Hindawi Publishing Corporation

Schizophrenia Research and Treatment

Volume 2013, Article ID 375020, 7 pages
http://dx.doi.org/10.1155/2013/375020

Clinical Study
QTc Prolongation in Patients Acutely Admitted to Hospital for
Psychosis and Treated with Second Generation Antipsychotics

Erik Johnsen,1,2 Kristina Aanesen,1 Sanjeevan Sriskandarajah,3 Rune A. Kroken,1

Else-Marie Løberg,1,4 and Hugo A. Jørgensen2
1
Division of Psychiatry, Haukeland University Hospital, Sandviken, Norway
2
Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway
3
Faculty of Medicine and Dentistry, University of Bergen, Norway
4
Department of Biological and Medical Psychology, University of Bergen, Norway

Correspondence should be addressed to Erik Johnsen; [email protected]

Received 31 July 2013; Accepted 21 November 2013

Academic Editor: Sonia Dollfus

Copyright © 2013 Erik Johnsen et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

QTc interval prolongation is a side effect of several antipsychotic drugs, with associated risks of torsade de pointes arrhythmias and
sudden cardiac death. There is an ongoing debate of whether or not electrocardiogram (ECG) assessments should be mandatory
in patients starting antipsychotic drugs. To investigate QTc prolongation in a clinically relevant patient group 171 adult patients
acutely admitted to an emergency ward for psychosis were consecutively recruited. ECGs were recorded at baseline and then at
discharge or after 6 weeks at the latest (discharge/6 weeks), thus reflecting the acute phase treatment period. The mean QTc interval
was 421.1 (30.4) ms at baseline and there was a positive association between the QTc interval and the agitation score whereas the
QTc interval was inversely associated with the serum calcium level. A total of 11.6% had abnormally prolonged QTc intervals and
another 14.3% had borderline prolongation. At discharge/6 weeks, the corresponding proportions were reduced to 4.2% and 5.3%,
respectively. The reduction of the proportion with prolonged QTc intervals reached statistical significance (chi-square exact test:
𝑃 = 0.046). The finding of about one-quarter of the patients with borderline or prolonged QTc intervals could indicate mandatory
ECG recordings in this population. This trial is registered with ClinicalTrials.gov ID: NCT00932529.

1. Introduction principally by blocking the rapidly activating potassium

current [2, 5, 6]. Antipsychotic drugs are associated with
Prolongation of the heart rate-corrected QT (QTc) interval dose related QTc prolongation, and some agents have been
of the electrocardiogram (ECG) is a major concern because intermittently or permanently withdrawn from the market
of the associated risk of torsade de pointes (TdP) arrythmias for this reason [2, 5, 7]. Treatment recommendations for
and sudden cardiac death [1]. QTc intervals longer than 500 schizophrenia differ substantially, however, with regard to
milliseconds (ms) or increases of more than 60 ms of the whether or not ECG recordings should be routinely under-
QTc interval are established thresholds for clear concern of taken in all patients starting antipsychotic drug treatment [8–
arrhythmia but increased risk is found also at lower levels of 12]. Some recommend ECG recordings in patients considered
QTc prolongation [2]. The QT interval represents the onset at increased risk from QTc prolongation only [8–10], whereas
of electrical depolarisation of the ventricles to the end of others recommend mandatory ECG in all patients [11], or
repolarisation of the heart [1, 2] and is influenced by both in those admitted to hospital [12]. Importantly, patients
physiological and pathological factors including emotional with schizophrenia may have a heightened background risk
stress, gender, obesity, food consumption, and electrolyte for QTc prolongation irrespective of the drug effects, as
disturbances, as well as diseases of the heart muscle and coro- recent studies report considerably increased prevalence of
nary artery disease [2–4]. Moreover, several drugs including cardiovascular disease (CVD) in schizophrenia [13, 14] and
psychotropics can induce prolongation of the QTc interval that CVD is suboptimally addressed in this population
2 Schizophrenia Research and Treatment

[15, 16]. Active psychosis may further increase the risk the ICD-10 diagnostic criteria (http://apps.who.int/classifica-
of QTc prolongation because of the associated emotional tions/icd10/browse/2010/en) for schizophrenia, schizoaffec-
stress involved although the literature is conflicting. Bär tive disorder, acute and transient psychotic disorder, delu-
et al. [17] found increased QT variability but shorter QT sional disorder, drug-induced psychosis, bipolar disorder
mean intervals in 25 unmedicated schizophrenia patients except for manic psychosis, or major depressive disorder with
with acute psychosis compared to healthy controls. Hatta psychotic features. The diagnoses were determined by the
et al. [18] on the other hand found in their cross-sectional hospital’s psychiatrists or specialists in clinical psychology.
study prolongation of the QTc interval in unmedicated acute Patients were excluded from the study if they were unable to
psychotic emergency patients, all of whom were involuntarily use oral antipsychotics, were suffering from manic psychosis,
admitted because of immediate danger to themselves or or for other behavioural or mental reasons related to the
others. Patients with prior drug abuse or alcohol dependence state of illness were unable to cooperate with assessments,
were excluded. A major obstacle might be that most available did not understand spoken Norwegian, were candidates for
studies include selected samples which could bias the results. electroconvulsive therapy, or were medicated with clozap-
Taken together acute admission to hospital may represent a ine on admittance. Patients with drug-induced psychoses
particular risk situation for QTc prolongation in schizophre- were included only when the condition did not resolve
nia patients. To the best knowledge of the authors, studies within a few days and when antipsychotic drug therapy was
investigating the QTc interval in samples representative of indicated.
acutely admitted patients with psychosis are scarce as patients
with, for example, illicit drug abuse and somatic disease are
typically excluded in antipsychotic drug studies [19]. 2.1. Assessments. Assessments were conducted at baseline
The primary aims of the study were to investigate the pro- and discharge/6 weeks. Before inclusion, eligible patients
portions with prolonged QTc interval at hospital admission underwent the PANSS structured clinical interview. Intra-
and discharge or at 6 weeks from baseline at the latest, if class correlation coefficients (ICC) were calculated based on
not discharged earlier (discharge/6 weeks). Secondary aims interrater assessments and showed high interrater reliability
were to assess the influence of electrolyte levels and emotional (0.92). The PANSS excited component (PANSS-EC), consist-
stress at baseline and antipsychotic drug use at discharge/6 ing of the PANSS items P4 (excitement), P7 (hostility), G4
(tension), G8 (uncooperativeness), and G14 (poor impulse
weeks on the QTc interval. The patient recruitment focused
control) as validated by Montoya et al. [22], was used
on all patients with psychosis acutely admitted to the emer-
as a proxy for emotional stress. Furthermore, the Calgary
gency ward to ensure a clinically relevant sample.
Depression Scale for Schizophrenia (CDSS) [23] and the
Clinical Drug and Alcohol Use Scales (CDUS/CAUS) [24]
2. Materials and Methods were used, as well as a neurocognitive test battery [25],
and the patients were rated according to the Clinical Global
The materials and methods used have been described in Impression—Severity of Illness scale (CGI-S) [26], and the
greater detail elsewhere [20]. The study is part of a pragmatic, Global Assessment of Functioning—Split Version, Functions
randomized trial comparing second generation antipsy- scale (GAF-F) [27]. A blood sample was collected from the
chotics (SGAs) in the treatment of psychosis including 226 patients between 08 and 10 a.m. for analyses of serum potas-
patients. The present paper reports data obtained at baseline sium, sodium and calcium, and serum level measurements of
and discharge/6 weeks in patients who underwent ECG antipsychotics at discharge/6 weeks.
recordings. Patients were consecutively recruited from March Drug doses were converted to mean defined daily doses
2004 until February 2009 from the Haukeland University (DDDs) as developed by the World Health Organization
Hospital with a catchment population of about 400,000. The Collaborating Centre for Drug Statistics Methodology [20].
study was approved by the Regional Committee for Medical The basic definition of the DDD unit is the assumed average
Research Ethics and the Norwegian Social Science Data Ser- maintenance dose per day for a drug used for its main
vices. The study was publicly funded and has not received any indication in adults.
financial or other support from the pharmaceutical indus-
try. The Regional Committee for Medical Research Ethics
allowed eligible patients to be included before informed 2.2. QTc Assessments. The QTc interval estimation was done
consent was provided, thus entailing a clinically relevant automatically by a Philips Pagewriter Trim II cardiograph
representation in the study. All adult patients were eligible at admission and discharge/6 weeks. Bazett’s formula
for the study if they were acutely admitted to the emergency was used for correction. The ECG recording at baseline
ward for symptoms of active psychosis as determined by was done before the first administration of the study
a score of ≥4 on one or more of the items delusions, hal- SGAs. The QTc ratings were for each gender divided
lucinatory behavior, grandiosity, suspiciousness/persecution, into normal, borderline, and prolonged groups according
or unusual thought content in the PANSS [21] and were to the Committee for Proprietary Medicinal Products
candidates for oral antipsychotic drug therapy. Accord- (http://www.fda.gov/ohrms/dockets/ac/03/briefing/pubs/
ingly the patient inclusion encompassed the consecutive cpmp.pdf). The cutoff points were for men less than 430
recruitment of a clinically representative sample of psychosis milliseconds (ms) (normal), 430 to 450 ms (borderline), and
patients acutely admitted to hospital. All eligible patients met more than 450 ms (prolonged) and for women less than
Schizophrenia Research and Treatment 3

450 ms (normal), 450–470 ms (borderline), and more than Table 1: Baseline demographics and clinical characteristics.
470 ms (prolonged).
Characteristics 𝑁 % of sample
Gender
2.3. Statistical Procedures. Categorical and continuous data at
baseline and at discharge/6 weeks, respectively, were analyzed Male 118 69.0
by means of exact 𝜒2 -tests, independent samples 𝑡-tests, Female 53 31.0
and one-way ANOVAs by using the SPSS software, version Antipsychotic drug naı̈ve 73 42.7
20.0 (IBM SPSS Statistics, 2011). For comparing mean QTc Alcohol use last 6 months
intervals at baseline and at discharge/6 weeks, paired-sample None 33 19.3
𝑡-tests were used. To investigate the association between Misuse 12 7.0
QTc intervals and the levels of individual electrolytes, as Illicit drug use last 6 months
well as the PANSS-EC, a bivariate analysis of correlation None 118 69.0
was performed using the Pearson correlation coefficient as Misuse 29 17.0
normal distribution was assumed. These variables were also Diagnosis1
analysed collectively by means of linear regression. The level Schz and related 95 57.5
of statistical significance was set at 𝛼 = 0.05, two-sided. Acute 13 7.9
Drug-induced 21 12.7
3. Results Affective 19 11.5
Rest 17 10.2
A total of 171 patients (75.7% of the total sample) underwent
Mean SD/range
ECG recordings on at least one of the time points. In the
Age 34.2 13.9/17–73
patients without ECG recordings the principal reasons were
refusal or inability to cooperate with the measurements. PANSS total 73.5 13.7/44–111
Baseline clinical and demographic characteristics are dis- PANSS positive 19.7 4.4/11–32
played in Table 1, and there were no differences between PANSS negative 19.2 7.5/7–39
those with and without ECG recordings. Those without ECG PANSS general 34.6 6.8/20–56
recordings had a numerically higher mean PANSS-EC score CDSS 6.9 5.3/0–23
compared to those with ECG recordings but the difference GAF-F 30.9 6.0/10–62
did not reach statistical significance (independent samples 𝑡- CGI 5.2 0.6/4–6
test, equal variances assumed: 𝑃 = 0.126; mean difference RBANS, 𝑡-scores 38.3 7.5/20–58
0.72; 95% confidence interval (CI) −0.20–1.64).
Notes. 𝑁 = number of patients with ECG at baseline and/or ECG at discharge;
The mean QTc interval was 421.1 (30.4) ms at baseline, SD = standard deviation; antipsychotic drug naive = no life-time exposure
and 11.6% of the patients had abnormally prolonged QTc to antipsychotic drugs before index admission; first admission = index
(Figure 1). Another 14.3% had borderline QTc intervals. Two admission was the first admission to a mental hospital; misuse = misuse
patients had QTc intervals above 500 ms at baseline. or dependence according to the Clinical Drug and Alcohol Use Scales
(CDUS/CAUS); patients with no illicit drug use could be included in the
There were no statistical differences among the genders category alcohol use last 6 months; Schz and related = schizophrenia and
or among the drug naı̈ve and those with prior antipsychotic related disorders: schizophrenia, schizoaffective disorder, acute polymorphic
drug exposure with regard to mean QTc interval or pro- psychotic disorder with symptoms of schizophrenia, acute schizophrenia-
portion with QTc prolongation. Mean serum levels with like psychotic disorder, and delusional disorder; acute = acute psychosis
standard deviations (SD) and reference ranges in brackets other than those categorized under Schz and related; affective = affective
psychosis; rest = miscellaneous psychotic disorders. All diagnoses are
of sodium, potassium, and calcium were 141.3 (2.3) (137.0– according to ICD-10; PANSS = the positive and negative syndrome scale;
145.0), 4.3 (0.4) (3.5–5.0), and 2.4 (0.1) (2.2–2.6) nanomoles CDSS = the Calgary Depression Scale for Schizophrenia; GAF-F = the
per litre, respectively. There was a statistically significant Global Assessment of Functioning—Split Version, Functions scale; CGI = the
negative association between QTc interval and serum calcium Clinical Global Impression, Severity of Illness scale; RBANS = the repeatable
level (Pearson correlation: 𝑟 = −0.186, 𝑃 = 0.027), battery for the assessment of neuropsychological status.
1
Patients with missing diagnoses are not included in the list.
whereas no association was found between the QTc interval
and sodium or potassium, respectively. There was a positive
association between the PANSS-EC and the QTc interval but are included in the analyses. There were no significant
(Pearson correlation: 𝑟 = 0.170, 𝑃 = 0.040). When the differences between those tested only at baseline and those
electrolytes and the PANSS-EC were entered as independent tested also at discharge/6 weeks with regard to baseline mean
variables into a linear regression model with the QTc interval QTc interval or proportions with borderline or prolonged
as the dependent variable the association between serum QTc intervals, neither were there baseline clinical or demo-
calcium and the QTc interval remained unaltered whereas graphic differences. The mean QTc at discharge/6 weeks was
the correlation between the PANSS-EC and the QTc interval 411.3 (23.1) ms. The proportions with prolonged or borderline
increased (Pearson correlation: 𝑟 = 0.205, 𝑃 = 0.008). QTc recordings were reduced to 4.2% and 5.3%, respectively
A total of 95 patients were reassessed at discharge/6 (Figure 2).
weeks. Three of these patients were for practical reasons One patient had QTc interval > 500 ms and 4 patients
tested later than 6 weeks, at weeks 7, 10, and 11, respectively, had their QTc intervals increased more than 60 ms from
4 Schizophrenia Research and Treatment

100 100

80 80

60 60
(%)

(%)
40 40

20 20

0 0
Normal Borderline Abnormal Normal Borderline Abnormal
QTc interval categorized QTc interval categorized
Gender Gender
Men Men
Women Women
Error bars represent 95% confidence interval. Error bars represent 95% confidence interval.

Figure 1: Distribution of QTc intervals at baseline. Figure 2: Distribution of QTc intervals at discharge/6 weeks.

baseline. The reduction of the proportion with prolonged QTc a particular risk phase with regard to QTc prolongation in
levels reached statistical significance (chi-square exact test: this patient group. The baseline ECG recording was done
𝑃 = 0.046). There was a trend only for the reduction of before administration of the study drugs and although about
the mean QTc (paired-samples 𝑡-test: 𝑃 = 0.063; mean half the sample had lifetime antipsychotic drug exposure it
difference 7.5 ms; 95% CI −0.4–15.4). The use of antipsychotic is reasonable to assume that only a minority had used their
drugs is displayed in Table 2. Two patients did not use antipsychotics according to the prescription in the last period
antipsychotics at discharge/6 weeks. of time before admittance [28]. The high proportion with QTc
The mean DDD with SD was 1.02 (0.55). There were no prolongation at baseline must accordingly be explained also
differences among the drug groups with respect to mean QTc by factors other than the antipsychotic drugs. The reduced
interval or proportions with QTc prolongation. Concomitant proportion with QTc prolongation at discharge/6 weeks
antidepressants and/or mood stabilizers (lithium and anti- further underscores this interpretation as one would expect
convulsants) and/or sporadic additional antipsychotics were that at least some of the SGAs under investigation should
used by 35.2%, 8.5%, and 18.3%, respectively, at discharge/6 drive the QTc interval towards prolongation [2]. The results
weeks. There were no differences among the antipsychotic thus may suggest that in heterogeneous sample such as ours
drug groups in this regard. There was no association between of acutely admitted psychosis patients the relative impacts on
QTc level and DDD, or serum levels, respectively, of the the QTc interval by antipsychotic drugs are outweighed by
antipsychotic drugs. other factors including emotional stress.
Although the mean electrolyte levels were all within
4. Discussion the reference ranges, there was a statistically significant
negative association between serum calcium levels and the
The main findings of the present study in acutely admit- QTc intervals at baseline. Hypocalcemia has been shown
ted patients with psychosis were that almost a quarter of to cause prolongation of the QTc interval [2, 4], and our
the patients had prolonged or borderline prolonged QTc results indicate that the association is present also within the
intervals at hospital admission and this proportion was reference range. Serum calcium levels in the lower end of the
significantly reduced at discharge/6 weeks after the initiation reference interval might accordingly represent an indepen-
of antipsychotic drug treatment with SGAs. Moreover, 2 dent risk factor for QTc prolongation. By using the PANSS-
patients at baseline and 1 patient at discharge/6 weeks had EC as a proxy for emotional distress, we found a positive
QTc intervals above the critical threshold of 500 ms, and association between the agitation score and the QTc interval
4 patients had their QTc intervals increased by more than in the linear regression model. The study thus supports the
60 ms between baseline and discharge/6 weeks. The findings findings indicated by Hatta et al. [18] that emotional distress
underscore that the acute admission situation may represent may increase the QTc interval, contributing to the increased
Schizophrenia Research and Treatment 5

Table 2: Antipsychotic drug use and QTc intervals at discharge/6 weeks.

Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole

𝑁 = 25 𝑁 = 31 𝑁 = 18 𝑁 = 18 𝑁=1
Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Mean dose (mg/d) 3.5 (1.2) 16.4 (5.9) 457.4 (222.2) 86.7 (39.0) 5.0 (—)
Serum level (nm/L)∗ 71.6 (47.9) 121.6 (77.7) 501.9 (555.1) 125.3 (99.8) 141 (—)
QTc (ms) 411.3 (24.6) 411.6 (27.0) 412.6 (16.4) 412.5 (19.9) 362.0 (—)
Notes. 𝑁 = number of patients; SD = standard deviation; mg/d = milligrams per day; nm/L = nanomoles per litre; ms = milliseconds.
∗
Reference ranges: risperidone 30–120; olanzapine 30–200; quetiapine 100–800; ziprasidone 30–200; aripiprazole 200–1300.

risk of QTc prolongation in active psychosis. Hatta et al. accepted by all acutely admitted patients with psychosis.
used the items anxiety, tension, mannerisms and posturing, One might expect that the most distressed patients were
hostility, uncooperativeness, and psychomotor excitement unable to cooperate with the procedure which was actually
from the 18-item Brief Psychiatric Rating Scale as a collected indicated by the higher PANSS-EC agitation score although
agitation score and found that psychiatric emergency patients not statistically significant and that these patients would
had had higher agitation scores compared to psychiatric have had even longer QTc intervals based on the positive
outpatients and that the latter group had a significantly longer association between agitation and the QTc interval. About
mean QTc interval. They did not however report analyses of half the sample had life-time exposure to antipsychotic drugs
direct comparisons between the QTc interval and agitation at study inclusion but noncompliance is a common problem
scores. Furthermore, we used the PANSS-EC as a proxy for in this patient group and a frequent cause of relapse [28],
emotional stress, which may not be directly comparable to and most likely only a minority had used antipsychotic drugs
the BPRS items chosen by Hatta et al. according to their prescriptions in the last period of time
Interestingly, the proportion with borderline or pro- before admittance. Serum drug levels were not measured
longed QTc intervals was significantly reduced from baseline at admittance, so the exact figures cannot be verified and
to discharge/6 weeks and there were no differences among accordingly comparisons between those taking and not tak-
the drugs regarding QTc intervals at discharge/6 weeks which ing antipsychotic drugs at baseline cannot be done although
could indicate that the SGAs studied are safe in this regard. this would have added value to the study. There was a high
This interpretation of the data is strengthened by the fact attrition rate from baseline to discharge/6 weeks which could
that serum level measurements of the antipsychotics were theoretically have introduced selection bias regarding the
conducted and, with the exception of aripiprazole which discharge/6 weeks recordings. We find this unlikely, however,
was used by only one patient, all the serum levels were in as attrition was not related to any of the baseline variables. If
the middle of the respective reference intervals. Among the present, the direction of any bias would be hard to predict. In
studied drugs ziprasidone was expected to have the longest our study the QTc interval was automatically recorded with-
QTc interval based on the previous literature [6]. Our finding out manual control. The automated methods have however
of equality may suggest that drug differences found elsewhere demonstrated noninferiority compared to manual recordings
are levelled out in more diagnostically heterogeneous samples of the QTc but both methods have their flaws [29]. Finally,
such as ours. Alternatively, the present study may be under- our study would have benefited from a control group for
powered resulting in a type II error but we find this unlikely comparison. Little research is done on the QT interval in the
given also the numerically equality among the drugs. normal population.
A major advantage of the present study is the consec-
utive inclusion of a diagnostically heterogeneous and thus 5. Conclusion
clinically relevant sample with psychosis. The findings should
accordingly be generalizable to patients acutely admitted The results may indicate that ECG recordings should be
to hospital for psychosis and eligible for oral antipsychotic mandatory in acutely admitted patients with psychosis to
medication. Based on this one could argue that ECG record- detect those at heightened risk of arrhythmias.
ings should be mandatory in all psychosis patients acutely
admitted to hospital. On the other hand the relationship
between QTc prolongation and arrhythmias is not clear-cut Conflict of Interests
[2] and may at best be considered a proxy for increased Erik Johnsen has received honoraria for lectures given
risk of malignant arrhythmias and sudden cardiac death. in meetings arranged by Bristol-Myers Squibb, Eli Lilly,
ECG is, however, an inexpensive investigation with minimal and AstraZeneca and for a contribution to an information
burden on the patient, and those patients at the highest risk brochure by Eli Lilly. Erik Johnsen has been reimbursed by
of arrhythmia (QTc interval > 500 ms) can easily be detected. the Eli Lilly company and the Janssen-Cilag company for
Some potential limitations should be mentioned. Only attending conferences. Rune Kroken has been reimbursed by
three-quarters of the total sample underwent ECG record- the Eli Lilly company, the Janssen-Cilag company, Bristol-
ings, thus reflecting that these measurements cannot be Myers Squibb, and AstraZeneca for attending conferences.
6 Schizophrenia Research and Treatment

Hugo A. Jørgensen has been reimbursed by the Eli Lilly com- [13] M. Lahti, J. Tiihonen, H. Wildgust et al., “Cardiovascular
pany for a contribution to an information brochure. Kristina morbidity, mortality and pharmacotherapy in patients with
Aanesen, Sanjeevan Sriskandarajah, and Else-Marie Løberg schizophrenia,” Psychological Medicine, vol. 42, no. 11, pp. 2275–
declare no conflict of interests regarding the publication of 2285, 2012.
this paper. [14] M. De Hert, J. M. Dekker, D. Wood, K. G. Kahl, R. I. G.
Holt, and H.-J. Möller, “Cardiovascular disease and diabetes
in people with severe mental illness position statement from
Acknowledgments the European Psychiatric Association (EPA), supported by the
European Association for the Study of Diabetes (EASD) and the
This work was supported by the Research Council of Norway, European Society of Cardiology (ESC),” European Psychiatry,
the Western Norway Regional Health Authority, and Hauke- vol. 24, no. 6, pp. 412–424, 2009.
land University Hospital. The Funding source had no role in [15] D. P. J. Osborn, G. Baio, K. Walters et al., “Inequalities in the
the study design; in collection, analyses, and interpretation of provision of cardiovascular screening to people with severe
data; in the writing of the report; or in the decision to submit mental illnesses in primary care. Cohort study in the United
the paper for publication. Kingdom THIN Primary Care Database 2000–2007,” Schizo-
phrenia Research, vol. 129, no. 2-3, pp. 104–110, 2011.
References [16] E. Johnsen, R. Gjestad, R. A. Kroken, L. Mellesdal, E.-
M. Løberg, and H. A. Jørgensen, “Cardiovascular risk in
[1] A. H. Glassman and J. T. Bigger Jr., “Antipsychotic drugs: pro- patients admitted for psychosis compared with findings from
longed QTc interval, torsade de pointes, and sudden death,” a population-based study,” Nordic Journal of Psychiatry, vol. 65,
American Journal of Psychiatry, vol. 158, no. 11, pp. 1774–1782, no. 3, pp. 192–202, 2011.
2001. [17] K.-J. Bär, M. Koschke, M. K. Boettger et al., “Acute psychosis
[2] P. M. Haddad and I. M. Anderson, “Antipsychotic-related QTc leads to increased QT variability in patients suffering from
prolongation, torsade de pointes and sudden death,” Drugs, vol. Schizophrenia,” Schizophrenia Research, vol. 95, no. 1–3, pp. 115–
62, no. 11, pp. 1649–1671, 2002. 123, 2007.
[3] C. van Noord, M. Eijgelsheim, and B. H. C. Stricker, “Drug- and [18] K. Hatta, T. Takahashi, H. Nakamura, H. Yamashiro, and Y.
non-drug-associated QT interval prolongation,” British Journal Yonezawa, “Prolonged QT interval in acute psychotic patients,”
of Clinical Pharmacology, vol. 70, no. 1, pp. 16–23, 2010. Psychiatry Research, vol. 94, no. 3, pp. 279–285, 2000.
[4] N. El-Sherif and G. Turitto, “Electrolyte disorders and arrhyth- [19] S. Leucht, S. Heres, J. Hamann, and J. M. Kane, “Methodolog-
mogenesis,” Cardiology Journal, vol. 18, no. 3, pp. 233–245, 2011. ical issues in current antipsychotic drug trials,” Schizophrenia
[5] J. Nielsen, C. Graff, J. K. Kanters, E. Toft, D. Taylor, and J. M. Bulletin, vol. 34, no. 2, pp. 275–285, 2008.
Meyer, “Assessing QT interval prolongation and its associated [20] E. Johnsen, R. A. Kroken, T. Wentzel-Larsen, and H. A. Jørgen-
risks with antipsychotics,” CNS Drugs, vol. 25, no. 6, pp. 473– sen, “Effectiveness of second-generation antipsychotics: a nat-
490, 2011. uralistic, randomized comparison of olanzapine, quetiapine,
[6] S. R. Beach, C. M. Celano, P. A. Noseworthy, J. L. Januzzi, and risperidone, and ziprasidone,” BMC Psychiatry, vol. 10, article
J. C. Huffman, “QTc prolongation, torsades de pointes, and 26, 2010.
psychotropic medications,” Psychosomatics, vol. 54, no. 1, pp. 1–
[21] S. R. Kay, A. Fiszbein, and L. A. Opler, “The positive and nega-
13, 2013.
tive syndrome scale (PANSS) for Schizophrenia,” Schizophrenia
[7] E. Lindström, L. Farde, J. Eberhard, and W. Haverkamp, “QTc Bulletin, vol. 13, no. 2, pp. 261–276, 1987.
interval prolongation and antipsychotic drug treatments: focus
[22] A. Montoya, A. Valladares, L. Lizán, L. San, R. Escobar, and S.
on sertindole,” International Journal of Neuropsychopharmacol-
Paz, “Validation of the Excited Component of the Positive and
ogy, vol. 8, no. 4, pp. 615–629, 2005.
Negative Syndrome Scale (PANSS-EC) in a naturalistic sample
[8] D. A. Addington, R. H. Bouchard, J. Goldberg et al., “Clinical of 278 patients with acute psychosis and agitation in a psy-
practice guidelines. Treatment of Schizophrenia,” Canadian chiatric emergency room,” Health and Quality of Life Outcomes,
Journal of Psychiatry, vol. 50, supplement 1, 2005. vol. 9, article 18, 2011.
[9] T. R. Barnes, “Evidence-based guidelines for the pharmaco-
[23] D. Addington, J. Addington, and B. Schissel, “A depression
logical treatment of Schizophrenia: recommendations from
rating scale for schizophrenics,” Schizophrenia Research, vol. 3,
the British Association for Psychopharmacology,” Journal of
no. 4, pp. 247–251, 1990.
Psychopharmacology, vol. 25, no. 5, pp. 567–620, 2011.
[10] A. F. Lehman, J. A. Lieberman, L. B. Dixon et al., “Practice [24] R. E. Drake, S. D. Rosenberg, and K. T. Mueser, “Assessing
guideline for the treatment of partients with Schizophrenia, substance use disorder in persons with severe mental illness,”
second edition,” American Journal of Psychiatry, vol. 161, no. 2, New Directions for Mental Health Services, no. 70, pp. 3–17, 1996.
p. 1-56, 2004. [25] C. Randolph, M. C. Tierney, E. Mohr, and T. N. Chase, “The
[11] A. M. Dons, Vejledning Om Behandling Med Antipsykotiske Repeatable Battery for the Assessment of Neuropsychological
Lægemidler Til Patienter Over 18 År, Sundhetsstyrelsen, Copen- Status (RBANS): preliminary clinical validity,” Journal of Clin-
hagen, Denmark, 2007. ical and Experimental Neuropsychology, vol. 20, no. 3, pp. 310–
319, 1998.
[12] National Institute for Clinical Excellence (NICE), “The NICE
Guideline on core interventions in the treatment and man- [26] W. Guy, Assessment Manual for Psychopharmacology—Revis-
agement of Schizophrenia in adults in primary and secondary ited, Vol. DHHS Publ NO ADM 91-338, US Department of
care—updated edition,” in National Institute for Clinical Excel- Health and Human Services, Rockville, Md, USA, 1976.
lence, London, UK, 2009, http://guidance.nice.org.uk/CG82/ [27] S. P. Karterud, G. Pedersen, H. Loevdahl, and S. Friis, Global
Guidance/pdf/English. Assessment of Functioning—Split Version (S-GAF): Background
Schizophrenia Research and Treatment 7

and Scoring Manual, Ullevaal University Hospital, Department

of Psychiatry, Oslo, Norway, 1998.
[28] S. Leucht and S. Heres, “Epidemiology, clinical consequences,
and psychosocial treatment of nonadherence in Schizophrenia,”
Journal of Clinical Psychiatry, vol. 67, supplement 5, pp. 3–8,
2006.
[29] B. Darpo, M. Agin, D. J. Kazierad et al., “Man versus machine:
is there an optimal method for QT measurements in thorough
QT studies?” Journal of Clinical Pharmacology, vol. 46, no. 6, pp.
598–612, 2006.
 MEDIATORS of

INFLAMMATION

The Scientific Gastroenterology Journal of

World Journal
Hindawi Publishing Corporation
Research and Practice
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Diabetes Research
Hindawi Publishing Corporation
Disease Markers
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of International Journal of

Immunology Research
Hindawi Publishing Corporation
Endocrinology
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Submit your manuscripts at

http://www.hindawi.com

BioMed
PPAR Research
Hindawi Publishing Corporation
Research International
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of
Obesity

Evidence-Based
Journal of Stem Cells Complementary and Journal of
Ophthalmology
Hindawi Publishing Corporation
International
Hindawi Publishing Corporation
Alternative Medicine
Hindawi Publishing Corporation Hindawi Publishing Corporation
Oncology
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Parkinson’s
Disease

Computational and
Mathematical Methods
in Medicine
Behavioural
Neurology
AIDS
Research and Treatment
Oxidative Medicine and
Cellular Longevity
Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014