- Email: [email protected]
Cardiovascular side effects of psychopharmacologic therapy
International Journal of Cardiology 219 (2016) 367–372
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Cardiovascular side effects of psychopharmacologic therapy Ines Potočnjak a,⁎, Vesna Degoricija b,a, Dina Vukičević Baudoin a, Josip Čulig c,d, Miro Jakovljević b,e a
University Hospital Center Sisters of Charity, Vinogradska cesta 29, 10000 Zagreb, Croatia University of Zagreb School of Medicine, Šalata 3, 10000 Zagreb, Croatia c Department of Pharmacoepidemiology, Andrija Štampar Teaching Institute of Public Health, Mirogojska 16, 10000 Zagreb, Croatia d Department of Pharmacology, School of Medicine, Josip Juraj Strossmayer University Osijek, J. Huttlera 4, 31000 Osijek, Croatia e Department of Psychiatry, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia b
a r t i c l e
i n f o
Article history: Received 18 April 2016 Accepted 18 June 2016 Available online 20 June 2016 Keywords: Psychopharmacology Psychotropic drugs Pharmacotherapy Cardiovascular system Side effects
a b s t r a c t WHO defined in 1976 psychopharmaca as drugs affecting psychological functions, behaviour and self-perception. Psychopharmacology is the study of pharmacological agents that affect mental and emotional functions. Creative approach to psychopharmacotherapy reflects a transdisciplinary, integrative and person-centered psychiatry. Psychiatric disorders often occur in cardiac patients and can affect the clinical presentation and morbidity. Cardiovascular (CV) side effects (SE) caused by psychopharmaceutic agents require comprehensive attention. Therapeutic approach can increase placebo and decrease nocebo reactions. The main purpose of this review is to comprehend CV SE of psychotropic drugs (PD). Critical overview of CV SE of PD will be presented in this review. Search was directed but not limited to CV effects of psychopharmacological substances, namely antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants and stimulants. Literature review was performed and data identified by searches of Medline and PubMed for period from 2004 to 2015. Only full articles and abstracts published in English were included. SE of PD are organized according to the following types of CV effects: cardiac and circulatory effects, abnormalities of cardiac repolarisation and arrhythmias and heart muscle disease. There is wide spectrum and various CV effects of PD. Results of this review are based on literature research. The reviewed data came largely from prevalence studies, case reports, and cross-sectional studies. Psychopharmacotherapy of psychiatric disorders is complex and when concomitantly present with CV disease, presentation of drug SEs can significantly contribute to illness course. Further development of creative psychopharmacotherapy is required to deal with CV effects of PD. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction This paper discusses cardiovascular side effects of psychopharmacotherapy. In the first part of this article overview of classification, commonly used psychotropic drugs, cardiovascular side effects and general data of cardiovascular effects are given. The second part deals with the cardiovascular side effects of psychopharmacs divided in groups as follows cardiac and circulatory effects, abnormalities of cardiac repolarisation and arrhythmias and heart muscle disease are described. This paper underlines the importance of cardiovascular effects of psychopharmacologic therapy in order to prevent them. Prescribing psychotropic drugs (PD) is frequent requirement in clinical practice. According to the definition of The World Health Organization (WHO) from 1976, psychopharmaca are drugs that affect psychological functions, behaviour and self-perception. This
⁎ Corresponding author. E-mail address: [email protected] (I. Potočnjak).
http://dx.doi.org/10.1016/j.ijcard.2016.06.057 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
chemical compounds in defined dose affect psychological behaviour. Psychopharmaceutic or PD are medications for treatment of psychological disorders. According to The Anatomical Therapeutic Chemical (ATC) Classification System, nervous system drugs are sorted into several groups as shown in Table 1 [1,2]. Medical group N includes anaesthetics, analgesics, hypnotics, anxiolytics, antidepressants, drugs against drug addiction and other drugs to treat diseases of nervous system [3]. PD have various cardiovascular (CV) side effects (SE). Furthermore, polypharmacy is the practice of administering or using multiple medications in the treatment of a single disease or several coexisting conditions. During the therapy it is important to contain pts' active participation. Thorough pt instruction has to be provided and they should be familiar with SE, their prevention, early detection and treatment. 1.1. Commonly used psychotropic drugs Psychopharmacotherapy is considered as the primary treatment for all serious mental disorders including schizophrenias, bipolar disorders, depressions, anxiety disorders, obsessive–compulsive disorders, etc. [4].
368
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
The number of the effective medications significantly increased [5]. Positive therapeutic context may significantly increase placebo and decrease nocebo responses [4]. It is known that creative approach to psychopharmacotherapy reflects a synergism in the frame of transdisciplinary holistic, integrative and person-centered psychiatry [4]. Commonly used PD are antipsychotics and antidepressants, comprising of tricyclic anti-depressants (TCAs), selective serotonin and other neurotransmitter re-uptake inhibitors (SSRI and SNRI), mood stabilizers, anxiolytic agents and medications for opioid addiction treatment [6]. Psychiatric medications are associated with a variety of possible adverse effects (AE) [7]. The mechanisms of AE in psychotropic medications might not always be known [7]. Awareness of the mechanisms for adverse drug reactions (ADR) can help to direct prescription choice [7]. ADR can be augmented and bizarre. Augmented ADR are predictable, depending on dose and pharmacological characteristics of the drug. In this paper augmented ADR will be presented. It is important to note that the incidence of mortality is higher among psychiatric pts than in general population [8]. Sudden death (SD) associated with PD is an issue which is currently debated worldwide [9].
Table 1 Classification of psychopharmaceutic agents registered in Republic of Croatia according to ATK system. N03 N03AA
Antiepileptics Barbiturates and derivatives
N03AB N03AC N03AD N03AE N03AF N03AG N03AX N05 N05A N05AA
Hydantoin derivatives Oxazolidine derivatives Succinimide derivatives Benzodiazepine derivatives Carboxamide derivatives Fatty acids derivatives Other antiepileptics Psycholeptics Antipsychotics Phenothiazines with aliphatic side-chain Phenothiazines with piperazine structure Phenothiazines with piperadine structure Butyrophenone derivatives Indole derivatives Diazepines, oksazepines, thiazepines and oxepines Benzamides Lithium Other antipsychotics Anxiolytics Benzodiazepine derivatives
N05AB N05AC N05AD N05AE N05AH N05AL N05AN N05AX N05B N05BA N05BC N05C N05CD N05CF N05CM N06 N06A N06AA N06AB N06AG N06AX N06B N06BX N06D N06DX
Carbamates Hypnotics and sedatives Benzodiazepine derivatives Benzodiazepine related drugs Other hypnotics and sedatives Psychoanaleptics Antidepressants Non-selective monoamine reuptake inhibitors Selective serotonin reuptake inhibitors Monoamine oxidase A inhibitors Other antidepressants Psychostimulants, agents used for ADHD and nootropics Other psychostimulants and nootropics Anti-dementia drugs Other anti-dementia drugs
Methylphenobarbital, phenobarbital, primidone Phenytoin Paramethadione Ethosuximide Clonazepam Carbamazepine Valproic acid, valpromide Lamotrigine, topiramate, gabapentin
Levomepromazine, promazine Fluphenazine, perazin Tioridazine Haloperidol Ziprasidone Clozapine, olanzapine, quetiapine Sulpiride Lithium Risperidone Alprazolam, bromazepam, diazepam, lorazepam, medazepam, oxazepam Meprobamate Flurazepam, midazolam, nitrazepam Zolpidem Valeriane radix
Amitriptyline, clomipramine, maprotiline Fluvoxamine, fluoxetine, sertraline, paroxetine, escitalopram Moclobemide Tianeptine, reboxetine, venlafaxine
Piracetam Donepezil Ginkgo folium
1.2. Cardiovascular side effects The WHO has defined an ADR as a response to a drug that is noxious and unintended and occurs at average dose in pts for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. Drug-related SE and ADR result from the intended use of pharmaceuticals. SE may vary individually, by age, weight, gender, ethnicity, diseases and general health. Further, SE can happen during initiation, decreasing or increasing dosages, or ending a medication treatment. When severe SE occur, medication may be discontinued, the dosage adjusted or a second medication prescribed. Drugs may cause various CV SE, from abnormal heart rate (HR) to heart attack or sudden death. CV disease (CVD) is an extensive class of disorders that involve the heart and the blood vessels [10]. CVDs include following conditions such as angina, atherosclerosis, cerebrovascular disease, coronary artery disease, heart attack, myocarditis, peripheral vascular disease and stroke [10]. CV SEs of antipsychotics and antidepressants are prolonged baseline QTc, myo(peri)carditis, cardiomyopathy, coronary disease and hypertension. The known CV complications of PD and the significant consequences of depression treatment in pts with previous cardiac history was already discussed in literature [10]. In cardiac pts PDs should be restricted because of SE they have on the CV system. They include orthostatic hypotension, tachycardia, reduction in HR variability and slowing of intraventricular conduction [10]. Psychopharmaca which have various CV effects may also harmfully affect clinical outcome of cardiac pts. The published data indicates that pts with severe mental illness should be considered as a ‘high risk’ population with concern to CV morbidity and mortality [11]. In addition, psychiatric pts are predisposed to abnormalities in cardiac rate, and SD. There is evidence that mortality rate is high in psychiatric pts versus general population [12]. There is an emergent evidence that people affected by psychiatric disorders are more likely to suffer from CV disease [11,13] [14,15,16]. Among modifiable factors that attribute to CV RFs are psychosocial factors [11]. The relative contributions to cardiac risk of specific antipsychotic agents rests to be clarified [14]. Pts must be closely monitored for the CV risks related to psychopharmaceutic agents. A comprehensive risk assessment needs to be applied before initiation of PD treatment to reduce the risk of serious CV SE. The evaluation must include a medical history of HD, present and previous CV symptoms, used medications, assessment of potential drug interactions, and an electrocardiogram (ECG) for assessment of HD signs, conduction disorders, or prolonged QT interval. ECG monitoring includes measure QTc in all pts prescribed antipsychotics. It should be repeated as clinically indicated. Integrated care approach can optimize health outcomes [17]. Special precaution is needed with drugs that may have effects, SEs or interactions [18]. Furthermore, drug consumption is high and many are used chronically [19]. Due to the risk of AE and drug–drug interactions, the prescribing and dosage of should be carefully re-evaluated [19]. Critical judgement and careful drug prescription is compulsory. Regular follow-up and re-evaluation should be performed according to the recommendations. Collaboration with patients may significantly improve treatment outcome [4]. Similarly, a significant increase in dose of these drugs requires re-evaluating symptoms and a new ECG. Drug discontinuation should be performed if necessary. If the psychiatric disease is life threatening, a higher CV risk may be accepted, but it demands close follow-up. 1.3. Data for Croatia According to the drug consumption in Croatia from 2007 to 2012, drugs that affect the nervous system, N group, are the second highest in total consumption, amounting to 815.6 million kunas in 2012 [3]. The same, second place in consumption and in financial terms, these drugs hold through the entire period from 2007 to 2012 [3]. Total consumption of drugs that act on the nervous system is 794,628,399 [20]. According to the report on the SE of drugs in 2014, by the Agency for Medicinal Products and Medical Devices (HALMED) on monitoring
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
adverse reactions occurring in the Republic of Croatia during the 2014 received a total of 3112 reports of suspected adverse reactions in the Republic of Croatia [21]. Those include augmented and bizarre ADR. The number of reports SE of drugs was 2658 (85%) [21]. The total number of drugs for which in 2014 reported suspected adverse reaction is 3807, and according to the ATC classification N group number of drugs is 451 [21]. The SE are listed [21]. According to the Medical Dictionary for regulatory Activities (MedDRA) classification of organ systems in 2014 there was 139 (1.7%) cardiac disorders and 191 (2.3%) circulatory disorders [21]. 2. Aim This review sought to present insights in CV SE of psychopharmacologic treatment. One of the main goals for this paper is promoting creative psychopharmacotherapy comprehensive, integrative and transdisciplinary approach in understanding and treatment of mental disorders and CVD. There is evident association between PD and CV AE. However, it is major area of interest due to lack of comprehensive investigation to determine multiple CV effects. Wide spectrum and various effects of PD have to be considered. In this text critical overview of CV SE of PD will be presented. 3. Methods 3.1. Literature search This paper is based on a systematic evidence review evaluating published literature. The literature search was made to identify relevant systematic reviews, randomized controlled trials, meta-analysis and other from 2004 through 2015. Data for this review were identified by searches of Medline, PubMed, and references from relevant articles. The search was limited to only studies in the English language. Totally approximately 200 scientific texts were reviewed. Only to full articles or abstract published in English language were included. The ATC classification system classification is used [1,2]. 4. Results In this review CV effects of psychopharmacological substances namely antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants and stimulants will be presented [2]. SE of psychopharmaceutic drugs are organized into groups according to the following types of CV effects: cardiac and circulatory effects, abnormalities of cardiac repolarisation and arrhythmias and heart muscle disease. 5. Cardiac and circulatory effects Researchers found a link between PD usage and sudden cardiac death (SCD). Epidemiological studies provide evidence that antipsychotics increase the risk of SCD. Published reports, show that when taking PD SCD is more likely to occur [12]. Additionally, PD have been shown to cause less severe cardiac problems, such as irregular heartbeat and high blood pressure (BP) that occur in pts with no cardiac risk prior to consumption of the drug [10]. Importantly, PD may cause hypertension as well as orthostatic hypotension and syncope, which occur due to effect of drugs on vascular system causing BP decrease. Anti-epileptics, antiepileptic drugs, anti-seizure drugs or anticonvulsants are a diverse group of medications used in the treatment of epileptic seizures. A number of investigations have detected interactions between anticonvulsant drugs and the CV system. Older anticonvulsants (i.e. carbamazepine, phenobarbital, phenytoin, primidone) were associated with metabolic deviations [22]. It is known that oldergeneration anticonvulsants may increase CV risk [22]. Psycholeptics are antipsychotics, anxiolytics, hypnotics and sedatives. Antipsychotics, also known as neuroleptics or major tranquilizers,
369
are psychiatric medications primarily used to manage psychosis. Available data shows, antipsychotic drug use may increase the prevalence of mortality and morbidity [23]. First-generation antipsychotic are associated with arterial stiffness, possibly due to elevated BP [24]. The antipsychotics are known to induce hypertension and arrhythmias [25]. It is known that coronary disease can be caused be phenothiazine. Secondgeneration antipsychotics have benefits over first-generation antipsychotics. It is determined they have better action on cognitive function and the negative symptoms of schizophrenia, and lower frequency of extrapyramidal SE; however, they are associated with metabolic and CV disturbances [25,26]. Anxiolytics or anxiolytic medications are used for the management of anxiety and related psychological and physical symptoms. Stress and anxiety may influence pts with CHD, so it is a reasonable to assess the anxiety-relieving drugs in prevention [27]. The combination of lorazepam with bendrofluazide was the only treatment which produced mean reductions in both the systolic and diastolic BP to below normal values [27]. Current data shows that effects of benzodiazepine receptor partial inverse agonist on cardiac reactivity are mediated via an activation of central muscarinic cholinergic mechanisms [28]. Hypnotics or soporific drugs are a class of psychoactive drugs with function to induce sleep. Sedatives are drugs that help to calm or relieve anxiety. AEs associated with the frequently use of analgesics, sedatives, and antipsychotics can affect all organ systems and result in substantial morbidity and mortality [29]. Etomidate is an intravenous (IV) hypnotic and has good clinical profile in haemodynamic high-risk scenarios [30]. Psycho-analeptics are antidepressants, psychostimulants, agents used for ADHD and nootropics and anti-dementia drugs. Antidepressants are used for the treatment of major depressive disorder and conditions, such as anxiety disorders, obsessive compulsive disorder, chronic and neuropathic pain. They can be used as single or in combination with other medications. Consumption of antidepressants is showing a trend in the economically developed countries [31]. Currently available data shows that antidepressants are safe and efficacious agents against depression, atherosclerosis, and coronary heart disease (CHD) [32]. As defined antidepressant pharmacotherapy with SSRIs in the first line should only be offered to pts with at least moderate severe depressive episodes [33]. Psychotherapy and SSRIs, particularly sertraline, have been proven to be safe [33]. Sibutramine is a combined norepinephrine and SRI [34]. Data suggests that several CV adverse events as hypertension, tachycardia, arrhythmias, and myocardial infarction (MI) were reported in sibutramine-treated pts [34]. Results of previously performed study advise that sertraline is a safe and effective treatment for recurrent depression in pts with recent MI or unstable angina and without other life-threatening medical condition [35]. Citalopram is a SSRI with a favourable cardiac-safety profile [36]. SSRIs interfere with the serotonin metabolism of blood platelets, so their use can lead to an increased bleeding risk [37]. The serotonin syndrome (SS) represents a life-threatening ADR, caused by serotonin overload in the central and peripheral nervous system, producing autonomic instability, and CV abnormalities [38,39]. The combination of phenethylamine, isocarboxazid, and lithium has been implicated in SS [38]. Cardiologists often use combination therapies including serotoninergic agents, and should therefore consider the risk of serotoninergic AE caused by inappropriate drug interactions [39]. In resistant cases combinations of drugs can be applied, and the choice depends on the leading symptoms [40]. If pharmacological antidepressant therapy is indicated in a CHD pt, SSRIs are recommended [37]. Tri- and tetracyclic antidepressants (TCA) should not be used for pharmacological therapy of CHD pts. They could only be given after a careful risk/benefit analysis [37]. Data suggests there is increased risk of death with the TCAs [41]. Phenelzine is an irreversible monoamine oxidase inhibitor (MAOI) [42]. Transient hypertensive crisis after ingestion of certain drugs such as pseudoephedrine or tyraminerich foods is a well-recognized complication of MAOI therapy [42]. Complications resulting in an acute cardiac event could be anticipated [42]. There is evidence that suggests that MI should be considered in the
370
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
spectrum of potential complications when a pt on MAOI ingests tyramine-containing foods [42]. Psychostimulants are used for ADHD and nootropics are psychoactive drugs that induce temporary improvements in mental or physical functions. Treatment of children with central nervous stimulants is not significantly associated with an increase in the short term risk of severe cardiac events [43]. Though, long term effects of slight increases in HR or BP are unknown [43]. Symptoms of ADHD can require lifelong therapy [44]. Furthermore regarding psychoactive drugs, cocaine is associated with a number of CVDs, including MI, heart failure (HF), cardiomyopathies, arrhythmias, aortic dissection, and endocarditis [45]. Data suggests that cocaine increases myocardial oxygen demand by increasing both HR and BP [45]. Anti-dementia drugs are used in dementia treatment. Drugs that are used to treat Alzheimer's disease include the acetyl cholinesterase inhibitors (ACHIs) donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine [46]. Adverse CV events with these drugs are very uncommon, but ACHI therapy is associated with increased risk of syncope and bradycardia [46]. 6. Abnormalities of cardiac repolarisation and arrhythmias Many psychotropic medications are linked with ECG deviations. QT prolongation can cause Torsades de Pointes (TdP), ventricular fibrillation (VF) and SD. Arrhythmias in pts with conduction and abnormalities of heart structures or coronary disease might be intensified by use of psychotropic or antidepressant drugs. The most common cardiac SE are a mild bradycardia, orthostatic hypotension, QRS lengthening or prolonged QT interval [10]. Serious conduction alterations are revealed in ECG as prolonged PR, QRS and QT intervals and T-wave flattening or inversion [10]. Prolongation of the QT interval can potentate a lethal ventricular arrhythmia. Tachycardia seems to occur primarily as result of the anticholinergic properties of antipsychotics. Psychotropic medications can cause serious cardiac SEs. It is well known that prolongation of the QT interval is associated with a greater risk of arrhythmia and SCD [47]. PD, especially antipsychotics, are known to have electrophysiological properties of prolonging ventricular repolarisation [48]. One of the most severe cardiologic AE represents a lengthening of the QT-interval, potentially leading to a ventricular arrhythmia called TdP [48]. TdP is a ventricular arrhythmia frequently connected to drug administration [49]. Drugs blamed most often are thioridazine, ziprasidone, IV haloperidol, quetiapine, amisupliride, most TCAs, SSRIs – citalopram, fluoxetine, paroxetin, and venlafaxine. Evidently, antipsychotic medications are associated with prolongation of QTc interval [50]. QT prolonging can be prevented by not exceeding the recommended dose, avoiding use in pts with RFs, performing ECG routinely before and after initiation or increase of dosage. ECG abnormalities associated with antipsychotics and antidepressants are tachycardia, bradycardia, heart blocks, repolarisation changes (ST-segment, T wave changes), QTc prolongation, and TdP/VF. Tachycardia can be caused by clozapine, TCAs, MAOIs, and anti-parkinsonian drugs. Bradycardia can be caused by SSRIs, lithium and cholinesterase inhibitors. Heart blocks can be caused by TCAs. Repolarisation changes (STsegment, T wave changes) can be caused by thioridazine and chlorpromazine. TdP/VF can be caused by haloperidol, thioridazine, mesoridazine and chlorpromazine. When treating pts with cardiac arrhythmias by psychopharmacological therapy, drug interactions must be carefully considered [37]. The main secondary SE are in metabolic, endocrine, neurologic, CV systems, haematological and liver functions [51]. TCAs are known to induce cardiac arrhythmias at therapeutic or supra-therapeutic doses. According to available report the TCA, amitriptyline, is reported to induce ST-segment elevation in the right precordial ECG leads [52]. The problem for psychiatry is that the TCA drugs are also class I antiarrhythmic [41]. SSRI are generally believed to cause fewer
pro-arrhythmic SE then TCAs [53]. Fluoxetine treatment has been associated with tachycardia and syncope [53]. Pts receiving a drug that prolongs the QTc interval should be measured by ECG at least once daily during therapy [54]. In addition, concomitant therapy with other QT interval-prolonging drugs, particularly non-CV QT interval-prolonging drugs (antidepressants, antipsychotics) should be avoided or performed cautiously [54]. In pts with cardiac arrhythmias the correspondent warning notices and contraindications, in particular those for TCAs, the SSRIs citalopram and escitalopram, as well as the antipsychotic haloperidol, should be considered [37]. PD known to elongate the QT interval should be avoided [37]. Available data shows that special caution has to be taken when combining antidepressants with antipsychotics from the phenothiazine group since this combination can lead to significantly elongated QT intervals and has been associated with SCD [37]. A recent American Heart Association statement recommended ECGs routinely for children before they start medications to treat ADHD [55]. Attention has been given to screening for causes of SD in ADHD [55]. ADHD medication in children with potentially dangerous cardiac arrhythmias should be used carefully [56]. Comprehensive medical history review and clinical examination must be performed. Current data shows that in children with known cardiac disease, arrhythmia or RFs for cardiac disease, ADHD management must be consulted with a paediatric cardiologist [56]. At the same time some addiction drugs, namely cocaine decreases oxygen supply via coronary vasoconstriction [45]. It causes systolic and diastolic dysfunction, arrhythmias (prolongs the PR, QRS, and QT intervals), and atherosclerosis [45]. There are also a few reports that drugs used to treat Alzheimer's disease include the ACHIs donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine may occasionally be associated with QT prolongation, TdP and ventricular tachycardia (VT) [46]. 7. Heart muscle disease Psychopharmaca use may also be associated with myocarditis, pericarditis and cardiomyopathy. Myocarditis and cardiomyopathy, are potentially reversible complications. However, pts with pre-existing CVD should be carefully evaluated before they begin any antipsychotic treatment [10]. Presentation of myo(peri)carditis can range from nonspecific symptoms to severe left ventricular impairment, pulmonary oedema, cardiogenic shock and death. They usually occur within weeks of introduction of drug. Cardiomyopathy can be caused by clozapine, risperidone, chlorpromazine and haloperidol. Cardiomyopathy is less frequent, but may have long-term consequences, commonly dilated type of left ventricular impairment, usually months from introduction of drug. Atypical antipsychotics induce weight gain, diabetes, and dyslipidaemia [57]. The pts with schizophrenia might be at increased risk for metabolic and CVD [57]. By available data, clozapine is an atypical antipsychotic medication which remains the gold standard in treatment of resistant psychosis [58]. However, clozapine has multiple SE, among which are myocarditis and cardiomyopathy [58]. There is known prolonged release of noradrenaline due to the alpha 2-antagonistic effect of clozapine. [59] Further, reports of valvulopathy led to the withdrawal and anti-parkinsonian drug pergolide from the market [60]. Regarding PD, recreational use of 4-fluoroamphetamine (4-FA) may present with life threatening toxicity including cardiomyopathy, cardiogenic shock, and pulmonary oedema [61]. 8. Discussion Resulting from population growth, the aging populations, and epidemiologic changes global deaths from CVD are increasing [62]. Health
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
care system is developing to the reduction of CVD. However it is important to note that an evidence suggests a possible increase in CV events in pts treated with PD. From a worldwide perspective CHD and depression are two of the most important diseases [37]. Anxiety and depressive disorders are common in the general population and are particularly prevalent in pts with CVD [63]. Importantly, depression has been found to predict early onset CHD. Depression could be an independent RF for CVD and it is common among pts treated with PCI [64,65]. Numerous psychosocial factors have been linked to CHD [66]. Mental stress may directly influence CHD and also a number of RFs [27]. Increased cardio-metabolic morbidity and increased overall mortality has been observed in pts with severe mental disorders [67]. Clinicians manage pts with CVD, possible receiving CV medication, and also requiring psychopharmacological interventions [68]. Over the last decade, studies of psychosocial RFs for CHD have increased [66]. It is reasonable that psychosocial RFs, certain personality traits may negatively influence the incidence and course of multiple CVD conditions [33]. Study among children with ADHD and conduct disorder/antisocial personality provided support for long-term safety of early psychostimulant treatment [69]. The relationship between psychopharmacology of the nervous and the CV system is still not adequately understood. Interestingly, non-CV adverse reactions were the most frequent manifestation of ADR caused by CV drugs and CV adverse reactions were most often caused by non-CV drugs [70]. PD have potent effects on the CV system. CV AE of treatment with psychopharmaca may occur even at standard dose. An individually adjusted multimodal treatment strategy should be offered to pts with CHD, HF and after heart surgery [33]. The prescription of PD requires a complex therapeutic approach, because the potential risk for CV events [10]. Several drugs used in the treatment of mental diseases are associated with an increased risk of SCD [6]. However, a cause relationship between the intake of these drugs and SCD is impossible. As previously mentioned, an ECG should be performed if the initial evaluation suggests increased cardiac risk or if the antipsychotic to be prescribed has an increased risk of TdP and SD [50]. Prior to psychopharmacological treatment, proper cardiology treatment is recommended [67].
8.1. Limitations Results of this review are based on literature research. The reviewed data came largely from prevalence studies and cross-sectional studies. Retrospective data sources were used in order to make critical overview of CV SE of psychopharmaceutic agents.
9. Conclusion Various PD have shown to have CV effects that can be therapeutically beneficial or harmful to pts. A variety of drugs for the treatment of the central nervous system diseases are associated with cardiac SE. Some of them are linked to reports of arrhythmia and SD [71]. The CV effects of PD depends on the potency of the drug. The correct CVD diagnosis can be beneficial in exposing a pt to the appropriate pharmacologic therapy. In pts with higher risk of CVD, the choice of PD has to be performed accordingly. It is important to note that one of the main problems of psychopharmacotherapy is variability of therapeutic effects. Goal should be to achieve the lowest risk of SE and the highest effectiveness of the active substance [72]. Psychotropic medications are frequently prescribed. However, there is well known danger of widespread illicit use of psychoactive drugs, including narcotics, psychostimulants, and central nervous system depressants [68]. Considering the high prevalence of psychiatric diseases, physician has to have skills to use psychopharmaca in the context of illness [73]. Prescription of PD should conform to established treatment guidelines and therapy be individualised to each patient.
371
Conflict of interest The enclosed manuscript has been read and approved by all the authors. The manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. The authors declare that they have no financial or any other conflict of interest. The authors declare no external financial support for making this article. The copyright shall be transferred to the journal after accepting this article for publication. Acknowledgments None. References [1] WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2015, Oslo, 18th Edition, 18th ed., 2014. [2] Online Anatomical Therapeutic Chemical Classification System, WHO Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health, 2009 (Available at: http://www.whocc.no/atc_ddd_methodology/purpose_of_the_atc_ ddd_system/Accessed 21.3.2016). [3] Halmed, Agencija za lijekove i medicinske proizvode - HALMED. Potrošnja lijekova u Hrvatskoj od 2007, 2012 (do, godine. Available at: http://www.halmed.hr/ fdsak3jnFsk1Kfa/publikacije/Potrosnja_lijekova_u_Hrvatskoj_2007-2012.pdf. Accessed 21.3.2016). [4] M. Jakovljević, How to increase treatment effectiveness and efficiency in psychiatry: creative psychopharmacotherapy - part 2: creating favorable treatment context and fostering patients' creativity, Psychiatr. Danub. 25 (2013) 274–279. [5] M. Jakovljević, How to Increase Treatment Effectiveness and Efficiency in Psychiatry: Creative Psychopharmacotherapy - Part 1: Definition, Fundamental Principles and Higher Effectiveness Polipharmacy Psychiatria Danubina, 25 (2013) 269–273. [6] S. Fanoe, D. Kristensen, A. Fink-Jensen, H.K. Jensen, E. Toft, J. Nielsen, P. Videbech, S. Pehrson, H. Bundgaard, Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management, Eur. Heart J. 35 (2014) 1306–1315. [7] D. Elbe, R. Savage, How does this happen? Part I: mechanisms of adverse drug reactions associated with psychotropic medications, J. Can. Acad. Child Adolesc. Psychiatry 19 (2010) 40–45. [8] S.A. Chong, M.R. Mythily, Cardiac effects of psychotropic drugs, Ann. Acad. Med. Singap. 30 (2001) 625–631. [9] S.V. Carreiro, R.R. Martins, A. De Carvalho, Psychotropic drugs and sudden death, Acta Medica Port. 19 (2006) 151–164. [10] G. Marano, G. Traversi, E. Romagnoli, V. Catalano, M. Lotrionte, A. Abbate, G. BiondiZoccai, M. Mazza, Cardiologic side effects of psychotropic drugs, J. Geriatr. Cardiol. 8 (2011) 243–253. [11] P. Mackin, Cardiac side effects of psychiatric drugs, Hum. Psychopharmacol. 23 (2008) 3–14. [12] Q. Timour, D. Frassati, J. Descotes, P. Chevalier, G. Christé, M. Chahine, Sudden death of cardiac origin and psychotropic drugs, Front. Pharmacol. 3 (2012) 1–9. [13] C. Enger, L. Weatherby, R.F. Reynolds, D.B. Glasser, A.M. Walker, Serious cardiovascular events and mortality among patients with schizophrenia, J. Nerv. Ment. Dis. 192 (2004) 19–27. [14] D.C. Goff, L.M. Sullivan, J.P. McEvoy, J.M. Meyer, H.A. Nasrallah, G.L. Daumit, S. Lamberti, R.B. D'Agostino, T.S. Stroup, S. Davis, J.A. Lieberman, A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls, Schizophr. Res. 80 (2005) 45–53. [15] N. Frasure-Smith, F. Lespérance, Recent evidence linking coronary heart disease and depression, Can. J. Psychiatr. 51 (2006) 730–737. [16] P. Mackin, D.R. Bishop, H.M.O. Watkinson, A prospective study of monitoring practices for metabolic disease in antipsychotic-treated community psychiatric patients, BMC Psychiatry 7 (2007) 28. [17] J. Purdy, Chronic physical illness: a psychophysiological approach for chronic physical illness, Yale J. Biol. Med. 86 (2013) 15–28. [18] J. Ræder, R. Støen, Dosage of ordinary medication prior to elective surgery, Tidsskr. Nor. Laegeforen. 132 (2012) 304–306. [19] K.N. van Dijk, C.S. de Vries, P.B. van den Berg, J.R. Brouwers, L.T. de Jong-van den Berg, Drug utilisation in Dutch nursing homes, Eur. J. Clin. Pharmacol. 55 (2000) 765–771. [20] Halmed, Ukupna potrošnja lijekova u 2014, 2015 (godini, Available at: http://www. halmed.hr/fdsak3jnFsk1Kfa/ostale_stranice/Ukupna_potrosnja_lijekova_u_2014_ godini-1281.pdf. Accessed 21.3.2016). [21] Halmed, Izvješće agencije za lijekove i medicinske proizvode (HALMED) o prijavama nuspojava lijekova u Republici Hrvatskoj za 2014, 2015 (godini, Available at: http://www.halmed.hr/fdsak3jnFsk1Kfa/novosti/Izvjesce_o_nuspojavama_u_ 2014.pdf. Accessed 21.3.2016). [22] E. Patorno, R.J. Glynn, S. Hernandez-Diaz, J. Avorn, P.M. Wahl, R.L. Bohn, D. Mines, J. Liu, S. Schneeweiss, Risk of ischemic cerebrovascular and coronary events in adult users of anticonvulsant medications in routine care settings, J. Am. Heart Assoc. 30 (2013) 2. [23] D. Ames, J. Camm, P. Cook, P. Falkai, C. Gury, R. Hurley, G. Johnson, R. Piepho, V. Vieweg, Cardiac safety in schizophrenia group. Minimizing the risks associated
372
[24]
[25]
[26]
[27] [28]
[29]
[30] [31] [32] [33]
[34] [35]
[36] [37]
[38] [39]
[40] [41] [42] [43]
[44] [45] [46] [47]
[48]
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372 with QTc prolongation in people with schizophrenia. A consensus statement by the cardiac safety in schizophrenia group, Encéphale 28 (2002) 552–562. J.G. Fiedorowicz, W.H. Coryell, J.P. Rice, L.L. Warren, W.G. Haynes, Vasculopathy related to manic/hypomanic symptom burden and first-generation antipsychotics in a sub-sample from the collaborative depression study, Psychother. Psychosom. 81 (2012) 235–243. G. Scigliano, G. Ronchetti, Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis, CNS Drugs 27 (2013) 249–257. T. Kishi, Y. Matsuda, N. Iwata, Cardiometabolic risks of blonanserin and perospirone in the management of schizophrenia: a systematic review and meta-analysis of randomized controlled trials, PLoS One 9 (2014). D. Wheatley, Psychological stress and cardiovascular diseases, Scand. J. Work Environ. Health 10 (1984) 415–417. G.G. Berntson, S. Hart, S. Ruland, M. Sarter, A central cholinergic link in the cardiovascular effects of the benzodiazepine receptor partial inverse agonist FG 7142, Behav. Brain Res. 74 (1996) 91–103. J.W. Devlin, S. Mallow-Corbett, R.R. Riker, Adverse drug events associated with the use of analgesics, sedatives, and antipsychotics in the intensive care unit, Crit. Care Med. 38 (2010) S231–S243. G. Erdoes, R.M. Basciani, B. Eberle, Etomidate-a review of robust evidence for its use in various clinical scenarios, Acta Anaesthesiol. Scand. 58 (2014) 380–389. K. Ružić, E. Dadić-Hero, T. Grahovac, V. Sabljić, T. Kosec, R. Knez, Switching among antipsychotics–focus on side effects, Psychiatr. Danub. 23 (2011) 89–91. G. Wozniak, A. Toska, M. Saridi, O. Mouzas, Serotonin reuptake inhibitor antidepressants (SSRIs) against atherosclerosis, Med. Sci. Monit. 17 (2011) RA205–RA214. C. Albus, K.H. Ladwig, C. Herrmann-Lingen, Psychocardiology: clinically relevant recommendations regarding selected cardiovascular diseases, Dtsch. Med. Wochenschr. 139 (2014) 596–601. A.J. Scheen, Sibutramine on cardiovascular outcome, Diabetes Care 34 (2011) S114–S119. A.H. Glassman, C.M. O'Connor, R.M. Califf, K. Swedberg, P. Schwartz, J.T. Bigger Jr., K.R. Krishnan, L.T. van Zyl, J.R. Swenson, M.S. Finkel, C. Landau, P.A. Shapiro, C.J. Pepine, J. Mardekian, W.M. Harrison, D. Barton, M. Mclvor, Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group, Sertraline treatment of major depression in patients with acute MI or unstable angina, JAMA 288 (2002) 701–709. A. Deshmukh, K. Ulveling, V. Alla, H. Abuissa, K. Airey, Prolonged QTc interval and torsades de pointes induced by citalopram, Tex. Heart Inst. J. 39 (2012) 68–70. K.H. Ladwig, F. Lederbogen, C. Albus, C. Angermann, M. Borggrefe, D. Fischer, K. Fritzsche, M. Haass, J. Jordan, J. Jünger, I. Kindermann, V. Köllner, B. Kuhn, M. Scherer, M. Seyfarth, H. Völler, C. Waller, C. Herrmann-Lingen, Position paper on the importance of psychosocial factors in cardiology: update 2013, Ger. Med. Sci. 12 (2014) (Doc09). N.K. Mehta, G. Aurigemma, Z. Rafeq, O. Starobin, Reverse takotsubo cardiomyopathy: after an episode of serotonin syndrome, Tex. Heart Inst. J. 38 (2011) 568–572. P.L. Temporelli, A. Boccanelli, G. Desideri, P. Faggiano, G. Mora, F. Oliva, P. Terrosu, The serotonin syndrome: why should cardiologists be aware and scared of it, G Ital Cardiol (Rome) 16 (2015) 34–43. E. Dadić-Hero, R. Knez, J. Rebić, Less is more-possible option in the treatment of depression, Collab. Anthropol. 38 (2014) 1207–1209. A.H. Glassman, S.P. Roose, Risks of antidepressants in the elderly: tricyclic antidepressants and arrhythmia-revising risks, Gerontology 40 (1994) 15–20. A.S. Ngo, R.Y. Ho, K.R. Olson, Phenelzine-induced myocardial injury: a case report, J. Med. Toxicol. 6 (2010) 431–434. A.G. Winterstein, T. Gerhard, P. Kubilis, A. Saidi, S. Linden, S. Crystal, J. Zito, J.J. Shuster, M. Olfson, Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study, BMJ 345 (2012), e4627. H. Sowinski, P.P. Karpawich, Management of a hyperactive teen and cardiac safety, Pediatr. Clin. N. Am. 61 (2014) 81–90. B.G. Schwartz, S. Rezkalla, R.A. Kloner, Cardiovascular effects of cocaine, Circulation 122 (2010) 2558–2569. L.G. Howes, Cardiovascular effects of drugs used to treat Alzheimer's disease, Drug Saf. 37 (2014) 391–395. N. Krishnadev, B.L. Abramson, R. Chisholm, L.A. Leiter, S. Hales, R. Schwartz, M. Barua, S. Scarrow, A. Mansour, M. Pearce, L.R. Pacione, L. Wasserman, T. Shaw, A. Lenny, C. Soare, S. Bhalerao, Atypical antipsychotics, schizophrenia, and cardiovascular risk: what family physicians need to know, BC Med. J. 50 (2008) 444–450. C. Spindelegger, K. Papageorgiou, M.W. Agelink, W. Greil, S. Bleich, E. Rüther, R. Grohmann, S. Toto, A. Konstantinidis, S. Kasper, Cardiological Changes During Antidepressant Treatment with SSRIs Compared to Other Classes of Antidepressants, A
[49]
[50] [51] [52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60] [61]
[62]
[63] [64]
[65]
[66] [67] [68] [69]
[70] [71] [72] [73]
Drug Surveillance Report of German Speaking Countries Between 1993‐ and 2010, Medical University of Vienna, Austria, 2012. E. Poluzzi, E. Raschi, A. Koci, U. Moretti, E. Spina, E.R. Behr, M. Sturkenboom, F. De Ponti, Antipsychotics and torsadogenic risk: signals emerging from the US FDA adverse event reporting system database, Drug Saf. 36 (2013) 467–479. A.A. Shah, A. Aftab, J. Coverdale, QTc prolongation with antipsychotics: is routine ECG monitoring recommended? J. Psychiatr. Pract. 20 (2014) 196–206. T. Huber-Gieseke, M. Perin, F. Narring, Which follow-up of the second generation antipsychotic in adolescents? Rev. Med. Suisse. 10 (1302) (2014) 1304–1307. Y. Minoura, J.M. Di Diego, H. Barajas-Martínez, A.C. Zygmunt, D. Hu, S. Sicouri, C. Antzelevitch, Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants, J. Cardiovasc. Electrophysiol. 23 (2012) 423–432. D. Thomas, B. Gut, G. Wendt-Nordahl, J. Kiehn, The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels, J. Pharmacol. Exp. Ther. 300 (2002) 543–548. G. Frendl, A.C. Sodickson, M.K. Chung, A.L. Waldo, B.J. Gersh, J.E. Tisdale, H. Calkins, S. Aranki, T. Kaneko, S. Cassivi, S.C. Smith Jr., D. Darbar, J.O. Wee, T.K. Waddell, D. Amar, D. Adler, American Association for Thoracic Surgery. 2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures, J. Thorac. Cardiovasc. Surg. 148 (2014) e153–e193. J.M. Perrin, R.A. Friedman, K. TK, Black box working group; section on cardiology and cardiac surgery. Cardiovascular monitoring and stimulant drugs for attentiondeficit/hyperactivity disorder, Pediatrics 122 (2008) 451–453. A. Berg, E. Bråtane, H.H. Odland, C. Brudvik, B. Rosland, A. Hirth, Cardiovascular risk assessment for the use of ADHD drugs in children, Tidsskr. Nor. Laegeforen. 134 (2014) 710–714. M. Gilca, G. Piriu, L. Gaman, C. Delia, L. Iosif, V. Atanasiu, I. Stoian, A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics, Psychopharmacology 231 (2014) 4703–4710. K. Kontoangelos, S. Loizos, J. Kanakakis, N. Smyrnis, M. Economou, J.D. Bergiannaki, G.N. Papadimitriou, Myocarditis after administration of clozapine, Eur. Rev. Med. Pharmacol. Sci. 18 (2014) 2383–2386. M. Mueck-Weymann, J. Acker, M.W. Agelink, Autonomic responses of blood vessels and sweat glands in patients with schizophrenia treated with olanzapine or clozapine, Psychopharmacology 157 (2001) 368–372. C.S. Elangbam, Drug-induced valvulopathy: an update, Toxicol. Pathol. 38 (2010) 837–848. S. Al-Abri, K.H. Meier, J.M. Colby, C.G. Smollin, N.L. Benowitz, Cardiogenic shock after use of fluoroamphetamine confirmed with serum and urine levels, Clin. Toxicol. (Phila) 52 (2014) 1292–1295. G.A. Roth, M.H. Forouzanfar, A.E. Moran, R. Barber, G. Nguyen, V.L. Feigin, M. Naghavi, G.A. Mensah, C.J. Murray, Demographic and epidemiologic drivers of global cardiovascular mortality, N. Engl. J. Med. 372 (2015) 1333–1341. S.J. Davies, P.R. Jackson, J. Potokar, D.J. Nutt, Treatment of anxiety and depressive disorders in patients with cardiovascular disease, BMJ 328 (2004) 939–943. P.J. Schramm, R.E. Poland, U. Rao, Bupropion response on sleep quality in patients with depression: implications for increased cardiovascular disease risk, Eur. Neuropsychopharmacol. 24 (2014) 207–214. Z.J. Wang, M. Guo, T.M. Si, M.M. Jiang, S.M. Liu, Y.Y. Liu, Y.X. Zhao, D.M. Shi, Y.J. Zhou, Association of depression with adverse cardiovascular events after percutaneous coronary intervention, Coron. Artery Dis. 24 (2013) 589–595. A. Rozanski, Behavioral cardiology: current advances and future directions, J. Am. Coll. Cardiol. 64 (2014) 100–110. J. Cordes, C. Lange-Asschenfeldt, C. Hiemke, K.G. Kahl, Psychopharmacotherapy in patients with cardiovascular diseases, Internist (Berl) 53 (2012) 1304 (1306-12, 1314). S.C. Risch, G.P. Groom, D.S. Janowsky, Interfaces of psychopharmacology and cardiology–part one, J. Clin. Psychiatry 42 (1981) 23–34. M.A. Ramos Olazagasti, R.G. Klein, S. Mannuzza, E.R. Belsky, J.A. Hutchison, E.C. Lashua-Shriftman, F.X. Castellanos, Does childhood attention-deficit/hyperactivity disorder predict risk-taking and medical illnesses in adulthood? J. Am. Acad. Child Adolesc. Psychiatry 52 (2013) 153–162 (e4). G.A. Keller, G. Di Girolamo, P.A. Alvarez, Pharmacovigilance and the cardiovascular system: two sides to every story, Curr. Drug Saf. 6 (2011) 224–229. H.J. Witchel, J.C. Hancox, D.J. Nutt, Psychotropic drugs, cardiac arrhythmia, and sudden death, J. Clin. Psychopharmacol. 23 (2003) 58–77. E.M. Zeidler, A.E. Goetz, C. Zöllner, Pharmacogenetics. Clinical relevance in anesthsiology, Anaesthesist 62 (2013) 874–886. D. Telles-Correia, D.F. Guerreiro, R. Coentre, P. Zuzarte, L. Figueira, Psychopharmacology in medical illness: cardiology, nephrology, hepatology, Acta Medica Port. 22 (2009) 797–808.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Cardiovascular side effects of psychopharmacologic therapy Ines Potočnjak a,⁎, Vesna Degoricija b,a, Dina Vukičević Baudoin a, Josip Čulig c,d, Miro Jakovljević b,e a
University Hospital Center Sisters of Charity, Vinogradska cesta 29, 10000 Zagreb, Croatia University of Zagreb School of Medicine, Šalata 3, 10000 Zagreb, Croatia c Department of Pharmacoepidemiology, Andrija Štampar Teaching Institute of Public Health, Mirogojska 16, 10000 Zagreb, Croatia d Department of Pharmacology, School of Medicine, Josip Juraj Strossmayer University Osijek, J. Huttlera 4, 31000 Osijek, Croatia e Department of Psychiatry, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia b
a r t i c l e
i n f o
Article history: Received 18 April 2016 Accepted 18 June 2016 Available online 20 June 2016 Keywords: Psychopharmacology Psychotropic drugs Pharmacotherapy Cardiovascular system Side effects
a b s t r a c t WHO defined in 1976 psychopharmaca as drugs affecting psychological functions, behaviour and self-perception. Psychopharmacology is the study of pharmacological agents that affect mental and emotional functions. Creative approach to psychopharmacotherapy reflects a transdisciplinary, integrative and person-centered psychiatry. Psychiatric disorders often occur in cardiac patients and can affect the clinical presentation and morbidity. Cardiovascular (CV) side effects (SE) caused by psychopharmaceutic agents require comprehensive attention. Therapeutic approach can increase placebo and decrease nocebo reactions. The main purpose of this review is to comprehend CV SE of psychotropic drugs (PD). Critical overview of CV SE of PD will be presented in this review. Search was directed but not limited to CV effects of psychopharmacological substances, namely antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants and stimulants. Literature review was performed and data identified by searches of Medline and PubMed for period from 2004 to 2015. Only full articles and abstracts published in English were included. SE of PD are organized according to the following types of CV effects: cardiac and circulatory effects, abnormalities of cardiac repolarisation and arrhythmias and heart muscle disease. There is wide spectrum and various CV effects of PD. Results of this review are based on literature research. The reviewed data came largely from prevalence studies, case reports, and cross-sectional studies. Psychopharmacotherapy of psychiatric disorders is complex and when concomitantly present with CV disease, presentation of drug SEs can significantly contribute to illness course. Further development of creative psychopharmacotherapy is required to deal with CV effects of PD. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction This paper discusses cardiovascular side effects of psychopharmacotherapy. In the first part of this article overview of classification, commonly used psychotropic drugs, cardiovascular side effects and general data of cardiovascular effects are given. The second part deals with the cardiovascular side effects of psychopharmacs divided in groups as follows cardiac and circulatory effects, abnormalities of cardiac repolarisation and arrhythmias and heart muscle disease are described. This paper underlines the importance of cardiovascular effects of psychopharmacologic therapy in order to prevent them. Prescribing psychotropic drugs (PD) is frequent requirement in clinical practice. According to the definition of The World Health Organization (WHO) from 1976, psychopharmaca are drugs that affect psychological functions, behaviour and self-perception. This
⁎ Corresponding author. E-mail address: [email protected] (I. Potočnjak).
http://dx.doi.org/10.1016/j.ijcard.2016.06.057 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
chemical compounds in defined dose affect psychological behaviour. Psychopharmaceutic or PD are medications for treatment of psychological disorders. According to The Anatomical Therapeutic Chemical (ATC) Classification System, nervous system drugs are sorted into several groups as shown in Table 1 [1,2]. Medical group N includes anaesthetics, analgesics, hypnotics, anxiolytics, antidepressants, drugs against drug addiction and other drugs to treat diseases of nervous system [3]. PD have various cardiovascular (CV) side effects (SE). Furthermore, polypharmacy is the practice of administering or using multiple medications in the treatment of a single disease or several coexisting conditions. During the therapy it is important to contain pts' active participation. Thorough pt instruction has to be provided and they should be familiar with SE, their prevention, early detection and treatment. 1.1. Commonly used psychotropic drugs Psychopharmacotherapy is considered as the primary treatment for all serious mental disorders including schizophrenias, bipolar disorders, depressions, anxiety disorders, obsessive–compulsive disorders, etc. [4].
368
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
The number of the effective medications significantly increased [5]. Positive therapeutic context may significantly increase placebo and decrease nocebo responses [4]. It is known that creative approach to psychopharmacotherapy reflects a synergism in the frame of transdisciplinary holistic, integrative and person-centered psychiatry [4]. Commonly used PD are antipsychotics and antidepressants, comprising of tricyclic anti-depressants (TCAs), selective serotonin and other neurotransmitter re-uptake inhibitors (SSRI and SNRI), mood stabilizers, anxiolytic agents and medications for opioid addiction treatment [6]. Psychiatric medications are associated with a variety of possible adverse effects (AE) [7]. The mechanisms of AE in psychotropic medications might not always be known [7]. Awareness of the mechanisms for adverse drug reactions (ADR) can help to direct prescription choice [7]. ADR can be augmented and bizarre. Augmented ADR are predictable, depending on dose and pharmacological characteristics of the drug. In this paper augmented ADR will be presented. It is important to note that the incidence of mortality is higher among psychiatric pts than in general population [8]. Sudden death (SD) associated with PD is an issue which is currently debated worldwide [9].
Table 1 Classification of psychopharmaceutic agents registered in Republic of Croatia according to ATK system. N03 N03AA
Antiepileptics Barbiturates and derivatives
N03AB N03AC N03AD N03AE N03AF N03AG N03AX N05 N05A N05AA
Hydantoin derivatives Oxazolidine derivatives Succinimide derivatives Benzodiazepine derivatives Carboxamide derivatives Fatty acids derivatives Other antiepileptics Psycholeptics Antipsychotics Phenothiazines with aliphatic side-chain Phenothiazines with piperazine structure Phenothiazines with piperadine structure Butyrophenone derivatives Indole derivatives Diazepines, oksazepines, thiazepines and oxepines Benzamides Lithium Other antipsychotics Anxiolytics Benzodiazepine derivatives
N05AB N05AC N05AD N05AE N05AH N05AL N05AN N05AX N05B N05BA N05BC N05C N05CD N05CF N05CM N06 N06A N06AA N06AB N06AG N06AX N06B N06BX N06D N06DX
Carbamates Hypnotics and sedatives Benzodiazepine derivatives Benzodiazepine related drugs Other hypnotics and sedatives Psychoanaleptics Antidepressants Non-selective monoamine reuptake inhibitors Selective serotonin reuptake inhibitors Monoamine oxidase A inhibitors Other antidepressants Psychostimulants, agents used for ADHD and nootropics Other psychostimulants and nootropics Anti-dementia drugs Other anti-dementia drugs
Methylphenobarbital, phenobarbital, primidone Phenytoin Paramethadione Ethosuximide Clonazepam Carbamazepine Valproic acid, valpromide Lamotrigine, topiramate, gabapentin
Levomepromazine, promazine Fluphenazine, perazin Tioridazine Haloperidol Ziprasidone Clozapine, olanzapine, quetiapine Sulpiride Lithium Risperidone Alprazolam, bromazepam, diazepam, lorazepam, medazepam, oxazepam Meprobamate Flurazepam, midazolam, nitrazepam Zolpidem Valeriane radix
Amitriptyline, clomipramine, maprotiline Fluvoxamine, fluoxetine, sertraline, paroxetine, escitalopram Moclobemide Tianeptine, reboxetine, venlafaxine
Piracetam Donepezil Ginkgo folium
1.2. Cardiovascular side effects The WHO has defined an ADR as a response to a drug that is noxious and unintended and occurs at average dose in pts for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. Drug-related SE and ADR result from the intended use of pharmaceuticals. SE may vary individually, by age, weight, gender, ethnicity, diseases and general health. Further, SE can happen during initiation, decreasing or increasing dosages, or ending a medication treatment. When severe SE occur, medication may be discontinued, the dosage adjusted or a second medication prescribed. Drugs may cause various CV SE, from abnormal heart rate (HR) to heart attack or sudden death. CV disease (CVD) is an extensive class of disorders that involve the heart and the blood vessels [10]. CVDs include following conditions such as angina, atherosclerosis, cerebrovascular disease, coronary artery disease, heart attack, myocarditis, peripheral vascular disease and stroke [10]. CV SEs of antipsychotics and antidepressants are prolonged baseline QTc, myo(peri)carditis, cardiomyopathy, coronary disease and hypertension. The known CV complications of PD and the significant consequences of depression treatment in pts with previous cardiac history was already discussed in literature [10]. In cardiac pts PDs should be restricted because of SE they have on the CV system. They include orthostatic hypotension, tachycardia, reduction in HR variability and slowing of intraventricular conduction [10]. Psychopharmaca which have various CV effects may also harmfully affect clinical outcome of cardiac pts. The published data indicates that pts with severe mental illness should be considered as a ‘high risk’ population with concern to CV morbidity and mortality [11]. In addition, psychiatric pts are predisposed to abnormalities in cardiac rate, and SD. There is evidence that mortality rate is high in psychiatric pts versus general population [12]. There is an emergent evidence that people affected by psychiatric disorders are more likely to suffer from CV disease [11,13] [14,15,16]. Among modifiable factors that attribute to CV RFs are psychosocial factors [11]. The relative contributions to cardiac risk of specific antipsychotic agents rests to be clarified [14]. Pts must be closely monitored for the CV risks related to psychopharmaceutic agents. A comprehensive risk assessment needs to be applied before initiation of PD treatment to reduce the risk of serious CV SE. The evaluation must include a medical history of HD, present and previous CV symptoms, used medications, assessment of potential drug interactions, and an electrocardiogram (ECG) for assessment of HD signs, conduction disorders, or prolonged QT interval. ECG monitoring includes measure QTc in all pts prescribed antipsychotics. It should be repeated as clinically indicated. Integrated care approach can optimize health outcomes [17]. Special precaution is needed with drugs that may have effects, SEs or interactions [18]. Furthermore, drug consumption is high and many are used chronically [19]. Due to the risk of AE and drug–drug interactions, the prescribing and dosage of should be carefully re-evaluated [19]. Critical judgement and careful drug prescription is compulsory. Regular follow-up and re-evaluation should be performed according to the recommendations. Collaboration with patients may significantly improve treatment outcome [4]. Similarly, a significant increase in dose of these drugs requires re-evaluating symptoms and a new ECG. Drug discontinuation should be performed if necessary. If the psychiatric disease is life threatening, a higher CV risk may be accepted, but it demands close follow-up. 1.3. Data for Croatia According to the drug consumption in Croatia from 2007 to 2012, drugs that affect the nervous system, N group, are the second highest in total consumption, amounting to 815.6 million kunas in 2012 [3]. The same, second place in consumption and in financial terms, these drugs hold through the entire period from 2007 to 2012 [3]. Total consumption of drugs that act on the nervous system is 794,628,399 [20]. According to the report on the SE of drugs in 2014, by the Agency for Medicinal Products and Medical Devices (HALMED) on monitoring
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
adverse reactions occurring in the Republic of Croatia during the 2014 received a total of 3112 reports of suspected adverse reactions in the Republic of Croatia [21]. Those include augmented and bizarre ADR. The number of reports SE of drugs was 2658 (85%) [21]. The total number of drugs for which in 2014 reported suspected adverse reaction is 3807, and according to the ATC classification N group number of drugs is 451 [21]. The SE are listed [21]. According to the Medical Dictionary for regulatory Activities (MedDRA) classification of organ systems in 2014 there was 139 (1.7%) cardiac disorders and 191 (2.3%) circulatory disorders [21]. 2. Aim This review sought to present insights in CV SE of psychopharmacologic treatment. One of the main goals for this paper is promoting creative psychopharmacotherapy comprehensive, integrative and transdisciplinary approach in understanding and treatment of mental disorders and CVD. There is evident association between PD and CV AE. However, it is major area of interest due to lack of comprehensive investigation to determine multiple CV effects. Wide spectrum and various effects of PD have to be considered. In this text critical overview of CV SE of PD will be presented. 3. Methods 3.1. Literature search This paper is based on a systematic evidence review evaluating published literature. The literature search was made to identify relevant systematic reviews, randomized controlled trials, meta-analysis and other from 2004 through 2015. Data for this review were identified by searches of Medline, PubMed, and references from relevant articles. The search was limited to only studies in the English language. Totally approximately 200 scientific texts were reviewed. Only to full articles or abstract published in English language were included. The ATC classification system classification is used [1,2]. 4. Results In this review CV effects of psychopharmacological substances namely antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants and stimulants will be presented [2]. SE of psychopharmaceutic drugs are organized into groups according to the following types of CV effects: cardiac and circulatory effects, abnormalities of cardiac repolarisation and arrhythmias and heart muscle disease. 5. Cardiac and circulatory effects Researchers found a link between PD usage and sudden cardiac death (SCD). Epidemiological studies provide evidence that antipsychotics increase the risk of SCD. Published reports, show that when taking PD SCD is more likely to occur [12]. Additionally, PD have been shown to cause less severe cardiac problems, such as irregular heartbeat and high blood pressure (BP) that occur in pts with no cardiac risk prior to consumption of the drug [10]. Importantly, PD may cause hypertension as well as orthostatic hypotension and syncope, which occur due to effect of drugs on vascular system causing BP decrease. Anti-epileptics, antiepileptic drugs, anti-seizure drugs or anticonvulsants are a diverse group of medications used in the treatment of epileptic seizures. A number of investigations have detected interactions between anticonvulsant drugs and the CV system. Older anticonvulsants (i.e. carbamazepine, phenobarbital, phenytoin, primidone) were associated with metabolic deviations [22]. It is known that oldergeneration anticonvulsants may increase CV risk [22]. Psycholeptics are antipsychotics, anxiolytics, hypnotics and sedatives. Antipsychotics, also known as neuroleptics or major tranquilizers,
369
are psychiatric medications primarily used to manage psychosis. Available data shows, antipsychotic drug use may increase the prevalence of mortality and morbidity [23]. First-generation antipsychotic are associated with arterial stiffness, possibly due to elevated BP [24]. The antipsychotics are known to induce hypertension and arrhythmias [25]. It is known that coronary disease can be caused be phenothiazine. Secondgeneration antipsychotics have benefits over first-generation antipsychotics. It is determined they have better action on cognitive function and the negative symptoms of schizophrenia, and lower frequency of extrapyramidal SE; however, they are associated with metabolic and CV disturbances [25,26]. Anxiolytics or anxiolytic medications are used for the management of anxiety and related psychological and physical symptoms. Stress and anxiety may influence pts with CHD, so it is a reasonable to assess the anxiety-relieving drugs in prevention [27]. The combination of lorazepam with bendrofluazide was the only treatment which produced mean reductions in both the systolic and diastolic BP to below normal values [27]. Current data shows that effects of benzodiazepine receptor partial inverse agonist on cardiac reactivity are mediated via an activation of central muscarinic cholinergic mechanisms [28]. Hypnotics or soporific drugs are a class of psychoactive drugs with function to induce sleep. Sedatives are drugs that help to calm or relieve anxiety. AEs associated with the frequently use of analgesics, sedatives, and antipsychotics can affect all organ systems and result in substantial morbidity and mortality [29]. Etomidate is an intravenous (IV) hypnotic and has good clinical profile in haemodynamic high-risk scenarios [30]. Psycho-analeptics are antidepressants, psychostimulants, agents used for ADHD and nootropics and anti-dementia drugs. Antidepressants are used for the treatment of major depressive disorder and conditions, such as anxiety disorders, obsessive compulsive disorder, chronic and neuropathic pain. They can be used as single or in combination with other medications. Consumption of antidepressants is showing a trend in the economically developed countries [31]. Currently available data shows that antidepressants are safe and efficacious agents against depression, atherosclerosis, and coronary heart disease (CHD) [32]. As defined antidepressant pharmacotherapy with SSRIs in the first line should only be offered to pts with at least moderate severe depressive episodes [33]. Psychotherapy and SSRIs, particularly sertraline, have been proven to be safe [33]. Sibutramine is a combined norepinephrine and SRI [34]. Data suggests that several CV adverse events as hypertension, tachycardia, arrhythmias, and myocardial infarction (MI) were reported in sibutramine-treated pts [34]. Results of previously performed study advise that sertraline is a safe and effective treatment for recurrent depression in pts with recent MI or unstable angina and without other life-threatening medical condition [35]. Citalopram is a SSRI with a favourable cardiac-safety profile [36]. SSRIs interfere with the serotonin metabolism of blood platelets, so their use can lead to an increased bleeding risk [37]. The serotonin syndrome (SS) represents a life-threatening ADR, caused by serotonin overload in the central and peripheral nervous system, producing autonomic instability, and CV abnormalities [38,39]. The combination of phenethylamine, isocarboxazid, and lithium has been implicated in SS [38]. Cardiologists often use combination therapies including serotoninergic agents, and should therefore consider the risk of serotoninergic AE caused by inappropriate drug interactions [39]. In resistant cases combinations of drugs can be applied, and the choice depends on the leading symptoms [40]. If pharmacological antidepressant therapy is indicated in a CHD pt, SSRIs are recommended [37]. Tri- and tetracyclic antidepressants (TCA) should not be used for pharmacological therapy of CHD pts. They could only be given after a careful risk/benefit analysis [37]. Data suggests there is increased risk of death with the TCAs [41]. Phenelzine is an irreversible monoamine oxidase inhibitor (MAOI) [42]. Transient hypertensive crisis after ingestion of certain drugs such as pseudoephedrine or tyraminerich foods is a well-recognized complication of MAOI therapy [42]. Complications resulting in an acute cardiac event could be anticipated [42]. There is evidence that suggests that MI should be considered in the
370
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
spectrum of potential complications when a pt on MAOI ingests tyramine-containing foods [42]. Psychostimulants are used for ADHD and nootropics are psychoactive drugs that induce temporary improvements in mental or physical functions. Treatment of children with central nervous stimulants is not significantly associated with an increase in the short term risk of severe cardiac events [43]. Though, long term effects of slight increases in HR or BP are unknown [43]. Symptoms of ADHD can require lifelong therapy [44]. Furthermore regarding psychoactive drugs, cocaine is associated with a number of CVDs, including MI, heart failure (HF), cardiomyopathies, arrhythmias, aortic dissection, and endocarditis [45]. Data suggests that cocaine increases myocardial oxygen demand by increasing both HR and BP [45]. Anti-dementia drugs are used in dementia treatment. Drugs that are used to treat Alzheimer's disease include the acetyl cholinesterase inhibitors (ACHIs) donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine [46]. Adverse CV events with these drugs are very uncommon, but ACHI therapy is associated with increased risk of syncope and bradycardia [46]. 6. Abnormalities of cardiac repolarisation and arrhythmias Many psychotropic medications are linked with ECG deviations. QT prolongation can cause Torsades de Pointes (TdP), ventricular fibrillation (VF) and SD. Arrhythmias in pts with conduction and abnormalities of heart structures or coronary disease might be intensified by use of psychotropic or antidepressant drugs. The most common cardiac SE are a mild bradycardia, orthostatic hypotension, QRS lengthening or prolonged QT interval [10]. Serious conduction alterations are revealed in ECG as prolonged PR, QRS and QT intervals and T-wave flattening or inversion [10]. Prolongation of the QT interval can potentate a lethal ventricular arrhythmia. Tachycardia seems to occur primarily as result of the anticholinergic properties of antipsychotics. Psychotropic medications can cause serious cardiac SEs. It is well known that prolongation of the QT interval is associated with a greater risk of arrhythmia and SCD [47]. PD, especially antipsychotics, are known to have electrophysiological properties of prolonging ventricular repolarisation [48]. One of the most severe cardiologic AE represents a lengthening of the QT-interval, potentially leading to a ventricular arrhythmia called TdP [48]. TdP is a ventricular arrhythmia frequently connected to drug administration [49]. Drugs blamed most often are thioridazine, ziprasidone, IV haloperidol, quetiapine, amisupliride, most TCAs, SSRIs – citalopram, fluoxetine, paroxetin, and venlafaxine. Evidently, antipsychotic medications are associated with prolongation of QTc interval [50]. QT prolonging can be prevented by not exceeding the recommended dose, avoiding use in pts with RFs, performing ECG routinely before and after initiation or increase of dosage. ECG abnormalities associated with antipsychotics and antidepressants are tachycardia, bradycardia, heart blocks, repolarisation changes (ST-segment, T wave changes), QTc prolongation, and TdP/VF. Tachycardia can be caused by clozapine, TCAs, MAOIs, and anti-parkinsonian drugs. Bradycardia can be caused by SSRIs, lithium and cholinesterase inhibitors. Heart blocks can be caused by TCAs. Repolarisation changes (STsegment, T wave changes) can be caused by thioridazine and chlorpromazine. TdP/VF can be caused by haloperidol, thioridazine, mesoridazine and chlorpromazine. When treating pts with cardiac arrhythmias by psychopharmacological therapy, drug interactions must be carefully considered [37]. The main secondary SE are in metabolic, endocrine, neurologic, CV systems, haematological and liver functions [51]. TCAs are known to induce cardiac arrhythmias at therapeutic or supra-therapeutic doses. According to available report the TCA, amitriptyline, is reported to induce ST-segment elevation in the right precordial ECG leads [52]. The problem for psychiatry is that the TCA drugs are also class I antiarrhythmic [41]. SSRI are generally believed to cause fewer
pro-arrhythmic SE then TCAs [53]. Fluoxetine treatment has been associated with tachycardia and syncope [53]. Pts receiving a drug that prolongs the QTc interval should be measured by ECG at least once daily during therapy [54]. In addition, concomitant therapy with other QT interval-prolonging drugs, particularly non-CV QT interval-prolonging drugs (antidepressants, antipsychotics) should be avoided or performed cautiously [54]. In pts with cardiac arrhythmias the correspondent warning notices and contraindications, in particular those for TCAs, the SSRIs citalopram and escitalopram, as well as the antipsychotic haloperidol, should be considered [37]. PD known to elongate the QT interval should be avoided [37]. Available data shows that special caution has to be taken when combining antidepressants with antipsychotics from the phenothiazine group since this combination can lead to significantly elongated QT intervals and has been associated with SCD [37]. A recent American Heart Association statement recommended ECGs routinely for children before they start medications to treat ADHD [55]. Attention has been given to screening for causes of SD in ADHD [55]. ADHD medication in children with potentially dangerous cardiac arrhythmias should be used carefully [56]. Comprehensive medical history review and clinical examination must be performed. Current data shows that in children with known cardiac disease, arrhythmia or RFs for cardiac disease, ADHD management must be consulted with a paediatric cardiologist [56]. At the same time some addiction drugs, namely cocaine decreases oxygen supply via coronary vasoconstriction [45]. It causes systolic and diastolic dysfunction, arrhythmias (prolongs the PR, QRS, and QT intervals), and atherosclerosis [45]. There are also a few reports that drugs used to treat Alzheimer's disease include the ACHIs donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine may occasionally be associated with QT prolongation, TdP and ventricular tachycardia (VT) [46]. 7. Heart muscle disease Psychopharmaca use may also be associated with myocarditis, pericarditis and cardiomyopathy. Myocarditis and cardiomyopathy, are potentially reversible complications. However, pts with pre-existing CVD should be carefully evaluated before they begin any antipsychotic treatment [10]. Presentation of myo(peri)carditis can range from nonspecific symptoms to severe left ventricular impairment, pulmonary oedema, cardiogenic shock and death. They usually occur within weeks of introduction of drug. Cardiomyopathy can be caused by clozapine, risperidone, chlorpromazine and haloperidol. Cardiomyopathy is less frequent, but may have long-term consequences, commonly dilated type of left ventricular impairment, usually months from introduction of drug. Atypical antipsychotics induce weight gain, diabetes, and dyslipidaemia [57]. The pts with schizophrenia might be at increased risk for metabolic and CVD [57]. By available data, clozapine is an atypical antipsychotic medication which remains the gold standard in treatment of resistant psychosis [58]. However, clozapine has multiple SE, among which are myocarditis and cardiomyopathy [58]. There is known prolonged release of noradrenaline due to the alpha 2-antagonistic effect of clozapine. [59] Further, reports of valvulopathy led to the withdrawal and anti-parkinsonian drug pergolide from the market [60]. Regarding PD, recreational use of 4-fluoroamphetamine (4-FA) may present with life threatening toxicity including cardiomyopathy, cardiogenic shock, and pulmonary oedema [61]. 8. Discussion Resulting from population growth, the aging populations, and epidemiologic changes global deaths from CVD are increasing [62]. Health
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372
care system is developing to the reduction of CVD. However it is important to note that an evidence suggests a possible increase in CV events in pts treated with PD. From a worldwide perspective CHD and depression are two of the most important diseases [37]. Anxiety and depressive disorders are common in the general population and are particularly prevalent in pts with CVD [63]. Importantly, depression has been found to predict early onset CHD. Depression could be an independent RF for CVD and it is common among pts treated with PCI [64,65]. Numerous psychosocial factors have been linked to CHD [66]. Mental stress may directly influence CHD and also a number of RFs [27]. Increased cardio-metabolic morbidity and increased overall mortality has been observed in pts with severe mental disorders [67]. Clinicians manage pts with CVD, possible receiving CV medication, and also requiring psychopharmacological interventions [68]. Over the last decade, studies of psychosocial RFs for CHD have increased [66]. It is reasonable that psychosocial RFs, certain personality traits may negatively influence the incidence and course of multiple CVD conditions [33]. Study among children with ADHD and conduct disorder/antisocial personality provided support for long-term safety of early psychostimulant treatment [69]. The relationship between psychopharmacology of the nervous and the CV system is still not adequately understood. Interestingly, non-CV adverse reactions were the most frequent manifestation of ADR caused by CV drugs and CV adverse reactions were most often caused by non-CV drugs [70]. PD have potent effects on the CV system. CV AE of treatment with psychopharmaca may occur even at standard dose. An individually adjusted multimodal treatment strategy should be offered to pts with CHD, HF and after heart surgery [33]. The prescription of PD requires a complex therapeutic approach, because the potential risk for CV events [10]. Several drugs used in the treatment of mental diseases are associated with an increased risk of SCD [6]. However, a cause relationship between the intake of these drugs and SCD is impossible. As previously mentioned, an ECG should be performed if the initial evaluation suggests increased cardiac risk or if the antipsychotic to be prescribed has an increased risk of TdP and SD [50]. Prior to psychopharmacological treatment, proper cardiology treatment is recommended [67].
8.1. Limitations Results of this review are based on literature research. The reviewed data came largely from prevalence studies and cross-sectional studies. Retrospective data sources were used in order to make critical overview of CV SE of psychopharmaceutic agents.
9. Conclusion Various PD have shown to have CV effects that can be therapeutically beneficial or harmful to pts. A variety of drugs for the treatment of the central nervous system diseases are associated with cardiac SE. Some of them are linked to reports of arrhythmia and SD [71]. The CV effects of PD depends on the potency of the drug. The correct CVD diagnosis can be beneficial in exposing a pt to the appropriate pharmacologic therapy. In pts with higher risk of CVD, the choice of PD has to be performed accordingly. It is important to note that one of the main problems of psychopharmacotherapy is variability of therapeutic effects. Goal should be to achieve the lowest risk of SE and the highest effectiveness of the active substance [72]. Psychotropic medications are frequently prescribed. However, there is well known danger of widespread illicit use of psychoactive drugs, including narcotics, psychostimulants, and central nervous system depressants [68]. Considering the high prevalence of psychiatric diseases, physician has to have skills to use psychopharmaca in the context of illness [73]. Prescription of PD should conform to established treatment guidelines and therapy be individualised to each patient.
371
Conflict of interest The enclosed manuscript has been read and approved by all the authors. The manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. The authors declare that they have no financial or any other conflict of interest. The authors declare no external financial support for making this article. The copyright shall be transferred to the journal after accepting this article for publication. Acknowledgments None. References [1] WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2015, Oslo, 18th Edition, 18th ed., 2014. [2] Online Anatomical Therapeutic Chemical Classification System, WHO Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health, 2009 (Available at: http://www.whocc.no/atc_ddd_methodology/purpose_of_the_atc_ ddd_system/Accessed 21.3.2016). [3] Halmed, Agencija za lijekove i medicinske proizvode - HALMED. Potrošnja lijekova u Hrvatskoj od 2007, 2012 (do, godine. Available at: http://www.halmed.hr/ fdsak3jnFsk1Kfa/publikacije/Potrosnja_lijekova_u_Hrvatskoj_2007-2012.pdf. Accessed 21.3.2016). [4] M. Jakovljević, How to increase treatment effectiveness and efficiency in psychiatry: creative psychopharmacotherapy - part 2: creating favorable treatment context and fostering patients' creativity, Psychiatr. Danub. 25 (2013) 274–279. [5] M. Jakovljević, How to Increase Treatment Effectiveness and Efficiency in Psychiatry: Creative Psychopharmacotherapy - Part 1: Definition, Fundamental Principles and Higher Effectiveness Polipharmacy Psychiatria Danubina, 25 (2013) 269–273. [6] S. Fanoe, D. Kristensen, A. Fink-Jensen, H.K. Jensen, E. Toft, J. Nielsen, P. Videbech, S. Pehrson, H. Bundgaard, Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management, Eur. Heart J. 35 (2014) 1306–1315. [7] D. Elbe, R. Savage, How does this happen? Part I: mechanisms of adverse drug reactions associated with psychotropic medications, J. Can. Acad. Child Adolesc. Psychiatry 19 (2010) 40–45. [8] S.A. Chong, M.R. Mythily, Cardiac effects of psychotropic drugs, Ann. Acad. Med. Singap. 30 (2001) 625–631. [9] S.V. Carreiro, R.R. Martins, A. De Carvalho, Psychotropic drugs and sudden death, Acta Medica Port. 19 (2006) 151–164. [10] G. Marano, G. Traversi, E. Romagnoli, V. Catalano, M. Lotrionte, A. Abbate, G. BiondiZoccai, M. Mazza, Cardiologic side effects of psychotropic drugs, J. Geriatr. Cardiol. 8 (2011) 243–253. [11] P. Mackin, Cardiac side effects of psychiatric drugs, Hum. Psychopharmacol. 23 (2008) 3–14. [12] Q. Timour, D. Frassati, J. Descotes, P. Chevalier, G. Christé, M. Chahine, Sudden death of cardiac origin and psychotropic drugs, Front. Pharmacol. 3 (2012) 1–9. [13] C. Enger, L. Weatherby, R.F. Reynolds, D.B. Glasser, A.M. Walker, Serious cardiovascular events and mortality among patients with schizophrenia, J. Nerv. Ment. Dis. 192 (2004) 19–27. [14] D.C. Goff, L.M. Sullivan, J.P. McEvoy, J.M. Meyer, H.A. Nasrallah, G.L. Daumit, S. Lamberti, R.B. D'Agostino, T.S. Stroup, S. Davis, J.A. Lieberman, A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls, Schizophr. Res. 80 (2005) 45–53. [15] N. Frasure-Smith, F. Lespérance, Recent evidence linking coronary heart disease and depression, Can. J. Psychiatr. 51 (2006) 730–737. [16] P. Mackin, D.R. Bishop, H.M.O. Watkinson, A prospective study of monitoring practices for metabolic disease in antipsychotic-treated community psychiatric patients, BMC Psychiatry 7 (2007) 28. [17] J. Purdy, Chronic physical illness: a psychophysiological approach for chronic physical illness, Yale J. Biol. Med. 86 (2013) 15–28. [18] J. Ræder, R. Støen, Dosage of ordinary medication prior to elective surgery, Tidsskr. Nor. Laegeforen. 132 (2012) 304–306. [19] K.N. van Dijk, C.S. de Vries, P.B. van den Berg, J.R. Brouwers, L.T. de Jong-van den Berg, Drug utilisation in Dutch nursing homes, Eur. J. Clin. Pharmacol. 55 (2000) 765–771. [20] Halmed, Ukupna potrošnja lijekova u 2014, 2015 (godini, Available at: http://www. halmed.hr/fdsak3jnFsk1Kfa/ostale_stranice/Ukupna_potrosnja_lijekova_u_2014_ godini-1281.pdf. Accessed 21.3.2016). [21] Halmed, Izvješće agencije za lijekove i medicinske proizvode (HALMED) o prijavama nuspojava lijekova u Republici Hrvatskoj za 2014, 2015 (godini, Available at: http://www.halmed.hr/fdsak3jnFsk1Kfa/novosti/Izvjesce_o_nuspojavama_u_ 2014.pdf. Accessed 21.3.2016). [22] E. Patorno, R.J. Glynn, S. Hernandez-Diaz, J. Avorn, P.M. Wahl, R.L. Bohn, D. Mines, J. Liu, S. Schneeweiss, Risk of ischemic cerebrovascular and coronary events in adult users of anticonvulsant medications in routine care settings, J. Am. Heart Assoc. 30 (2013) 2. [23] D. Ames, J. Camm, P. Cook, P. Falkai, C. Gury, R. Hurley, G. Johnson, R. Piepho, V. Vieweg, Cardiac safety in schizophrenia group. Minimizing the risks associated
372
[24]
[25]
[26]
[27] [28]
[29]
[30] [31] [32] [33]
[34] [35]
[36] [37]
[38] [39]
[40] [41] [42] [43]
[44] [45] [46] [47]
[48]
I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372 with QTc prolongation in people with schizophrenia. A consensus statement by the cardiac safety in schizophrenia group, Encéphale 28 (2002) 552–562. J.G. Fiedorowicz, W.H. Coryell, J.P. Rice, L.L. Warren, W.G. Haynes, Vasculopathy related to manic/hypomanic symptom burden and first-generation antipsychotics in a sub-sample from the collaborative depression study, Psychother. Psychosom. 81 (2012) 235–243. G. Scigliano, G. Ronchetti, Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis, CNS Drugs 27 (2013) 249–257. T. Kishi, Y. Matsuda, N. Iwata, Cardiometabolic risks of blonanserin and perospirone in the management of schizophrenia: a systematic review and meta-analysis of randomized controlled trials, PLoS One 9 (2014). D. Wheatley, Psychological stress and cardiovascular diseases, Scand. J. Work Environ. Health 10 (1984) 415–417. G.G. Berntson, S. Hart, S. Ruland, M. Sarter, A central cholinergic link in the cardiovascular effects of the benzodiazepine receptor partial inverse agonist FG 7142, Behav. Brain Res. 74 (1996) 91–103. J.W. Devlin, S. Mallow-Corbett, R.R. Riker, Adverse drug events associated with the use of analgesics, sedatives, and antipsychotics in the intensive care unit, Crit. Care Med. 38 (2010) S231–S243. G. Erdoes, R.M. Basciani, B. Eberle, Etomidate-a review of robust evidence for its use in various clinical scenarios, Acta Anaesthesiol. Scand. 58 (2014) 380–389. K. Ružić, E. Dadić-Hero, T. Grahovac, V. Sabljić, T. Kosec, R. Knez, Switching among antipsychotics–focus on side effects, Psychiatr. Danub. 23 (2011) 89–91. G. Wozniak, A. Toska, M. Saridi, O. Mouzas, Serotonin reuptake inhibitor antidepressants (SSRIs) against atherosclerosis, Med. Sci. Monit. 17 (2011) RA205–RA214. C. Albus, K.H. Ladwig, C. Herrmann-Lingen, Psychocardiology: clinically relevant recommendations regarding selected cardiovascular diseases, Dtsch. Med. Wochenschr. 139 (2014) 596–601. A.J. Scheen, Sibutramine on cardiovascular outcome, Diabetes Care 34 (2011) S114–S119. A.H. Glassman, C.M. O'Connor, R.M. Califf, K. Swedberg, P. Schwartz, J.T. Bigger Jr., K.R. Krishnan, L.T. van Zyl, J.R. Swenson, M.S. Finkel, C. Landau, P.A. Shapiro, C.J. Pepine, J. Mardekian, W.M. Harrison, D. Barton, M. Mclvor, Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group, Sertraline treatment of major depression in patients with acute MI or unstable angina, JAMA 288 (2002) 701–709. A. Deshmukh, K. Ulveling, V. Alla, H. Abuissa, K. Airey, Prolonged QTc interval and torsades de pointes induced by citalopram, Tex. Heart Inst. J. 39 (2012) 68–70. K.H. Ladwig, F. Lederbogen, C. Albus, C. Angermann, M. Borggrefe, D. Fischer, K. Fritzsche, M. Haass, J. Jordan, J. Jünger, I. Kindermann, V. Köllner, B. Kuhn, M. Scherer, M. Seyfarth, H. Völler, C. Waller, C. Herrmann-Lingen, Position paper on the importance of psychosocial factors in cardiology: update 2013, Ger. Med. Sci. 12 (2014) (Doc09). N.K. Mehta, G. Aurigemma, Z. Rafeq, O. Starobin, Reverse takotsubo cardiomyopathy: after an episode of serotonin syndrome, Tex. Heart Inst. J. 38 (2011) 568–572. P.L. Temporelli, A. Boccanelli, G. Desideri, P. Faggiano, G. Mora, F. Oliva, P. Terrosu, The serotonin syndrome: why should cardiologists be aware and scared of it, G Ital Cardiol (Rome) 16 (2015) 34–43. E. Dadić-Hero, R. Knez, J. Rebić, Less is more-possible option in the treatment of depression, Collab. Anthropol. 38 (2014) 1207–1209. A.H. Glassman, S.P. Roose, Risks of antidepressants in the elderly: tricyclic antidepressants and arrhythmia-revising risks, Gerontology 40 (1994) 15–20. A.S. Ngo, R.Y. Ho, K.R. Olson, Phenelzine-induced myocardial injury: a case report, J. Med. Toxicol. 6 (2010) 431–434. A.G. Winterstein, T. Gerhard, P. Kubilis, A. Saidi, S. Linden, S. Crystal, J. Zito, J.J. Shuster, M. Olfson, Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study, BMJ 345 (2012), e4627. H. Sowinski, P.P. Karpawich, Management of a hyperactive teen and cardiac safety, Pediatr. Clin. N. Am. 61 (2014) 81–90. B.G. Schwartz, S. Rezkalla, R.A. Kloner, Cardiovascular effects of cocaine, Circulation 122 (2010) 2558–2569. L.G. Howes, Cardiovascular effects of drugs used to treat Alzheimer's disease, Drug Saf. 37 (2014) 391–395. N. Krishnadev, B.L. Abramson, R. Chisholm, L.A. Leiter, S. Hales, R. Schwartz, M. Barua, S. Scarrow, A. Mansour, M. Pearce, L.R. Pacione, L. Wasserman, T. Shaw, A. Lenny, C. Soare, S. Bhalerao, Atypical antipsychotics, schizophrenia, and cardiovascular risk: what family physicians need to know, BC Med. J. 50 (2008) 444–450. C. Spindelegger, K. Papageorgiou, M.W. Agelink, W. Greil, S. Bleich, E. Rüther, R. Grohmann, S. Toto, A. Konstantinidis, S. Kasper, Cardiological Changes During Antidepressant Treatment with SSRIs Compared to Other Classes of Antidepressants, A
[49]
[50] [51] [52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60] [61]
[62]
[63] [64]
[65]
[66] [67] [68] [69]
[70] [71] [72] [73]
Drug Surveillance Report of German Speaking Countries Between 1993‐ and 2010, Medical University of Vienna, Austria, 2012. E. Poluzzi, E. Raschi, A. Koci, U. Moretti, E. Spina, E.R. Behr, M. Sturkenboom, F. De Ponti, Antipsychotics and torsadogenic risk: signals emerging from the US FDA adverse event reporting system database, Drug Saf. 36 (2013) 467–479. A.A. Shah, A. Aftab, J. Coverdale, QTc prolongation with antipsychotics: is routine ECG monitoring recommended? J. Psychiatr. Pract. 20 (2014) 196–206. T. Huber-Gieseke, M. Perin, F. Narring, Which follow-up of the second generation antipsychotic in adolescents? Rev. Med. Suisse. 10 (1302) (2014) 1304–1307. Y. Minoura, J.M. Di Diego, H. Barajas-Martínez, A.C. Zygmunt, D. Hu, S. Sicouri, C. Antzelevitch, Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants, J. Cardiovasc. Electrophysiol. 23 (2012) 423–432. D. Thomas, B. Gut, G. Wendt-Nordahl, J. Kiehn, The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels, J. Pharmacol. Exp. Ther. 300 (2002) 543–548. G. Frendl, A.C. Sodickson, M.K. Chung, A.L. Waldo, B.J. Gersh, J.E. Tisdale, H. Calkins, S. Aranki, T. Kaneko, S. Cassivi, S.C. Smith Jr., D. Darbar, J.O. Wee, T.K. Waddell, D. Amar, D. Adler, American Association for Thoracic Surgery. 2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures, J. Thorac. Cardiovasc. Surg. 148 (2014) e153–e193. J.M. Perrin, R.A. Friedman, K. TK, Black box working group; section on cardiology and cardiac surgery. Cardiovascular monitoring and stimulant drugs for attentiondeficit/hyperactivity disorder, Pediatrics 122 (2008) 451–453. A. Berg, E. Bråtane, H.H. Odland, C. Brudvik, B. Rosland, A. Hirth, Cardiovascular risk assessment for the use of ADHD drugs in children, Tidsskr. Nor. Laegeforen. 134 (2014) 710–714. M. Gilca, G. Piriu, L. Gaman, C. Delia, L. Iosif, V. Atanasiu, I. Stoian, A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics, Psychopharmacology 231 (2014) 4703–4710. K. Kontoangelos, S. Loizos, J. Kanakakis, N. Smyrnis, M. Economou, J.D. Bergiannaki, G.N. Papadimitriou, Myocarditis after administration of clozapine, Eur. Rev. Med. Pharmacol. Sci. 18 (2014) 2383–2386. M. Mueck-Weymann, J. Acker, M.W. Agelink, Autonomic responses of blood vessels and sweat glands in patients with schizophrenia treated with olanzapine or clozapine, Psychopharmacology 157 (2001) 368–372. C.S. Elangbam, Drug-induced valvulopathy: an update, Toxicol. Pathol. 38 (2010) 837–848. S. Al-Abri, K.H. Meier, J.M. Colby, C.G. Smollin, N.L. Benowitz, Cardiogenic shock after use of fluoroamphetamine confirmed with serum and urine levels, Clin. Toxicol. (Phila) 52 (2014) 1292–1295. G.A. Roth, M.H. Forouzanfar, A.E. Moran, R. Barber, G. Nguyen, V.L. Feigin, M. Naghavi, G.A. Mensah, C.J. Murray, Demographic and epidemiologic drivers of global cardiovascular mortality, N. Engl. J. Med. 372 (2015) 1333–1341. S.J. Davies, P.R. Jackson, J. Potokar, D.J. Nutt, Treatment of anxiety and depressive disorders in patients with cardiovascular disease, BMJ 328 (2004) 939–943. P.J. Schramm, R.E. Poland, U. Rao, Bupropion response on sleep quality in patients with depression: implications for increased cardiovascular disease risk, Eur. Neuropsychopharmacol. 24 (2014) 207–214. Z.J. Wang, M. Guo, T.M. Si, M.M. Jiang, S.M. Liu, Y.Y. Liu, Y.X. Zhao, D.M. Shi, Y.J. Zhou, Association of depression with adverse cardiovascular events after percutaneous coronary intervention, Coron. Artery Dis. 24 (2013) 589–595. A. Rozanski, Behavioral cardiology: current advances and future directions, J. Am. Coll. Cardiol. 64 (2014) 100–110. J. Cordes, C. Lange-Asschenfeldt, C. Hiemke, K.G. Kahl, Psychopharmacotherapy in patients with cardiovascular diseases, Internist (Berl) 53 (2012) 1304 (1306-12, 1314). S.C. Risch, G.P. Groom, D.S. Janowsky, Interfaces of psychopharmacology and cardiology–part one, J. Clin. Psychiatry 42 (1981) 23–34. M.A. Ramos Olazagasti, R.G. Klein, S. Mannuzza, E.R. Belsky, J.A. Hutchison, E.C. Lashua-Shriftman, F.X. Castellanos, Does childhood attention-deficit/hyperactivity disorder predict risk-taking and medical illnesses in adulthood? J. Am. Acad. Child Adolesc. Psychiatry 52 (2013) 153–162 (e4). G.A. Keller, G. Di Girolamo, P.A. Alvarez, Pharmacovigilance and the cardiovascular system: two sides to every story, Curr. Drug Saf. 6 (2011) 224–229. H.J. Witchel, J.C. Hancox, D.J. Nutt, Psychotropic drugs, cardiac arrhythmia, and sudden death, J. Clin. Psychopharmacol. 23 (2003) 58–77. E.M. Zeidler, A.E. Goetz, C. Zöllner, Pharmacogenetics. Clinical relevance in anesthsiology, Anaesthesist 62 (2013) 874–886. D. Telles-Correia, D.F. Guerreiro, R. Coentre, P. Zuzarte, L. Figueira, Psychopharmacology in medical illness: cardiology, nephrology, hepatology, Acta Medica Port. 22 (2009) 797–808.