Irritability Symptoms in Gilles de la Tourette Syndrome

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, in association with behavioral symptoms.¹ The estimated prevalence of GTS is up to 1% in school-age children, and typical onset occurs before 18 years of age.² Although its exact etiology is still unknown, a significant genetic component has been shown, alongside disturbances in dopamine neurotransmission in the basal ganglia and cortico-striato-thalamo-cortical circuitry.³ In up to 90% of patients, GTS is associated with other neuropsychiatric comorbidities, most commonly obsessive-compulsive disorder (OCD), attention-deficit and hyperactivity disorder (ADHD), and mood disorders.⁴ Patients with GTS often experience difficulties in controlling urges to carry out reward-seeking behavior, regardless of the consequences, sometimes fulfilling diagnostic criteria for impulse control disorders (ICDs). It has been hypothesized that the basal ganglia play an important role in facilitating rewarding behaviors and inhibiting unwanted ones, which further substantiates the evidence surrounding its dysfunction in GTS. Previous studies have suggested a link between GTS and ICDs, particularly intermittent explosive disorder (IED) and self-injurious behavior.^5,6

IED is characterized by rage attacks and explosive outbursts, behaviors that may be precipitated by irritability. Irritability is a commonly reported symptom, especially across neuropsychiatric patients; however a single definition has not yet been universally agreed. One frequently cited definition states that “irritability is a feeling state characterized by reduced control over temper, which usually results in irascible verbal or behavioral outbursts, although the mood may be present without observed manifestation.”⁷ Arguably, irritability is different from other mood disorders such as depression, although psychiatry classification systems do not recognize irritable mood disorder as such and tend to include irritability as a ‘minor’ symptom of other diagnoses (e.g., depression or anxiety). Irritability is considered a part of normal human behavior; however, it may also underlie some of the aforementioned behaviors commonly associated with GTS. Patients with GTS often complain of feeling irritable, which is understandable in those constantly trying to suppress tics⁸; however, there is a lack of research focusing on this symptom in this patient population.

Given the frequency and relevance of irritability across neuropsychiatric disorders, we set out to investigate the clinical correlates of irritability symptoms in adult patients with GTS, and specifically to assess whether there is any relationship with tic severity. A better understanding of the sources of frustration and irritability in this patient population may provide clinicians with useful indications about treatment priorities, as well as improving awareness of the condition.

Methods

Data were collected as part of a broad study assessing clinical correlates of health-related quality of life in adults with GTS. Consecutive eligible patients with a diagnosis of GTS, as defined by the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR),¹ were recruited from the specialist GTS clinic at the Department of Neuropsychiatry, BSMHFT and University of Birmingham, United Kingdom. Patients under 16 years of age, with limited understanding of English or learning disabilities were excluded from the study. Informed consent was gained from all participants, and ethical approval was obtained from the South Birmingham NHS Research Ethics Committee, BSMHFT R&D Unit and the University of Birmingham Internal Ethics Committee.

Data were collected from 148 participants with a diagnosis of GTS using a semistructured clinical interview, plus a battery of clinician-rated psychometric scales and self-report questionnaires. Demographic and clinical data were obtained using the National Hospital Interview Schedule (NHIS) for GTS, the Yale Global Tic Severity Scale (YGTSS), and the Diagnostic Confidence Index (DCI). Irritability symptoms were assessed using the Irritability Questionnaire (IRQ).

National Hospital Interview Schedule (NHIS)

The NHIS⁹ is a detailed semistructured diagnostic interview used to collect demographic and clinical data from patients with a suspected diagnosis of GTS. Questions were originally developed according to diagnostic criteria set out in the DSM and the International Classification of Diseases (ICD). The NHIS covers personal and family medical history, as well as comorbidities such as OCD, ADHD, and affective disorders. Good levels of internal consistency have been demonstrated, and the NHIS has proven to be a reliable and accurate diagnostic tool. Clinical variables collected for this study included: age at interview, age at first tic onset, disease duration, family history of tics, neuropsychiatric comorbidities, and medication use.

Yale Global Tic Severity Scale Score (YGTSS)

Tic severity was measured in this cohort using the YGTSS,¹⁰ a clinician-rated scale assessing the severity of both motor and vocal tics across five different domains: number, frequency, intensity, complexity, and interference. Each of these is scored from 0 to 5, and combined to produce a global tic severity score. There is an additional measure of impairment that addresses overall functioning in social, academic, and occupational environments, and this is scored from 0 to 50. These two scores are combined to produce the total YGTSS score, ranging from 0 to 100, with higher scores indicating increased tic severity. The development and validation process showed that this psychometric tool is characterized by high internal consistency ratings (Cronbach’s alpha coefficients) for both total tic severity and motor/vocal tic severity scores.¹¹

Diagnostic Confidence Index (DCI)

The DCI is a clinician-rated measure of lifetime likelihood of GTS diagnosis in patients presenting with tic symptoms. It covers 27 clinical features associated with GTS, all of which have a corresponding weighted score. The total DCI score is expressed as a percentage, with higher scores indicating higher confidence that the patient has GTS. As with the NHIS, it was developed based on DSM and ICD diagnostic criteria for GTS, and has been shown to correlate with tic severity as measured by the YGTSS.¹²

Irritability Questionnaire (IRQ)

The IRQ, a self-report scale specifically developed to assess the severity of irritability symptoms in both healthy subjects and patients with neuropsychiatric disorders, was used to measure irritability in the GTS cohort. It consists of 21 statements concerning irritability feelings or behaviors, for which participants are required to rate the frequency and intensity, on a four point Likert-type scale. Scores range from 0 to 126, where higher scores indicate increased severity of irritability. The IRQ has been shown to correlate with other measures of irritability (construct validity), and is characterized by high internal consistency for the total score, alongside the two subscales measuring irritability symptom frequency and intensity. The scale’s test-retest reliability was also found be satisfactory.¹³ Overall, the IRI was chosen as it was designed to comprehensively assess irritability as a multidimensional phenomenon, encompassing cognitive (e.g., ‘I feel as if people make my life difficult on purpose’), emotional (e.g., ‘I have been feeling like a bomb, ready to explode’) and behavioral aspects of irritability (e.g., ‘I lose my temper and shout or snap at others’). Importantly, the IRI was validated in a sample of patients with neuropsychiatric conditions, including Huntington’s disease and Alzheimer’s disease, in addition to patients with affective disorders and healthy controls.¹³

Statistical Analysis

Descriptive statistics were used to illustrate the demographic and clinical characteristics of the patient population. This involved calculating frequencies and percentages, as well as means and standard deviations. Kolmogorov-Smirnov tests were used to ascertain which variables followed a normal distribution, and appropriate nonparametric tests were used when data were not normally distributed. In the case of normally distributed data, Pearson’s correlation coefficients were calculated, whereas Spearman’s rank correlation coefficients were calculated when data did not follow normal distribution. All statistical tests were two-tailed. Further bivariate analyses investigated which demographic variables or clinical characteristics were associated with irritability. Where the independent variable was continuous, Pearson’s or Spearman’s rank correlation coefficients were used, whereas independent samples t tests or Mann-Whitney U tests were used for binary categorical data. All variables found to be significantly related (p <0.1) to total irritability score, or its subscale scores (frequency and intensity), were subsequently entered into stepwise multiple linear regression models, where irritability score was the dependent variable. The effect of tic severity and other clinical and demographic variables on total irritability score was tested. Furthermore, the frequency and intensity subscale scores of the IRQ were tested to investigate whether there are any specific predictors of either aspect of irritability, resulting in a total of three regression models. R² values, coefficients, and 95% confidence intervals were reported for each model. In accordance with the assumptions for linear regression, the models were tested for multicollinearity, and all residuals tested for normality. All participants who did not complete the IRQ were excluded from the study, and incomplete or missing data (less than 5%), were replaced using individual mean imputation.¹⁴ All data were analyzed using Statistical Package for the Social Sciences (SPSS) version 19.0.

Results

After exclusion of ineligible patients and patients with incomplete data, statistical analyses were undertaken on a total of 101 patients. The demographic and clinical characteristics of the sample are shown in Table 1. The male to female ratio was approximately 2:1, and the mean age at interview was 31.7 years (range 16–64).

IRQ scores were available for all patients, with a small number of missing values (<1%) in the individual item responses. Results of bivariate analyses between tic severity and irritability are shown in Table 2. A moderate positive correlation was found between total YGTSS score and total IRQ score (r=0.37, p <0.001), and similar positive correlations existed between each subscale score of the YGTSS. The relationship between irritability and tic severity appeared to be stronger for vocal tics compared with motor tics. Severity of irritability symptoms, measured by mean IRQ score, was found to be higher in patients with comorbid ADHD, and this difference was statistically significant (t=−1.98, df=99, p=0.05). Similar patterns were found for the two subscale scores of the IRQ.

Multiple linear regression methods produced three models (Table 3). For each of the three regression models, the same five associated variables were included: YGTSS motor and vocal tic severity scores, YGTSS impairment score, plus comorbid OCD and ADHD diagnosis. Of these five variables, only vocal tic severity scores appeared to be a statistically significant predictor of irritability, according to confidence intervals analysis. This was the same across all three models.

The percentage of variability in irritability score which can be attributed to these five clinical variables ranged from 16% (F=4.734, df=5, p=0.001) for the intensity domain of the IRQ to almost 23% (F=6.934, df=5, p <0.001) for the frequency domain, with the variables predicting just less than 20% (F=5.971, df=5, p <0.001) of the variability in total IRQ score.

Discussion

This study set out to investigate the clinical correlates of irritability symptoms in adult patients with GTS, specifically focusing on tic severity. Our results indicate a moderate but significant association between irritability and tic severity, particularly vocal tics, suggests that patients with more severe tics are more likely to develop irritability. We also found a significant relationship between irritability and ADHD; however, no association was found in other comorbidities such as OCD, obsessive compulsive symptoms, affective disorders, anxiety disorders, autistic spectrum disorders, or other neuropsychiatric comorbidities. Gender, age at interview, age at tic onset, disease duration, and family history of tics had no significant effect on irritability scores, suggesting that underlying neurological mechanisms involved in GTS and comorbid ADHD may have a prominent role in irritability.

Although there are no previous studies looking specifically at irritability in patients with GTS, there are a number of studies, which have looked at IED and rage attacks in this clinical population. It has been shown that up to 40% of patients with GTS report behavioral symptoms associated with IED, including irritability.⁵ Because feeling irritable may act as a precipitant to explosive outbursts, rage attacks, or similar behaviors, this study prompts further research into these aspects.

Irritability and Tic Severity

This is the first study on the expression of irritability in GTS, as previous research focused on the association between tic severity and behavioral outbursts, with mixed findings. A study looking at explosive outbursts in children with GTS found that neither tic severity nor tic type had any relationship with the presence of explosive outbursts, although they did find explosive outbursts to be significantly associated with motor hyperactivity.¹⁵ In contrast, a more recent study found that the mean YGTSS score was significantly higher among patients who do have explosive outbursts, compared with those who do not.¹⁶ The authors of this study also found that the mean age of tic onset was significantly lower in those who experience explosive outbursts, a finding not corroborated by our study on irritability. In addition, a small study of Japanese children and adolescents with GTS found that tic severity was associated with aggressive behaviors; however, there was no distinction made between motor and vocal tic severity.¹⁷

The association found in our study may indicate that vocal tics in particular are more likely to increase irritability in patients. Tic suppression is known to expose to uncomfortable premonitory urges,¹⁸ which in turn might cause or exacerbate irritability. More severe tics are likely to be associated with more intense suppressing efforts. This hypothesis may be truer for vocal tics compared with motor tics, as they could be considered more noticeable, embarrassing or socially stigmatizing by patients. Alternatively, some patients with GTS may have a higher underlying level of irritability, causing their tics to be more severe. The frequency and severity of tics is already known to be higher during periods of stress, a phenomenon which may also occur during periods of irritability.³ Inconsistencies in the existing literature are not surprising, as irritability could be only in part related to IED, and the majority of previous studies were carried out on smaller samples, which may not have had adequate power to detect significant effect sizes.

Irritability and Neuropsychiatric Comorbidities

Severity of irritability symptoms was higher in patients with GTS and comorbid ADHD, and the coexistence of these conditions seems to predict irritability score. A similar pattern was seen in patients with OCD; however the difference did not reach statistical significance. This suggests that there may be some underlying neurobiological mechanism connecting ADHD and irritability, or that ADHD symptoms increase feelings of irritability. In addition, these patients may take different medications to patients without comorbid ADHD, which may affect irritability levels. No significant differences were found in the irritability levels of patients with other neuropsychiatric comorbidities.

These findings are generally consistent with previous studies which looked at IED and rage attacks. A number of studies have shown that the prevalence of both IED and rage attacks is higher among patients with GTS who also suffer with neuropsychiatric comorbidities,¹⁹ particularly ADHD,¹⁶ and, to a lesser extent, OCD.¹⁵ However, other studies have shown no relationship between neuropsychiatric comorbidities and rage attacks,¹⁷ and the results of our multiple variable regression model raise the possibility that the significant association between comorbid ADHD and irritability might have been confounded by tic severity. Likewise, as irritability symptoms are often reported in the context of clinical depression, the presence of comorbid mood disorders in one third of the sample could have affected our findings. A potential explanation for these mixed results is that irritability, which has not previously been investigated, may act as a mediator between comorbid behavioral conditions and explosive outbursts.

Limitations

Despite efforts to ensure methodological rigor and transparency throughout this study, there are a number of limitations, which could have affected our results. First, participants were recruited from a population of patients with GTS attending a single specialist clinic. Although patients are referred to this clinic from a large geographical area, the sample may not be representative of the general population of patients with GTS. Many patients with GTS are managed in the community, particularly if their symptoms are mild and do not interfere with functioning. This may mean that our sample includes more patients with severe or complex clinical pictures, as opposed to the full spectrum of GTS, and for this reason our results may not be generalizable to community populations. Second, the reported male:female ratio of patients with GTS is 3–4:1,² however, in our sample 67% of participants were male, with a male:female ratio of approximately 2:1. Again, the disparity between gender distributions in our sample compared with the general population of patients with GTS may reduce the generalizability of our study. Third, the IRQ, a self-report questionnaire, was used to assess severity of irritability symptoms in our population. The use of self-report questionnaires is associated with several limitations, a number of which may have affected our study. Recall and social acceptability bias may reduce the validity of the data, and participants may not fill out the questionnaire accurately or truthfully. At the time of data collection, participants were asked to complete multiple questionnaires, which can be time-consuming and for this reason some of them might have chosen to rush their answers, leading to inaccuracy. Finally, it was not possible to compare irritability ratings between patients with GTS and other clinical and healthy populations, as IRI score ranges from control groups were not available.

Clinical Implications

Findings from this study may help inform clinicians and other health care professionals about irritability in this population, enabling them to identify patients who may be at risk of behavioral outbursts. Focused interventions to manage irritability symptoms may help preventing the occurrence of explosive outbursts or rage attacks, thus, reducing the risk of violent behavior and contact with the legal justice system. Furthermore, tailoring behavioral or pharmacological therapies in patients at risk, for example those with severe tics or comorbid ADHD, may be key to improving patients’ quality of life.

Suggestions for Future Research

Future research into the relationship between GTS, irritability, and impulsivity should involve large scale studies, potentially across clinical and community-based populations of patients with GTS of all ages. The relationship between medication use and irritability deserves more in-depth analysis, as previous studies have shown that medication classes which are commonly used in GTS (e.g., antidopaminergic agents for tics and selective serotonin reuptake inhibitors for compulsions) have potential beneficial effects on irritability symptoms in other neuropsychiatric conditions, such as Huntington’s disease.²⁰ Research is also needed to explore the characteristics of irritability using validated rating systems, to confirm its prevalence, and to allow comparisons with other patient populations. In addition, qualitative methods could be used to investigate the effects that irritability has on patients, their actions, behavior, and wellbeing. This may help elucidate whether irritability is a significant problem for individual patients, and what effect it has on them.