Suicide in Tourette’s and Chronic Tic Disorders

Author’s Accepted Manuscript Suicide in Tourette’s and DisordersSuicide in tic disorders

Chronic

Tic

Lorena Fernández de la Cruz, Mina Rydell, Bo Runeson, Gustaf Brander, Christian Rück, Brian M. D’Onofrio, Henrik Larsson, Paul Lichtenstein, David Mataix-Cols www.elsevier.com/locate/journal

PII: DOI: Reference:

S0006-3223(16)32723-8 http://dx.doi.org/10.1016/j.biopsych.2016.08.023 BPS12970

To appear in: Biological Psychiatry Received date: 7 June 2016 Revised date: 19 August 2016 Accepted date: 19 August 2016 Cite this article as: Lorena Fernández de la Cruz, Mina Rydell, Bo Runeson, Gustaf Brander, Christian Rück, Brian M. D’Onofrio, Henrik Larsson, Paul Lichtenstein and David Mataix-Cols, Suicide in Tourette’s and Chronic Tic DisordersSuicide in tic disorders, Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2016.08.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Suicide in Tourette’s and Chronic Tic Disorders Short title: Suicide in tic disorders Lorena Fernández de la Cruz, PhD,1 Mina Rydell, PhD,3 Bo Runeson, MD, PhD,1,2 Gustaf Brander, MSc,1 Christian Rück, MD, PhD,1,2 Brian M. D’Onofrio, PhD,4 Henrik Larsson, MD, PhD,3,5 Paul Lichtenstein, PhD,3 and David Mataix-Cols, PhD1,2

1

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden 2

Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden

3

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 4

Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA 5

Department of Medical Sciences, Örebro University, Örebro, Sweden

Correspondence to: Dr. Lorena Fernández de la Cruz, Karolinska Institutet, Department of Clinical Neuroscience; Child and Adolescent Psychiatry Research Center, Gävlegatan 22 (Entré B), floor 8; SE-11330 Stockholm, Sweden. Email: [email protected]

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ABSTRACT Background: Persons with neuropsychiatric disorders are at increased risk of suicide, but there is little data concerning Tourette’s and chronic tic disorders (TD/CTD). We aimed to quantify the risk of suicidal behavior in a large nationwide cohort of patients with TD/CTD, establish the contribution of psychiatric comorbidity to this risk, and identify predictors of suicide. Methods: Using a validated algorithm, we identified 7,736 TD/CTD cases in the Swedish National Patient Register during a 44-year period (1969–2013). Using a matched case-cohort design, patients were compared with general population controls (1:10 ratio). Risk of suicidal behavior was estimated using conditional logistic regressions. Predictors of suicidal behavior in the TD/CTD cohort were studied using Cox regression models. Results: In unadjusted models, TD/CTD patients had an increased risk of both dying by suicide (OR=4·39 [95% CI, 2·89 – 6·67]) and attempting suicide (OR=3·86 [95% CI, 3·50 – 4·26]), compared with controls. After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial. Persistence of tics beyond young adulthood and a previous suicide attempt were the strongest predictors of death by suicide in TD/CTD patients (HR=11·39 [95% CI, 3·71 – 35·02] and 5.65 [95% CI, 2·21 – 14·42], respectively). Discussion: TD/CTD are associated with substantial risk of suicide. Suicidal behavior should be monitored in these patients, particularly in those with persistent tics, history of suicide attempts, and psychiatric comorbidities. Preventive and intervention strategies aimed to reduce the suicidal risk in this group are warranted.

Keywords: Tourette's disorder; chronic tic disorders; premature mortality; suicide; suicide attempt; psychiatric epidemiology

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INTRODUCTION Tourette’s disorder (TD) and chronic tic disorder (CTD) are neurodevelopmental movement disorders characterized by multiple motor tics and at least one phonic tic in TD, and multiple motor or phonic tics in CTD, lasting more than a year (1). TD/CTD affect more boys than girls (3:1 ratio) and typically start between ages four and six and are at their worse around ages ten to twelve. By the end of the second decade of life, many individuals are virtually free of tics, while approximately 20% of cases continue to experience clinically impairing tics as adults (2, 3). TD/CTD were once thought to be rare, but increased recognition has resulted in a combined prevalence of about 1% of the population (4-6). The etiology is currently unknown, although genetic factors are thought to play a major role, together with environmental risk factors (7). Individuals with psychiatric disorders are at high risk to die by suicide (8), with about 90% of people who kill themselves thought to suffer from a psychiatric disorder (9). However, very little is known about suicidal behavior in TD/CTD. In these disorders, suicidal ideation seems to be present in 6 to 10% of cases (10-13). However, despite the relatively high occurrence of suicidal thoughts, deaths by suicide and suicide attempts have been scarcely reported in the literature. A literature search performed by the authors (see Supplementary material) identified only 17 relevant publications on suicide and tic disorders, mostly consisting on single case studies or case series. Combined, these studies reported a total of seven deaths by suicide (14-17) and suicide attempts in 68 patients (10-12, 14, 18-27). Given the small numbers and the heterogeneity of the relevant studies, it is difficult to draw conclusions regarding the clinical characteristics and risk factors of suicidal behavior in this patient group. The scarce attention that suicide has received in TD/CTD contrasts with the fact that a majority of patients (80-90%) with tic disorders have one or multiple psychiatric 3

comorbidities, including attention-deficit/hyperactivity disorder (ADHD), obsessivecompulsive disorder (OCD), and depression (7, 28). These comorbidities are often more problematic and require more attention than the tics themselves and, crucially, are associated with increased risk of suicidal behavior in their own right (29-31). For example, it is estimated that more than half of all people who die by suicide meet criteria for current depressive disorder (8). Moreover, depressive symptoms and negative affect are prominent in patients with TD (32-34). These symptoms, which have been shown to result in reduced quality of life in TD/CTD patients, could potentially lead to suicidal behavior in this group (32). In addition to psychiatric comorbidities, individuals with tic disorders often experience multiple stressors such as social isolation, bullying, and rejection (35, 36), which are in turn well-documented risk factors for suicide (29, 37). Despite this, the risk of suicidal behavior in patients with TD/CTD is currently unknown. Given the relatively low prevalence of both TD/CTD and suicide, large samples of patients studied over long periods of time are needed to provide reliable risk estimates of suicide in this group. In this study, we used a large cohort of 7,736 patients from the Swedish national registers diagnosed with TD/CTD over four decades (1969–2013) in order to: a) provide robust estimates of the risk of death by suicide and attempted suicide in this patient group, compared to matched controls; b) determine to what extent tic disorders themselves are associated with suicidal behavior, after adjusting for comorbid psychiatric disorders; and c) identify predictors associated with suicidal behavior among individuals with TD/CTD.

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METHODS The study was approved by the Regional Ethical Review Board in Stockholm (2013/86231/5). The requirement for informed consent was waived because the study was registerbased and the included individuals were not identifiable at any time.

National Registers Using the unique national identification numbers assigned to Swedish citizens as key and recoded for anonymity (38), we linked several Swedish nationwide population-based registers. The National Patient Register (NPR) includes diagnostic information on individuals admitted to a Swedish hospital since 1969. From 2001, the NPR also contains data on outpatient consultations in specialized care (39). Diagnoses are based on the International Classification of Diseases (ICD), eighth (ICD-8; 1969–1986), ninth (ICD-9; 1987–1996), and tenth (ICD-10; 1997–2013) revisions. The Cause of Death Register (CDR) contains a record of all deaths in Sweden since 1952, with compulsory reporting nationwide. Each record contains the date of death and codes for causes of death, also in accordance to ICD codes. The CDR covers more than 99% of all deaths in Swedish residents, including those occurring abroad, resulting in minimal loss of information (40). Demographic and socio-economic data were derived from the Swedish Register of Total Population with supplementary data from the Education Register.

Variables Patients with a diagnosis of TD or CTD (ICD-8 code 306,2; ICD-9 code 307C; ICD-10 codes F95.0 [transient tic disorder], F95.1 [chronic motor or vocal tic disorder], F95.2 [TD], F95.8 [other tic disorders], or F95.9 [unspecified tic disorder]) between January 1, 1969 and 5

December 31, 2013 were identified from the NPR. Using a previously validated algorithm (41), individuals who had transient tics as their only or final diagnostic code within the same year of the initial diagnosis were excluded. Furthermore, individuals who received an initial diagnosis of transient, other, or unspecified tics were only included if they received at least an additional diagnosis of a tic disorder, except if the last available diagnosis was of transient tic disorder given within the same year of the initial diagnosis. This approach results in nearly perfect inter-rater reliability and highly valid diagnoses, with a positive predictive value of 0.89 in ICD-8, 0.86 in ICD-9, and 0.97 in ICD-10 (41). Patients with at least one inpatient record were classed as inpatients, while the remaining were classed as outpatients. Additionally, based on previous research on the natural history of tic disorders (2), we divided our cohort in two groups in order to identify those patients with persistent tics through to adult life: individuals whose tics had resolved by age 19 (i.e., no additional tic disorder diagnoses were registered beyond this point) and those who received diagnoses of TD/CTD beyond age 19. Suicidal behavior was defined as a record of death by suicide (identified through the CDR) or lifetime suicide attempts (hospital admissions or outpatient consultations in specialized care due to suicide attempts identified through the NPR). To avoid underestimation of suicidal behavior rates and be consistent with recent suicide research (31, 42), we included both certain and undetermined causes in our definitions of death by suicide and attempted suicide, as follows: ‘suicide and self-inflicted injury’ (ICD-8 and ICD-9 codes E950-E959); ‘intentional self-harm’ (ICD-10 codes X60-X84); ‘injury undetermined whether accidental or purposely inflicted’ (ICD-8 and ICD-9 codes E980-E989); and ‘events of undetermined intent’ (ICD-10 codes Y10-Y34). Methods of suicide were classified according to ICD grouping codes (for specific ICD codes, see Supplementary material). Further,

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methods were grouped into self-poisoning (poisoning) and self-injury (remaining methods) (31, 43). Because psychiatric disorders are known to increase the risk of suicide (29), we also obtained information on lifetime psychiatric disorders from the NPR. Comorbid diagnoses were grouped into OCD, ADHD, pervasive developmental disorders (PDD), conduct disorders, psychotic disorders, personality disorders, anxiety disorders, intellectual disabilities, affective disorders, substance use disorders, and ‘other disorders’ (including reaction to severe stress, adjustment, dissociative, somatoform, and other neurotic disorders; for specific ICD codes, see Supplementary material). Parental education level was used as a proxy for the participants’ socio-economic status (30, 31). The highest attained education among the parents of patients and controls was categorized into three groups: elementary education (≤9 years), secondary education (10–12 years), and higher education (>12 years).

Statistical analyses We used a matched case-cohort design to estimate the risk of suicidal behavior in individuals diagnosed with TD/CTD, compared to general population controls. Each TD/CTD patient in the cohort was matched on sex, birth year, and county of residence at the time of the first TD/CTD diagnosis with 10 general population controls from the Swedish Register of Total Population who had never been diagnosed with TD/CTD by the date of the corresponding cohort member’s date of first diagnosis. Conditional logistic regression analyses were used to estimate the association between TD/CTD and suicidal behavior and other variables of interest, expressed as odds ratios (OR) with 95% confidence intervals (CI). In adjusted models, we included parental level of 7

education and different groups of psychiatric comorbidities. For the main outcomes, analyses were stratified by sex. The specific methods of death by suicide and attempted suicide were also described and, when sample sizes allowed, frequencies in both cohorts were compared using OR and the corresponding 95% CI. In order to study predictors of suicidal behavior, individuals in the TD/CTD cohort were followed-up from the date of the first diagnosis of TD/CTD to the date of the outcomes of interest (death by suicide and attempted suicide), death other than suicide, emigration, or end of follow-up (December 31, 2013). Cox regression models were used to compute hazard ratios (HR) with 95% CI, taking time at risk into account. All analyses were performed using SAS, version 9.4 for Windows (SAS Institute Inc., Cary, NC, USA).

RESULTS Descriptive variables Our validated algorithm identified a total of 7,736 cases (5,904 men, 76.32%; median age at first diagnosis of TD/CTD=13; mode age at first diagnosis of TD/CTD=10) diagnosed with TD/CTD in the NPR during the 44-year study period. As expected, individuals with TD/CTD had higher rates of other lifetime psychiatric disorders, compared to the general population (Table 1). A total of 72.07% (n=5,575) of the TD/CTD cases had at least one comorbid psychiatric disorder, as compared to 11.57% (n=8,951) of the control group (OR=22.36 [95% CI, 21.03 – 23.77]). Parents of individuals with TD/CTD had higher levels of education, compared to the parents of the general population controls (Table 1). Approximately two thirds of the TD/CTD cohort had resolved their tics by age 19 (n=5,134; 66.37%), while the rest continued to have repeated diagnoses of TD/CTD beyond this age (n=2,602; 33.63%). 8

Risk of death by suicide and attempted suicide In the 44-year study period, 32 individuals (0.41%) from the TD/CTD cohort had died by suicide, and 594 (7.68%) had attempted suicide at least once. Individuals with TD/CTD had an increased risk of both dying by suicide and attempting suicide compared with the matched controls (OR=4.39 [95% CI, 2.89 – 6.67] and OR=3.86 [95% CI, 3.50 – 4.26], respectively). The risk of suicidal behaviors was similar across genders (Table 1). TD/CTD had a higher risk of attempting suicide on multiple occasions, compared to the controls (OR=2.01 [95% CI, 1.24 – 3.27]). Adjusting for parental level of education did not significantly change the risk estimates (Table 2). Twenty-five (78.13%) of the 32 individuals who died by suicide in the TD/CTD cohort had other recorded psychiatric comorbidities, versus 31 of the 74 individuals (41.89%) in the control group. This pattern was more pronounced for suicide attempts, where almost all the patients in the TD/CTD cohort that had attempted suicide had recorded comorbidities (n=560; 94.28%), versus nearly half of the controls (n=770; 46.14%). When psychiatric comorbidities were included in the models, the risk of dying by suicide and attempting suicide was generally reduced – although not significantly (ORs ranging from 2.92 to 4.37 and 2.13 to 3.30, respectively) (Table 2). TD/CTD cases were marginally older than controls both at the time of death by suicide (mean: 36.87 vs 34.93 years, median: 31 vs 28, respectively) and at the time of the first suicide attempt (mean: 22.98 vs 20.72 years, median: 20 vs 18, respectively). This difference was significant for attempts (t=-3.73, p-value<0.001), but not for deaths by suicide (t=-0.52, p-value=0.60).

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As expected, the risk of dying by suicide was higher – although not statistically significant – in those patients that had been admitted as inpatients at least once, compared to outpatients (OR=5.03 [95% CI, 3.03 – 8.34] and 3.33 [95% CI, 1.57 – 7.09], respectively). The risk of attempting suicide was significantly higher in the inpatient group, compared to the outpatient only group (OR=6.75 [95% CI, 5.48 – 8.31] and OR=3.32 [95% CI, 3.71 – 4.10], respectively). Because the diagnostic criteria for TS have changed over time, no longer requiring distress/impairment in more recent versions of the DSM, there is a possibility that more severe/complex patients were included in ICD-8 and ICD-9, compared to the current ICD-10. This may have, in turn, inflated our risk estimates. To rule out this possibility, we ran additional analyses restricted to ICD-10 patients only (n=7,109; 91.90% of our total sample). The results remained largely unchanged, with a risk of death by suicide of 4.50 (95% CI, 2.58 – 7.85) and a risk of attempted suicide of 4.04 (3.65 – 4.47). Therefore, the inclusion of preICD-10 patients in our analyses did not appear to inflate our risk estimates.

Methods of suicide and attempted suicide Among those who died by suicide, the specific methods used did not differ between the TD/CTD and the control cohorts, with approximately the same proportion of self-poisoning (25.00% vs 20.27%, respectively) and self-injury methods in both groups (75.00% vs 79.73%, respectively). For suicide attempts, self-poisoning was significantly more frequent in the TD/CTD cohort than in the control group (63.97% vs 41.52%, respectively; OR=2.41 [95% CI, 1.44 – 4.05]). The overall self-injury category did not show differences between cases and controls (52.19% vs 62.97%, respectively; OR=0.77 [95% CI, 0.49 – 1.21]). However, among the specific self-injury methods, the hanging, strangulation, and suffocation category

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was more common among the TD/CTD group (4.88%) than among the controls (1.02%; OR=11.71 [95% CI, 1.49 – 92.33]; Table 3).

Predictors of death by suicide and suicide attempts The strongest predictor of suicide in individuals diagnosed with TD/CTD was the persistence of tic disorders in adulthood (HR=11.39 [95% CI, 2.20 – 15.95]). Fourteen of the 32 (43.75%) individuals with TD/CTD who died by suicide had a record of a previous suicide attempt. A previous suicide attempt increased the risk of subsequent death by suicide approximately 6-fold (HR=5.92 [95% CI, 2.20 – 15.95]). Additionally, a comorbid personality disorder also increased the risk of death by suicide approximately 3-fold (HR=2.95 [95% CI, 1.07 – 8.09]). Regarding attempted suicides, persistent tics, being a woman, and all the examined comorbid psychiatric disorders – except for intellectual disabilities – were found to increase the risk, particularly the comorbidity with substance use disorders (Table 4).

DISCUSSION Our results indicate that individuals with TD/CTD had an approximately 4-fold increased risk of suicide, compared to matched general population controls. The risk was similar across genders and remained substantial after adjusting for different groups of psychiatric comorbidities. Thus, for the first time, we show that TD/CTD are associated with an increased risk of suicide in their own right. The results potentially contribute to the clinical management of these patients in psychiatry, neurology, and primary care settings. Our predictors’ analyses identified patients who are most likely to attempt and die by suicide and who should therefore receive the highest attention and long term monitoring of risk. 11

A persistent diagnosis of tic disorders – defined as those individuals who continued to receive a diagnosis of TD/CTD beyond the end of the second decade of life – was the strongest predictor of risk of suicide (HR=11.4). Suicidal thoughts and behaviors should therefore be explored and closely monitored in patients with TD/CTD who continue to experience symptoms into adulthood. A previous suicide attempt was also a strong predictor of subsequent suicide (HR=5.6), as has been consistently reported in the suicide literature (29, 31). Patients with TD/CTD were also more likely to attempt suicide on multiple occasions, compared to the population controls. This may provide clinicians with an opportunity to implement risk management strategies to prevent further attempts and potential deaths. Although the presence of comorbid psychiatric disorders did not entirely explain the risk of suicide, our predictors’ analyses showed that comorbid personality disorders significantly increased the risk suicide approximately 3-fold, which is consistent with the known risk associated with these disorders (29, 44). Regarding suicide attempts, all psychiatric comorbidities – except for intellectual disabilities – increased the risk, especially substance use disorders (HR=3.9). The latter finding is consistent with a previous report that found high levels of drug (50% of the sample) and alcohol abuse (43.5% of the sample) in 25 TD patients that had attempted suicide (11). Given the high rates of psychiatric comorbidity in TD/CTD (28, 45) (over 70% in our cohort), the risk of suicide should probably be systematically explored and monitored in all patients. Treatment of these comorbid conditions should also be a priority, as these can adversely affect the long-term outcome of patients with TD/CTD if left untreated (46). Overall, the methods of suicide in the TD/CTD cohort were similar to those in the general population, with self-injury methods – which include more violent methods such as hanging or jumping before a moving object – being the most frequent methods in both 12

cohorts. Some interesting patterns emerged regarding the methods of attempted suicide. TD/CTD patients were more likely to use self-poisoning methods than their matched controls, which might reflect the ready availability of psychotropic medication in this group.(31) Overall, there were no differences between the TD/CTD and the control cohorts regarding the use of specific self-injury methods to attempt suicide. However, hanging, strangulation, or suffocation were more frequently used in the TD/CTD group. This could be especially relevant for prevention purposes given that hanging, strangulation or suffocation methods are a strong predictor of subsequent suicide (42). The increased risk of suicide in TD/CTD is both alarming and previously underrecognized. The identification of risk factors for suicidal behavior in TD/CTD should guide the development of empirically-based preventive and intervention strategies aimed at reducing suicide rates in this group. In other neurological disorders, management of psychiatric comorbidities, the development of a ‘safety contract’, or the modification of factors contributing to the patient’s suicidal ideation, such social isolation, are recommended strategies to reduce the risk of suicide (47). Other strategies such as restricting access to means (e.g., lethal drugs), encouraging self-help, increasing the likelihood of intervention by a third party, or education of physicians, for example, have also shown to be helpful in reducing the number of suicides (48). Strengths of this study include the use of the world’s largest population-based cohort of patients with TD/CTD and a 4-decade study period long enough to capture the outcomes of interest. Additionally, the diagnostic validity and reliability of the TD/CTD diagnoses in the Swedish national registers is high (41). There were, however, some limitations. First, because suicide is a sensitive issue, it is likely that it is under-reported. Suicide may be misclassified as an accident or another cause of death, especially in those who have not been previously diagnosed with a mental disorder. However, in line with previous studies (49, 50), 13

we tried to minimize this issue by also including the events diagnosed as undetermined causes of death or attempts of suicide (49). Second, because outpatient data was only introduced in the Swedish registers in 2001, during years 1969-2000 the cohort only included individuals whose attempted suicide led to inpatient care, potentially leaving out attempts of lower lethality. Additionally, patients with TD/CTD included in the NPR register may not be representative of all TD/CTD cases in the population as the register only includes specialist care visits and not patients seen in general practitioner clinics. In the same way, the NPR does not include patients diagnosed by professionals other than physicians. These limitations also apply to the identification of the comorbid psychiatric conditions. Finally, despite the large cohort, some of the specific methods of suicidal behavior were relatively uncommon. Thus, these comparisons based on small numbers have to be interpreted with caution.

Conclusion This is the first study showing that TD/CTD are associated with a substantial risk of suicide. This risk was present even after taking psychiatric comorbidity into account. Suicidal behavior should be carefully assessed and monitored in these patients, particularly in those whose tics persist into adulthood, those who have previously attempted suicide, and in patients with comorbid personality disorders. Preventive and intervention strategies should be developed and implemented, including the management of psychiatric comorbidities and the modification of factors contributing to the patient’s suicidal ideation.

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Disclosures and acknowledgements: Dr. Fernández de la Cruz was supported by a Junior Researcher grant from the Swedish Research Council for Health, Working Life and Welfare (FORTE grant number 2015-00569) and a grant from the David and Astrid Hagelén Foundation. Dr. Rydell was supported by grant from the Swedish Research Council for Health, Working Life and Welfare (FORTE grant number 2015-00075). Mr. Brander was supported by a scholarship from KID-funding (Karolinska Institutet PhD stipend). Dr. Rück was supported by a grant from the Swedish Research Council (K2013-61P-22168). Prof. D'Onofrio was supported by grants from the American Foundation for Suicide Prevention and the Indiana Clinical and Translational Sciences Institute (Networks, Complex System and Health Project Development Team). Prof. Larsson has served as a speaker for Eli-Lilly and Shire and has received a research grant from Shire Pharmaceuticals. Prof. Lichtenstein has served as a speaker for Medice. Profs. Runeson and Mataix-Cols report no biomedical financial interests or potential conflicts of interest.

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41. Rück C, Larsson KJ, Lind K, Perez-Vigil A, Isomura K, Sariaslan A, et al. (2015): Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register. BMJ Open 5:e007520. 42. Runeson B, Tidemalm D, Dahlin M, Lichtenstein P, Langstrom N (2010): Method of attempted suicide as predictor of subsequent successful suicide: national long term cohort study. BMJ 341:c3222. 43. Runeson B, Haglund A, Lichtenstein P, Tidemalm D (2015): Suicide risk after nonfatal self-harm: A national cohort study, 2000–2008. J Clin Psychiatry 77: 240-246. 44. Tidemalm D, Langstrom N, Lichtenstein P, Runeson B (2008): Risk of suicide after suicide attempt according to coexisting psychiatric disorder: Swedish cohort study with long term follow-up. BMJ 337:a2205. 45. Robertson MM, Orth M (2006): Behavioral and affective disorders in Tourette syndrome. Adv Neurol 99:39-60. 46. Hassan N, Cavanna AE (2012): The prognosis of Tourette syndrome: implications for clinical practice. Funct Neurol 27:23-27. 47. Arciniegas DB, Anderson CA (2002): Suicide in neurologic illness. Curr Treat Options Neurol 4:457-468. 48. Mann JJ, Apter A, Bertolote J, Beautrais A, Currier D, Haas A, et al. (2005): Suicide prevention strategies: a systematic review. JAMA 294:2064-2074. 49. Neeleman J, Wessely S (1997): Changes in classification of suicide in England and Wales: time trends and associations with coroners' professional backgrounds. Psychol Med 27:467-472. 50. Haglund A, Tidemalm D, Jokinen J, Langstrom N, Lichtenstein P, Fazel S, et al. (2014): Suicide after release from prison: a population-based cohort study from Sweden. J Clinical Psych 75:1047-1053.

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Table 1. Distribution of study variables among individuals with Tourette’s Disorder/Chronic Tic Disorder (TD/CTD) and matched controls, and odds ratios (OR) and corresponding 95% confidence intervals (CI) for TD/CTD associated with suicide related events, comorbid disorders, and parental education.

cases (n = 7,736)

General population controls (n = 77,360)

OR (95% CI)

Death by suicide (n, %) Men Women

32 (0.41) 28 (0.47) 4 (0.22)

74 (0.10) 65 (0.11) 9 (0.05)

4.39 (2.89 – 6.67) 4.36 (2.79 – 6.81) 4.65 (1.39 – 15.56)

Suicide attempt (n, %) Men Women

594 (7.68) 405 (6.86) 189 (10.32)

1,669 (2.16) 1,220 (2.07) 449 (2.45)

3.86 (3.50 – 4.26) 3.57 (3.17 – 4.02) 4.67 (3.90 – 5.59)

Suicide attempts per individual (n, %)1 One attempt Two or more attempts

343 (57.74) 251 (42.26)

1,183 (70.88) 486 /29.12)

0.50 (0.30 – 0.81) 2.01 (1.24 – 3.27)

Age at death by suicide2 mean, sd median, IQR

36.87 (16.76) 31.00 (19.50)

34.93 (17.92) 28.00 (26.00)

– –

Age at first suicide attempt1 mean, sd median, IQR

22.98 (12.28) 20.00 (11.00)

20.72 (12.82) 18.00 (10.00)

– –

Comorbid psychiatric conditions (n, %) Obsessive-compulsive disorder Attention-deficit/hyperactivity disorder Pervasive developmental disorders Conduct disorders Psychotic disorders Personality disorders Anxiety disorders Intellectual disabilities Affective disorders Substance use disorders Other psychiatric disorders

1,306 (16.88) 3,604 (46.59) 1,977 (25.56) 538 (6.95) 451 (5.83) 349 (4.51) 1,611 (20.82) 598 (7.73) 1,621 (20.95) 823 (10.64) 877 (11.34)

370 (0.48) 2,577 (3.33) 1,184 (1.53) 282 (0.36) 430 (0.56) 368 (0.48) 2,294 (2.97) 712 (0.92) 2,695 (3.48) 2,416 (3.12) 1,725 (2.23)

44.37 (39.02 – 50.44) 31.55 (29.32 – 22-94) 23.42 (21.54 – 25.47) 21.42 (18.40 – 24.93) 11.55 (10.06 – 13.26) 10.59 (9.08 – 12.36) 9.41 (8.75 – 10.12) 9.10 (8.13 – 10.19) 8.28 (7.71 – 8.90) 3.90 (3.58 – 4.25) 5.93 (5.43 – 6.48)

Parental level of education (n, %) Elementary education (≤ 9 years) Secondary education (10-12 years) Higher education (> 12 years) Missing data

654 (8.45) 3,597 (46.50) 2,946 (38.08) 539 (6.97)

6,430 (8.31) 31,259 (40.41) 33,369 (43.13) 6,302 (8.15)

0.99 (0.91 – 1.09) 1.28 (1.22 – 1.34) 0.77 (0.74 – 0.81) 0.75 (0.66 – 0.84)

TD/CTD

1

In those with at least one suicide attempt. 2 In those who have died by suicide. Abbreviations: CI confidence interval; IQR interquartile range; OCD obsessive-compulsive disorder; OR odds ratio.

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Table 2. Risk of death by suicide and attempted suicide among individuals with Tourette’s Disorder/Chronic Tic Disorder (TS/CTD) compared with matched controls, unadjusted and adjusted by parental level of education and psychiatric comorbidities.

Unadjusted Adjusted for parental level of education Adjusted for obsessive-compulsive disorder Adjusted for attention-deficit/hyperactivity disorder Adjusted for pervasive developmental disorders Adjusted for conduct disorders Adjusted for psychotic disorders Adjusted for personality disorders Adjusted for anxiety disorders Adjusted for intellectual disabilities Adjusted for affective disorders Adjusted for substance use disorders Adjusted for other psychiatric disorders

OR (95% CI) Deaths by suicide

Suicide attempts

4.39 (2.89 – 6.67) 5.20 (3.27 – 8.30) 3.90 (2.46 – 6.20) 3.69 (2.22 – 6.13) 4.02 (2.53 – 6.36) 4.10 (2.67 – 6.30) 3.19 (2.01 – 5.06) 3.45 (2.21 – 5.38) 3.71 (2.35 – 5.85) 4.54 (2.98 – 6.93) 2.92 (1.84 – 4.65) 2.97 (1.91 – 4.62) 4.37 (2.84 – 6.73)

3.86 (3.50 – 4.26) 3.67 (3.31 – 4.06) 3.30 (2.95 – 3.70) 2.19 (1.92 – 2.50) 3.15 (2.81 – 3.53) 3.50 (3.16 – 3.88) 3.09 (2.78 – 3.44) 2.97 (2.67 – 3.30) 2.26 (2.02 – 2.52) 3.68 (3.33 – 4.08) 2.13 (1.91 – 2.38) 2.71 (2.43 – 3.01) 2.86 (2.57 – 3.17)

Note: ICD codes of the specific diagnoses grouped under each category of comorbid disorders are listed in the Supplemental material. Abbreviations: CI confidence interval; OR odds ratio.

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Table 3. Methods of suicide and attempted suicide in Tourette’s Disorder/Chronic Tic Disorder (TD/CTD) cases and matched controls.

cases (n = 32)

General population controls (n = 74)

OR (95% CI)1

8 (25.00) 24 (75.00) 8 (25.00) 5 (15.63) 4 (12.50) 2 (6.25) 1 (3.13) 1 (3.13) 1 (3.13) 0 (0) 0 (0) 2 (6.25)

15 (20.27) 59 (79.73) 19 (25.68) 11 (14.86) 3 (4.05) 5 (6.76) 8 (10.81) 6 (8.11) 3 (4.05) 2 (2.70) 2 (2.70) 0 (0)

– – – – – – – – – – – –

cases (n = 594)

General population controls (n = 1,669)

OR (95% CI)1

380 (63.97) 310 (52.19) 136 (22.90) 29 (4.88) 23 (3.87) 20 (3.37) 10 (1.68) 7 (1.18) 3 (0.51) 2 (0.34) 1 (0.17) 134 (22.56)

693 (41.52) 1,051 (62.97) 214 (12.82) 17 (1.02) 37 (2.22) 31 (1.86) 7 (0.42) 8 (0.48) 10 (0.60) 6 (0.36) 8 (0.48) 738 (44.22)

2.41 (1.44 – 4.05) 0.77 (0.49 – 1.21) 1.49 (0.80 – 2.77) 11.71 (1.49 – 92.23) 1.19 (0.29 – 4.82) – 2.00 (0.33 – 12.28) 3.00 (0.31 – 28.84) – – – 0.34 (0.18 – 0.66)

TD/CTD Method of suicide (n, %) Self-Poisoning Self-Injury Hanging, strangulation, suffocation Jumping or lying before moving object Drowning Gassing Firearm or explosive Jumping from a height Smoke, fire, and flames Cutting or piercing Crashing of motor vehicle Other means

TD/CTD Method of attempted suicide2 (n, %) Self-Poisoning Self-Injury Cutting or piercing Hanging, strangulation, suffocation Gassing Jumping from a height Smoke, fire, and flames Jumping or lying before moving object Firearm or explosive Crashing of motor vehicle Drowning Other means 1

Odds ratios for some of the methods and groups could not be calculated due to small numbers. 2 Column totals for

the methods of attempted suicide do not add up to the total of individuals who attempted suicide because the same person may have attempted suicide more than once using different methods in each occasion. Abbreviations: CI confidence interval; OCD obsessive-compulsive disorder; OR odds ratio.

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Table 4. Predictors of suicide and attempted suicide in the cohort of individuals with Tourette’s Disorder /Chronic Tic Disorder (n=7,736).

Predictors Previous suicide attempt Persistent TD/CTD* Woman Obsessive-compulsive disorder Attention-deficit/hyperactivity disorder Pervasive developmental disorders Conduct disorders Psychotic disorders Personality disorders Anxiety disorders Intellectual disabilities Affective disorders Substance use disorders Other psychiatric disorders Parental level of education: elementary vs secondary elementary vs higher

HR (95% CI) Deaths by suicide Suicide attempts 5.65 (2.21 – 14.42) 11.39 (3.71 – 35.02) 0.33 (0.09 – 1.14) 0.96 (0.37 – 2.46) 0.77 (0.32 – 1.84) 0.66 (0.25 – 1.73) 0.59 (0.07 – 4.68) 1.54 (0.62 – 3.84) 2.95 (1.07 – 8.09) 0.34 (0.12 – 0.95) 0.26 (0.03 – 1.97) 1.54 (0.67 – 3.57) 1.38 (0.55 – 3.47) 0.38 (0.11 – 1.39)

– 1.50 (1.24 – 1.82) 1.48 (1.22 – 1.78) 1.24 (1.02 – 1.50) 1.21 (1.01 – 1.46) 1.42 (1.19 – 1.71) 1.65 (1.26 – 2.15) 1.86 (1.49 – 2.31) 1.51 (1.20 – 1.90) 1.39 (1.14 – 1.70) 0.96 (0.73 – 1.27) 1.67 (1.38 – 2.03) 3.94 (3.25 – 4.79) 1.44 (1.18 – 1.76)

1.31 (0.42 – 4.10) 1.57 (0.48 – 5.12)

1.18 (0.90 – 1.54) 1.11 (0.84 – 1.47)

* Defined as patients who received a diagnosis of TD/CTD beyond 19 years of age. Note: Significant predictors are highlighted in bold. Abbreviations: CI confidence interval; CTD chronic tic disorder; HR hazard ratio; TD Tourette’s disorder.

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