Assesment of Risk Factors for Tardive Dyskinesia

Abstract

Objective

Aim of the study is to evaluate sociodemographic and clinical features that may be associated with the development of Tardive dyskinesia (TD).

Methods

80 patients attending an outpatient psychiatry clinic in Istanbul, Turkey were divided into TD (n = 50) and control groups (CG) (n = 30). Sociodemographic and clinical data was collected through face-to-face interviews and a retrospective search of medical records.

Results

There was a significant difference between TD and control group (CG) in terms of mean; onset of psychiatric disease at or after 35 years of age; first use of APD at or after 35 years of age; use of long-acting injectable APD; history of extrapyramidal side-effects; history of akathisia and family history of psychiatric disease. There was no significant difference between the two groups in terms of DSM- IV-based psychiatric diagnosis distributions, the existence of complete recovery periods during the course of the disease; total duration of APD use for at least 10 years; APD holidays; regular APD use; history of ECT and smoking or alcohol and substance abuse/addiction.

Conclusion

Advancing age seemed to be the most significant risk factor in the development of TD. Clinicians need to be cautious about TD when prescribing APD for elderly patients.

Introduction

Tardive dyskinesia (TD) is a late side effect of dopamine antagonists (DA), including antipsychotic drugs (APD). TD is a movement disorder with no specific treatment, which may have a permanent negative impact on patients lives. A meta-analysis of studies conducted between 2000 and 2015 reported an average prevalence of 25.3% for TD.¹ In Turkey, the incidence of TD was found to be 22.5% in long-term hospitalized patients with schizophrenia.² Regarding the high prevalence and the negative consequences it is essential to identify risk factors for the development of TD to prevent it.

Advanced age has been reported as one of the most prevalent and consistent sociodemographic risk factor for TD.^3,4 The use of APDs at high doses and over long periods, long disease durations, high total dose of APD exposure, treatment with first- generation (FG) APDs, use of long-acting injectable (LAI) FGAPDs, drug holidays (at least three drug holidays for more than 2 months), development of extrapyramidal side effects (EPSs) in the early period (first 31 days), affective diseases, use of anticholinergic drugs (ACDs), electroconvulsive therapy (ECT), smoking and alcohol/substance abuse/addiction, family history of psychiatric disorders, family history of TD, and genetic predisposition have been reported among other clinical features that increase the risks of developing TD.^4–16

The negative consequences of TD are, impaired patient compliance with treatment, psychosocial problems, and reduction in quality of life, functionality, activity, and productivity, as well as an increase in mortality.^17–19 Patients with TD have been reported to have more severe psychopathology, longer periods of hospitalization, lower remission rates, more severe EPS, higher resistance to treatment, and a worse prognosis.^7–18 TD has also been reported to cause ethical and legal problems for physicians.²⁰

Currently, there is no effective and safe treatment for TD. The current treatment modality is a preventive approach that includes risk reductions. With this approach, individualized evaluation of APD treatment is recommended, considering the risk factors responsible for the development of TD.²¹ In this study, it was aimed to evaluate some sociodemographic and clinical features that may be associated with the development of TD; because its prevalence is high, it can have negative consequences for both patients and physicians and treatment options for TD are not efficient enough. To the best of our knowledge, there are few case reports and only one study regarding TD risk factors in Turkey.^2,22–24 Therefore, the present study aims to enrich the available literature on the risk factors of TD in Turkish psychiatric patients.

Methods

Subjects

Patients who were attending the Outpatient Clinic at Bakırköy Psychiatric Hospital, Istanbul, Turkey, and met the inclusion criteria were given verbal and written information about the study; those who agreed to participate in the study were included after providing their written consent. A total of 80 subjects were divided into a TD group of 50 subjects and a control group of 30 subjects.

Inclusion Criteria

Patients who had been on APDs for at least a year with clinical diagnosis of TD based on DSM-IV-TR (APA, 2000) were assigned to the TD group, whereas those who had used APDs for at least 3 months without TD were assigned to the control group (CG).²⁵

Exclusion Criteria

Presence of any neurological or other medical condition or a history of drug use that could cause movement disorders, if no information could be obtained from them or their relatives, or if retrospective medical information was unavailable.

Demographic and Clinical Characteristics

Age, duration and age at onset of illness, types and dosages of current and past medications, remission history, ECT history, alcohol/substance abuse/use disorder history, family history of psychiatric disorder were collected through face-to-face interviews and a retrospective search of medical records.

Abnormal Involuntary Movements Scale (AIMS)

AIMS was developed by Guy (1976) to assess the presence and severity of dyskinesia.²⁶ In this study, the presence and severity of abnormal movements in the seven body areas defined by AIMS, including the muscles of facial expression, lips and perioral area, jaw, tongue, and upper and lower extremities, were graded from 0 to 4 points (0 = No involuntary movements, 4 = Severe involuntary movements).

Statistical Analysis

The Statistical Package for Social Sciences (SPSS) software (version 16) was used for statistical analysis of the data in the study. The results of the descriptive analysis were expressed as numbers and percentages, and continuous variables were expressed as mean, standard deviation (SD), median, and minimum and maximum values. Fisher’s exact and Pearson’s chi-square tests were used for the analysis of categorical variables, the Mann–Whitney U test was used for the analysis of the correlation between numerical and categorical data, and Student’s t-test was used for pairwise comparison of numerical parameters. Statistical significance was defined as p < 0.05.

Results

According to the AIMS scale, 10% of the TD group had severe TD, 50% had moderate TD, 38% had mild TD, and 77.6% had abnormal movements in the facial and perioral regions. The mean AIMS score was 11.28 (SD = 5.07), and the mean duration of TD was 25.65 months (SD = 17.91). At the onset of TD, the mean dose of APD used was equivalent to chlorpromazine 650.6 mg/day (SD = 424.46), and 71.9% of the patients were using FGAPDs. No significant difference was observed between the groups in terms of drugs used in addition to APDs [anticholinergics (p = 0.598), antiepileptics (p = 0.600), benzodiazepines (p = 0.600), or antidepressants (p = 0.951)]. There was no significant difference between the two groups in terms of DSM-IV-based psychiatric diagnosis distributions (p = 0.335, X² = 11.30; Table 1).

Table 1. Psychiatric Diagnosis of Tardive Dyskinesia and Control Group.

		CONTROL GROUP				TD GROUP
		N		%		N		%
Schizophrenia		7		23.3		15		30
Delusional D.		–		–		6		12
Schizoaffective D.		2		6.7		3		6
Unipolar Depressive D.		2		6.7		5		10
Bipolar Affective D.		11		36.7		9		18
Anxiety D.		–		–		1		2
Psychoactive SRD		1		3.3		–		–
Psychotic Disorder NOS		6		20		6		12
Mood Disorder NOs		1		3.3		3		6
Dementia		–		–		1		2
Psychotic D.RTGMC		–		–		1		2

TD: Tardive Dyskinesia, D: Disorder; SRD: Substance related disorder; NOS: not otherwise specified; RTGMC: related to a general medical condition.

The mean age was significantly higher in the TD group (TD = 50.5 ± 14.94 years; control = 37.0 ± 12.05 years; p < 0.001). The incidence for the onset of psychiatric disease at or after 35 years of age was significantly different between the groups (TD = 28%, CG= 6.7%; p = 0.032). There was no significant difference between the two groups in terms of the existence of complete recovery periods during the course of the disease (p = 0.203) (Table 2).

Table 2. Comparison of the Groups in Terms of Certain Risk Factors for Tardive Dyskinesia Related to the Psychiatric Disorder.

				CONTROL GROUP				TD GROUP
				N		%		N		%		Χ2		P
PD Onset		<18 years of age		3		10		8		16
18–35 years of age			25		83.3		28		56
>35 years of age			2		6.7		14		28		6.87		0.032*
Complete remission periods		Yes		13		43.3		29		58
No			17		56.7		21		42		1.61		203

TD: Tardive Dyskinesia, PD: Psychiatric Disorder, *p < 0.05.

The first use of APD at or after 35 years of age was significantly different between the groups (TD = 40.0%, CG = 6.7%; p = 0.002). The total duration of APD use was longer than 10 years in 60.0% of the TD group and 43.3% of the CG (p = 0.505). There was no significant difference between the two groups in terms of APD holidays and regular APD use (p = 0.951, p = 0.182; respectively). It was found that all the patients using LAIAPDs were using FGLAIAPDs (flupenthixol decanoate, fluphenazine decanoate, zuclopenthixol decanoate, and haloperidol decanoate). The rates of the use of LAIAPDs were 56.0% in the TD group and 33.3% in the CG (p = 0.049). While the mean age of initiation of LAIAPDs was 38.2 (SD = 14.14) years in the TD group, it was 27.7 (SD = 6.38) years in the CG (p = 0.46). A summary of the comparison of groups in terms of antipsychotic drug use patterns are given on Table 3.

Table 3. Comparison of Groups in Terms of Antipsychotic Drug use Patterns.

				CONTROL GROUP				TD GROUP
				N		%		N		%		Χ2		P
First APD Use		<18 years of age		2		6.7		6		12
		18–35 years of age		26		86.7		24		48
		>35 years of age		2		6.7		20		40		12.59		0.002*
APD Holiday		No		10		33.3		17		34
		Yes		20		66.7		33		66		0.01		951
Regular APD use		No		5		16.7		15		30
		Yes		25		83.3		35		70		1.77		182
Long acting APD use		No		20		66.7		22		44
		Yes		10		33.3		28		56		3.86		0.049**

TD: Tardive dyskinesia, APD: Antipsychotic drug, *p < 0.001, **p < 0.05.

History of EPS and akathisia were significantly more in the TD group. There was a history of EPS in 60.0% of the TD group and 36.7% of the CG (p = 0.043). The rate of a history of akathisia was 72.3% in the TD group and 43.3% in the CG (p = 0.011). There was a history of ECT in 52.0% of the TD group and 46.7% of the control group, with no significant difference (p = 0.644). Family history of psychiatric diseases was 60.0% in the TD group and 36.7% in the CG (p = 0.043). No significant difference was observed between the groups in terms of smoking (p = 0.217) or alcohol (p = 0.424)/substance (p = 0.686) abuse/addiction. (Table 4)

Table 4. Comparison of Groups in Terms of Certain Risk Factors for Tardive Dyskinesia.

				CONTROL GROUP				TD GROUP
				N		%		N		%		Χ2		P
EPS in the acute period (first 31 days)		No		19		63.3		20		40
		Yes		11		36.7		30		60		4.08		0.043*
History of akathisia		No		17		56.7		13		27.7
		Yes		13		43.3		34		72.3		6.47		0.011*
History of ECT		No		16		53.3		24		48
		Yes		14		46.7		26		52		0.21		644
Family history of psychia tric disorder		No		19		63.3		20		40
		Yes		11		36.7		30		60		4.08		0.043*

TD: Tardive dyskinesia, EPS: Extrapyramidal side-effect, ECT: Electroconvulsive therapy, *p < 0.05.

Discussion

It is important to know the risk factors for TD to reduce the risk of developing TD and its related negative consequences. In most studies age is reported as one of the important risk factors for TD development, with the incidence of TD evidently increasing with advancing age.^1,4,12,27,28 While the annual incidence of TD in young people is around 3–5%, it is reported to be over 30% in patients above 45 years of age.^4,29 In the current study, there was a significantly higher mean age in the TD group (TD = 50.5 ± 14.94 years; CG = 37.0 ± 12.05 years) consistent with the findings of two recent studies.^13,30 However, studies have also reported that there is no relationship between age and the development of TD, age is not a factor that increases the risk of TD, and patients taking APDs are at serious risk of developing TD regardless of age.^5,31,32

The increase in the risk of TD with advancing age may be due to the accumulation of the drug with age-related neurological changes and a slowdown in metabolism.^{1,4,5,9,33,34} Jeste et al. (1995) found that the incidences of TD were 26%, 52%, and 60% at the end of the first, second, and third years, respectively in patients older than 45 years.¹⁴ The incidence of TD increased from 25% to 53% after 3 years of using neuroleptic drugs in patients aged 55 years and older.⁵ These two studies included patients older than 45 years of age, so it is not possible to comment on the effects of advancing age. However, the study by Bakker et al. (2011) included younger age groups and they reported an increase in the incidence of TD with advancing age, with a rate of 15.4% under 40 years of age and 37.5% at age 53 and over.³⁵ Therefore, increase in the incidence of TD may not be associated with increased exposure to APDs but may be related to advanced age. Findings of the current study support this view, because the incidence for the onset of psychiatric disease at or after 35 years of age was significantly different between the groups and the first use of APD at or after 35 years of age was significantly different between the groups (TD = 40.0%, CG = 6.7%; p = 0.002). Besides, there was no significant difference between the groups in terms of 10 years or more APD use (TD = 60.0% CG = 43.3%, p = 0.505). In the current study longer exposure time to APD did not affect TD development. Both the US-based Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and the meta-analysis of 21 studies state that prolongation of the disease increases the tendency to develop TD which may as well be interpreted as a projection of advancing age.^1,7 In the current study, neither earlier onset of psychiatric disease nor earlier age of APD use onset resulted in significant difference between TD and controls.

A previous review reported a lack of sufficient data to suggest that interruptions in drug therapy increase the risk of developing TD.³⁶ However, subsequent studies have reported that discontinuation and irregular use of APDs are among the risk factors for TD.^4,11 Van Harten et al. (1998) emphasized that two or more APD holidays cause a threefold increase in the risk of TD compared with fewer holidays.¹¹ In the current study, no significant difference was found between the groups in terms of the regularity of drug use and the presence of APD holidays.

There are conflicting data in the literature on the relationship between the TD risk and the diagnosis of mood disorders. Rajan et al. (2018) reported a prevalence of around 10% for TD among patients with bipolar disorder type-1.³⁷ Patterson-Lomba et al. (2019) reported a higher risk of developing TD in patients with affective diseases.¹³ Patel et al. (2019) found a fourfold higher odds ratio for the incidence of TD in patients with schizophrenia and bipolar disorder in a large sample of 77,022 adult inpatients. In contrast, it was reported that 77.1% of TD patients were diagnosed with schizophrenia spectrum disorder in a meta-analysis.¹ In the current study schizophrenia spectrum patients made-up 62% of TD and 50% of CG, while patients in the affective spectrum (including unipolar depression) made-up 34% of TD and 46.7% of CG. However, the cross-sectional nature of the study and the small sample size makes it hard to interpret these findings.

It has been reported that treatment with FGAPDs increases the risk of TD.⁷ Second- generation APDs (SGAPDs) have been reported to reduce the risk of developing TD and the severity of an established TD, and they may also be used in the treatment of TD.³⁸ A comparative meta-analysis of randomized controlled trials showed that FGAPDs were significantly associated with a higher rate of TD than SGAPDs were, regardless of the dose.1 Consistent with these findings, in the current study there was a significantly higher number of patients using FGAPDs in TD group. However, some studies have shown no significant difference between the two groups of APD in terms of the risk of developing TD.^4,7,33 Bransgrove and Kelly (1994) reported that the use of LAIFGAPD increases the risk of TD in an earlier study.¹⁰ Recent studies state that the risk of TD is lower with the use of long-acting injectable (LAI)SGAPD.^39,40 Since all patients in the current study used LAIFGAPDs, no comparison was made between LAIFGAPDs and LAI SGAPDs in terms of the risk of TD development. In our study, there was a significantly higher rate of use of LAIFGAPDs in the TD group, but we can’t differentiate whether this increase in TD is solely related to LAIFGAPD or to FGAPD use which is a more pronounced risk factor for TD. The mean age of initiation of LAIAPDs was significantly higher in the TD group. This result can be explained by the increasing sensitivity to TD with advancing age.

A risk of developing TD in patients with EPS in the early period after the use of APDs has been identified.^5,7,34 Jeste et al. (1993) reported that the emergence of tremor is also associated with an increased risk of TD.³ Consistently, in the current study, there was a significantly higher rate of early EPS development and a history of akathisia in the TD group.

Some other relatively less studied risk factors for TD development are ECT, smoking, alcohol/substance abuse/addiction and family history of psychiatric illness.^7,12,14,41 In the current study no significant relation was found for the association between ECT and TD similar to the study by Go et al.⁹ And TD risk was not increased in smokers and alcohol/substance abusers/addicts like previous two studies.^9,42 There was a significantly higher rate of a family history of psychiatric disorders in the TD group. In the familial occurrence study of TD, Muller et al. (2001) stated that a family history of TD, rather than a family history of mental disorders, is a risk factor for the development of TD.¹⁵ It is hard to make a comment regarding the effect of family history of psychiatric disease on TD in the current sample because unlike Muller et al.’s study a family history of TD can’t be in the current sample was not asked.

There are some limitations of the study. The cross-sectional nature of the study prevents us to comment on the longitudinal effects of risk factors such as prolonged exposure to APDs and smoking and alcohol/substance use. Lack of patients who were on LAISGAPDs is another limitation, because most LAISGAPDs have been developed to prevent various disabling side-effects of APDs such as TD. With a larger sample size we would have better opinion on the association between TD and psychiatric diagnosis.

The results of the study indicate that there is a higher risk for the development of TD in patients with advanced age, treatment with FGAPDs, use of LAI FGAPDs, acute EPS development, development of akathisia, and a family history of psychiatric disorders. However, there was no correlation between the development of TD and the type of psychiatric diagnosis, the duration and regularity of APDs, APD holidays, the presence of remission, the use of ACDs, a history of ECT, or smoking and alcohol/substance abuse/addiction. In conclusion, this study is significant as the second to evaluate the risk factors affecting the development of TD in Turkey. Advancing age seemed to be the most significant risk factor in the development of TD. Clinicians need to be cautious about TD when prescribing APD for elderly patients. Further longitudinal follow-up studies are needed to determine the risk factors, prognostic factors, course, and outcome of TD.