Irritability Symptoms in Gilles de la Tourette Syndrome

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.

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

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

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

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.

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.

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.

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.

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.

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.