International Journal of Cardiology 219 (2016) 367–372

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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
b
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

a r t i c l e i n f o a b s t r a c t

Article history: WHO defined in 1976 psychopharmaca as drugs affecting psychological functions, behaviour and self-perception.
Received 18 April 2016 Psychopharmacology is the study of pharmacological agents that affect mental and emotional functions. Creative
Accepted 18 June 2016 approach to psychopharmacotherapy reflects a transdisciplinary, integrative and person-centered psychiatry.
Available online 20 June 2016
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.
Keywords:
Psychopharmacology
Therapeutic approach can increase placebo and decrease nocebo reactions. The main purpose of this review is
Psychotropic drugs to comprehend CV SE of psychotropic drugs (PD).
Pharmacotherapy Critical overview of CV SE of PD will be presented in this review. Search was directed but not limited to CV effects
Cardiovascular system of psychopharmacological substances, namely antipsychotics, anxiolytics, hypnotics, sedatives, antidepressants
Side effects 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 chemical compounds in defined dose affect psychological behaviour.

This paper discusses cardiovascular side effects of psycho-
pharmacotherapy. In the first part of this article overview of classifica-
tion, 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 psycho-
pharmacologic 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
Psychopharmaceutic or PD are medications for treatment of psycho-
logical 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). Further-
more, 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 partic-
ipation. 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

⁎ Corresponding author. all serious mental disorders including schizophrenias, bipolar disorders,
E-mail address: ines.potocnjak@yahoo.com (I. Potočnjak). depressions, anxiety disorders, obsessive–compulsive disorders, etc. [4].

http://dx.doi.org/10.1016/j.ijcard.2016.06.057
0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
368 I. Potočnjak et al. / International Journal of Cardiology 219 (2016) 367–372

The number of the effective medications significantly increased [5]. Pos- 1.2. Cardiovascular side effects
itive therapeutic context may significantly increase placebo and
decrease nocebo responses [4]. It is known that creative approach to The WHO has defined an ADR as a response to a drug that is noxious
psychopharmacotherapy reflects a synergism in the frame of transdisci- and unintended and occurs at average dose in pts for the prophylaxis,
plinary holistic, integrative and person-centered psychiatry [4]. Common- diagnosis or therapy of disease, or for modification of physiological
ly used PD are antipsychotics and antidepressants, comprising of tricyclic function. Drug-related SE and ADR result from the intended use of phar-
anti-depressants (TCAs), selective serotonin and other neurotransmitter maceuticals. SE may vary individually, by age, weight, gender, ethnicity,
re-uptake inhibitors (SSRI and SNRI), mood stabilizers, anxiolytic agents diseases and general health. Further, SE can happen during initiation,
and medications for opioid addiction treatment [6]. Psychiatric medica- decreasing or increasing dosages, or ending a medication treatment.
tions are associated with a variety of possible adverse effects (AE) [7]. When severe SE occur, medication may be discontinued, the dosage
The mechanisms of AE in psychotropic medications might not always adjusted or a second medication prescribed. Drugs may cause various
be known [7]. Awareness of the mechanisms for adverse drug reactions CV SE, from abnormal heart rate (HR) to heart attack or sudden death.
(ADR) can help to direct prescription choice [7]. ADR can be augmented CV disease (CVD) is an extensive class of disorders that involve the
and bizarre. Augmented ADR are predictable, depending on dose and heart and the blood vessels [10]. CVDs include following conditions
pharmacological characteristics of the drug. In this paper augmented such as angina, atherosclerosis, cerebrovascular disease, coronary artery
ADR will be presented. It is important to note that the incidence of disease, heart attack, myocarditis, peripheral vascular disease and
mortality is higher among psychiatric pts than in general population [8]. stroke [10]. CV SEs of antipsychotics and antidepressants are prolonged
Sudden death (SD) associated with PD is an issue which is currently baseline QTc, myo(peri)carditis, cardiomyopathy, coronary disease and
debated worldwide [9]. hypertension. The known CV complications of PD and the significant
consequences of depression treatment in pts with previous cardiac his-
tory 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
Table 1 slowing of intraventricular conduction [10]. Psychopharmaca which
Classification of psychopharmaceutic agents registered in Republic of Croatia according to have various CV effects may also harmfully affect clinical outcome of
ATK system.
cardiac pts. The published data indicates that pts with severe mental
N03 Antiepileptics illness should be considered as a ‘high risk’ population with concern
N03AA Barbiturates and derivatives Methylphenobarbital, phenobarbital, to CV morbidity and mortality [11]. In addition, psychiatric pts are
primidone predisposed to abnormalities in cardiac rate, and SD. There is evidence
N03AB Hydantoin derivatives Phenytoin
N03AC Oxazolidine derivatives Paramethadione
that mortality rate is high in psychiatric pts versus general population
N03AD Succinimide derivatives Ethosuximide [12]. There is an emergent evidence that people affected by psychiatric
N03AE Benzodiazepine derivatives Clonazepam disorders are more likely to suffer from CV disease [11,13] [14,15,16].
N03AF Carboxamide derivatives Carbamazepine Among modifiable factors that attribute to CV RFs are psychosocial factors
N03AG Fatty acids derivatives Valproic acid, valpromide
[11]. The relative contributions to cardiac risk of specific antipsychotic
N03AX Other antiepileptics Lamotrigine, topiramate, gabapentin
N05 Psycholeptics agents rests to be clarified [14]. Pts must be closely monitored for the
N05A Antipsychotics CV risks related to psychopharmaceutic agents. A comprehensive risk
N05AA Phenothiazines with aliphatic Levomepromazine, promazine assessment needs to be applied before initiation of PD treatment to
side-chain reduce the risk of serious CV SE. The evaluation must include a medical
N05AB Phenothiazines with Fluphenazine, perazin
piperazine structure
history of HD, present and previous CV symptoms, used medications,
N05AC Phenothiazines with Tioridazine assessment of potential drug interactions, and an electrocardiogram
piperadine structure (ECG) for assessment of HD signs, conduction disorders, or prolonged
N05AD Butyrophenone derivatives Haloperidol QT interval. ECG monitoring includes measure QTc in all pts prescribed
N05AE Indole derivatives Ziprasidone
antipsychotics. It should be repeated as clinically indicated. Integrated
N05AH Diazepines, oksazepines, Clozapine, olanzapine, quetiapine
thiazepines and oxepines care approach can optimize health outcomes [17]. Special precaution is
N05AL Benzamides Sulpiride needed with drugs that may have effects, SEs or interactions [18]. Further-
N05AN Lithium Lithium more, drug consumption is high and many are used chronically [19]. Due
N05AX Other antipsychotics Risperidone to the risk of AE and drug–drug interactions, the prescribing and dosage of
N05B Anxiolytics
N05BA Benzodiazepine derivatives Alprazolam, bromazepam, diazepam,
should be carefully re-evaluated [19]. Critical judgement and careful drug
lorazepam, medazepam, oxazepam prescription is compulsory. Regular follow-up and re-evaluation should
N05BC Carbamates Meprobamate be performed according to the recommendations. Collaboration with
N05C Hypnotics and sedatives patients may significantly improve treatment outcome [4]. Similarly, a
N05CD Benzodiazepine derivatives Flurazepam, midazolam, nitrazepam
significant increase in dose of these drugs requires re-evaluating
N05CF Benzodiazepine related drugs Zolpidem
N05CM Other hypnotics and sedatives Valeriane radix symptoms and a new ECG. Drug discontinuation should be performed
N06 Psychoanaleptics if necessary. If the psychiatric disease is life threatening, a higher CV
N06A Antidepressants risk may be accepted, but it demands close follow-up.
N06AA Non-selective monoamine Amitriptyline, clomipramine,
reuptake inhibitors maprotiline
N06AB Selective serotonin reuptake Fluvoxamine, fluoxetine, sertraline,
1.3. Data for Croatia
inhibitors paroxetine, escitalopram
N06AG Monoamine oxidase A Moclobemide According to the drug consumption in Croatia from 2007 to 2012,
inhibitors drugs that affect the nervous system, N group, are the second highest
N06AX Other antidepressants Tianeptine, reboxetine, venlafaxine
in total consumption, amounting to 815.6 million kunas in 2012 [3].
N06B Psychostimulants, agents used
for ADHD and nootropics The same, second place in consumption and in financial terms, these
N06BX Other psychostimulants and Piracetam drugs hold through the entire period from 2007 to 2012 [3]. Total
nootropics consumption of drugs that act on the nervous system is 794,628,399
N06D Anti-dementia drugs Donepezil [20]. According to the report on the SE of drugs in 2014, by the Agency
N06DX Other anti-dementia drugs Ginkgo folium
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 num-
ber 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 psychopharmaco-
logic treatment. One of the main goals for this paper is promoting creative
psychopharmacotherapy comprehensive, integrative and transdisciplin-
ary 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 deter-
mine 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 pub-
lished 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 classi-
fication system classification is used [1,2].
4. Results
In this review CV effects of psychopharmacological substances
namely antipsychotics, anxiolytics, hypnotics, sedatives, antidepres-
sants 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 antipsy-
chotics increase the risk of SCD. Published reports, show that when tak-
ing 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 hyperten-
sion 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 anticonvul-
sants are a diverse group of medications used in the treatment of epilep-
tic seizures. A number of investigations have detected interactions
between anticonvulsant drugs and the CV system. Older anticonvul-
sants (i.e. carbamazepine, phenobarbital, phenytoin, primidone) were
associated with metabolic deviations [22]. It is known that older-
generation anticonvulsants may increase CV risk [22].
Psycholeptics are antipsychotics, anxiolytics, hypnotics and seda-
tives. Antipsychotics, also known as neuroleptics or major tranquilizers,
369
are psychiatric medications primarily used to manage psychosis. Avail-
able data shows, antipsychotic drug use may increase the prevalence of
mortality and morbidity [23]. First-generation antipsychotic are associ-
ated with arterial stiffness, possibly due to elevated BP [24]. The antipsy-
chotics are known to induce hypertension and arrhythmias [25]. It is
known that coronary disease can be caused be phenothiazine. Second-
generation antipsychotics have benefits over first-generation antipsy-
chotics. 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 lor-
azepam 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 activa-
tion 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. Antidepres-
sants are used for the treatment of major depressive disorder and con-
ditions, such as anxiety disorders, obsessive compulsive disorder,
chronic and neuropathic pain. They can be used as single or in combina-
tion with other medications. Consumption of antidepressants is show-
ing 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 sertra-
line, have been proven to be safe [33]. Sibutramine is a combined nor-
epinephrine 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 previous-
ly performed study advise that sertraline is a safe and effective treat-
ment 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 instabil-
ity, 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 inappro-
priate 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 in-
creased 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 tyramine-
rich 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 psychoac-
tive 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 inten-
sified by use of psychotropic or antidepressant drugs. The most com-
mon cardiac SE are a mild bradycardia, orthostatic hypotension, QRS
lengthening or prolonged QT interval [10]. Serious conduction alter-
ations 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 abnor-
malities associated with antipsychotics and antidepressants are tachy-
cardia, 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 inhibi-
tors. Heart blocks can be caused by TCAs. Repolarisation changes (ST-
segment, T wave changes) can be caused by thioridazine and chlor-
promazine. 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 meta-
bolic, endocrine, neurologic, CV systems, haematological and liver func-
tions [51].
TCAs are known to induce cardiac arrhythmias at therapeutic or
supra-therapeutic doses. According to available report the TCA, amitrip-
tyline, 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 arrhyth-
mias 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 antide-
pressants 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 as-
sociated 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 non-
specific 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 epide-
miologic 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 impor-
tant 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 nega-
tively 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 psychophar-
macology 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 reac-
tions were most often caused by non-CV drugs [70]. PD have potent ef-
fects on the CV system. CV AE of treatment with psychopharmaca may
occur even at standard dose. An individually adjusted multimodal treat-
ment 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
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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.
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