QTc interval in patients on psychotropic medications

Abstract

Background:

Prolonged QTc intervals, psychiatric medications, and associated risks such as sudden cardiac deaths and their cardiovascular safety profile are still being studied globally, given the revolution brought by them in the field of psychiatry.

Aim:

To study the cardiac safety profile of psychotropics in terms of QTc prolongation and establish the safety of psychotropics as a group.

Materials and Methods:

In this study, 121 subjects receiving psychotropic medications were included. ECG of all the patients was performed and followed up to 4 weeks.

Results:

The control group showed no difference at any of the three-time intervals, with the mean QTc interval at baseline being 391.3 + 49.70, at one week being 391.3 + 49.70 and at four weeks being 391.3 + 49.70. In contrast, the mean QTc interval for the patients’ group was 352.9 + 64.68 at baseline, 353.3 + 649.70 at one week, and 354.4 + 64.82 after four weeks. The difference was found to be substantial (P < 0.001) but negligible (P = 0.078) when the baseline QTc interval was examined for one week. The point that needs to be highlighted here is that significant QTc changes after 4 weeks of starting some psychotropics were noted. However, the number of patients leading to QTc prolongation, i.e. QTc >470 mm/sec in females and >440 mm/sec in males, were, in fact, negligible (3 in number).

Conclusion:

Based on the prescribed doses of the medications and any Torsade de pointes (TdP) risk factors, those taking psychiatric medications should have a personalized cardiac monitoring routine. Overall, psychotropics have emerged as a safe option for treating psychiatric illnesses. They do impact the QTc interval, but the number of cases presenting with arrhythmia and other life-threatening cardiac side effects are very few that too if monitored, these risks can be avoided.

Psychotropic medicines are medications indicated to treat mental illnesses. Typically, these medications are categorized based on their primary therapeutic uses, such as antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, stimulants, and cognitive enhancers.[1]

Lately, emphasis is being given to the cardiac safety profile of psychotropics. However, due to the non-availability of sufficient clinical data on the patients from psychiatric hospitals, no clear remark could be made on their safety profile. Our study is one of its kind in this regard, as it has been performed on actual patients attending psychiatric hospitals. Little data is available regarding the impact of psychotropics on QTc has now been achieved through a review of data obtained from various pharmaceutical companies, and no such major study has been conducted that could assess the effect of psychotropics on QTc.

Psychiatric drugs, prolonged QTc intervals, and related dangers such as abrupt cardiac death are still receiving therapeutic attention.[2] A prolonged QT interval is a risk factor for the development of Torsade de pointes (TdP), a potentially fatal cardiac arrhythmia. The risk of TdP increases as the corrected QT (QTc) interval lengthens; a QTc interval greater than 500 ms is associated with a two- to threefold higher risk of TdP compared to intervals below 500 ms. Various factors contribute to QTc prolongation, including delayed cardiac repolarization, bradycardia, female sex, aging, electrolyte imbalances (hypokalemia and hypomagnesemia), congenital long-QT syndrome, a history of QTc prolongation, family history of sudden cardiac death, concurrent use of QTc-prolonging drugs, drug interactions, toxicity, liver or kidney dysfunction, and acute illnesses.[3]

Psychotropic medications, commonly prescribed in psychiatric practice, are known to prolong QTc intervals, increasing the risk of TdP. Studies have reported the prevalence of psychotropic-induced QTc prolongation as 5.7%, 7.6%, and 9.9%, respectively.[4,5,6] Cardiovascular mortality is notably high in psychiatric patients, with a review indicating a relative risk of sudden death ranging from 1.3 to 2.4 among those using psychotropic drugs.[7] QTc interval changes developing during psychotropic medication can be a cause for concern. Electrocardiogram (ECG) values at or near the maximum daily blood level of drugs altering the QT interval should be obtained in order to obtain the most reliable assessment of pharmacologic QT prolongation.[8]

ECG measurements should be taken at or near the drug’s maximum daily blood concentration to ensure an accurate assessment of drug-induced QT prolongation. Early identification of QTc changes and associated risk factors during treatment can help reduce cardiac morbidity and mortality in these patients. This study was conducted to evaluate QTc intervals in patients receiving psychotropic medications.

MATERIALS AND METHODS

The prospective observational study was conducted from December 2019 to May 2021.

The inclusion criteria are as follows:

• Patients are willing to provide written informed consent.

• Patients were on psychotropic medications for the defined period, which was defined as a period of drug usage of 1 week in the case of oral psychotropics and 3 months in the case of depot preparation.

The exclusion criteria are as follows:

• Patients who have already been diagnosed with a cardiac ailment.

• Patients who have an abnormal baseline ECG.

In this study, 121 participants were enrolled after obtaining their informed consent. Additionally, a control group of 121 healthy individuals, matched for age and sex with the study participants, was recruited from volunteers attending routine health check-ups. This control group compared the QTc changes observed in patients with age-matched healthy individuals. All participants were informed about the study, and their consent was obtained. Demographic data and medical history were also collected for analysis.

A baseline ECG was recorded in all cases, and QTc was measured using Bazett’s square root formula, i.e., QTC=QT/√RR interval. Psychotropics were started by the consultant in charge as indicated, patients were followed up after one week of achieving therapeutic dose, and ECG and QTc were recorded. Next, follow-up ECG and QTc recordings were performed after 4 weeks. ECG and QTc of age and sex-matched comparison groups, preferably of first-degree relatives and healthy controls, were recorded for comparison.

Statistical analysis

The categorical data were summarized as frequencies and percentages, whereas the continuous variables were reported as mean ± SD. Repeated measures ANOVA was used to find the QTc changes at different intervals. P values below 0.05 were regarded as statistically significant. QT intervals were measured manually from patients’ ECG and corrected by the most commonly used correction formula that of Bazett (QTc = QT/RR^0.5). A senior cardiologist consultant interpreted the data.

RESULTS

Our study’s mean age of study cases and controls was 34.5 ± 9.64 years and 35.1 + 11.75 years. Most patients in both the study cases, 39 (32.2%), and controls, 36 (29.8%), were aged between 21–30 years [Figure 1]. Study shows the male dominance in both groups [Figure 2].

Figure 1.

Age distribution of study subjects

Figure 2.

Gender distribution

In the control group, the mean QTc interval at baseline was 391.3 + 49.70; at 1 week, it was 391.3 + 49.70, while at 4 weeks, the mean QTc change was 391.3 + 49.70 which confirms that there was no difference at three different time intervals. Whereas, in the cases group, the mean QTc interval at baseline was 352.9 + 64.68; at 1 week, it was 353.3 + 649.70; at 4 weeks, the mean QTc change was 354.4 + 64.82. When the baseline QTc interval was compared to 1 week, the difference was found to be insignificant (P = 0.078), while it was significant (P < 0.001) when baseline QTc was compared with 4 weeks [Table 1].

Table 1.

QTc changes in Control and Cases at various intervals of time

Groups	QTc interval	Mean	SD	QTc changes	Comparison	P
Control Group	Baseline	391.3	49.70	-	-	-
	1 Week	391.3	49.70	0.0	Baseline vs. 1 week	-
	4 Weeks	391.3	49.70	0.0	Baseline vs. 3 weeks	-
Cases Group	Baseline	352.9	64.68	-	-	-
	1 Week	353.3	64.77	0.4	Baseline vs. 1 week	0.078
	4 Weeks	354.4	64.82	1.5	Baseline vs. 4 weeks	<0.001*

*Statistically significant difference with respect to baseline (P<0.05)

In this study, most subjects were on monotherapy (67.7%). Most of the study subjects were suffering from anxiety disorders (16.53%) followed by major depressive disorders (14.05%), bipolar affective disorder (12.4%), obsessive-compulsive disorder (10.74%), schizophrenia spectrum, and other psychotic disorders (9.91%). The most commonly observed comorbidity among study subjects was hypertension (3.3%), as presented in Table 2. Further, it was observed that three patients had prolonged QTc interval, and among them, two patients (66.7%) were at Known 1 TdP risk, and one patient (33.3%) was at conditional 1 TdP risk.

Table 2.

General characteristics of patients

	No. of Patients (n=121)	Percentage
Prescribed drugs
1	82	67.77
>2	39	32.23
Diagnosis
Anxiety Disorder	20	16.53
Major Depressive Disorder	17	14.05
Bipolar Affective Disorder	15	12.40
Obsessive compulsive Disorder and related disorders	13	10.74
Schizophrenia spectrum and other psychotic disorders	12	9.91
Dementia	11	9.09
Attention Deficit Hyperactivity Disorder	7	5.78
Migraine and headache	6	4.96
Trauma and stress related disorders	5	4.13
Substance use disorders	4	3.30
Intellectual disability with behavioural disorder	2	1.65
Seizure Disorder	2	1.65
Somatic disorder and other related disorders	2	1.65
Borderline personality disorder	2	1.65
Conversion disorder	1	0.82
Sleep Disorder (insomnia)	1	0.82
Brief Psychotic Episode	1	0.82
Hypertension	4	3.30
Diabetes mellitus	2	1.65
Hypothyroidism	2	1.65

In our study, the study subjects were analyzed for drugs received. At the same time, no statistical significance was found among patients using fluoxetine, fluvoxamine, paroxetine, mirtazapine, bupropion, lurasidone, aripiprazole, lamotrigine, valproate, donepezil and memantine, clonazepam, methylphenidate, lithium, venlafaxine, and sertraline as the P > 0.05.

Among antidepressants, patients on nortriptyline and escitalopram showed QTc changes after 4 weeks of use. Among Antipsychotics, such changes were shown with haloperidol, olanzapine, and risperidone. Among mood stabilizers, patients on valproate showed changes. However, QTc prolongation was observed in three patients only (two on haloperidol and one on olanzapine), and these three also did not land in any fatal arrhythmia or other life-threatening cardiovascular consequences. The mean QTc changes at baseline, and after one and four weeks by patients on nortriptyline, escitalopram, haloperidol, olanzapine, risperidone, escitalopram and clonazepam, valproate, and olanzapine are given in Table 3.

Table 3.

QTc changes in study patients at 1 week and 4 weeks of use of different psychotropic medications

Medication	Qtc interval	Mean	SD	Qtc changes	Comparison	P
Nortriptyline	Baseline	305.8	61.06	-	-	-
	1 Week	305.8	61.06	0.0	-	-
	4 Weeks	309.2	62.17	3.4	Baseline vs. 4 weeks	0.007*
Escitalopram	Baseline	336.1	84.65	-	-	-
	1 Week	336.7	83.73	0.6	Baseline vs. 1 week	0.356
	4 Weeks	339.3	84.69	3.2	Baseline vs. 4 weeks	0.001*
Haloperidol	Baseline	399.5	73.00	-	-	-
	1 Week	403.8	73.18	4.3	Baseline vs. 1 week	0.007*
	4 Weeks	404.8	72.50	5.3	Baseline vs. 4 weeks	0.002*
Olanzapine	Baseline	360.9	70.41	-	-	-
	1 Week	361.1	70.61	0.2	Baseline vs. 1 week	0.351
	4 Weeks	364.3	70.41	3.4	Baseline vs. 4 weeks	0.015*
Risperidone	Baseline	358.8	79.62	-	-	-
	1 Week	359.5	78.84	0.7	Baseline vs. 1 week	0.215
	4 Weeks	361.3	79.85	2.5	Baseline vs. 4 weeks	0.030*
Escitalopram and Clonazepam	Baseline	339.4	73.25	-	-	-
	1 Week	340.2	73.25	0.8	Baseline vs. 1 week	0.192
	4 Weeks	342.6	72.95	3.2	Baseline vs. 4 weeks	0.021*
Valproate and Olanzapine	Baseline	355.8	74.69	-	-	-
	1 Week	356.7	75.30	0.9	Baseline vs. 1 week	0.185
	4 Weeks	359.2	75.49	3.4	Baseline vs. 4 weeks	0.003*

*Statistically significant difference with respect to baseline (P<0.05)

DISCUSSION

Our study is one of its kind and holds importance for several reasons. It includes follow-up cases, which helped establish clear and precise results. Also, the study considered the controls, which added in discrete comparison and temporality of psychotropics and QTc changes. It is pertinent to mention here that such type of study with follow-up controls on the Indian population is unique and holds an indispensable position, which is one class of drugs that has revolutionized the branch of psychiatry Our study included 121 patients, of which the majority were males. Male preponderance could be attributed to overall male patients visiting the psychiatry outpatient department (OPD). This is in concordance with an earlier study conducted from this center where there was male preponderance among patients visiting OPD.[9] The majority of the patients belonged to the age group between 21 and 30 (30.58%). Our results are similar to another study which showed major depressive disorder in 32%, followed by anxiety disorders in 20%, somatoform disorder in 19%, substance use disorder in 12%, schizophrenia in 10%, and bipolar disorder in 7%. Hypertension was found to be the most common comorbidity (03.30%) out of the other two, diabetes and hypothyroidism (both standing at 01.65%).[10]

All the patients showing QTc prolongation were males, which agrees with an earlier study.[11] In our study, three patients showed QTc prolongation, two of them in the age group of 31 to 40, and one in the age group of 21 to 30. This is consistent with the result of an earlier study where most patients showing QTc prolongation belonged to the age group 21 to 30. All the patients showing QTc prolongation were on monotherapy.[4] All three patients who showed QTc prolongation had the diagnosis of schizophrenia spectrum and other psychotic disorders, and they all had no comorbidity. In contrast, another study found most patients with prolonged QTc with a diagnosis of major depressive disorder (47.8%) followed by bipolar affective disorder (3%). The drugs that caused the QTc prolongation belonged to the antipsychotic class of psychotropics, two of them on haloperidol and one of them on olanzapine.[4]

A total of 38 patients showed a significant effect on QTc interval after 4 weeks of attaining the therapeutic doses of psychotropics. Among them, 27 were on single drug therapy, and the rest 11 were on two drug therapy. The classes of drugs that showed significant QTc interval changes belonged to the antidepressants (TCA and SSRI) and the antipsychotics (first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs)). Among the TCAs, nortriptyline showed the change in four patients (10.52%); among SSRIs, escitalopram showed the same in seven (18.42%). Studies have found nortriptyline to be associated with great QTc-prolonging risk. It has been reported that TCAs significantly prolonged the QTc interval from 413.2 ± 17 ms before treatment to 419.9 ± 18.9 ms, P < 0.01. Among newer antidepressants, citalopram and escitalopram have also been implicated in QTc prolongation.[12] In the setting of long-QT syndrome (LQTS), selective serotonin reuptake inhibitors (SSRIs) can precipitate TdP.[13]

Research has documented that the antipsychotics most commonly associated with TdP were ziprasidone, haloperidol, risperidone, and quetiapine. Ziprasidone is rarely prescribed in our center; our study results concord with the above-mentioned studies.[14,15] Moderate QTc prolongation is sometimes seen under treatment with risperidone, even at therapeutic doses, mainly in older patients. The degree of QTc prolongation is dose-dependent and varies between antipsychotics, reflecting their different capacity to block cardiac ion channels. Significant prolongation is not a class effect.[16]

There were 11 patients on polytherapy, and they showed significant QTc interval changes. Out of 11, six were on the combination of valproate and olanzapine, whereas the other five were on escitalopram and clonazepam combination. An earlier study showed that abnormal values were present in 40 (8%) of 495 patients overall, 23 (8%) of 286 who were taking antipsychotic drugs alone, five (11%) of 44 on tricyclic antidepressants (TCA) alone, and eight (15%) of 53 who were taking combinations of antipsychotics and TCA.[11]

The point that needs to be highlighted here is that significant QTc changes after 4 weeks of starting some psychotropics were noted. However, the number of patients with QTc prolongation, i.e. QTc >470 mm/sec in females and >440mm/sec in males, was negligible (3 in number). Hence, we are focusing on reducing the stigma related to the cardiac safety profile of psychotropics, especially antipsychotics.

Limitations

In this study, patients were followed up for only 4 weeks after achieving the therapeutic doses. Several patients were lost in follow-up, patients on long-acting depot preparations could not be included, the effect of the individual drugs in patients on combined drugs could not be calculated, and all psychotropics could not be included.

Future directions

Future studies should examine the long-term comparative safety of different psychotropic drugs in patients with different ages, primary diagnoses, and multiple comorbidities and concomitant drugs. Novel technology applications and adequate statistical methods should be used for routine analysis of psychotropic-induced QT prolongation and cardiac arrhythmias. More studies that follow a prospective observation of patients over time can cover the lacunae of extended follow-up. Proper consideration should be offered to the assessment of QTIP and the selection of drug therapy in the patients in the presence of QTc, which prolongs risk factors to ensure patient safety and prevent life-threatening cardiac arrhythmias. Further observational studies with larger samples of patients, comparing QTc intervals, plasma levels of psychotropic, and daily doses of psychotropic drugs are necessary to perform statistical comparisons for each psychotropic and for each kind of antipsychotic-antidepressant association commonly used in clinical practice.

CONCLUSION

Lately, emphasis is being given to the side effect profile of psychotropics, especially cardiac safety. The results of the study confirm that the patients on certain psychotropics show QTc prolongation after a specific period of intake. However, several patients showed significant QTc prolongation, leading to fatal consequences is quite a. Hence, psychotropics as a group are generally safe if given within therapeutic doses with frequent monitoring. The current study concluded that to protect patients’ safety and avoid potentially fatal cardiac arrhythmias, due care should be given to the evaluation of QTc and the choice of medication therapy in people with a mental health condition with QT-prolonging risk factors. Psychiatric medication users should have their cardiac monitoring schedule based on their prescription drugs and any TdP risk factors.

Authors’ contributions

Concept: AH; Design, Literature review: IRS; Data acquisition: RAM, SS, FRB, AH; Data analysis: IRS, RAM, SS, FRB, HKS; Manuscript preparation: SS; Manuscript review; FRB, AH, HKS.

Ethical statement

The study was approved by the Institutional Ethics Committee of Govt. Medical College, Srinagar, Vide letter No.: IRBGMC-SGR/Psy /799, Dated 24/10/2024. Written informed consent was obtained from all participants prior to inclusion in the study.

Conflicts of interest

There are no conflicts of interest.

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Funding Statement

Nil.