curto et al., 2016; Freudenreich, 2015); •Include under routine lab investigation markers of inflammation (CRP or ESR) and cardiac muscle damage (Troponin or CPK) to the already mandated weekly routine bloods for first 4 weeks.
2.3.2. Rechallenge with clozapine in Subclinical Clozapine associated cardiotoxicity (SCAC) No published data or guidelines exist for re-challenging patients with SCAC. Extrapolating the findings from the seminal paper by Chow et al. (2014) it is safe to suggest extreme caution may need to be 3
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Table 1 Case definition of clozapine-induced myocarditis (table from Youssef et al, 2016). At least ONE symptom AND/OR sign of cardiac dysfunction: Chest pain Flu-like symptoms Persistent tachycardia (heart rate > 100 beats per minute) Signs of heart failure (third heart sound, basal crepitations, peripheral oedema) PLUS At last ONE of the following diagnostic abnormalities: Elevated troponin 1 (> 2 ULN) Echocardiographic evidence of systolic dysfunction Evolution ECG changes involving T-wave inversion or > 1 mm ST-segment deviation in at least 2 contiguous leads
ULN = upper limit of normal; ECG = electrocardiogram.
2013). A second antipsychotic is often added to clozapine for antipsychotic augmentation. In such cases it is important to consider safety issues which may range from mild to severe complications even death. In one case the addition of risperidone resulted in mild increase in plasma clozapine with transient light-headedness caused by possible pharmacokinetic interaction of competitive cytochrome P450 2D6 enzyme metabolism (Tyson et al., 1995). Potential risks may increase with more complex polypharmacy regimens. In another case a 40 year old man with acute mania who was treated aggressively with combinations of drugs that were dosed individually within recommended range died. Pharmacokinetic interactions resulted in potentially toxic, high serum drug concentrations of haloperidol, clozapine, and promazine caused by enzyme inhibitory effects of valproate (Curto et al., 2019).
Table 2 Case definition of clozapine-induced cardiomyopathy (table from Youssef et al, 2016). New onset systolic dysfunction on any echocardiogram in the follow-up period characterised as
LVEF
AND At least a 10 % reduction in LVEF from baseline OR most recent echocardiogram
EVE = Left ventricular ejection fraction.
•Monitor vital signs including temperature on the day of blood work (first 4 weeks at a minimum) •Educate all patients and their families about early warning signs of myocarditis. •Conduct a fresh ECG and cardiac enzymes as soon as clinical concerns for myocarditis arise. If a recent baseline ECG is on file, any changes can be better interpreted. •Monitor any increase in eosinophil count after the high-risk period which may indicate a subclinical case of myocarditis •Obtain clozapine serum levels to avoid unnecessarily high blood levels. •Refer to cardiologist for second opinion •Competency certification in clozapine prescribing and monitoring to be incorporated as part of training in mental health services (Farooq et al., 2019)
5. Conclusions Clozapine associated cardiotoxicity is a potentially fatal complication which often is underreported due to several confounding factors. Improved awareness of myocarditis, cardiomyopathy and subclinical cardiotoxicity associated with clozapine may help reduce mortality and morbidity associated in this subgroup of patients many of whom may have no options other than to be re-challenged with clozapine. Practical, cost-effective clinical monitoring protocol and appropriate competency training may improve patient outcome. Financial We have not received any financial help in any shape of form in preparing this manuscript.
4.3. Reduce polypharmacy Other psychotropic medicines while titrating the dosage of clozapine should be kept to minimum in order to avoid pharmacokinetic or pharmaco-dynamic drug interactions Ronaldson et al. (2012a). Sodium valproate demonstrates a significant association, in increasing the risk of myocarditis in people commencing clozapine possibly by increasing plasma clozapine in non-smokers and decreased it in smokers (Ronaldson et al., 2012b). Lamotrigine, another anticonvulsant, may cause four to five fold increase in clozapine levels (Kossen et al., 2001) thus increasing the risk of clozapine toxicity including CACT. Another class of medication with potential to cause or exacerbate CACT, especially myocarditis is Lithium (Talati et al., 2009, 2009). Lithium when combined with clozapine may also cause severe bradycardia (Waring, 2007) prolongation of the QT interval van Noord et al. (2009v) and severe ventricular arrhythmias potentially leading to VF and sudden death Cruchaudet et al. (2012). Risk associated with co-administration of lithium and clozapine should be counterbalanced with the fact that these two are often the only two psychotropic medications with the potential to lower suicide risk (Hennen, and Baldessarini, 2005; Baldessarini et al., 2006). Among selective serotonin reuptake inhibitors (SSRIs), fluvoxamine resulted in marked increased in plasma clozapine level. Clozapine is metabolised by cytochrome P450 3A3/4 and 1A2 and fluvoxamine inhibits both 3A3/4 and 1A2 (Singh et al.,
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Chow, V., Yeoh, T., Ng, A.C., Pasqualon, T., Scott, E., Plater, J., et al., 2014. Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicentre cross-sectional cohort study. Open Heart 26 (1), 1. https://doi.org/10.1136/openhrt-2013-000030. eCollection 2014 e000030. Chung, W.H., Hung, S.I., Hong, H.S., Hsih, M.S., Yang, L.C., Ho, H.C., et al., 2004. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428 (6982), 486. Cohen, R., Lysenko, A., Mallet, T., Mirrer, B., Gale, M., Loarte, P., et al., 2015. A Case of Clozapine-Induced Myocarditis in a Young Patient with Bipolar Disorder. Case Rep. Cardiol., 283156. https://doi.org/10.1155/2015/283156. Published online 2015 Aug 30. Cook, S.C., Ferguson, B.A., Cotes, R.O., Heinrich, T.W., Schwartz, A.C., 2015. Clozapineinduced myocarditis: prevention and considerations in rechallenge. Psychosomatics 56 (6), 685–690. Cruchaudet, B., Eicher, J.C., Sgro, C., Wolf, J.E., 2012. Reversible cardiomyopathy induced by psychotropic drugs: case report and literature overview. Ann Cardiol Angeiol (Paris). 51 (6), 386–390. Curto, M., Comparelli, A., Ciavarella, G.M., Gasperoni, C., Lionetto, L., Corigliano, V., Uccellini, A., Mancinelli, I., Ferracuti, S., Girardi, P., Baldessarini, R.J., 2015. Impairment of left ventricular function early in treatment with clozapine: a preliminary study. Int. Clin. Psychopharmacol. 30 (5), 282–289. Curto, M., Girardi, N., Lionetto, L., Ciavarella, G., Ferracuti, S., Baldessarini, R., et al., 2016. Systematic review of clozapine cardiotoxicity. Curr. Psychiatry Rep. 18 (7), 1. https://doi.org/10.1007/s11920-016-0704-3. Curto, M., Lionetto, L., David, M.C., Maiese, A., Ferracuti, S., Simmaco, M., Baldessarini, R.J., 2019. Sudden death associated with complex treatment of acute mania: case report and toxicological findings. Curr Psychopharmacology. 8 (3), 238–243. Daly, A.K., Donaldson, P.T., Bhatnagar, P., Shen, Y., Pe’er, I., Floratos, A., et al., 2009. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 41 (7), 816–819. Datta, T., Solomon, A.J., 2018. Clozapine-induced myocarditis. Oxf. Med. Case Reports 1, 11–14. de Leon, J., Tang, Y.L., Baptista, T., Cohen, D., Schulte, P.F., 2015d. Titrating clozapine amidst recommendations proposing high myocarditis risk and rapid titrations. Acta Psychiatr. Scand. 132 (4), 242–243. Farooq, S., Choudry, A., Cohen, D., Naeem, F., 2019. Barriers to using clozapine in treatment-resistant schizophrenia: systematic review. Br. J. Psychiatry 43 (1), 8–16. Freudenreich, O., 2015. Clozapine-induced myocarditis: prescribe safely but do prescribe. Acta Psychiatr. Scand. 132 (4), 240–241. Hennen, J., Baldessarini, R.J., 2005. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr. Res. 73 (2–3), 139–145. Hung, S.I., Chung, W.H., Liou, L.B., Chu, C.C., Lin, M., Huang, H.P., et al., 2005. HLAB*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 102 (11), 4134–4139. Ittasakul, P., Archer, A., Kezman, J., Atsariyasing, W., Goldman, M.B., 2016. Rapid Rechallenge with clozapine following pronounced myocarditis in a treatment-resistance schizophrenia patient. Clin. Schizophr. Relat. Psychoses 10 (2), 120–122. Kane, J., Honigfeld, G., Singer, J., Meltzer, H., 2000. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45 (9), 789–796. Kilian, J.G., Kerr, K., Lawrence, C., Celermajer, D.S., 1999. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 354 (9193), 1841–1845. Kossen, M., Selten, J.P., Kahn, R.S., 2001. Elevated clozapine plasma level with lamotrigine. Am. J. Psychiatry 158 (11), 1930. Kropp, S., Tountopoulou, A., Schneider, U., Lichtinghagen, R., 2005. N-terminal fragment of B-type natriuretic peptide (NT-proBNP), a marker of cardiac safety during antipsychotic treatment. Ann. Gen. Psychiatry 4 (1), 10. Layland, J.J., Liew, D., Prior, D.L., 2009. Clozapine-induced cardiotoxicity: a clinical update. Med J Australia. 190 (4), 190–192. Lucas, A., Nolan, D., Mallal, S., 2007. HLA-B*5701 screening for susceptibility to abacavir hypersensitivity. J. Antimicrob. Chemother. 59 (4), 591–593.
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Contents lists available at ScienceDirect
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Clozapine associated cardiotoxicity: Issues, challenges and way forward
T
Guna Kanniah*, Shailesh Kumar Waikato Clinical Campus, University of Auckland, New Zealand
A R T I C LE I N FO
A B S T R A C T
Keywords: Clozapine Cardiotoxicity Myocarditis Cardiomypathy Subclinical Cozapine Cardiotoxicity
Objective: To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge. Results: Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Rechallenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5–24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT. Conclusion: Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.
1. Introduction Clozapine is unequivocally deemed as the most effective medicine for treatment refractory schizophrenia (Kane et al., 2000; Rosenheck et al., 1997; Wahlbeck et al., 1999). The superiority of clozapine over other second generation antipsychotics (SGAs) has been established on a number of outcome measures such as response to treatment, medication, adherence to, patient satisfaction (McEvoy et al., 2006) and reduced mortality Tiihonen et al. (2009). Clozapine is, by no means, without its problems- to the extent that it is also seen as the most toxic in its class. Severe adverse effects, notably blood dyscrasia,- neutropenia, agranulocytosis, sedation, hypotension, seizures metabolic syndrome, cardiotoxicity, constipation and hypersalivation have relegated it to third and fourth in line of treatment. Three types of clozapine associated cardiotoxicity (CACT) have been identified in the literature: Clozapine associated Myocarditis (CAM), Clozapine Associated Cardiomyopathy (CAC) and Subclinical Clozapine Associated Cardiotoxicity (SCAC) (Youssef et al., 2016; Chow et al.,
⁎
2014). With prevalence figures of 3.88 % for CAC and 4.65 % for CAM and CAC (Youssef et al., 2016) and reported rates of mortality figures of 10 % CACT is often overlooked in the literature (Topliss et al., 2007; Ronaldson et al., 2015). Myocarditis is defined pathologically as an inflammatory disorder of the myocardium. Heterogeneous symptomatology may make diagnosis difficult and explain the lack of precise data on incidence and prevalence of CAM. The most probable aetiopathological mechanism for CAM is a medicine-induced, acute hypersensitivity (type 1, IgE-mediated) reaction, (Kilian et al. (1999)). Genetic factors, living in areas such as Australia and New Zealand with high ozone concentrations which in turn increases the risk of M2 receptors blockade and cholinergic receptor dysfunction and elemental deficiencies have also been proposed as alternative aetio-pathological models for CAM. There is however no evidence in favour of one of these mechanisms in particular (Datta and Solomon, 2018). Cardiomyopathy is a more chronic disease of myocardial contractile dysfunction (Youssef et al., 2016). The term “subclinical” in SCAC refers to the subclinical asymptomatic episodes of
Corresponding author at: Waikato Hospital, Private bag 3200, Hamilton 3200, New Zealand. E-mail address: [email protected] (G. Kanniah).
https://doi.org/10.1016/j.ajp.2020.101950 Received 18 November 2019; Received in revised form 28 December 2019; Accepted 9 February 2020 1876-2018/ © 2020 Elsevier B.V. All rights reserved.
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•Subclinical LV dysfunction •Benign ECG abnormalities •Asymptomatic mild LV function impairment •Adverse effects on LV function at modest doses •Asymptomatic, dilated cardiomyopathy, •Biventricular dysfunction.
paroxysmal atrial fibrillation or 'silent' AF including benign ECG abnormalities, asymptomatic mild LV function impairment, asymptomatic, dilated cardiomyopathy and biventricular dysfunction (Chow et al., 2014; Thyagarajan et al., 2016). Even asymptomatic mild Left Ventricular (LV) impairment may be associated with metabolic syndrome (including increased triglycerides, low high-density lipoprotein cholesterol (HDL-C), high-sensitivity C reactive protein and BMI), elevated neutrophil count, elevated heart rate, smoking and N-terminal probrain natriuretic peptide thus increasing the risk of mortality and morbidity in SCAC (Chow et al., 2014). SCAC may indeed be a “silent killer”. In a preliminary prospective study of cardiac status of patients with treatment-resistant schizophrenia with no evidence of cardiovascular disease (n = 15; aged 18–55 years), subclinical but substantial decrease in LV functioning occurred in surprisingly high proportions of participants. The finding was based on a number of echocardiographic indices with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index. The changes in these indices were uncorrelated with drug concentrations (Curto et al., 2015). Several reliable laboratory parameters for diagnosing myocarditis and cardiomyopathy exist but clear protocols for monitoring them among patients taking clozapine are lacking. Laboratory tests such as raised peripheral eosinophil counts; C-Reactive Protein (CRP), troponins T and I, creatine kinase-MB (CK-MB), B-type natriuretic peptide (BNP), the N-terminal fragment of pro-BNP (NT-pro-BNP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and ECG help diagnose CAM but are not pathognomic (Rostagno et al., 2011; Ronaldson et al., 2011). CAC, a serious and poorly understood cardiac side effect of clozapine presents with physical signs and symptoms including dyspnoea, tachycardia, palpitations, chest pain and fatigue. These features are also common to heart failure and can be misleading. To make matters worse 40–83 % of reported cases of CAC can be asymptomatic (Curto et al., 2016). Echocardiographic evidence of myocardial dysfunction with an ejection fraction (EF) < 50 % and increased serum concentrations of BNP support the diagnosis of CAC (Curto et al., 2016). SCAC includes the laboratory measures outlined above along with a range of often non-specific symptoms. CAC, CAM and SCAC are often underreported possibly because of the nonspecific nature of presenting signs and symptoms, poorly understood pathophysiological mechanisms and the lack of specificity of diagnostic tests (Rostagno et al., 2011; Curto et al., 2016; Layland et al., 2009). Incidence of early (≤2 months) CAM ranges from < 0.1 to 1.0 % and later (3–12 months) figures for CAC being approximately 10 times less (Curto et al., 2016). SCAC incidence may be higher than CAC and CAM (Thyagarajan et al., 2016; Rostagno et al., 2011; Ronaldson et al., 2011; Curto et al., 2016). Significant geographical variations have also been reported (Ronaldson et al., 2011). In many cases not all the features associated with CACT may manifest with only evidence of reduced LV output after exercise rather than a physiological increase (Chow et al., 2014). By understanding the serious but relatively infrequent full range of clozapine associated cardiotoxicity we can not only manage the side effect better but also have an informed debate about the issue of re-challenging clozapine in a sub group of patient where clozapine had to be discontinued.
2.1. Diagnosing of Clozapine associated myocarditis (CAM) Diagnosing CAM on clinical grounds is challenging. In its non-fulminant form symptomatology of CAM resembles that of clozapine titration. Often the most common clinical features reported in adverse reactions to clozapine (fever, tachycardia, chest pain, dyspnoea, electro- or echocardiographic abnormality, raised levels of troponin, CK, leucocytosis) resemble features of patients presenting with biopsyproven viral myocarditis (abnormal ECG, dyspnoea, palpitations, chest pain, tachycardia, arrhythmia, elevated levels of cardiac biomarkers, influenza-type symptoms, viral prodrome, leucocytosis) (Layland et al., 2009). Given the often confusing clinical picture operationalised diagnostic criteria for CAM and CAC was proposed by Youssef et al. (2016) 2.1.1. Management of Clozapine associated myocarditis (CAM) The management of CAM usually includes empirical and supportive use of medications to improve cardiac functioning and minimise the risk of cardiac failure such as diuretics, beta-blockers, and ACE inhibitors, corticosteroids. Diuretics essentially reduce fluid overload and subsequent progression of cardiac failure (Curto et al., 2016). Betablockers may improve ventricular function, limit further worsening of heart failure, and reduce mortality risks in patients with myocarditis. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are other options that has been utilised to manage cardiac failure (Curto et al., 2016). This undoubtedly involves discontinuing clozapine, being cognisant of the risk of relapse of psychosis and switching to another class of antipsychotic. (Cohen et al., 2015; Pieroni et al., 2004). 2.1.2. Rechallenge with clozapine in Clozapine associated myocarditis CAM The general consensus is against a re-challenge with clozapine in patients who have experienced CAM especially in the presence of convincing evidence of cardiac damage. In some patients a retrial may have to be considered. This should be a last resort and before doing so factors such as the degree of severity of psychosis and its associated disability and risk of suicide, the initial clinical response to clozapine and failure of other medications will need to be considered. Extreme caution will need to be exercised and retrial should only be considered after full clinical resolution of myocarditis and absence of evidence of cardiac impairment, supervised under closely controlled conditions, in hospital settings. It is imperative to restart clozapine, follow the dictum of “start low, go slow” while frequently repeating cardio markers (Kropp et al., 2005; Cook et al., 2015; Munshi et al., 2013; Ittasakul et al. (2016); Ronaldson et al. (2012a)). This option of retrial is not routinely advocated, but may be reserved as last resort for patients with very limited options. 2.2. Diagnosing Clozapine associated cardiomyopathy (CAC)
2. Nature of Clozapine associated Cardiotoxicity (CACT) Symptoms of CAC are similar with those of heart failure that includes dyspnoea, tachycardia, palpitations, chest pain and fatigue but in up to 40–83 % patients may present asymptomatic. (Curto et al., 2016). A definitive diagnosis is based echocardiographic evidence of a reduction of LV ejection fraction (LVEF) < 50 %, increased serum concentrations of BNP, and echocardiographic evidence of myocardial dysfunction (Alawami et al., 2014). The reported mortality is about 12.5–24.0 % which is similar to mortality risks associated with myocarditis (Curto et al., 2016). Similar to CAM, Youssef eta l (2016) have also operationalised diagnostic criteria for CAC
CAC and CAM are rare but potentially life-threatening conditions. CAM often manifests early in the course of treatment ranges (≤2 months) with an incidence of < 0.1 to 1.0 % whereas CAC occurs later (3–12 months) and the incidence is about 10 times less than CAM (Curto et al., 2016). More than 85 % of CAM cases occurring the first 2 months and up to 75 % within 3 weeks(Layland et al., 2009). SCAC is diagnosed using echocardiography and N-terminal pro-B-type natriuretic peptide assay but other parameters may also be helpful (Chow et al., 2014; Layland et al., 2009). 2
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exercised with re-challenging with clozapine in patients with SCAC especially If impaired LV function is identified. An individualised approach will be required for each patient in consultation with treating psychiatrists and cardiologists while re-challenging for SCAC
2.2.1. Management of Clozapine associated cardiomyopathy (CAC) The treatment of CAC warrants suspension of clozapine treatment and is evidenced by improvement in LV dysfunction in most cases. Haemodynamic stabilisation includes, as in the case of myocarditis, management with angiotensin-converting enzyme inhibitors, diuretics, β-blockers and possibly aldosterone antagonists (Kropp et al., 2005).
3. Variations in global prevalence of Clozapine associated cardiotoxicity and its implication for clinical practice
2.2.2. Rechallenge with clozapine in Clozapine associated cardiomyopathy (CAC) This is generally not recommended. In the critical presence of LV dysfunction Clozapine should be suspended and discontinued without further deliberation. There is very limited data on the safety of drug rechallenge in clozapine induced cardiomyopathy. Only three case reports of such patients: one experienced a recurrence of exacerbation of cardiomyopathy (Curto et al., 2016). Thus safety of clozapine rechallenge in CAC is far from established. Re-challenge in the rare instance based on criteria stated for myocarditis, may be considered in carefully selected cases but close monitoring and frequent echocardiography are required (Kropp et al., 2005).
Considerable differences in the prevalence rates of CACT have been reported globally (Ronaldson et al., 2011; Reinders et al., 2004). Ethnogenetic and practice factors may explain such variation (Ronaldson et al., 2015). Predisposing genetic polymorphisms have been identified for several drug hypersensitivity reactions including abacavir (Lucas et al., 2007) Stevens Johnson syndrome with carbamazepine (Chung et al., 2004) severe skin reactions with allopurinol (Hung et al., 2005) and cholestatic hepatitis with flucloxacillin (Daly et al., 2009). With regard to side effects associated with clozapine the role of genetic factors including Human leukocyte antigen (HLA) genes in the causation of neutropaenia has been of considerable interest. The role of genetic factors in the causation of CACT is purely at a speculative level. Even if there was a case for genetic factors to help us understand some of the differences in global prevalence for CACT they may not be hugely helpful for the clinician tasked with the responsibility to reducing the risk of adverse events. Clinical practice factors may be more helpful in this regard. The rate of clozapine titration and co prescribed medications are some of the practice factors that contribute to the variation (de Leon et al. (2015d); Swart et al., 2016). We review such and other practice factors and propose a protocol for monitoring CACT.
2.3. Diagnosing Subclinical Clozapine associated cardiotoxicity (SCAC) In one study (n = 38 patients), subclinical heart dysfunction occurred in one-third of young, previously healthy, clozapine treated patients (Rostagno et al., 2011). NT-pro-BNP values relate inversely with LVEF. At 1 year follow up the whole group did not show significant changes in clinical, ECG and echocardiographic measurement, however a LVEF decrease > 5% was found in 33 % of patients with baseline normal LVEF while LVEF remained below 55 % in 70 % of the patients. None of the subjects with cardiac abnormalities reported clinical symptoms (Rostagno et al., 2006). Two-dimensional (2D) speckle-tracking strain and strain rate measurement by transthoracic echocardiogram (TTE) is considered to be better than traditional parameters such as LVEF in detecting subtle changes in LV function (Chow et al., 2014) By early identification and recognition of signs of SCAC, potential risks can be minimized before significant clinical manifestations and cardiac function impairments manifest.
4. A protocol for monitoring Clozapine associated Cardiotoxicity (CACT) Noting the wide variation in the prevalence figures of CACT (Datta and Solomon, 2018), the clinical determinants (de Leon et al. (2015d); Swart et al., 2016) and its poorly understood aetio-pathological mechanisms it is our recommendation that clinicians may wish to follow a three step process for prevention of CACT: 1. slow titration (Ronaldson et al., 2012b; de Leon et al. (2015d)), 2. close cardiac monitoring and 3. reducing polypharmacy especially of medications that are known to increase risk of cardiotoxicity. These steps will be examined in greater detail below.
2.3.1. Management of Subclinical Clozapine associated cardiotoxicity (SCAC) Chow et al. (2014) found SCAC may be related to the degree of systemic inflammation, low plasma HDL-C and/or higher resting heart rate. In the absence of specific diagnostic markers the authors recommended regular echocardiographic surveillance, clinical evaluation and ECG among patients with SCAC in order to exclude clozapine-induced acute myocarditis and to monitor for long-term cardiomyopathy. Findings consistent with myocarditis (new onset tachycardia with HR > 120 bpm, raised hsCRP, HsTropT, acute deterioration in LVEF and/or systemic symptoms suggestive of myocarditis or cardiac failure) must prompt immediate cardiology review in order to consider clozapine cessation and commencement of cardio-protective drugs such as β blockers and ACE inhibitors. Such monitoring consisting of clinical review, ECG and echocardiograph should be 3 months, 12 months, 2 years, 5 years and 10 years following the start of clozapine to assess for impaired and/or deteriorating cardiac function. Although data from clinical trials are lacking, interventions supportive of cardiac function with medications such as ACE inhibitors or beta blockers may be worth considering in patients with SCAC. This may improve the long-term cardiac outcome as has been reported in other studies of CAC and CAM (Curto et al., 2016; Kropp et al., 2005).
4.1. Slow Titration We recommend starting clozapine therapy: 12.5 mg (half a 25 mg tablet) once or twice daily on the first day, followed by one or two 25 mg tablets on the second day. If well-tolerated, the daily dose increased slowly in increments of 25–50 mg in order to achieve a dose level of up to 300 mg/day within 2–3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50–100 mg at half-weekly or, preferably, weekly intervals. After the two week period (when the risk of CACT potentially reduces), the dosage can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages Tables 1 and 2. 4.2. Close cardiac monitoring Combining recent recommendations we recommend the following protocol for cardiac monitoring (Curto et al., 2016; Freudenreich, 2015); •Include under routine lab investigation markers of inflammation (CRP or ESR) and cardiac muscle damage (Troponin or CPK) to the already mandated weekly routine bloods for first 4 weeks.
2.3.2. Rechallenge with clozapine in Subclinical Clozapine associated cardiotoxicity (SCAC) No published data or guidelines exist for re-challenging patients with SCAC. Extrapolating the findings from the seminal paper by Chow et al. (2014) it is safe to suggest extreme caution may need to be 3
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Table 1 Case definition of clozapine-induced myocarditis (table from Youssef et al, 2016). At least ONE symptom AND/OR sign of cardiac dysfunction: Chest pain Flu-like symptoms Persistent tachycardia (heart rate > 100 beats per minute) Signs of heart failure (third heart sound, basal crepitations, peripheral oedema) PLUS At last ONE of the following diagnostic abnormalities: Elevated troponin 1 (> 2 ULN) Echocardiographic evidence of systolic dysfunction Evolution ECG changes involving T-wave inversion or > 1 mm ST-segment deviation in at least 2 contiguous leads
ULN = upper limit of normal; ECG = electrocardiogram.
2013). A second antipsychotic is often added to clozapine for antipsychotic augmentation. In such cases it is important to consider safety issues which may range from mild to severe complications even death. In one case the addition of risperidone resulted in mild increase in plasma clozapine with transient light-headedness caused by possible pharmacokinetic interaction of competitive cytochrome P450 2D6 enzyme metabolism (Tyson et al., 1995). Potential risks may increase with more complex polypharmacy regimens. In another case a 40 year old man with acute mania who was treated aggressively with combinations of drugs that were dosed individually within recommended range died. Pharmacokinetic interactions resulted in potentially toxic, high serum drug concentrations of haloperidol, clozapine, and promazine caused by enzyme inhibitory effects of valproate (Curto et al., 2019).
Table 2 Case definition of clozapine-induced cardiomyopathy (table from Youssef et al, 2016). New onset systolic dysfunction on any echocardiogram in the follow-up period characterised as
LVEF
AND At least a 10 % reduction in LVEF from baseline OR most recent echocardiogram
EVE = Left ventricular ejection fraction.
•Monitor vital signs including temperature on the day of blood work (first 4 weeks at a minimum) •Educate all patients and their families about early warning signs of myocarditis. •Conduct a fresh ECG and cardiac enzymes as soon as clinical concerns for myocarditis arise. If a recent baseline ECG is on file, any changes can be better interpreted. •Monitor any increase in eosinophil count after the high-risk period which may indicate a subclinical case of myocarditis •Obtain clozapine serum levels to avoid unnecessarily high blood levels. •Refer to cardiologist for second opinion •Competency certification in clozapine prescribing and monitoring to be incorporated as part of training in mental health services (Farooq et al., 2019)
5. Conclusions Clozapine associated cardiotoxicity is a potentially fatal complication which often is underreported due to several confounding factors. Improved awareness of myocarditis, cardiomyopathy and subclinical cardiotoxicity associated with clozapine may help reduce mortality and morbidity associated in this subgroup of patients many of whom may have no options other than to be re-challenged with clozapine. Practical, cost-effective clinical monitoring protocol and appropriate competency training may improve patient outcome. Financial We have not received any financial help in any shape of form in preparing this manuscript.
4.3. Reduce polypharmacy Other psychotropic medicines while titrating the dosage of clozapine should be kept to minimum in order to avoid pharmacokinetic or pharmaco-dynamic drug interactions Ronaldson et al. (2012a). Sodium valproate demonstrates a significant association, in increasing the risk of myocarditis in people commencing clozapine possibly by increasing plasma clozapine in non-smokers and decreased it in smokers (Ronaldson et al., 2012b). Lamotrigine, another anticonvulsant, may cause four to five fold increase in clozapine levels (Kossen et al., 2001) thus increasing the risk of clozapine toxicity including CACT. Another class of medication with potential to cause or exacerbate CACT, especially myocarditis is Lithium (Talati et al., 2009, 2009). Lithium when combined with clozapine may also cause severe bradycardia (Waring, 2007) prolongation of the QT interval van Noord et al. (2009v) and severe ventricular arrhythmias potentially leading to VF and sudden death Cruchaudet et al. (2012). Risk associated with co-administration of lithium and clozapine should be counterbalanced with the fact that these two are often the only two psychotropic medications with the potential to lower suicide risk (Hennen, and Baldessarini, 2005; Baldessarini et al., 2006). Among selective serotonin reuptake inhibitors (SSRIs), fluvoxamine resulted in marked increased in plasma clozapine level. Clozapine is metabolised by cytochrome P450 3A3/4 and 1A2 and fluvoxamine inhibits both 3A3/4 and 1A2 (Singh et al.,
Declaration of Competing Interest We declare we have no conflict of interest in preparing this manuscript Acknowledgement We are grateful to Rishi Kumar for help with bibliography. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.ajp.2020.101950. References Alawami, M., Wasywich, C., Cicovic, A., Kenedi, C., 2014. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol. 2. 176, 315–320. https://doi.org/10. 1016/j.ijcard.2014.07.103. Baldessarini, R.J., Tondo, L., Davis, P., Pompili, M., Goodwin, F.K., Hennen, J., 2006. Decreased risk of suicides and attempts during long-term lithium treatment: a metaanalytic review. Bipolar Disord. 8 (5 Pt 2), 625–639.
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