©2010 Taipei Medical University
O R I G I N A L A R T I C L E
1.
Introduction
Cardiovascular disease is the principal cause of natural mortality in patients with bipolar disorder and schizophre-nia.1,2 Circulatory disease is the most prevalent disease
in patients with bipolar disorder and schizophrenia.3–6
Bipolar and schizophrenic patients may have underlying autonomic nervous system dysfunction.7–9
Mujica-Parodi et al found a decreased RR interval vari-ability in schizophrenic patients through 24-hour Holter monitoring.8 According to electrocardiophysiological
activity recorded by high-resolution electrocardiograms
Background: Cardiovascular disease is the principal cause of death among patients with
bipolar disorder and schizophrenia. We hypothesized that a combination of psychophysi-ology and the use of lithium, along with antipsychotics, alter electrocardiophysiological activity in bipolar and schizophrenic patients.
Purpose: The goal of this study was to evaluate the effects of psychotropic agents and the
pathophysiology using 12-lead electrocardiograms (EKGs) in bipolar and schizophrenic patients.
Methods: The study involved three groups of patients: (1) 30 lithium/haloperidol-treated
patients with bipolar mania (15 males, 15 females); (2) 33 lithium-free patients with bipolar mania (21 males, 12 females); and (3) 31 lithium-free schizophrenic patients (15 males, 16 females). Clinical data were obtained through a retrospective review of the medical records of all subjects.
Results: The mean PQ interval, QRS complex, and corrected QT (QTc) intervals did not
dif-fer among the three groups. Among those in the lithium/haloperidol-treated bipolar mania group, the QTc interval demonstrated a marginally significant correlation with serum lithium levels (r = 0.373; p = 0.05).
Conclusion: Pathophysiological changes or minor abnormalities of
electrocardiophysio-logical activity in schizophrenia and bipolar disorder patients might not be displayed by routine 12-lead EKGs. Because of the limitations of 12-lead EKGs, bipolar manic patients who have higher serum lithium levels might have increased risks for QTc prolongation, and thus QTc intervals should be carefully followed-up in these patients.
Received: Dec 29, 2009 Revised: Mar 17, 2010 Accepted: Apr 27, 2010 KEY WORDS: bipolar mania; electrocardiography; lithium; QTc interval; schizophrenia
Effects of Medication and Pathophysiology on
12-lead Electrocardiograms in Bipolar Disorder and
Schizophrenia
Pao-Huan Chen
1,3, Shang-Ying Tsai
2,3,4*, Kuo-Hsuan Chung
31Department of Adult Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan
2Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan
3Department of Psychiatry and Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan 4Department of Psychiatry, Po-Jen General Hospital, Taipei, Taiwan
*Corresponding author. Department of Psychiatry, School of Medicine, Taipei Medical University, 252 Wu-Hsing Street, Taipei 110, Taiwan. E-mail: tmcpsyts@tmu.edu.tw
(EKGs), Cohen et al7 and Bär et al9 reported low heart rate variability in euthymic bipolar and acute schizo-phrenic subjects. Those study results highlight the im-portance of investigation of electrocardiophysiological activity in schizophrenic and bipolar patients. However, it remains unknown whether the effects of psycho-tropic agents such as lithium and haloperidol or the underlying pathophysiology of the psychotic disorder itself play a role in changes in electrocardiophysiologi-cal activity in bipolar manic patients.10
The use of routine 12-lead EKGs provides the most accessible means of evaluating the heart in clinical prac-tice. However, little information is available on the results of 12-lead EKG studies among acutely manic patients. Females are overrepresented in studies that have been performed, and study populations often include a mixture of medicated and unmedicated bipolar patients.11
It is hypothesized that various psychopathologies of major psychotic disorders and antipsychotics combined with or without lithium may alter the electrocardio-physiological activity of patients with bipolar disorder or schizophrenia. Bipolar manic patients who take lith-ium and haloperidol might have higher levels of 12-lead EKG abnormalities than lithium-free bipolar manic and schizophrenic patients. The first goal of this study was to identify any difference in 12-lead EKG changes between lithium-treated bipolar manic patients, and lithium-free bipolar manic and schizophrenic patients. The second goal of the study was to evaluate the ef-fects of lithium and haloperidol on any changes reported in the 12-lead EKGs of bipolar patients.
2.
Methods
2.1. Subjects
Subjects were selected from an overall group of acute in-patients at Taipei City Psychiatric Center, Taipei, Taiwan, from January 1, 1990 to December 31, 2007. The inclusion criteria were: (1) fulfilling the Diagnostic and Statistical Manual of Mental Disorders-IV diagnostic criteria for schizophrenic disorder or bipolar I disorder, manic; and (2) having a score severity of psychiatric symptoms of > 35, rated on the Brief Psychiatric Rating Scale for schizo-phrenic patients or a score of > 26 on the Young Mania Rating Scale for bipolar patients.12,13 A clinical diagnosis of each subject and grading of severity of psychiatric symptoms were made by a board-certified psychiatrist at the time of admission.
The experimental group included patients who were taking both lithium and haloperidol at the same time that EKGs were performed. The comparison groups in-cluded patients with bipolar disorder or schizophrenia who had not taken lithium or any oral antipsychotics for at least 2 weeks before the EKGs were performed. Depot preparations, antipsychotics other than haloperidol, and
tricyclic and tetracyclic antidepressants were not allowed in any subjects. Patients with a significant, potentially life-threatening physical disease which was extracted from the case notes and who were not receiving regular follow-up were excluded. Patients aged over 50 years or with a significant physical disease were also ex-cluded from the study. The institutional review board at the Taipei City Psychiatric Center approved this pro-tocol.
2.2. Collection of clinical data
Clinical data were obtained through a retrospective re-view of the medical records of all subjects. Data abstrac-tion was done manually by the authors and informaabstrac-tion was collected pertaining to demographics, substance use, prescription medication (including daily dosage and total duration of haloperidol and lithium), results of laboratory examinations (including electrolytes, bio-chemical and hormone levels that were routinely con-ducted on the morning after admission), measurement of vital signs, and records of 12-lead EKGs.
The Kenz-Cardico 302 (Suzuken Co. Ltd., Nagoya, Japan) was used to record the EKGs. Each recording consisted of 10 seconds of the 12 leads recorded simulta-neously; with a paper speed of 25 mm/second. The ventricular rate, PQ interval, QRS complex, QT interval, amplitude of the R wave in V5, and amplitude of the S wave in V1 were calculated by the Kenz-Cardico 302’s computerized analysis. The PQ interval was measured from the beginning of the P wave to the beginning of the QRS complex. The QT interval was measured from the beginning of the QRS complex to the end of the T wave. Because the QT interval shortens when the heart rate increases, a rate-related corrected QT (QTc) interval, calculated as the ratio of the QT interval to the square of the RR intervals,14 was determined.
2.3. Statistical analysis
The three patient groups were compared for continuous variables using analysis of variance or χ2 test. Pearson’s correlation test was used to assess any association be-tween the continuous clinical variables and EKG pa-rameters. A two-tailed p value of < 0.05 was considered significant. All statistical analyses were performed with SPSS version 10.0 (SPSS Inc., Chicago, IL, USA) for Windows.
3.
Results
We recruited 30 lithium/haloperidol-treated patients (15 males, 15 females) with bipolar mania, 33 lithium-free bipolar manic patients (21 males, 12 females), and 31 lithium-free schizophrenic patients (15 males, 16 females). The mean Young Mania Rating Scale score of acute mania at the time of the study was 36.2 (range, 26–45).
In the lithium/haloperidol-treated group, all subjects had taken their medication for at least 4 days before the 12-lead EKGs were recorded. The mean duration of med-ication use prior to the 12-lead EKG recording was 39.0 ± 8.9 days. The mean dosage of psychotropic drugs was 8.4 ± 5.2 mg/day of haloperidol and 860.0 ± 274.9 mg/day of lithium, with a mean serum level of 0.66 ± 0.23 mmol/L. The demographic and clinical variables of the pa-tients are shown in Table 1. Papa-tients in the three groups had comparable mean ages, blood pressure, and levels of serum glucose, uric acid, total cholesterol, triglycerides, and thyroxine. Subjects in the lithium-free schizophrenic group had significantly lower mean serum potassium levels than those in the lithium/haloperidol-treated and lithium-free bipolar mania groups (p = 0.006).
The results of the 12-lead EKGs are shown in Table 2. The mean PQ interval, and amplitude of the R wave in V5 (RV5) and of the S wave in V1 (SV1) were not different among the three groups. QTc intervals were shortest in the lithium/haloperidol-treated bipolar mania group;
however, the difference was not statistically significant [df = (2, 91), F = 1.548; p = 0.218]. In the lithium/haloperidol-treated bipolar mania group, the mean ventricular rate was lower than that in the lithium-free bipolar mania and schizophrenic groups, but the significance was mar-ginal [df = (2, 91), F = 2.943; p = 0.058].
Correlations between 12-lead EKG parameters and continuous clinical variables were also examined in the lithium/haloperidol-treated bipolar mania group. Ven-tricular rates had a significantly positive correlation with diastolic blood pressure (r = 0.385; p = 0.036), and a mar-ginally significant correlation with daily haloperidol chlorpromazine (CPZ) equivalent dosages (r = 0.308; p = 0.098), daily lithium dosages (r = 0.358; p = 0.052), and the total duration of lithium use (r = 0.341; p = 0.065). QTc intervals demonstrated a marginally significant corre-lation with serum lithium levels (r = 0.373; p = 0.05), but not with symptom severity, daily haloperidol CPZ equiv-alent dosage, daily lithium dosage, or the duration of lith-ium use (data not shown). EKG parameters did not show
Table 1 Demographic and clinical variables in the lithium/haloperidol-treated bipolar manic, lithium-free bipolar manic,
and lithium-free schizophrenic groups*
Lithium/haloperidol-treated Lithium-free bipolar Lithium-free bipolar mania (n = 30) mania (n = 33) schizophrenia (n = 31)
Sex, male 15 (50.0) 21 (63.6) 15 (50.0) Cigarette smoking 10 (33.3) 13 (39.4) 9 (29.0) Alcohol use 2 (6.7) 0 (0.0) 0 (0.0) Age (yr) 31.0 ± 9.6 31.3 ± 7.6 32.8 ± 8.4 Symptom severity YMRS 36.0 ± 6.0 36.4 ± 5.1 – BPRS – – 52.5 ± 7.7 Daily SBP (mmHg) 120.3 ± 15.1 125.8 ± 14.8 122.1 ± 19.1 Daily DBP (mmHg) 74.6 ± 11.5 80.2 ± 13.9 74.6 ± 16.9 Serum [K+] (mmol/L) 4.17 ± 0.52† 4.17 ± 0.36† 3.81 ± 0.36†
*Data presented as n (%) or mean ± standard deviation; †analysis of variance, df = (2, 88), F = 7.084, and p = 0.001 by post-hoc analysis: lithium-free schizophrenic group versus lithium/haloperidol-treated bipolar mania group, p = 0.006, and lithium-free schizophrenic group versus lithium-free bipolar mania group, p = 0.006. YMRS = Young Mania Rating Scale; BPRS = Brief Psychiatric Rating Scale; SBP = systolic blood pres-sure; DBP = diastolic blood pressure.
Table 2 Twelve-lead electrocardiographic characteristics in the lithium/haloperidol-treated bipolar mania, lithium-free
bipolar mania, and lithium-free schizophrenia groups*
Lithium/haloperidol-treated Lithium-free bipolar Lithium-free bipolar mania (n = 30) mania (n = 33) schizophrenia (n = 31) Ventricular rate (beats/min) 74.4 ± 16.3† 84.2 ± 16.6† 81.0 ± 15.8 PQ interval (s) 0.155 ± 0.242 0.156 ± 0.308 0.147 ± 0.206
QRS complex (s) 0.089 ± 0.014 0.091 ± 0.013 0.089 ± 0.013 QTc interval (s) 0.410 ± 0.026 0.418 ± 0.044 0.430 ± 0.055 RV5 (mV) 1.19 ± 0.49 1.31 ± 0.53 1.23 ± 0.41 SV1 (mV) 0.87 ± 0.39 0.96 ± 0.44 0.89 ± 0.43
*Data presented as mean ± standard deviation; †analysis of variance, df = (2, 91), F = 2.943, and p = 0.058 by post-hoc analysis: lithium/ haloperidol-treated bipolar mania group versus lithium-free bipolar mania group, p = 0.062. RV5 = the amplitude of the R wave in V5; SV1 = the amplitude of the S wave in V1.
significant correlations with levels of serum glucose, uric acid, triglycerides, thyroxine, or potassium. The daily haloperidol CPZ-equivalent dosage had a significantly positive correlation with daily diastolic blood pressure (r = 0.546; p = 0.002) when an analysis of the correlation between dosages and durations of psychotropic drugs and continuous clinical variables was performed. There was no correlation of serum lithium levels with serum potassium levels, or of serum potassium levels with the QTc interval.
4.
Discussion
In contrast to our hypothesis, the present data showed that the routine 12-lead EKGs did not alter in bipolar manic and schizophrenic patients, regardless of whether the patients used lithium and haloperidol. The compari-son between lithium/haloperidol-treated and lithium-free bipolar manic patients examined the possible effect of medication on EKG changes. The serum lithium level of acutely manic patients may be positively asso-ciated with the QTc interval. However, in bipolar manic patients, the combination of lithium and haloperidol did not lead to an abnormal EKG; in particular, there was not a prolonged QT interval. This finding is similar to that of a retrospective study of 30 acute bipolar and 31 schizophrenic patients.11 One explanation is that the 12-lead EKG is not sensitive enough to detect altera-tions in electrocardiophysiological activity.
The finding that acute schizophrenic patients in our study had lower levels of serum potassium than bipolar manic patients is consistent with the finding that acute schizophrenic patients tend to have lower than normal serum potassium levels.15 Bipolar illness appears to be associated with a wide range of ion regulation abnor-malities. These changes include altered activities of Na/K ATPase, calcium ATPase, and intracellular sodium.16–19 These anomalies may have contributed to differences in serum potassium levels between acute schizophrenic and bipolar manic patients in our study. This hypothe-sis will need to be evaluated in future studies.
Approximately 20–30% of patients treated with lithium have cardiovascular side effects such as arrhyth-mias,20 T-wave flattening, and possible T-wave inver-sion. Lithium with similar univalent cations as potassium may interfere with the outward potassium current, re-sulting in QTc prolongation.21 However, the mechanisms of QT prolongation by lithium have not been clarified in bipolar manic patients. The present data support the possibility that an increasing serum lithium level, rather than manic severity, may prolong the QTc interval. Nevertheless, this implication needs to be further in-vestigated because the correlation of serum lithium levels with the QTc interval was not strong in this study.
Some methodological limitations should be ad-dressed. First, the half-lives of psychotropic agents are
generally shorter than the study period of 2 weeks. Although we included bipolar manic and schizophrenic patients who did not have lithium and oral antipsy-chotics for at least 2 weeks before recording the rou-tine 12-lead EKGs, psychotropic agents may still have long-term effects on the cardiovascular system.4,22 Such effects were not examined in our study. Second, the present subjects were all in the acute phase of their illness and might have received haloperidol or benzo-diazepine injections at some time to attenuate their psychiatric symptoms. We did not exclude such pa-tients or record EKGs at a definite time point after any psychotropic agents were given. Third, to investigate the effects of lithium and antipsychotics on electrocar-diophysiological activity, it is essential to compare EKG records after administration of medications with those at baseline in such a small number of subjects. Examining more time points is necessary to determine any altera-tions in the recordings of 12-lead EKGs in further studies. Fourth, although Bazett’s formula remains in wide-spread clinical use today, this correction was found to undercorrect the QT interval at low heart rates and to overcorrect it at high rates.23 Fifth, the sample size might not have been sufficient to reveal small differences using this method.
In conclusion, manifestations of routine 12-lead EKGs were not altered in bipolar manic and schizophrenic patients, regardless of whether the patients used lith-ium and haloperidol. However, serum lithlith-ium levels of acutely manic patients were positively associated with the QTc interval. Due to limitations of routine 12-lead EKGs, QTc intervals should be carefully followed-up in bipolar manic patients treated with lithium.
Acknowledgments
This study was supported by research grants (NSC93-2314-B-038-006 and NSC94-2314-B-038-001) from the National Science Council of Taiwan.
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