Gilles de la Tourette Syndrome,Depression,Depressive Illness,and Correlates in a Child and Adolescent Population

Abstract

Objective:

Gilles de la Tourette syndrome (GTS) and depression are both common disorders. It has been suggested that depression occurs in 13%–76% GTS patients. Despite this, there are few studies into the specific relationships and correlates between the two disorders. There is only some consensus as to the precise relationship between the two disorders.

Materials and Methods:

We undertook the study to investigate the relationship between depressive symptomatology and the core clinical features of GTS in a well-characterized clinical population of youth with this disorder. Our aim was to verify the association between depression and comorbid obsessive-compulsive disorder and explore further other potential associations highlighted in some, but not all, of the studies focused on this topic.

Results:

Our results demonstrated that (1) the GTS patients were significantly older than the controls, (2) the GTS patients were significantly more depressed than controls, (3) depression was associated with tic severity, (4) the Diagnostic Confidence Index scores were higher in GTS patients without depression, (5) anxiety, attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and behavioral problems were significantly associated with depression, and (6) finally, patients with GTS and depression have a positive family history of depression. However, obsessionality (CY-BOCS) did not differentiate between depressed and not depressed GTS patients.

Conclusions:

Depression is common in patients with GTS and occurs significantly more in GTS than in controls. Depression is significantly associated with GTS factors such as tic severity, comorbidity with ADHD, and the presence of coexistent anxiety, CDs, and behavior problems. Depression is importantly significantly associated with a positive family history of depression. Intriguingly, depression in our sample was not related to obsessionality.

Introduction

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with onset before 18 years of age, characterized by multiple motor and one or more vocal/phonic tics [Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (American Psychiatric Association 2013)] (WHO 1992) and affecting ∼1% of the general population (Robertson 2008, 2014). Only 10%–15% of individual patients with GTS have tics only (i.e., pure GTS) in both clinical sample (Freeman et al. 2000) and community (Khalifa and von Knorring 2003, 2005; Hirschtritt 2015), while the remaining patient population (85%+) manifests comorbid obsessive-compulsive behaviors/obsessive-compulsive disorder (OCB/OCD), attention-deficit/hyperactivity disorder (ADHD), autism/autistic spectrum disorders, or other psychopathologies such as conduct disorder (CD), oppositional defiant disorder, and depression (Robertson 2014). A study from Taiwan (Chou et al. 2013) confirmed that GTS patients have a significantly higher risk of developing depression than patients without GTS.

In a recent public health database study, Hirschtritt (2015) estimated the lifetime prevalence of any psychiatric comorbidity among 1374 individuals with GTS to be 85.7%, with 57.7% of patients exhibiting two or more disorders and a mean number of comorbid disorders equal to 2.1. After ADHD and OCD, the most common disorders were mood disorders, anxiety, and disruptive behaviors, each of which occurred in ∼30% of GTS patients (especially if the individuals had GTS+OCD).

The presence of depression in GTS remains an area in which further research is warranted. In reviewing the frequency of depressive symptomatology in GTS patients, Robertson (2006) reported a rather broad frequency range of 13%–76%. In this review, studies differed greatly in general design (clinical vs. community-based), diagnostic criteria, patient severity spectrum, and age, with the majority of studies focusing on adult populations. In addition, studies have more consistently reported an association between comorbid depression and comorbid OCD in GTS (Termine et al. 2011; Lebowitz et al. 2012; Rizzo et al. 2014; Hirschtritt 2015), which seemed to account, in large part, also for the genetic correlation between GTS and mood disorders (Hirschtritt 2015). Other studies reported an association of comorbid depression with tic severity (Lewin et al. 2012), including one prospective study on a relatively small patient sample suggesting that depressive symptoms in children and adolescents could predict short-term future tic severity (Lin et al. 2007). Less consistently, comorbid depression was found to be associated in GTS also with ADHD comorbidity (Haddad et al. 2009), CD in childhood (Snijders et al. 2006), and minor life events (Steinberg et al. 2013). It is well demonstrated that GTS patients are exposed to different sources of psychosocial stress that are also potentially linked to depression, among which are social isolation and rejection, peer victimization (Storch et al. 2007; Zinner et al. 2012), illness-related stigma (Davis et al. 2004), and low self-esteem (Thibert et al. 1995). Moreover, symptoms of depression appear to have a widespread negative impact on quality of life (QoL) in GTS patients (Eddy et al. 2011a, 2011b). Robertson et al. (1988) demonstrated that depression in their cohort was not related to medication.

Despite its relative frequency and its impact on QoL, the characteristics of depression in GTS remain insufficiently understood. In particular, little is known about the clinical features of GTS that correlate more strongly with depression as well as the pathobiological basis for these correlations. We conducted a cross-sectional study to investigate the relationship between depressive symptomatology and the core clinical features of GTS, a chronic complex condition, in a well-characterized clinical population of youth with this disorder. Our aim was to verify the association between depression and comorbid OCD and explore further other potential associations highlighted in some, but not all, of the studies focused on this topic.

Materials and Methods

Patient selection

Ninety-eight children and adolescents/young people (CYP) with a diagnosis of having GTS [according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-R) (American Psychiatric Association 2000) or DSM-5 criteria] were consecutively selected among eligible outpatients attending the tertiary referral service for GTS of the University of Catania. GTS patients were deemed eligible to the study if their IQ was within the normal range (110 ± 2 standard deviation [SD]) and if they had received comprehensive neuropsychiatric assessment (as outlined below) both at baseline and after at least 1 year of follow-up (FU). Patients with other neurological or systemic medical illnesses were excluded from the study.

Participating patients were compared with 102 neurologically healthy control (HC) subjects without any history of tics or obsessive-compulsive symptoms, recruited from local schools, who had neither chronic diseases nor psychiatric disorders. All HCs were clinically evaluated by a clinician with expertise in tic disorders. Moreover, family history (first-degree relatives) was obtained from parents with a focus on neuropsychiatric disorders.

Clinical evaluation

The study was approved by the Catania University Hospital Ethics Committee. All parents of the CYP gave written informed consent while the CYP assented. All diagnoses of GTS and associated psychiatric comorbidities were made according to both DSM-IV-TR and DSM-5 criteria by the same senior child neurologist (R.R.). All patients were assessed initially and again after 1–2 years (mean 1.3 SD 0.7) at FU. Data obtained from the clinical assessment at the FU time point were used for the analysis.

Assessment

To diagnose GTS and assess the core tic symptoms and severity, we administered the following list of physician-administered clinical rating instruments: The National Hospital Interview Schedule for Gilles de la Tourette Syndrome (NHIS) (Robertson and Eapen 1996), a semistructured interview used to diagnose GTS and its associated conditions, behaviors, and relevant family history; the GTS Diagnostic Confidence Index (DCI) (Robertson et al. 1999); Yale Global Tic Severity Rating Scale (YGTSS) (Leckman et al. 1989) for tic severity (global score); and Children's Yale–Brown Obsessive-Compulsive Scale (CY-BOCS) (Scahill et al. 1997). CDs were diagnosed using DSM-IV-TR or DSM-5 criteria (American Psychiatric Association 2000, 2013), while echo/paliphenomena, self-injurious behaviors (SIBs), and sleep disorders were evaluated using the NHIS. All patients and HCs were also assessed using the Wechsler Intelligence Scale for Children (WISC-III) (Wechsler 1991).

Patients with GTS and HCs completed several self-rating scales such as the Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES) scale (Gaffney et al. 1994) used to describe severity of tics and obsessions/compulsions; the Youth Quality of Life Instrument-Research Version (YQOL-R) (Topolski et al. 2003); the Multidimensional Anxiety Scale for Children (MASC) (March et al. 1997); the Conners ADHD/DSM-IV Scale (CADS) (Conners 1978); and the Child Behavior Checklist (CBCL) (Achenbach 1991). Depressive symptomatology was assessed using the patient-administered Child Depression Inventory (CDI) (Kovacs 1988): a cutoff score of 16 was used to predict a diagnosis of depressive disorder based on previous evidence of optimal accuracy (Timbremont et al. 2004).

Parents of patients and HCs completed the Conners ADHD Rating Scale/DSM-IV Scale (Conners 1978), both providing information on ADHD-related symptoms and the CBCL (Achenbach 1991) to assess internalizing and externalizing behaviors. Anxiety was assessed using the self-administered MASC (March et al. 1997).

Statistical analysis

To compare the behavioral and cognitive characteristics among the different groups, statistical analysis was performed using Mann–Whitney U test or chi-squared statistics, as appropriate. A p-value of ≤0.05 was considered statistically significant. Data analysis was performed using the PRIMER Statistical Package for Biomedical Sciences (Glanz 2002).

Results

Comparison between GTS patients and healthy volunteers

Ninety-eight GTS patients (81 males, age range 7–18 years; mean ± SD age 12.2 ± 0.7 years) and 103 HCs (53 males; age range 4–18 years; mean ± SD age 15.7 ± 2.5 years) entered the study (Table 1). GTS patients had a mean ± SD age at onset of 6.1 ± 2.3 years and a mean ± SD disease duration of 9.3 ± 4.1 years; their mean ± SD YGTSS score was 26.5 ± 7.9, whereas the mean ± SD CY-BOCS score was 28 ± 7.8. Diagnostic confidence scores were overall very high, with a mean ± SD DCI score of 88.3 ± 4.1.

Table 1.

Demographic and Clinical Characteristics of Gilles de la Tourette Patients and Healthy Control Subjects

	TS (n = 98)	HC (n = 103)	p-Value
Sex M:F	81:17	53:50	<0.001
Age (years)	12.2 (0.7)	15.7 (2.5)	<0.001
Tic onset (age years)	6.12 (2.2)	—	—
DCI%	88.3 (4.1)	—	—
YGTSS	26.58(7.9)	—	—
CY-BOCS	28 (7.8)	—	—
CDI	8.6 (5.4)	7.3 (2.6)	0.035
MASC	44.8 (13.7)	41.8 (17.2)	0.164
CBCL Total	32.7 (7.4)	22.1 (6.2)	<0.001
CBCL Int	9.9 (2.9)	8.1 (2.2)	<0.001
CBCL Ext	10.9 (2.6)	8.8 (2.7)	<0.001
CONNERS	18.8 (2.7)	14 (2.4)	<0.001
QoL TOT	295.4 (52.7)	320.0 (47.7)	0.000
QoL SELF	94.6 (18.4)	101.2 (20)	0.016
QoL REL	98.4 (21.3)	114.7 (22)	0.000
QoL ENV	90.4 (22)	83.2 (11.4)	0.003
QoL GEN	24.6 (6.4)	25.7 (5.8)	0.204

CBCL, Child Behavior Checklist; CDI, Child Depression Inventory; CY-BOCS, Children's Yale–Brown Obsessive-Compulsive Scale; DCI, Diagnostic Confidence Index; Env, environment; Gen, general; MASC, Multidimensional Anxiety Scale for Children; QoL, quality of life; Rel, relationship; Tot, total.

GTS patients were significantly younger and had a greater percentage of male subjects when compared with healthy volunteers.

Forty-one of the 98 GTS patients (41.8%) had evident depressive symptomatology (i.e., corresponding to a CDI score equal or above 9): 29 of 68 (42.7%) GTS patients with an age between 5 and 12 years at the time of study and 12 of 30 (40%) GTS patients with an age between 13 and 18 years had a CDI score of 9 or above. A CDI score of 16 or above (indicating clinically relevant depression) was found in 15 of our 98 (15.3%) GTS patients, all of whom were older than 13 years at the time of study. CDI scores were significantly greater among GTS patients than among our healthy volunteers (p = 0.003). The GTS patients exhibited greater CBCL scores (total, internalizing, and externalizing) as well as greater Conners scores than healthy volunteers, whereas MASC scores were not significantly different between the two groups.

The difference between GTS patients and healthy volunteers was statistically significant in the sections assessing relationships, self, and environment domains of QoL. The difference in general domain did not show any statistically significant differences between the two groups (GTS and HCs).

Finally, GTS patients had lower scores compared with the HC group with regard to QoL (i.e., GTS+Dep, GTS−Dep depression, HCs+Dep HCs−Dep).

Comparison between GTS patients with and without clinically relevant depression

Family history and depression

GTS patients with depression GTS+Dep (GTS+Dep: CDI >16) did not differ from patients without depression (GTS−Dep: CDI <16) with respect to tic disorder/GTS, ADHD, and OCB/OCD, whereas there was a statistically significant higher incidence of depression among first-degree relatives of GTS+Dep patients compared with those of GTS patients without clinically relevant depression (p = 0.02) (Table 2).

Table 2.

Frequency of Family History (First-Degree Relatives) of Gilles de la Tourette Syndrome and Main Comorbid Psychopathologies in Patients With and Without Depression

	Depressed (%)	Not depressed (%)	p-Value
GTS/tic	82.1	78.6	0.897
Depression	66.7	34.9	0.020
ADHD	27	36.1	0.233
OCD	69.8	60	0.448

ADHD, attention-deficit/hyperactivity disorder; GTS, Gilles de la Tourette syndrome; OCD, obsessive-compulsive disorder.

Tic severity and depression

Tic severity was significantly greater (p = 0.013) in GTS+Dep compared with GTS−Dep patients (Table 3).

Table 3.

Comparison of Mean Measure Scores in Patients with Gilles de la Tourette Syndrome With and Without Depression (Child Depression Inventory ≥16)

Measure	Patients with depression (n = 15)	Patients without depression (n = 83)	p-Value
DCI	82.5 (3.9)	86.9 (2.8)	0.039
MOVES	25.3 (11.2)	15.2 (7.8)	0.000
QIT	96.9 (12.7)	94.9 (13.1)	0.627
CBCL TOT	56.7 (24.6)	31.8 (18.3)	0.000
CBCL INT	20 (10.9)	9.2 (7.9)	0.033
CBCL EXT	16.8 (12.1)	11.6 (7.9)	0.000
MASC	57.1 (18.2)	40.9 (14.5)	0.000
CDI	19.1 (2.0)	7.4 (4.5)	0.000
YGTSS	29.6 (5.1)	24.6 (2.1)	0.013
CY-BOCS	27.6 (4.3)	26.9 (3.9)	0.906
CD (%)	61.5	32.53	0.040
Echophenomena (%)	61.6	38.5	0.118
Coprophenomena (%)	69.2	34.9	0.018
SIB (%)	33.3	12.5	0.035
Sleep disorder (%)	26.7	12.1	0.136
Palilalia (%)	46.6	18.1	0.014
OCD (%)	86.6	85.54	0.908
ADHD (%)	73.3	45.7	0.049
CDI item 9 ≥ 1 (%)	93.3	28.9	0.000
CDI item 9 = 2 (%)	40	1.20	0.000
QoL TOT	273.8 (56.3)	317.1 (53.6)	0.005
QoL SELF	87.6 (20.1)	102.4 (16.6)	0.002
QoL REL	81.5 (23.3)	99.3 (21.3)	0.004
QoL ENV	73.4 (14.7)	82.9 (18.6)	0.064
QoL GEN	21 (6)	27.5 (4.7)	0.000

Standard deviation is shown between parentheses.

ADHD, attention-deficit/hyperactivity disorder; CBCL, Child Behavior Checklist; CD, conduct disorder; CDI, Child Depression Inventory; CY-BOCS, Children's Yale–Brown Obsessive-Compulsive Scale; DCI, Diagnostic Confidence Index; Env, environment; Gen, general; MASC, Multidimensional Anxiety Scale for Children; MOVES, Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey; OCD, obsessive-compulsive disorder; QoL, quality of life; Rel, relationship; SIB, self-injurious behavior; TIQ, total IQ; Tot, total.

DCI scores provide a figure indicating the lifetime likelihood of suffering from GTS, although some authors suggested this as indicative of lifetime cumulative severity given the documented correlation between DCI and YGTSS scores (Robertson et al. 1999). Our GTS+Dep patients have a significantly lower DCI score than GTS−Dep patients (p = 0.039).

A statistically significant difference (p < 0.0001) in MOVES scores was observed between GTS−Dep and GTS+Dep patients, with greater scores observed in GTS+Dep patients. With respect to echo-, pali-, and coprophenomena, GTS+Dep patients exhibited significantly higher percentages of palilalia and coprophenomena (p = 0.014 and 0.02, respectively), whereas the difference in frequency of echophenomena, although the latter were more prevalent among GTS+Dep patients, did not reach statistical significance (p = 0.12).

GTS comorbidities and depression

In our sample, we did not find statistically significant differences between GTS+Dep and GTS−Dep patients (p = 0.963) in CY-BOCS scores (Table 3).

On the other hand, our GTS−Dep patients showed significantly higher MASC scores (p < 0.0001), higher CADS scores (p = 0.004), higher CBCL total, internalizing, and externalizing scores (p < 0.0001, 0.03, and <0.0001, respectively), and higher frequency of CDs (p = 0.04).

33.3% of the patients in the GTS+Dep group had SIBs compared with 12.5% in the GTS−Dep group, and this difference was statistically significant (p = 0.035).

Sleep disorders were reported more frequently by patients in the GTS+Dep group than by patients in the GTS−Dep group (26.7% vs. 12.1%); despite this, it did not reach statistical significance (p = 0.12).

Item 9 CDI and depression

Fourteen of the 15 GTS+Dep patients (93.3%) answered positively (item score ≥1) to item 9 of the CDI (“I wish I could be dead”), whereas a positive answer to this item was provided by 24/83 (28.9%) of the GTS−Dep patients; this difference was statistically significant (p < 0.0001) (Table 3). Six of the 15 GTS+Dep patients (40%) and only 1 of the 83 GTS−Dep patients (1.2%) scored 2 on item 9 of the CDI (p < 0.0001).

GTS QoL and depression

GTS+Dep patients reported lower scores than GTS−Dep patients on all QoL domains; differences on total, self, relationship, and general domain scores were statistically significant (Table 3).

Discussion

The present study aimed at enriching the existing literature on the association between depressive symptomatology and other core behavioral features of GTS through the analysis of a well-characterized clinical sample representative of the general population of GTS patients attending a tertiary referral center for this syndrome and related disorders.

As we found, previous authors have also suggested a higher frequency of depressive symptoms in GTS patients compared with the HC group, with a large proportion of GTS patients fulfilling reference diagnostic criteria for major depressive disorder (MDD), (Comings and Comings 1987; Robertson et al. 1993, 1997, 2002; Rickards and Robertson 2003). Interestingly, and again in agreement with our findings, a large body of evidence highlighted the concurrence of depression in GTS with greater tic severity (Robertson et al. 2006; Robertson 2006; Snijders et al. 2006; Lin et. 2007; Cohen et al. 2008) and need for hospitalization (Coffey et al. 2000a), childhood onset OCB/OCD (Robertson et al. 2006; Termine et al. 2011; Lebowitz et al. 2012; Baglioni et al. 2014; Hirschtritt 2015), ADHD (Robertson et al. 2006; Cohen et al. 2008; Haddad et al. 2009), childhood CD (Snijders et al. 2006), and echo/paliphenomena (Robertson et al. 1988). Self-directed aggressive behaviors were found to be associated with depression (Robertson et al. 1988, 1989), while outwardly directed aggressive behaviors were found to be associated with depression by some (Storch et al. 2015), but not others (Robertson et al. 1988).

A clinically relevant impact of depression upon QoL has also been demonstrated previously (Elstner et al. 2001; Müller-Vahl et al. 2010; Eddy et al. 2011a, 2011b). Finally, among demographic features, female gender and older age were detected by some authors as potentially associated with depression in GTS (Robertson et al. 1988, 1989, 1993, 2002, 2006; Elstner et al. 2001; Eapen et al. 2004; Snijders et al. 2006; Robertson and Cavanna 2007).

Robertson (2006) conducted a literature review, which documented in 16 uncontrolled studies from specialist centers examining mood changes among 5409 GTS patients a variable frequency of depressive symptomatology, dysthymia, mood swings, and MDD/depressive illness between 13% and 76%, with MDD as the most prevalent diagnosis; the same systematic review showed that 13 controlled investigations, including patients of different ages with GTS (n = 741), overall reported significantly higher rates of depression in patients than in control subjects.

Hirschtritt (2015) recently reported a lifetime prevalence of mood disorders and comorbidity in individuals with GTS of 29.8%, which was lower than the one estimated for the obsessive-compulsive spectrum (66.1%), ADHD (54.3%), or anxiety disorders (36.1%).

Factor analytic studies have confirmed a similar frequency (36%) of depressive disorders in a large clinical population of 639 GTS patients (Cavanna et al. 2011), whereas a previous report by the same authors (Robertson and Cavanna 2007) detected that depressive symptomatology was included in one of four identified factors in association with anxiety, obsessionality, and SIBs. We could also confirm that clinically relevant symptomatology was more likely to be apparent in older patients within the first two decades, in line with previous observations proposing older age as a general risk factor for depression in GTS (Snijders et al. 2006).

Despite the association with the diagnosis of GTS, a surprising finding of our study is the significantly lower DCI score among GTS patients with clinically significant depression scores compared with those with CDI score lower than 16. This finding is particularly striking if we consider that the mean DCI score in our total GTS patient sample was 88.3%, that is, considerably higher than the scores reported in the original publications that used this index, which ranged between 60% (Robertson et al. 1999) and 66% (Rickards and Robertson 2003). This is counterintuitive as the DCI can only increase with age, and the present study was exclusively in CYP, while the others were mixed with CYP and adult cohorts, respectively. We found that GTS−Dep patients had statistically significantly lower scores on the DCI than the GTS+Dep patients (p-value 0.039). This is in contrast to the results of Robertson et al. (1988) who reported that in GTS patients, depressive symptomatology was significantly higher in those exhibiting echophenomena (note: echo-lalia and echo-praxia each add 5 points each to the DCI).

In our clinical sample, tic severity was significantly higher in patients with clinically relevant depression compared with those without. This finding is in line with several previous studies, which found an association between tic severity (measured using the YGTSS) and depression and anxiety (Comings and Comings 1987; Coffey et. al. 2000b; Cath et al. 2001; Robertson et al. 2006; Snijders et al. 2006; Cohen et al. 2008; Gorman et al. 2010; Conelea et al. 2011).

Lewin et al. (2012), using an Internet-based survey in a nonclinical sample of 460 GTS adults, compared 185 women with 275 men with self-reported GTS and reported that women in the survey reported twice as many comorbid conditions as the men despite similar tic severity.

When comparing the impact of tic severity and depression upon the risk of psychiatric hospitalization in 156 GTS youth, Coffey et al. (2000a) found that comorbid MDD was one of the strongest predictors, whereas tic severity exerted only a marginal predictive effect. Another important recent study (Storch et al. 2015) observed that suicidal thoughts were associated with tic severity and tic-related impairment measured using the YGTSS.

Overall, the majority of the body of evidence suggests that depressive symptomatology and tic severity correlate; the limited longitudinal observations available in the literature (Lin et al. 2007) support a stronger influence of depression upon the severity of tics compared with the influence exerted by tics upon depressive symptomatology, indicating that satisfactory treatment of depression in GTS could have an important beneficial effect on tic management.

Our results confirm the higher incidence of depression in first-degree relatives of depressed GTS patients compared with nondepressed ones. This is in line with previous seminal work by Pauls et al. (1994) and later work by Snijders et al. (2006), who reported a slightly higher frequency (62%) of family history of depression among depressed patients compared with the one reported in those without depression (56%). In the recent community-based study by Hirschtritt (2015), the familial clustering of GTS and mood disorders may be explained, at least in part, by OCD comorbidity.

In our study population, we could not observe any significant association between clinically relevant depression and obsessive-compulsive behaviors or OCD. Although these findings are discrepant with the majority of studies that evaluated concurrence of depression with other psychopathological comorbidities in GTS (Robertson et al. 1993, 2002, 2006), there is also evidence suggesting two distinct psychopathological factors in GTS consisting, respectively, of depression/anxiety and OCB/OCD (Eapen et al. 2004); these two factors accounted for 72% of the overall variance.

The uniformly high frequency of OCB/OCD, which appears to be a much more common trait in GTS patients than depression, indicates that concurrent depression may not be a strong determinant of obsessive-compulsive traits in GTS patients. Depressed GTS patients in our population still exhibited a higher rate of OCD comorbidity than nondepressed ones, but the overall high rate of OCD comorbidity in the whole cohort did not allow this difference to reach statistical significance.

We also showed a trend for a higher rate of ADHD comorbidity among depressed GTS patients. This is similar to a previous finding from our group (Rizzo et al. 2007), which showed that pure GTS and GTS+ADHD scored higher than control subjects on both CDI and MASC. In a subsequent study, Rizzo et al. (2012) described 53 pure GTS patients, 44 with GTS+OCD and 3 with GTS+ADHD+OCD; the depression scores on the CDI were lower (4.18) in pure GTS compared with 12.54 in GTS+OCD and 11.91 in GTS+ADHD+OCD. Likewise, Eddy et al. (2011a) reported that young patients with GTS have more depressive symptoms than HCs and patients with epilepsy; at the same time, the CDI scores for the pure GTS group appear to be lower than in other patient groups.

We also confirmed a higher rate of echo/pali- and coprophenomena among depressed GTS patients. Likewise, SIBs were significantly more represented among our GTS patients, in line with a previous work by Robertson et al. (1989).

Our cohort confirms the association between reduced QoL and depressive comorbidity in GTS patients. Previous studies from different groups, including ours, have commented on how tic severity may exert a highly variable degree of impact on QoL (Eddy et al. 2011a). On the other hand, a body of evidence supports the fact that anxiety and depression have a substantial impact on QoL in GTS (e.g., Elstner et al. 2001; Müller-Vahl et al. 2010; Eddy et al. 2011b; Jalenques et al. 2012). Eddy et al. (2011b) reported clinical correlates of QoL in 50 CYP with GTS: symptoms of depression (CDI, CBCL internalizing) were correlated with all four domains of QoL, much in keeping with our findings. Rizzo et al. (2014) showed that in GTS patients, depression was related to comorbidity.

The exact determinants of depression in GTS remain elusive and require more research. Conelea et al. (2014) studied 509 adults using the Tourette Syndrome Impact Survey (TSIS) who completed self-report measures of demographics, tic severity, emotional functioning, QoL, and tic-related general and social activity restriction and found that activity restriction significantly predicted lower QoL. However, it is unclear if this tic-specific activity restriction is part of a more global pattern of avoidance that is consistent with coexisting psychiatric conditions such as anxiety, mood disorders, ADHD, and OCD. Lin et al. (2007) observed higher levels of psychological stress in 45 children and adolescents with GTS and OCD than in HCs. Increases in past depressive symptoms predicted higher levels of current psychosocial stress, which in turn modestly, but significantly, predicted increases in future tic severity. Increases in current depressive symptoms were also predictive of increases in future tic severity. Of note, the impact of stressful life events on the severity of tics and comorbidities was best predicted when stress was measured by parental report. More recently, Steinberg et al. (2013) reported data on 60 patients aged 7–17 years with GTS or TD, showing that minor negative events, mainly those that involved relationships with friends, were moderately but significantly related to the severity of motor tics. Negative minor life events were significantly correlated with depression; there was also an inverse significant correlation between positive life events and depression. Similarly, anxiety symptoms and compulsions were also significantly correlated with negative life events.

Limitations of the Study

We acknowledged a number of limitations in our study. First, our cohort was collected from a tertiary referral clinic and thus the results may not be generalized to the whole population of GTS patients encompassing also patients who do not seek and/ or needed regular medical surveillance. Second, the comprehensive and systematic clinical assessment performed on our patients within a single center guaranteed uniformity of data collection and patient evaluation, but at the same time posed restrictions on our sample size. The small size of the group of patients with clinically relevant depression (n = 15), in particular, did not allow adjustment for potential confounding effects, and future expansion of this single-center clinical cohort will allow to check for spurious results in our case–control comparison. Moreover, it is a cross-sectional study.

Conclusion

Depression is common in GTS patients and is associated with tic severity, comorbid ADHD, coexisting anxiety, CDs and behavioral problems.

Clinical Significance

The diagnoses and management of GTS could be a challenge for the clinician. Early diagnosis and treatment of comorbid depression could prevent severe comorbidities and poor QoL.

Footnotes

Authors' Contributions

Research Project—conception and organization: Renata Rizzo and Mary M. Robertson; patient evaluation: Renata Rizzo and Mariangela Gulisano; and statistical analysis: Mariangela Gulisano and Davide Martino. Manuscript—writing of the first draft: Renata Rizzo and Mary M. Robertson; and review and critique: Renata Rizzo, Mary M. Robertson, and Davide Martino.

Disclosures

Renata Rizzo, Mariangela Gulisano, Davide Martino, and Mary May Robertson have nothing to disclose.

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