Systematic review of co-occurring OCD and TD: Evidence for a tic-related OCD subtype?

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

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Systematic review of co-occurring OCD and TD: Evidence for a tic-related OCD subtype?

T

Lisa Kloft , Theresa Steinel, Norbert Kathmann ⁎

Humboldt-Universität zu Berlin, Berlin, Germany

ABSTRACT

Objective: The aim of this review is to summarize the current knowledge of associated features of co-occurring obsessive-compulsive disorder (OCD) and tic disorders (TD) and to critically evaluate hypotheses regarding the nature of their comorbidity. Method: We conducted a systematic review following PRISMA guidelines. To this aim, the PubMed, PsychInfo and ISI Web of Knowledge databases were searched up to August 30, 2018. For gender and age-of-onset we additionally conducted meta-analyses. Results: One hundred eighty-nine studies met inclusion criteria. We substantiate some acknowledged features and report evidence for differential biological mechanisms and treatment response. In general, studies were of limited methodological quality. Conclusions: Several specific features are reliable associated with co-occurring OCD + TD. The field lacks methodological sound studies. The review found evidence against and in favor for different hypotheses regarding the nature of comorbidity of OCD and TD. This could indicate the existence of a stepwise model of comorbidity, or could be an artefact of the low methodological quality of studies.

1. Introduction Obsessive-compulsive disorder (OCD) and tic disorders (TD) are closely related and considered to etiologically overlap. Both disorders are characterized by repetitive behaviors: in patients with OCD, these are compulsions which are defined as recurrent excessive acts performed in response to an obsession, in patients with TD, these are tics, i.e. rapid, repetitive, non-rhythmic movements or vocalizations. It is assumed that the repetitive behaviors of both groups are due to alterations in fronto-striatal loops (Eddy and Cavanna, 2014). Further evidence for the close relationship of OCD and TD stems from their frequent co-occurrence (Leonard et al., 1993; Pauls et al., 1995) and increased cross-disorder prevalence in affected family members (Pauls et al., 1995, 1986) However, the nature of this close relationship is still unknown. For example, for the new editions of the international classification schemes – 5th edition of the Diagnostic and Statistical Manual (APA, 2013) and the 11th edition of the World Health Organization’s International Classification of Diseases and Related Health Problems (ICD11) - it was debated to include TD under the newly introduced chapter of “Obsessive-Compulsive and Related Disorders” (OCRD). This chapter acknowledges the existence of an obsessive-compulsive (OC)-spectrum of psychiatric and neurological disorders that are all characterized by

repetitive thoughts and/ or behaviors (Hollander, 1993). Yet, despite TD being considered as part of the OC-spectrum, it is continuously classified under the chapter of neurodevelopmental disorders in the new DSM. According to the DSM-V OC-spectrum working group, this owes to the fact that there are numerous arguments for and against overlap between OCD and TD. For example, only complex tics bear similarities with compulsions while simple tics are readily distinguishable, or that the phenomenological overlaps like sensory phenomena (e.g. not-just-right experiences) and childhood-onset are only present in some OCD cases (Walkup et al., 2010). To capture the overlap between OCD and TD, a tic-related specifier is introduced in DSM-V to categorize OCD patients with current or past comorbid TD (OCD + TD) (APA, 2013). In addition to sensory phenomena and earlier age-of-onset, further clinical features are used to contrast OCD + TD with OCD. These include more obsessions concerning symmetry and exactness and ordering and arranging compulsions, higher rates of comorbid attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), and differing treatment responses to serotonin reuptake inhibitors (SSRIs) and neuroleptic augmentation (Leckman et al., 2010; Miguel et al., 2005). Whether and in what way these phenomenological differences reflect differences in underlying psychopathological pathways is

⁎ Corresponding author at: Institute of Psychology, Department of Clinical Psychology, Humboldt-Universität zu Berlin, Rudower Chaussee 18, 12489, Berlin, Germany. E-mail address: [email protected] (L. Kloft).

https://doi.org/10.1016/j.neubiorev.2018.09.021 Received 28 December 2017; Received in revised form 19 September 2018; Accepted 25 September 2018 Available online 29 September 2018 0149-7634/ © 2018 Elsevier Ltd. All rights reserved.

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

L. Kloft et al.

currently a matter of debate and different nosological models exist to explain the comorbidity of OCD + TD. One is the assumption that it represents a tic-related subtype which is influenced by genetic vulnerability for TD and may represent a variant expression of genetic TD vulnerability (Pauls et al., 1986). This model assumes higher similarity, e.g. in genetic and neural factors, between OCD + TD with TD. Related to this is the hypothesis that OCD + TD is a more severe form of TD (Coffey et al., 1998) which is indicated by a higher number of comorbid disorders and more complex and more severe symptoms. Mansueto and Keuler (2005) have articulated the concept of “Tourettic OCD” which is characterized by specific tic-like clinical features but not necessarily by the presence of lifetime tics/ TD. These features are childhood or adolescent onset, compulsions being motivated by sensory phenomena and just-right experiences rather than harm avoidance, personal or family history of tics, weaker or non-response to selective serotonin response inhibitors (SSRIs) and/ or to exposure and response prevention therapy, and multiple comorbid diagnoses like ADHD, learning disorders, and impulse control disorders. Their concept is that of a hybrid or additive combination of OCD and TD which predicts the additive combination of deficits associated with the disorders compared to when they occur alone (Neale and Kendler, 1995). Finally, in addition to phenotypic variance or additive combination, it is also possible that OCD + TD represents a unique syndrome, maybe even another OCRD, as it is represented in the concept of Obsessive-Compulsive Tic Disorder (Dell’Osso et al., 2017).This would be reflected by specific dysfunctions that are not merely the additive combination deficits found in OCD and TD (Neale and Kendler, 1995) The present review aims at 1) depicting the empirical findings associated with the co-occurrence of OCD and TD, 2) investigating the existence of further features associated with OCD + TD that go beyond clinical features, and 3) searching for evidence in favor or against differing nosologic hypotheses.

17,475 records identified in database search

4,794 from PsycINFO 3,971 from ISI Web of Knowledge 8,710 from PubMed

7,842 records after duplicates removed

7,600 records excluded after screening

242 full-text articles assessed for eligibility

53 full-text exclusions

189 records included in the systematic review

Fig. 1. Systematic review inclusion flow chart.

The following inclusion criteria were applied: a) data reported on patients with a primary diagnosis of OCD, TD or comorbid OCD and TD; b) reference to standardized diagnostic criteria for the assessment of OCD and TD; c) comorbidity could be defined as current or lifetime; d) comparison with a control group (an exception was made for studies referring to prevalence rates of comorbidity or familiarity); f) english language. Articles were excluded if they were: a) reviews or abstracts; b) based on case reports or small case series. 3. Results

2. Methods

A total of 17,475 studies were retrieved from the search. Among these, 9633 duplicates were identified and removed. The remaining 7842 studies were screened on the title or abstract level. The full texts of 242 studies considered relevant were assessed for inclusion and exclusion criteria. Finally, 189 studies were included. The PRISMA flowchart is shown in Fig. 1.

The systematic literature review was conducted following the PRISMA guidelines (Moher et al., 2009). The search strategy, as well as inclusion and exclusion criteria, and data to be extracted, were defined in advance. First, we conducted a structured literature search in PubMed, PsychInfo and ISI Web of Knowledge. For this, we combined MeSH-equivalent terms for OCD or TD with search and MeSH equivalent terms for genetic, comorbid, prevalence, subtype, latent class, factor analysis, therapy, cognitive, symptom dimension, imaging, clinical features, sensory phenomena, eeg, TMS, risk factor or neurotransmitter. The search was conducted until 30 August 2018. After duplicates were removed, all records were screened at the title and/ or abstract levels. The full text of the remaining papers was examined for inclusion. For this purpose, an electronic spreadsheet was designed with information of the included studies. For each article identified, we extracted information on study characteristics (authors, publication year, sample size), study design (i.e., case-control study), subject characteristics (e.g. gender, age, psychiatric diagnosis), assessment methods, variables on interest (e.g. symptom dimensions, task parameters, neural structures), and results. For age-of-onset and gender we conducted a meta-analysis in order to weight study differences in terms of number of participants and heterogeneity. Meta-analyses were conducted using the R-based software OpenMetaAnalyst (Wallace et al., 2012). For ageof-onset, a weighted-average effect size based on the standardized mean difference (SMD) was than computed using the Hedges-Olkin random effects method (Hedges and Olkin, 1985). For gender, we calculated the male-to-female odds ratio., i.e. the odds of being male in the group of OCD compared to the odds of being male in the group of OCD + TD patients (Loomes et al., 2017). This was done by applying the DerSimonian and Laird random effects model (DerSimonian and Laird, 1986). The Q and I2 values were calculated to examine heterogeneity between studies.

3.1. Epidemiology In Tables 1 and 12, prevalence rates are summarized across studies. In order to give an approximation on the prevalence rates of comorbid OCD and TD, here we focus on studies that fulfilled three criteria: specification of whether point or lifetime prevalence rates were assessed, larger sample sizes (> 100 patients), and use of rigorous assessment methods (i.e. diagnoses were made with (semi-)structured clinical interviews) (Table 2). 3.1.1. Prevalence rates of OCD in TD 3.1.1.1. Clinical samples. One study exclusively examined pediatric TD patients and reported lifetime prevalence rates of OCD of 37.6% 42.5% (depending on recruitment site) (Augustine et al., 2017). Studies that included pediatric and adult patients report lifetime rates of 14% (Sambrani et al., 2016), 20% (Hirschtritt et al., 2015), 35.95% (Huisman-van Dijk et al., 2016), 37% (Abdulkadir et al., 2016), 50% (Robertson, 2008a), 60% (Greenberg et al., 2018) and 61.5% (O’Rourke et al., 2011). 3.1.1.2. Community samples. In pediatric community samples, prevalence rate of OCD in TD ranged between 0% (Heyman et al., 2003) and 11% (Scharf et al., 2012). None of the community studies that included adult patients fulfilled the above mentioned criteria. 281

cross-sectional; outpatients from specialized treatment sites Cross-sectional; TIC Genetics study

811 with TS

Greenberg et al. (2018) Abdulkadir et al. (2018)

282

2512 9-12 year old children

257 children and adolescents with OCD

Alvarenga et al. (2016) Arildskov et al. (2016)

782 children and adolescents with TS and 250 with OCD/OCB

60 children and adolescents with OCD

Chowdhury et al. (2016)

Sambrani et al. (2016)

225 with TS (children and adults), 371 family members

Huisman-van Dijk et al. (2016)

83 with TS

longitudinal; outpatients from specialized treatment sites; the Nordic Long-term OCD Treatment Study (NordLOTS) cross-sectional; community sample

25 children and adolescents with OCD

Agarwal et al. (2016)

Eapen et al. (2016)

cross-sectional; population-based

236 with OCD (from the United States) and 951 with OCD from Brazil

cross-sectional; Outpatient study in specialized unit; unmatched case-case

cross-sectional; outpatients from specialized treatment service institution (sample overlaps with Scharf et al., 2012) cross-sectional; outpatients from specialized treatment site

cross-cultural; outpatients from specialized treatment sites; Brown Longitudinal Obsessive-Compulsive Study; Brazilian Research Consortium on ObsessiveCompulsive Spectrum Disorders cross-sectional; outpatients from specialized treatment sites

longitudinal, population based family clustering study

Medeiros et al. (2017)

cross-sectional; outpatients from specialized treatment site

Cross-sectional; register-based study on three finish registers

30,082 with OCD, 7279 with TD (1276 had both)

1358 with OCD, 1195 TS/ CTD

Chudal et al. (2017)

Mataix-Cols et al. (2017)

332 children and adolescents with OCD

Peris et al. (2017)

114 children with TD

205 children with TD (91% TS, 4,5% CTD, 4,5% TD NOS) 100 normal controls 227 children with TD

Agustine et al. (2017) Groth et al. (2017)

cross-sectional; outpatients from academic and clinical sites; International College of Obsessive-Compulsive Spectrum Disorders cross-sectional; outpatients from specialized treatment sites longitudinal; outpatients from specialized treatment sites outpatients from specialized treatment sites

Pringsheim (2017)

425 with OCD patients

Dell’Osso et al. (2018)

465 with TS

Longitudinal; outpatients from specialized treatment sites

58 with TD

Theriault et al. (2018)

Longitudinal, population-based study

5597 with TD

Brander et al. (2018)

Study design

N

First author, year

Table 1 Prevalence rates of co-morbid OCD and TD.

Clinical interview according to DSM-III-R and DSM-IV-TR

NHIS

K-SADS-PL; CY-BOCS

DAWBA (DSM-IV); CBCL

SCID-I: YGTSS; Y-BOCS; clinical interview according to DSM-IV DAWBA (ICD-10); CY-BOCS

K-SADS-PL; CY-BOCS

SCID-I; Y-BOCS;

Register-based according to ICD-8, ICD-9 or ICD-10

Structured clinical interview; YGTSS; CY-BOCS

ICD-8, ICD-9, ICD-10

ADIS C/P; CYBOCS; COIS-R

SCID-I; YGTSS; MOVES; DISCIV-OCD module DAWBA; YGTSS; Y-BOCS

SCID-I; Y-BOCS

Clinical interview according to the Tourette Syndrome Classification Study Group; YGTSS; Y-BOCS TICS Inventory; YGTSS; YBOCS Clinical interview according to DSM-IV-TR; YGTSS, Y-BOCS

Register-based according to ICD-8, ICD-9 or ICD-10

OCD and Tic assessment

Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Point prevalence rates

Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Prevalence rates (not reported whether current or lifetime) Lifetime prevalence rates

Prevalence rates (not reported whether current or lifetime) Prevalence rates (not reported whether current or lifetime) Prevalence rates (not reported whether current or lifetime) Prevalence rates (not reported whether current or lifetime) Lifetime prevalence

Point prevalences

Lifetime prevalence rates

Prevalence rates (not reported whether current or lifetime) Lifetime prevalence rates

Lifetime prevalence rates

Prevalence rates (not reported whether current or lifetime) Prevalence rates (not reported whether current or lifetime)

Outcome measure

(continued on next page)

4.4 % OCD 9.6 % OCD/OCS/ANX/AD/SIB

25.3 % OCD; 8.2 % OCD + ADHD

18.0 % CTD; 13.3 % TS

3.9 % OCD + TD, 1.84 % OCS + TD

8.3 % Tic Disorder

35.95 % OCD

4 % TD

4.3 % TS in United States sample, 8.1 % in Brazilian sample

0.02 % of general population with comorbid OCD + TD

7.02 % OCD; 35.09 % OCS

TS/ CTD in OCD 5.1%. 5.8% OCD in TS/ CTD

11% with TD

37.6 % - 42.5 % of TS with OCD (depending on study site) vs. 5.1 % in HC 39.2 % OCD at follow-up

41.9 % TD in OCD patients with suicide attempts

60% OCD

53% OCD

15.2% OCD, 30.3% subclinical OCB

18.51 % OCD

Result (cases vs. controls)

L. Kloft et al.

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

236 children and adults with CTD/TS, 518 unaffected family members 431 children and adults with OCD

437 pediatrics and adults with TS (n = 121 patients from Costa Rica, n = 133 patients of Ashkenazi Jew descent, n = 183 from the Netherlands) 1374 children and adults with TS (27.8 % TS, 20.2 % TS + OCD, 22.4 % TS + ADHD, 28 % TS + OCD + ADHD), 1142 TS-unaffected family members 89 with OCD, 21 OCD + TD; pediatric sample

Abdulkadir et al. (2016) Dell’Osso et al., 2016

de Haan et al. (2015)

283

Micali et al. (2010)

Brakoulias et al. (2011) Nakatani et al. (2011)

Scharf et al. (2012)

Bienvenu et al. (2012)

de Alvarenga et al. (2012)

124 children and adolescents with OCD

Conelea et al. (2014) Arumugham et al. (2014) Neal and Cavanna (2013) de Mathis et al. (2013) Lebowitz et al. (2012)

cross-sectional; outpatients from specialized clinic

cross-sectional; patients from specialized OCD clinic

365 children with EO-OCD

142 children and adolescents with OCD

cross-sectional; outpatients from a specialized clinic

family association study; matched case-control; crosssectional; outpatients from specialized clinics; sample overlaps with Johns Hopkins OCD Family Study & OCD Collaborative Genetics Study prospective, population based study; Avon Longitudinal Study of Parents and Children (sample overlaps with Huisman-van Dijk et al., 2016)

cross-sectional; outpatients in specialized unit; Brazilian OCD Research Consortium

cross-sectional; outpatients from specialized treatment site cross-sectional; outpatients from specialized treatment site cross-sectional; outpatient study in specialized unit; unmatched case-case cross-sectional; outpatients in specialized unit; Brazilian OCD Research Consortium cross-sectional; outpatients from specialized treatment site; Tourette Syndrome Study Group

cross-sectional; Outpatients from specialized treatment center; uncontrolled case-relatives; Tourette Syndrome Association International Consortium for Genetics (TSAICG) cross-sectional; Outpatients from specialized treatment center; uncontrolled case-case Cross-sectional; outpatients from specialized clinics; The International College of Obsessive–Compulsive Spectrum Disorders (ICOCS) cross-sectional; outpatients from specialized clinic

cross-sectional; outpatients from specialized treatment centers; matched case-case; TIC Genetic Study cross-sectional; outpatients from specialized treatment centers; matched case-case; ICOCS; sample overlaps with Lochner et al., 2014; Dell’Osso et al., 2017, 2018 cross-sectional; outpatients and subjects from the community recruitment in a multicenter approach

cross-sectional; outpatient study in specialized unit

Study design

77 with OCD

813 with OCD patients Brazilian OCD Research Consortium 1001 OCD 382 with OCD (68 any tic disorder), 974 FDR of OCD 73 normal controls (0 any tic disorder), 233 control relatives 6768 children

143 children and adolescents with TS 10 children and adolescents with CTD

1001 with OCD

71 with TS

802 familial and sporadic OCD patients

135 children and adolescents with CTD and TS

Theriault et al. (2014)

Tanidir et al. (2015) Lochner et al. (2014)

457 children and adults with OCD

112 children and adolescents with OCD

Ortiz et al. (2016)

Hirschtritt et al. (2015)

N

First author, year

Table 1 (continued)

DAWBA; Y-BOCS

MINI; Shapiro Tic Severity Scale; Y-BOCS CY-BOCS, ChOCI; clinical interview according to ICD-10

DAWDA (DSM-IV-TR)

SADS-LA; Kiddie-SADS; SKID

Y-BOCS; DY-BOCS; YGTSS; SCID-I

NHIS; NJRE-QR; MOVES; OCI-R; GTS-QoL; YGTSS Y-BOCS; DY-BOCS; YGTSS; SCID-I DISC-IV; YGTSS; CY-BOCS

ADIS-C/P; DSM-IV; YGTSS; CYBOCS MINI-Plus; Y-BOCS

YGTSS; YBOCS; Clinical interview according to DSM-IV

MINI; Y-BOCS; SCID-OCSD

KSADS-PL-T

SCID-I; SADS; tic severity scale; OCD severity scale; structured clinical interview

STOBS; YGTSS; DCI; Y-BOCS

CY-BOCS; OCI-CV; K-SADS-PL; DSM-IV YGTSS; Y-BOCS; Semistructured interview DSM-IV-TR SCID-I/ II, Y-BOCS

OCD and Tic assessment

Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime)

Point and lifetime tics

Point prevalence

Lifetime prevalence

Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Lifetime prevalence rates

Lifetime prevalence rates

Point prevalence

Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Lifetime prevalence rates

Lifetime prevalence rates

Lifetime prevalence rates

(continued on next page)

11.1 % TS, 4.8 % other tics

17.8 % of OCD patients Any tic disorder (TS was an exclusion criteria), 0 % of Any tic disorder; Fisher´s exact test = 0.0005 OR 16 CI 95 % 2.1115 2 % OCD in TS narrow (OR 95 % CI 13.0 (3.7, 37.1); 22 % OCD in TS (OR 95 % CI 12.0 (5.2, 25.2); 9 % OCD in CTD narrow (OR 95 % CI 4.4 (0.9, 14.3); 10 % OCD in CTD (OR 95 % CI 5.0 (1.9, 11.3); 20% OCD in intermediate 12.8 % Current Tics; lifetime tics could not be assessed 11.7 % CTD; 12.8 % TS

TS = 8.9 %; Chronic TD = 21.1 %

53.8 % OCD, 24.1 % OCD + ADHD

TD = 28.4 %

6 % tics in familial OCD vs 4 % Tics in sporadic OCD, ns 18% OCD, 59 % OCS

25.8 % CTD, 28.2 % TS

54.8 % OCB according to Y-BOCS

12.5 % TD

19.1 % TD

66.1% OCS; 20.2 % TS + OCD

61.4 % OCD in Ashkenazi Jew sample, 4.3 % in Costa Rica sample, 30 % in Dutch sample

15.5 % with TD

Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Lifetime prevalence rates

8.03 % TD, 1.78 % TD + ANX, 0.89 % TD + ANX + AD 37.3 % OCD vs. 13.2 %

Result (cases vs. controls)

Lifetime prevalence rates

Outcome measure

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cross-sectional; outpatients from a psychiatric clinic cross-sectional; outpatients and general population; German Epidemiologic Network Study cross-sectional; outpatient study in specialized unit

cross sectional; patients from specialty clinic cross-sectional; outpatients from specialized treatment site

35 children and adolescents with TS

252 with OCD

58 pediatrics with OCD

113 children and adolescents with OCD (27% with TD)

314 children and adolescents with TS

1274 with TS, 1142 FDR of TS

257 EO children and adults with OCD

74 children with OCD

Ghanizadeh and Mosallaei (2009) Janowitz et al. (2009) Garcia et al. (2009)

Ivarsson et al. (2008)

Mol Debes et al. (2008)

Robertson (2008a)

Mancebo et al. (2008) Storch et al. (2008)

284 cross-sectional; outpatient study in specialized unit cross-sectional; outpatient study in specialized unit

293 OCD patients

17 children and adolescents with TS, 17 normal controls

141 with OCD

317 with OCD

50 with OCD

72 with OCD, 263 FDR, 32 normal controls, 154 case FDR

125 children and adolescents with tics

334 with OCD

420 with OCD

Grant et al. (2007)

Termine et al. (2006)

Karadag et al. (2006)

Hasler et al. (2005)

Hanna et al. (2005)

Fyer et al. (2005)

Cardona et al. (2004)

LaSalle et al. (2004) Denys et al. (2004)

cross-sectional; outpatients from specialized unit

family study; cross-sectional; out- or inpatients from specialized clinics; unmatched case-control

cross-sectional; outpatient study in specialized unit

cross-sectional; outpatient study in specialized unit

cross-sectional; outpatients from specialized clinic

cross-sectional; outpatients and inpatients

prospective study; outpatients from specialized clinics; sample overlaps with Pinto et al. (2016)

3500 children, adolescents and adults with TS

Freeman (2007)

cross-sectional; multicenter; outpatients from specialized treatment sites

cross-sectional; patients from specialty clinics

cross-sectional; outpatients from specialized clinic

cross-sectional; outpatients in specialized unit

cross-sectional; outpatients from a specialized clinic

279 children with OCD and/or TD

Lewin et al. (2010)

Study design

N

First author, year

Table 1 (continued)

MINI; Y-BOCS; clinical interview according to DSM-IV

Clinical interviews (TD: according to TSCSG); YGTSS; CY-BOCS; CBCL SCID-I; Y-BOCS, YGTSS

K-SADS; Schedule for Tourette and Other Behavioral Syndromes; SCID-I DSM-IV; SADS-LA—R

SCID-I; TBI

SCID-I; Y-BOCS

YGTSS; CY-BOCS; K-SADS

SCID-I; Y-BOCS, Y-BOCS-SC

Clinical interview according to DSM-III-R and DSM-IV

SCID-I; SADS-PL; structured clinical interview specifically developed for TS genetic studies K-SADS-PL; SCID-P; CY-BOCS; Y-BOCS K-SADSPL, CY-BOCS

Clinical interview according to DSM-IV

CY-BOCS; K-SADS-PL; DSM-IV

K-SADS; ADIS-IV-C; CY-BOCS

Y-BOCS; SADS-LA

K–SADS–PL

ADIS; K-SADS

OCD and Tic assessment

Point prevalence rates

Current OCD diagnosis, no information if current or lifetime TD diagnosis Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Lifetime prevalence rates

Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Outcome measure

(continued on next page)

2.1 % TS; 1.5 % Tic Disorder NOS

3.9 % TS

19 % OCD, 46 % OCS

58 % Tic Disorder in familial OCD (including 36 % TS); 29 % Tic Disorder in sporadic OCD (including 12 % TS) 7 % TD vs. 0% (OCD vs. normal controls)

11.8 % TS

1.4 % TD

41.2 % OCD: 23.5 % ADHD + OCD

5.12 % Any Tic Disorder

22.3 % OCD, 32.6 % OCS

62.2 % CTD and TS

20.62 % Any Tic Disorder

50 % OCD in TS patients

39.8 % OCD, 6.7 % subclinical OCS

29 % Any Tic Disorder; 10 % Chronic TD; 19.75 % TS

1.7 % TS, 20.7 % Any TD

8.70 % Any tic/TS

25.7 % OCD

10.95 % TD; 56.4 % OCD; 8.8 % OCD + TD

Result (cases vs. controls)

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134 with TS

Leckman et al. (1994a,b)

285 cross-sectional; outpatients from specialized clinic; matched case-control

cross-sectional; community sample; Physical examination for the Israel Defence Force follow-up; no information regarding patient recruitment

Cross-sectional; outpatients from specialized treatment site; unmatched case-case

family study (the HOPKINS OCD family study); unmatched case-case/ control cross-sectional; outpatients from specialized clinics cross-sectional; outpatients from specialized treatment site cross-sectional; community sample; Physical examination for the Israel Defence Force Cross-sectional; outpatients from specialized treatment site; unmatched case-case

Leyton Scale; DICA (DSM-III)

DICA; SADS; Yale-STOBS

YSTOBS

Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS Clinical interview according to DSM-III; Y-BOCS; YGTSS

YSTOBS

K-SADS-E

Y-BOCS; CY-BOCS; YGTSS; KSADS-PL; SADS-LA-R IV; FISC

DISC; LOI-CV; YGTSS

Behavior Rating Scale, DSM-IV

Clinical interview according to DSM-III-R; CY-BOCS

CY-BOCS; CBCL

DAWDA

OCD and Tic assessment

Lifetime prevalence rates

Point and lifetime prevalence rates

Prevalence rates (not reported whether point or lifetime) Lifetime prelavence rates

Y-BOCS, YGTSS

Lifetime and point prevalence rates Lifetime prevalence rates

Prevalence rates (not reported whether point or lifetime) Prevalence rates (not reported whether point or lifetime) Lifetime prevalence rates

Lifetime prevalence rates

Lifetime prevalence rates

Point prevalence rates

Outcome measure

At baseline, 30 % had a current or transient or chronic TD, and additional 27.8 % had lifetime transient or chronic TD. At follow-up 15 % had lifetime TS, 22 % had CTD, and 22 % had transient TD In TS group, 25 % co-occurring OCD, X2 = 0.1325, p = 0.05

41.7 % of TS patients had comorbid OCD

239 % OCD, 4552 % OCS

OCD = 2.32 %, OCS = 2.32 % 1.74 % with co-occurring TD 31,63 with TD %

29.5 % OCD

10.9 % OCD in children with tics, OR 95 % 1.55 (1.02, 2.35), 7.4 % OCD in children without tics, p < 0.04 6.5 % Chronic TD vs. 0 %, (Fischer’s exact test = 0.06, two-tailed; p = .04, one-tailed)

2.1 % OCD in patients with tics, 0.32 % OCD in HC; no significant difference

16.3 % Transient tics 23.8 % CTD/TS 25 % tics

0.24 % OCD, 0 % with comorbid Tic Disorder

Result (cases vs. controls)

Abbreviations: AD Affective Disorders; ADHD Attention Deficit Hyperactivity Disorder; ADIS-C/P Anxiety Disorders Interview Schedule-Child and Parent Version; ANX Anxiety Disorders; CI Confidence Interval; CTD Chronic Tic Disorders; COIS-R Children’s Obsessive-Compulsive Impact Scale – Revised; CY-BOCS Children´s Yale-Brown Obsessive-Compulsive Disorder Scale; DCI Diagnostic Confidence Interview; DICA Diagnostic Interview for Children and Adolescents; DISC-IV Diagnostic Interview Schedule for Children; DAWBA Development and Wellbeing Assessment; DSM-IV Diagnostic and Statistical manual for Mental Disorders; FISC the Family Informant Schedule and Criteria; HC Healthy Controls; MINI The Mini Neuropsychiatric Interview; NHIS National Hospital Interview Schedule for the assessment of tics and related behaviours; NOS not otherwise specified; K-SADS-PL Kiddie-Sads-Present and Lifetime Version; LOI-CV Children´s Obsessional Inventory-Children´s Version; MOVES The Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey; OCI-CV Obsessive-Compulsive Inventory Children´s Version; OCS Obsessive-Compulsive Scale; OR Odds ratio; SADS Schedule for Affective Disorders and Schizophrenia for School Aged Children; SCID-I Structured Clinical Interview for DSM Disorders; SCID-OCSD Structured Clinical Interview for Obsessive-Compulsive Spectrum Disorder; YSTOBS Yale Schedule for Tourette Syndrome and Other Behavioral Disorders SIB Self-injurious Behavior; TICS The Tic and Co-morbid Symptom Inventory; TD Tic Disorders; TBI Thoughts and Behavior Inventory; TS Tourette Syndrome; Y-BOCS Yale-Brown Obsessive-Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

25 children with TS, 25 normal controls

177 OCD

Leckman et al. (1994a)

Grad et al. (1987)

861 adolescents

Zohar et al. (1997)

54 children and adolescents with OCD

190 children and adolescents with CTD

Coffey et al. (2000)

Leonard et al. (1993)

77 with OCD (5 with TD), 66 matched controls, 323 case relatives 289 control relatives

Grados et al. (2001)

28,073 16-17 year old adolescents

339 children with tics, 1257 healthy controls

Kurlan et al. (2002)

Apter et al. (1993)

3006 children and adolescents

Gadow et al. (2002) cross-sectional; community sample; no matching information

cross-sectional; outpatients from specialized treatment site; matched case-case cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; sample overlaps with Hanna et al., 2005; Dickel et al., 2007 cross-sectional; community sample

32 with OCD + TD, 48 with OCD; all pediatrics

60 children and adolescents with OCD

national epidemiological study

10,438 children and adolescents

Heyman et al. (2003) Scahill et al. (2003) Hanna et al. (2002)

Study design

N

First author, year

Table 1 (continued)

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270 with OCD, 170 with OCD + TD

577 with OCD, 236 with TD

365 children with EO-OCD (151 with very early onset < 10 years) 50 with OCD + TD, 141 with OCD

de Vries et al. (2016a)

de Alvarenga et al. (2012)

Nakatani et al. (2011) Jaisoorya et al. (2008) de Mathis et al. (2008) Dickel et al. (2007)

286

28 with pediatric TS, 23 with OCD, 18 with OCD + TD

45 with pediatric OCD, 15 with OCD + TS

64 children diagnosed with TS and/or OCD; pediatric sample

77 with OCD (5 with TD), 66 matched controls, 323 case relatives, 289 control relatives

354 with OCD (26.6% TD)

20 with OCD, 21 with TS, 20 with OCD + TS

35 with OCD, 35 with OCD + tics

121 OCD, 56 OCD + TD

Findley et al. (2003)

Hanna et al. (2002)

Lin et al. (2002)

Grados et al. (2001)

Mataix-Cols et al. (1999) Miguel et al. (1997)

Holzer et al. (1994)

Leckman et al. (1994a)

Cross-sectional; outpatients from specialized treatment site; case-case and case-control; Hopkins OCD Family Study Cross-sectional; Outpatients from specialized treatment center; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; unmatched case-case

Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Prospective and longitudinal; outpatients from specialized treatment site; unmatched case-case

Cross-sectional; uncontrolled case-case, controlled case-control Prospective study; uncontrolled case-case; The Netherlands Obsessive-Compulsive Association (NOCDA) study Cross-sectional; outpatients from specialized treatment centers; uncontrolled case-case; Brazilian Research Consortium (C-TOC) cross-sectional; patients from specialized OCD clinic Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; no matching information; outpatients from specialized treatment site; sample overlaps with Hanna et al., 2002, 2005 cross-sectional; family base genetic study: outpatients from specialized clinic; matched case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Study design

Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS

Clinical interview according to DSM-IV; Y-BOCS; NIHM OCD scale Y-BOCS; YGTSS; USP-HARVARD Repetitive Behaviours Interview STOBS; Y-BOCS

Tic inventory of the TS Association International Consortium for Genetics; YGTSS; Y-BOCS; Clinical interview according to DSM-IV Clinical interview according to DSM-III-R; CYBOCS Clinical Interview according to DSM-IV; Selfand-family report from the Tourette Syndrome Association International Consortium for Genetics; SADS Y-BOCS; CY-BOCS; YGTSS; K-SADS-PL; SADSLA-R IV; FISC

SCID-I; Y-BOCS; YGTSS; USP-HARVARD Repetitive Behaviors Interview CY-BOCS; CBCL

No difference

OCD + tics = OCD

OCD + TS < TS < OCD, F = 6.23, df = 2, 58, p = 0.004

OCD > OCD + TD, F = 4.05, df = 1, 90, p = 0.04

OCD + TD = OCD, p = 0.97

No difference

No difference

no apparent association between early-onset OCD and a positive tic history OCD > TS > TS + OCD

OCD > OCD + CMVT > OCD + CTD, p = 0.002

OCD > OCD + TD, rf = 0.11; p =.007

OCD > OCD + TD, t (24) = 2.12, p < .05

K-SADS-E-5; SCID; Schedule for Tourette´s Syndrome and Other Behavioral Syndromes SCID-I; KIDDIE-SADS; Y-BOCS; YGTSS

OCD + TD < OCD, p = 0.001

OCD + TICS < OCD, p = .010, 95 % CI = 0.873-0.981

Higher comorbidity with tics in the very early onset group

No statistical difference

7.1% vs. 1.1% comorbid TD in patients with EO vs. LOOCD; < 0.001 OCD > OCD + TD, t (223) = 2.7, p = .008, 95 % CI = 0.7-4.7

Result

SCID-I; DY-BOCS; Y-BOCS; YGTSS

CY-BOCS, ChOCI; clinical interview according to ICD-10 Y-BOCS; CY-BOCS; SCID-I; STOBS

SCID-I; Y-BOCS; DY-BOCS; YGTSS; USP-SPS

SCID-I; Y-BOCS; ten items tic screener; YGTSS

SCID-I; Y-BOCS;

OCD and TD assessment

Abbreviations: CBCL Child Behavior Checklist; CY-BOCS Children’s Yale-Brown Obsessive Compulsive Scale; DY-BOCS Dimensional Yale-Brown Obsessive Compulsive Scale; DSM-IV Diagnostic and Statistical Manual for Mental Disorders; FISC Family Informant Schedule and Criteria; K-SADS-PL Kiddie-Schedule for Affective Disorders and Schizophrenia-Present Lifetime; OCD Obsessive-Compulsive Disorder; SADS-LA-R IV Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety Version; SCID-I Structured Clinical Interview for DSM-IV; STOBS Schedule for Tourette and Other Behavioral Syndromes; TD Tic Disorders; TS Tourette Syndrome; USP-SPS University of São Paulo Sensory Phenomena Scale; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

32 with pediatric OCD + TD, 48 with OCD

98 with OCD, 31 with OCD + CTD, 30 OCD + TS

Scahill et al. (2003)

Diniz et al. (2006)

Stewart et al. (2007)

339 EO-OCD, 276 LO-OCD

Kang et al. (2017)

239 with early-onset OCD, 91 with early-onset OCD + TD 54 parent-child trios of early onset OCD patients (15 case probands with OCD-only, 11 with OCD + TD; 85 relatives (47 with OCD syndrome lifetime, 6 with subthreshold OCD lifetime, 11 any TD lifetime) 22 with OCD + TD, 35 with OCD

N

First author, year

Table 2 Age-of-onset.

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3.1.2. Prevalence rates of TD in OCD (OCD + TD) 3.1.2.1. Clinical samples. A study that included pediatric and adult patients reports lifetime prevalence of TD in OCD to be 12% (Lochner et al., 2014). When only adults were examined, lifetime prevalence rates were between 1.74%(Zohar et al., 1997) and 28.4% (de Alvarenga et al., 2012). Studies that specifically examined prevalence rates of TD in early-onset OCD, often did not specify whether they examined point or lifetime rates. Rates varied between 18.7% (Nissen et al., 2016) – 46.2% (do Rosario-Campos et al., 2005) which are much higher than in other OCD.

3.2.2. Symptom severity, course of symptoms, quality of life, and suicide attempts Regarding severity of tics and obsessive-compulsive symptoms (OCS), the large majority of the 20 studies, including the ones with large sample sizes, shows that there is no difference in severity of tic and OCS between comorbid and “only” groups (Table 3). This is strong evidence against the idea that co-occurring TD and OCD is a more severe subtype of TD (Coffey et al., 1998). However, when tics and OCS are present in the same subject they appear to be highly correlated (Lin et al., 2002; Peterson et al., 2001a) (Table 4). Peterson et al. (2001a) also observed that tics in childhood or early adolescence predicted OCD symptoms later in adolescence or in early adulthood, and OCD in late adolescence predicted tics in adulthood (Table 4). Preliminary evidence indicates that comorbidity leads to differing courses of disorder compared to cases without comorbidity. In children with OCD, comorbidity with TD was associated with briefer time to remission which let the authors to conclude that OCD + TD follows the trajectory of TD rather than OCD (Bloch et al., 2009). On the contrary, in children with TS, comorbidity of OCD was associated with more severe OCS in later age and these symptoms were more likely to persist than tic symptoms (Bloch et al., 2006b). In terms of quality of life, there is evidence to suggest lower quality of life in co-morbid patients (Neal and Cavanna, 2013; Rizzo et al., 2014) (Table 5). TD was also found to be significantly more represented than other psychiatric comorbidities in OCD patients with suicide attempts (Dell’Osso et al., 2018).

3.1.2.2. Community sample. de Alvarenga et al. (2012) examined 9937 school-aged children and found comorbidity of OCD + TD to be 5.7%. In an adult sample, prevalence was 8.7% (Janowitz et al., 2009). Due to the large variation of numbers, it is difficult to give an estimation of the prevalence rate of comorbidity of OCD and TD. This depends on the age of subjects, whether clinical or epidemiological samples are studied and assessment methods. In prospective, longitudinal studies from childhood to early adulthood it has been shown that comorbidity changes with age (Bloch et al., 2006b; Groth et al., 2017; Peterson et al., 2001a). For example, Peterson et al. (2001a) showed that young children with tics have a higher risk to develop OCD, that young adolescents with tics are more risk prone to have or develop OCD or those that had tics, their comorbid OCD will persistent into earl adulthood. Hence, depending of the age of the assessed subjects and type of prevalence rate (point or lifetime) rates can vary. Rates are also higher in clinical than epidemiological samples which may have to do with the greater disease severity which leads to an earlier seek for help and diagnosing (Shilon et al., 2008). Differences in assessment methods may also affect prevalence rates. However, even when assessment methods are held constant like in multisite studies, rates vary (de Haan et al., 2015). This may stem from problems with diagnosing tics and/ or the worldwide variation of TS prevalence rates due to environmental or genetic differences (Robertson, 2008b). The absence of standardized instruments with good reliability and validity for diagnosing TD in adults may lead to problems with diagnosing TD due to waxing and waning nature of tics, their suppressibility and since patients may be unaware of their tics (Pappert et al., 2003; Robertson, 2008b). The absence of such standardized assessment instrument may also be a reason that TD is often not assessed and reported in OCD research. This may lead to an underestimation of prevalence rates of comorbidity between OCD and TD since roughly two third of tic patients will remit/ show a reduction to minimal or mild tics over the course of adolescence (Leckman et al., 1998). This may also be influenced by the difficulty to separate complex tics from compulsions, i.e. particularly in adult patients, complex tics may misleadingly be classified as compulsions. Main recommendations for future research are the development of (semi-)structured interviews of good test quality for diagnosing TD in adults, the assessment and report of lifetime prevalences of OCD/ TD in all studies with these patients, and the realization of large clinical and epidemiological studies of TD in OCD and of OCD in TD.

3.2.3. Co-existing disorders Patients with comorbid OCD and TD also present with additional disorders, the most frequent one being anxiety disorders and ADHD (de Alvarenga et al., 2012; de Mathis et al., 2008; de Vries et al., 2016a; Hirschtritt et al., 2015; Lebowitz et al., 2012; Lewin et al., 2010; Scahill et al., 2003; Wanderer et al., 2012) (Table 6).However, results of the 15 studies are mixed, with some large studies finding differences in comorbidity patterns and others not. 3.2.4. Gender Of the 27 studies that examined gender ratio between OCD and comorbid TD, 18 reported the number of male and female participants and could thus be included in the meta-analysis (Table 7). The included studies comprised 4135 patients with OCD or OCD + TD. As shown in Fig. 3, the pooled male-to-female ratio was 1.63 [95% CI (1.18; 2.26)], p < 0.001. There was significant amount of heterogeneity between studies (Q14 = 61.76, I2 = 72.48%, p < 0.001). Hence, the number of males is almost 1.6 times higher in patients with OCD + TD compared to OCD. 3.2.5. Symptom dimensions Analyses of the 20 studies that examined symptom dimensions associated with co-occurring OCD and TD provide a very inconsistent picture with the most often replicated result being that patients with OCD + TD score higher on miscellaneous (de Groot et al., 1994; Diniz et al., 2004; Holzer et al., 1994; Miguel et al., 1997; Petter et al., 1998) and symmetry/ ordering scales (de Groot et al., 1994; de Vries et al., 2016a; Jaisoorya et al., 2008; Petter et al., 1998) and OCD patients without tics score higher on cleaning/ contamination scales (Anholt et al., 2006; Holzer et al., 1994; Jaisoorya et al., 2008). However, most of these results were found in studies with small sample sizes and were not replicated with larger number of participants and generally there exist more studies that did not find differences with regard to single scales (Table 8).

3.2. Clinical features 3.2.1. Age-of-onset An earlier age of onset is one of the features most often named as characterizing OCD + TD compared to OCD. Seventeen studies included age-of-onset in their analysis but only 14 reported sufficient data to be included in the meta-analysis. 2619 patients were included in the meta-analysis which yielded a weighted average SMD of 0.43 [95% CI (0.20, 0.65), p < 0.001 (Fig. 2). This indicates a significantly earlier age-of-onset for patients with OCD + TD. However, heterogeneity was high and studies differed significantly (Q13 = 65.60, I2 = 80.65, p < 0.001).

3.2.6. Sensory phenomena Regarding the presence of sensory phenomena, e.g. intrusive sensory experiences like the feeling of incompleteness or the urge to perform an action just-right (Miguel et al., 1997), eight studies consistently 287

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Fig. 2. Forest-plot showing standardized mean differences in age-of-onset in patients with obsessive-compulsive disorder “only” and comorbid with tic disorders.

of Hasler et al. (2007) but no significant association with TD was observed. Five factor analysis studies were done that included patients with TD. These studies differed in terms of the scales that were used to measure tic symptoms (YGTSS, NHIS-GTS, STOBS, Y-BOCS). Three of these identified OC-related factors (Alsobrook and Pauls, 2002; Huisman-van Dijk et al., 2016; Robertson and Cavanna, 2007) whereas two did not (Cavanna et al., 2011; de Haan et al., 2015). In the study of Alsobrook and Pauls (2002) the compulsive factor was significantly associated with ADHD and OCD in first-degree relatives. Low consistency is also observed in two cluster analytic studies eligible for this review. Although both identified a “complex tic factor”, only Mathews et al. (2007) observed that this factor was associated with OCD + ADHD, an earlier age of onset, family history of tics, and increased tic severity whereas McGuire et al. (2013) did not reproduce an association with clinical correlates like OCD and/ or ADHD.

observe that patients with comorbid OCD + TD report more sensory phenomena than patients with pure OCD (Chee and Sachdev, 1997; de Alvarenga et al., 2012; Diniz et al., 2006; Miguel et al., 1997) (Table 9). No difference between TS and TS + OCD was found in studies that used non-standardized instruments to examine sensory phenomena (Chee and Sachdev, 1997; Santangelo et al., 1994). Several studies specifically addressed not-just-right-experiences and with the exception of Leckman et al. (1994a) all of them found higher rates in comorbid patients (de Alvarenga et al., 2012; Diniz et al., 2006; Miguel et al., 1997; Neal and Cavanna, 2013). 3.2.6.1. Summary clinical features. Our review further substantiates acknowledged clinical features of OCD+TD like an earlier age-ofonset, higher frequency of sensory phenomena, and male preponderance (by factor 1.6). Preliminary evidence indicates that comorbidity affects quality of life and the course of OCD/ TD. Regarding other clinical features like association with specific symptom dimensions and comorbidities, it cannot be excluded that patients with OCD+TD present more often with symmetry/ ordering and miscellaneous as well as comorbid anxiety disorders and ADHD but evidence is weak and controversial. Recommendations for future studies include sufficiently powered data to examine heterogeneity between studies which should follow a prospective design since all studies so far collected data retrospectively.

3.3.1. Summary latent class, factor, and cluster analysis Different statistical approaches were used to classify patients by means of symptoms and/ or clinical correlates. Although not fully consistent, the studies show that independent of the statistical method, entities of co-occurring OCS/ OCD and TD can often be revealed. 3.4. Pre-, peri- and postnatal risk factors In the only controlled study of pre- and perinatal risk factors, the presence of OCD in TS was related to delivery complications and neonatal complications, the latter being also related to severity of OCD (Abdulkadir et al., 2016) (Table 11). The assessment of risk factors was retrospectively using self-report data which lowers methodological quality. Also, replication is warranted. The only potential postnatal riskfactor examined were autoimmune diseases like infection with group-A beta-hemolytic streptococci. This infection has been described as leading to the development of Pediatric Autoimmune Neuropsychiatry Disorders Associated with Streptococcal Infections (PANDAS) (Swedo et al., 1998), which affects functioning of the basal ganglia, and may lead to OCS and tics. The two studies that examined an association between autoimmune diseases and OCD/ TD either followed a controlled or register-based study design and did not find any differences between groups (Gause et al., 2009; Mataix-Cols et al., 2017).

3.3. Latent class analysis, factor analysis, cluster analysis Three studies that used latent class analysis were eligible for inclusion in the present review (Table 10). Two of them identified a class of comorbid OCD and tics (Grados and Mathews, 2008; Nestadt et al., 2008). Grados and Mathews (2008) additionally found classes of “TS + OCD”, and “TS + ADHD + OCD”. In the third study (Darrow et al., 2017), which also included first-degree relatives of TS patients, the authors went beyond categorical diagnoses and used symptoms to identify latent classes. They found a symptom based phenotype of symmetry that went across categories of OCD and TS. This class was heritable, specifically found in mothers of TS patients, and correlated with polygenic risk scores of TS patients but not OCD patients. Three studies conducted factor analysis of Y-BOCS derived factors in subjects with OCD and lifetime TD. It was found that patients with OCD + TD load significantly on factors of symmetry/ ordering/ hoarding (Baer, 1994; Mataix-Cols et al., 1999) and religious, aggressive, sexual, checking, and somatic obsessions (Hasler et al., 2007). However, a symmetry/ ordering factor was also identified in the study

3.4.1. Summary environmental risk factors Environmental factors are clearly understudied in the emergence of OCD+TD so that no conclusions can be drawn in this regard. More, and 288

782 children and adolescents with TS and 250 with OCD/OCB 46 with TS,20 with TS + OCD 20 with TS + ADHD, 6 with TS + OCD + ADHD,102 normal controls; pediatric sample 42 with TS + OCD, 29 with TS

Sambrani et al. (2016) Rizzo et al. (2014)

239 with early-onset OCD, 91 with early-onset OCD + TD

98 with OCD, 31 with OCD + CMVT, 31 with OCD + TS

50 with OCD, 19 with OCD + TS, 18 with TS, 30 normal controls

64 children diagnosed with TS and/or OCD; pediatric sample

45 with OCD, 15 with OCD + TD; all pediatrics

32 with TS, 10 with OCD + TS, 21 with OCD, 29 normal controls

13 OCD + TS, 13 OCD

de Mathis et al. (2008)

Diniz et al. (2006)

Anholt et al. (2006)

Lin et al. (2002)

Hanna et al. (2002)

Cath et al. (2001a)

Petter et al. (1998)

50 TS patients (24 with OCD with TS + OCD, 15 TS + ADHD, 11 TS + OCD + ADHD

Eddy et al. (2012)

206 with pediatric OCD, 40 with TD, 33 with OCD + TD

85 TD + OCD, 61 TD + ADHD, 12 TD + OCD + ADHD

Lebowitz et al. (2012)

Lewin et al. (2010)

577 with OCD, 236 with TD

de Alvarenga et al. (2012)

1001 with OCD patients (28.4% co-occurring TD)

270 with OCD, 170 with OCD + TD

de Vries et al. (2016a)

Neal and Cavanna (2013) de Mathis et al. (2013)

N

First author, year

Table 3 Severity of OCD and tic symptoms.

289 Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case/case-control Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Prospective study; uncontrolled casecase; The Netherlands ObsessiveCompulsive Association (NOCDA) study Cross-sectional; Outpatient study in specialized unit; unmatched case-case Retrospective data; Outpatient study in specialized unit; unmatched casecase Cross-sectional; Outpatient study in specialized unit; unmatched case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment centers; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Prospective; outpatients from specialized treatment centers; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case/ case-control Prospective and longitudinal; outpatients from specialized treatment site; unmatched case-case

Study design

Clinical interview according to DSM-III-R: Y-BOCS; TSURS

Leiden GTS/OCD semi-structured interview; Y-BOCS

Clinical Interview according to DSM-IV; Self-and-family report from the Tourette Syndrome Association International Consortium for Genetics; SADS Clinical interview according to DSM-III-R; CY-BOCS

Padua-R

SCID-I; Y-BOCS; YGTSS; USP-HARVARD Repetitive Behaviors Interview

SCID-I; DY-BOCS; Y-BOCS; YGTSS

ADIS; CSR; KSADS; CY-BOCS

YGTSS; CBCL; CY-BOCS

DISC-IV; YGTSS; CY-BOCS

SCID-I; Y-BOCS; DY-BOCS; YGTSS; USPSPS

NHIS; NJRE-QR; MOVES; OCI-R; GTSQoL; YGTSS SCID-I; Y-BOCS; DY-BOCS; YGTSS; USPSPS

Clinical interview according to DSM-III-R and DSM-IV-TR; STSS CBCL; YGTSS; CY-BOCS

SCID-I; Y-BOCS; ten items tic screener; YGTSS

OCD and Tic assessment

Y-BOCS; Tourette Syndrome Association Unified Tic Rating Scale

Y–BOCS

CY-BOCS

YGTSS; CY-BOCS

Padua-R scores

YGTSS; Y-BOCS

DY-BOCS

ADIS;CSR, CY-BOCS

CY-BOCS

YGTSS

Y-BOCS and DY-BOCS global scores

Y-BOCS and DY-BOCS global scores

No difference

(continued on next page)

OCD + tic > TS (p = .004); OCD > TS (p = .006)

No difference

No difference at baseline

Padua-R scores: OCD > TS, HC, F = 25.74, (df = 3, 111, p < 0.001); OCD > OCD + TS, p = 0.056

YGTSS: OCD + TS > OCD + CMVT (p < .001); YBOCS: no difference OCD = OCD + CMVT = OCD + TS

mean global DY-BOCS scores: EOG without tic disorders > EOG with tic

No difference

TS < TS + OCD; F (7,1) = 3.467; p = .021 and TS < TS + OCD + ADHD; F (7,1) = 3.093, p = .038

OCD + TD > TD, F (1) = 14.6, p < 0.001

No difference

TS + OCD > TS; CI = 12.87–22.44; t (69) = −2.54, p = .013; no difference on YGTSS scores No difference

No difference

YGTSS tic severity

TS only < TS + comorbidity, t = 2.43, p < 0.05

No difference

Result

Mean tic severity

Y-BOCS

Outcome measure

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Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS

35 with OCD, 35 with OCD + TD

92 with TS (36.5% with OCD)

121 OCD, 56 OCD + TD

Holzer et al. (1994)

Santangelo et al. (1994)

Leckman et al. (1994a)

Abbreviations: ADIS Anxiety Disorder Interview Schedule for DSM-IV: Child and Parent version; ADIS CSR Clinician Severity Rating for tic severity and OCD severity; CBCL Child Behavior Checklist; CY-BOCS Children’s Yale-Brown Obsessive Compulsive Scale; DSM-IV Diagnostic and Statistical Manual for Mental Disorders; DY-BOCS Dimensional Yale-Brown Obsessive Compulsive Scale; FISC Family Informant Schedule and Criteria; GTS-QoL Gilles de la Tourette Syndrome – Quality of Life scale; GSR Global Severity Ratings; K-SADS-PL Kiddie-Schedule for Affective Disorders and Schizophrenia-Present Lifetime; LOI Leyton Obsessive Inventory; MOVES Motor tic Obsession and compulsion and Vocal tic Evaluation Survey; NJRE-QR Not Just Right Experiences-Questionnaire Revised; OCD Obsessive-Compulsive Disorder; OCI-R Obsessive Compulsive InventoryRevised; Padua-R Padua Inventory Revised; SADS-LA-R IV Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety Version; SCID-I Structured Clinical Interview for DSM-IV; STOBS Schedule for Tourette and Other Behavioral Syndromes; STSS Shapiro Tourette-Syndrome Severity Scale; TD Tic Disorders; TS Tourette Syndrome; TSURS Tourette Syndrome Association Unified Tic Rating Scale; USP-SPS University of São Paulo Sensory Phenomena Scale; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

No difference

No difference

Likert scale of tic severity at home, school, and work Y-BOCS Clinical interview according to DSM-III-R; SADS-K; DIS

No difference Y-BOCS STOBS; Y-BOCS

No difference Y-BOCS Y-BOCS; YGTSS; USP-HARVARD Repetitive Behaviours Interview 20 with OCD, 21 with TS, 20 with OCD + TS Miguel et al. (1997)

Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; unmatched case-case Cross-sectional; outpatients from specialized treatment site; unmatched case-case

N First author, year

Table 3 (continued)

Study design

OCD and Tic assessment

Outcome measure

Result

L. Kloft et al.

prospective studies are needed to examine if and how the interaction of environmental and biological factors is involved in producing different phenotypes. 3.5. Genetics Early family studies of case probands with OCD or TS provided the first hint for a close relationship between the two disorders by showing that they are familial, i.e. that higher rates are found in relatives of affected individuals than in relatives of normal controls (Pauls et al., 1995, 1986). As can be seen in table 12, 19 family studies addressing the relationship of OCD and TD have been conducted since. The majority of these studies found increased cross-disorder rates in case compared to control relatives (Bienvenu et al., 2012; Chabane et al., 2005; do Rosario-Campos et al., 2005; Grados et al., 2001; Hanna et al., 2005; O’Rourke et al., 2011; Pauls et al., 1995, 1991) but some others did not (Black et al., 1992; Hanna et al., 2005; Reddy et al., 2001). The failure to find differences might be due to specific sample characteristics since the number of TS-affected control relatives in the study of Hanna et al. (2005) was comparably high (2.5% compared to 0.3%-1% normally found in the general population). Most studies that did not find increased cross-disorder prevalence rates used smaller sample sizes (< 107) and smaller number of co-morbid case patients (Black et al., 1992; Kano et al., 2004; Reddy et al., 2001) which indicates that null results are due to insufficient power. For summarizing prevalence rates in family studies, we applied the same criteria as with prevalence rates in cases (i.e. specification of whether point or lifetime prevalence rates were assessed, larger sample sizes (> 100 patients), and use of rigorous assessment methods). Prevalence rates of TD in OCD case relatives vary between 0.9% - 14% (Grados et al., 2001; Reddy et al., 2001). Of the family TD studies, only one study fulfilled our criteria since most of them did not specify what kind of prevalence rates were assessed. In this study (Pauls et al., 1991) the rate of OCD in relatives of TS patients was 11.5%. Further information towards the role of genetic factors involved in the comorbidity of OCD and TD comes from three large twin studies. These found rather consistent phenotypic correlation between tics and OCS across twins of 0.25 - 0.34 (Bolton et al., 2007; Pinto et al., 2016; Zilhao et al., 2016) which indicate moderate genetic overlap between OCS and tics. Results differ regarding the influence of genetic and nonshared environmental factors on these correlations: two of three studies (Pinto et al., 2016; Zilhao et al., 2016) found higher monozygotic than dizygotic correlation of cross-twin cross-trait analysis, which indicates that a significant proportion of the co-occurrence of tics and OCS can be explained by genetic influences. The third study found these rates to be quite similar in pediatric patients, highlighting the role of shared environmental factors (Bolton et al., 2007). Results of genetic model fitting analysis to estimate the influence of genetic and non-shared environmental factors was either unable to determine the source of familial aggregation (Bolton et al., 2007), found an equal proportion of genetic and non-shared environmental contributions (Pinto et al., 2016), or found genetic factors to play a larger role (Zilhao et al., 2016). The hypothesis that OCD + TD may represent a variant expression of genetic TD vulnerability predicts increased rates of TD in family members of co-morbid patients compared to family member of OCDonly patients. However, of the few studies that addressed this question, none of them found significantly increased rates of TD in relatives of patients with comorbid OCD and TD (Chabane et al., 2005; do RosarioCampos et al., 2005; Grados et al., 2001; Pauls et al., 1991, 1986). Related to the alternate expression hypothesis is the idea that in families affected with TD, OCD is more associated with female relatives of TS patients whereas TS is more associated with male relatives of TS patients. However, results are equivocal with studies that did find this gender effect (Hanna et al., 1999; O’Rourke et al., 2009; Pauls et al., 1991) and studies that did not, including large register-based studies (Cavallini et al., 2000, 1999; do Rosario-Campos et al., 2005; Pauls 290

45 children with OCD

Bloch et al. (2009) Bloch et al. (2006b) Lin et al. (2002)

1030 children

64 children diagnosed with TS and/or OCD; pediatric sample

prospective, longitudinal; community sample

propective, longitudinal; outpatients from specialized treatment site prospective, longitudinal; outpatients from specialized treatment site Prospective and longitudinal; outpatients from specialized treatment site; unmatched case-case

Longitudinal; outpatients from specialized treatment sites

Study design

Clinical interview according to DSM-IV; Self-andfamily report from the Tourette Syndrome Association International Consortium for Genetics; SADS DISC

STOBS; YGTSS;CY-BOCS

Clinical interview according to the Tourette Syndrome Classification Study Group; YGTSS; YBOCS SCID-I; YGTSS; CY-BOCS; STOBS

OCD and Tic assessment

lifetime prevalence; crosssectional association and temporal antecedents

Symptom severity fluctuation

lifetime prevalence

lifetime prevalence

Prevalence rates (not reported whether current or lifetime)

Outcome measure

significant co-morbidity between OCD and tics in temporal cross-section (OR = 1.10 and OR = 1.34); tics in childhood or early adolescence predicted OCD symptoms later in adolescence or in early adulthood, and OCD in late adolescence predicted tics in adulthood

18 % TS; OCD + TS associated with briefer time to remission 41.3 % OCD; severity of OCD symptoms increased from childhood to adulthood significant covariation of tics and obsessive-compulsive symptoms

Y-BOCS decreases from 13.4. to 8.6

Result

291

425 with OCD

46 with TS, 20 with TS + OCD, 20 with TS + ADHD, 6 with TS + OCD + ADHD, 102 normal controls; pediatric sample

42 with TS + OCD, 29 with TS

50 TS patients (13 with TS + OCD, 15 TS + ADHD, 11 TS + OCD + ADHD) Adolescent sample

Dell’Osso et al. (2018)

Rizzo et al. (2014)

Neal and Cavanna (2013)

Eddy et al. (2012)

cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

cross-sectional; Outpatient study in specialized unit; unmatched case-case

retrospective data; Outpatient study in specialized unit; unmatched case-case

outpatients; multicenter

Study design

NHIS; NJRE-QR; MOVES; OCI-R; GTS-QoL; YGTSS YGTSS; CBCL; CYBOCS

CBCL; YGTSS; CYBOCS

SCID I, II; Y-BOCS

OCD and Tic assessment

YQoL

QoL

YQoL

Suicide Attempts

Outcome measure

No difference

TD and TS was found to be significantly more represented than other psychiatric comorbidities (41.9 % and 1.9 %, respectively) OCD + TS subgroup < HC and < TS in the total (p < .01), relationship (p < .01), and general domains (p < .01) OCD + TS = HC and = TS in the self and environment domains TS + OCD > TS CI = 21.75–39.63) (t(69) = −2.70, p = 0.009

Result

Abbreviations: ADHD Attention Deficit Hyperactivity Disorder; CBCL Child Behavior Checklist; CY-BOCS Children’s Yale-Brown Obsessive Compulsive Scale; Y-BOCS Dimensional Yale-Brown Obsessive Compulsive Scale; GTS-QoL Gilles de la Tourette Syndrome – Quality of Life scale; MOVES Motor tic Obsession and compulsion and Vocal tic Evaluation Survey; OCD Obsessive-Compulsive Disorder; OCI-R Obsessive Compulsive InventoryRevised; Padua-R Padua Inventory; TS Tourette Syndrome; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale; YQoL-R Youth Quality of Life Instrument–Research Version.

N

First author, year

Table 5 Quality of Life and suicide attempts.

Abbreviations: CY-BOCS Children Yale-Brown Obsessive Compulsive Scale; DISC Diagnostic Interview Schedule for Children; OCD Obsessive-Compulsive Disorder; TS Tourette Syndrome; DSM-IV Diagnostic and Statistical Manual; SADS Schedule for Affective Disorders and Schizophrenia; YGTSS Yale Global Tic Severity Scale; STOBS Schedule for Tourette and Other Behavioral Syndrome.

Peterson et al. (2001a)

58 with TD

Theriault et al. (2018)

46 children with TS

N

First author, year

Table 4 Course of co-occurring OCD and TD.

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Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

270 with OCD, 170 with OCD + TD

89 with OCD, 21 OCD + TD; pediatric sample

50 OCD, 12 OCD + TD

de Vries et al. (2016a)

Tanidir et al. (2015)

Skarphedinsson et al. (2015) Hirschtritt et al. (2015)

292

206 with OCD, 40 with TD 33 with OCD + TD, pediatric sample

239 with early-onset OCD, 91 with early-onset OCD + TD 50 with OCD + TD, 141 with OCD

98 with OCD, 31 with OCD + CTD, 30 OCD + TS

32 with pediatric OCD + TD, 48 with OCD

13 OCD + TS, 13 OCD

Lewin et al. (2010)

de Mathis et al. (2008)

Diniz et al. (2006)

Scahill et al. (2003)

Petter et al. (1998)

Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Data from the Tourette Syndrome International Database Consortium; outpatients from specialized treatment centers; uncontrolled casecase Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Prospective; outpatients from specialized treatment centers; uncontrolled case-case

CBT augmentation to SRI; cross-sectional; matched case-case; outpatients in three specialized treatment sites Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment centers; uncontrolled case-case; Brazilian Research Consortium (C-TOC)

Prospective study; uncontrolled case-case; The Netherlands Obsessive-Compulsive Association (NOCDA) study Cross-sectional; Outpatients from specialized treatment center; uncontrolled case-case 16 weeks of sertraline treatment; cross-sectional; unmatched case-case; outpatients; NordLOTS Cross-sectional; Outpatients from specialized treatment center; uncontrolled case-relatives

Study design

Clinical interview according to DSM-III-R; Y-BOCS; TSURS

SCID-I; Y-BOCS; YGTSS; USPHARVARD Repetitive Behaviors Interview CY-BOCS; CBCL

Y-BOCS; CY-BOCS; SCID-I; STOBS

SCID-I; DY-BOCS; Y-BOCS; YGTSS

ADIS; CSR; KSADS

Clinical interview according to the Tourette Syndrome Classification Study Group

DISC-IV; YGTSS; CY-BOCS

SCID-I; Y-BOCS; DY-BOCS; YGTSS; USP-SPS

SCID-I; Y-BOCS; DY-BOCS; YGTSS; USP-SPS

ADIC-C/P; YGTSS; CY-BOCS; NIHM-GOCS

SCID-I; SADS; tic severity scale; OCD severity scale; structured clinical interview

K-SADS-PL; CY-BOCS

KSADS-PL-T

SCID-I; Y-BOCS; ten items tic screener; YGTSS

OCD and Tic assessment

OCD + TD > OCD score in the Attention Problems scale, t = 2.0, p = 0.05 Eight subjects with OCD and TS had a childhood history of ADHD, compared to none of the pure OCD subjects

OCD patients that presented with tic disorders as first diagnosis had higher frequencies of OC spectrum disorders (p = 0.03) along their life span OCD < OCD + TD : separation anxiety disorder (p = .003), social phobia (p < .001), specific phobia (p = .04), generalized anxiety disorder (p = .005), post-traumatic stress disorder (p = .004), attention-deficit hyperactivity disorder (p = .019), impulse control disorders in general (p = .04), and skin picking (p = .025) TD + OCD > TD anxiety F(1) = 5.33, p < 0.05; depression F(1) = 17.3, p < 0.001; and psychosocial stress F(1) = 16.1, p < 0.001 OCD + TS > TS any comorbidity, Mann-Whitney U test Z = -8.34, p < .001; in childhood: OCD + TS > TS ADHD, mood disorders, OD/ CDD, anxiety disorders; in adolescents OCD + TS > TS: anxiety disorders OCD > OCD + TD, TD anxiety disorders, χ2 = (2, 233) = 20.46, p = 0.000; no difference between OCD and OCD + TD for ADHD; TD, OCD + TD > OCD for ODD/CD, χ2 (2, 40) = 7.65, p = 0.02 OCD + TD > OCD, ADHD p < 0.001 and anxiety disorders, p = 0.04 OCD + TD > OCD: Trichotillomania p = .017; number of comorbid disorders p < .001 OCD + TD/TS OCD higher number of comorbidities p = .049

No difference in Anxiety Disorder, Mood Disorder, Adjustment Disorder; OCD + tic > OCD Disruptive behavior (p = 0.021) OCD + TD > OCD externalizing disorders, χ2 (49) = 3.94, p = 0.05 TS + OCD > TS mood disorders OR = 3.8, 95 % CI = 2.9-4.9, p < .001; anxiety disorders OR = 2.8, 95 % CI = 2.2-3.6, p < .001; disruptive behavior disorders OR = 2.0, 95% CI = 1.4-2.9, p < .001; and substance use disorder OR = 3.9, 95% CI = 2.5-6.0, p < .001 No difference in any, ADHD, Anxiety/ mood, or ODD

ADHS: OCD + TD > OCD p < .001; Autism: OCD + TD > OCD p = .005; OCD + TD > OCD ADHD

Result

Abbreviations: ADHD Attention Deficit Hyperactivity Disorder; ADIS Anxiety Disorder Interview Schedule for DSM-IV: Child and Parent version; ADIS CSR Clinician Severity Rating for tic severity and OCD severity; CYBOCS Children’s Yale-Brown Obsessive Compulsive Scale; DY-BOCS Dimensional Yale-Brown Obsessive Compulsive Scale; FISC Family Informant Schedule and Criteria; K-SADS-PL Kiddie-Schedule for Affective Disorders and Schizophrenia-Present Lifetime; OCD Obsessive Compulsive Disorder; SADS Schedule for Affective Disorders and Schizophrenia–Lifetime Version; SADS-LA-R IV Schedule for Affective Disorders and SchizophreniaLifetime Anxiety Version; SCID-I Structured Clinical Interview for DSM-IV; TSURS Tourette Syndrome Association Unified Tic Rating Scale; TD Tic Disorder; TS Tourette Syndrome; USP-SPS University of São Paulo Sensory Phenomena Scale; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

Jaisoorya et al. (2008)

4086 children and adolescent with TS +/- other comorbidities, 974 children and adolescents with TS + OCD +/- other co-morbidities

Wanderer et al. (2012)

577 with OCD 236 with TD

de Alvarenga et al. (2012)

85 TD + OCD, 61 TD + ADHD, 12 TD + OCD + ADHD

1001 with OCD patients (28.4 % co-occurring TD)

de Mathis et al. (2013)

Lebowitz et al. (2012)

124 OCD partial responders (n = 66 with TD)

Conelea et al. (2014))

1374 participants with TS (27.8 % TS, 20.2 % TS + OCD, 22.4 % TS + ADHD, 28 % TS + OCD + ADHD) ; 1142 TS-unaffected family members

N

First author, year

Table 6 Comorbidities.

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Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

811 with TS (422 with OCD)

Greenberg et al. (2018) Peris et al. (2017) de Vries et al. (2016a)

1363 participants with TS (27.8 % TS, 20.2 % TS + OCD, 22.4 % TS + ADHD, 28 % TS + OCD + ADHD); 1142 TSunaffected family members 124 OCD partial responders (n = 66 with TD)

Hirschtritt et al. (2015)

577 with OCD, 236 with TD

206 with OCD, 40 with TD 33 with OCD + TD, pediatric sample 624 patients and family members with OCD, 82 probable (26.2 % Tics)

239 with early-onset OCD, 91 with early-onset OCD + TD

113 children and adolescents with OCD (27% with TD)

50 with OCD + TD, 141 with OCD

25 families with TD + OCD, 41 with OCD, 31 with TD

50 with OCD, 19 with OCD + TS, 18 with TS, 30 normal controls

106 with EO-OCD, 325 FDR, 44 normal controls, 140 control relatives 32 with OCD + TD, 48 with OCD; all pediatrics

45 with OCD, 15 with OCD + TD; all pediatrics

64 children diagnosed with TS and/or OCD; pediatric sample

32 with TS, 10 with OCD + tics, 21 with OCD

77 with OCD (5 with TD), 66 matched controls

354 with OCD (26.6 % TD)

de Alvarenga et al. (2012)

Lewin et al. (2010)

Nestadt et al. (2003, 2009)

de Mathis et al. (2008)

Ivarsson et al. (2008)

Jaisoorya et al. (2008)

Stewart et al. (2007)

Anholt et al. (2006)

do Rosario-Campos et al. (2005) Scahill et al. (2003)

Hanna et al. (2002)

Lin et al. (2002)

Cath et al. (2001a)

Grados et al. (2001)

Mataix-Cols et al. (1999)

Conelea et al. (2014)

Tanidir et al. (2015)

782 children and adolescents with TS and 250 with OCD/ OCB 89 with OCD, 21 OCD + TD; pediatric sample

Sambrani et al. (2016)

332 children and adolescents with OCD 270 with OCD, 170 with OCD + TD

N

First author, year

Table 7 Gender proportion in OCD, TD, and OCD + TD.

293 Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case/casecontrol Cross-sectional; outpatients from specialized treatment site; case-case and case-control; Hopkins OCD Family Study outpatients from specialized treatment site; cross sectional; unmatched case-case

CBT augmentation to SRI; cross-sectional; matched case-case; outpatients in three specialized treatment sites Cross-sectional; outpatients from specialized treatment centers; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case cross-sectional; outpatients from specialized treatment site; unmatched case-case; the OCD collaborative genetics study (OCGS) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case cross-sectional; family base genetic study: outpatients from specialized clinic; matched case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case/ casecontrol family study; cross-sectional; outpatients from specialized clinic; matched case-control Cross-sectional; outpatients from specialized treatment site; matched case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Prospective and longitudinal; outpatients from specialized treatment site; unmatched case-case

cross-sectional; outpatients from specialized treatment sites outpatients from specialized treatment sites Prospective study; uncontrolled case-case; The Netherlands Obsessive-Compulsive Association (NOCDA) study Cross-sectional; Outpatient study in specialized unit; unmatched case-case Cross-sectional; Outpatients from specialized treatment center; uncontrolled case-case Cross-sectional; Outpatients from specialized treatment center; uncontrolled case-relatives

Study design

Clinical interview according to DSM-IV; Y-BOCS; NIHM OCD scale

Y-BOCS; CY-BOCS; YGTSS; K-SADS-PL; SADS-LA-R IV; FISC

Clinical interview according to DSM-IV; Self-andfamily report from the Tourette Syndrome Association International Consortium for Genetics; SADS Leiden GTS/OCD semi-structured interview; Y-BOCS

Clinical interview according to DSM-III-R; CY-BOCS

CY-BOCS; CBCL

STOBS, K-SADS, SCID

Padua-R

SCID-I; KIDDIE-SADS; Y-BOCS; YGTSS

Y-BOCS; CY-BOCS; SCID-I; STOBS

CY-BOCS; KSADS-PL

(continued on next page)

OCD + TD > OCD male, χ2 = 4.76, df = 1, p = 0.0

No difference

No difference

No difference between OCD and TS + OCD

No difference

More males in comorbid tic group χ2 = 7.46, df = 1, P = 0.006). No difference

TS > OCD, OCD + TS male p < .01

No difference

More male than female any tic disorder (p = .006), no diff for CMT OCD + TD > OCD male p = .023

no difference

OCD + TD class more male (OR for being female 0.48, p < 0.05)

SCID-I; SADS-LA-R; Y-BOCS SCID-I; DY-BOCS; Y-BOCS; YGTSS

No difference

More male OCD + tic, p = . 005

No difference

Male TS patients more often comorbid with OCD

No difference

No difference Trend level significance for larger proportion of men in the OCD + TD group No difference

No difference

Result

ADIS; CSR; KSADS

SCID-I; Y-BOCS; DY-BOCS; YGTSS; USP-SPS

ADIC-C/P; YGTSS; CY-BOCS; NIHM-GOCS

SCID-I; SADS; tic severity scale; OCD severity scale; structured clinical interview

Clinical interview according to DSM-III-R and DSM-IVTR KSADS-PL-T

ADIS C/P; CYBOCS; COIS-R SCID-I; Y-BOCS; ten items tic screener; YGTSS

TICS Inventory; YGTSS; Y-BOCS

OCD and Tic assessment

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121 OCD, 56 OCD + TD

Leckman et al. (1994a) Leonard et al. (1993)

Abbreviations: DIS Anxiety Disorder Interview Schedule for DSM-IV; Child and Parent version; CBCL Child Behavior Checklist; CY-BOCS Children’s Yale-Brown Obsessive Compulsive Scale; DSM-III Diagnostic and Statistical Manual for Mental Disorders; DY-BOCS Dimensional Yale-Brown Obsessive Compulsive Scale; FISC Family Informant Schedule and Criteria; SADS Schedule for Affective Disorders and Schizophrenia–Lifetime Version; K-SADS-PL Kiddie-Schedule for Affective Disorders and Schizophrenia-Present Lifetime; OCD Obsessive-Compulsive Disorder; ObQ 87 Obsessional Beliefs Questionnaire, Padua-R Padua Inventory; SADS-LA-R IV Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety Version; SCID-I Structured Clinical Interview for DSM-IV; TS Tourette Syndrome; TD Tic Disorders; USP-SPS University of São Paulo Sensory Phenomena Scale; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

15 with OCD + tics, 25 with OCD Zohar et al. (1997)

54 children and adolescents with OCD

YSTOBS

cross-sectional; community sample; Physical examination for the Israel Defence Force Cross-sectional; outpatients from specialized treatment site; unmatched case-case follow-up; no information regarding patient recruitment

Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS DICA; SADS; Yale-STOBS

Male to female ratio was 14:1 for OCD + tics:OCD OCD + TD > OCD more male, X’ = 6.2, df = 1, p < .02 OCD + TD > OCD more male

OCD and Tic assessment Study design N First author, year

Table 7 (continued)

Result

L. Kloft et al.

et al., 1995; Pinto et al., 2016; Zilhao et al., 2016). Comorbid OCD + TD overlap in clinical features with early-onset OCD, i.e. a potential subtype of OCD that starts before puberty (Leckman et al., 2010). Both are assumed to have increased familial loading and male preponderance, and early-onset OCD is often comorbid with TD. Seven family studies report on age-of-onset effects on the risk for TD in OCD case relatives. Five of them find increased rates of TD in EO−OCD case relatives (Chabane et al., 2005; do RosarioCampos et al., 2005; Grados et al., 2001; Hanna et al., 2005; Nissen et al., 2016) which together provides good evidence for a linkage between EO−OCD with tics. Few studies exist that examined an association between OCD and TD and polymorphisms, including polymorphisms of the adenosin receptor gene (ADORA1), the neuronal cadherin gene (CDH2), and catechol-O-methyltransferase (COMT) enzyme. (Table 13). So far, however, there are no demonstrated polymorphisms. In a GWAS that combined OCD and TD the question of overlapping and differing genetic architecture was addressed in a large sample (Yu et al., 2015). The authors showed that adding comorbid cases to an OCD sample led to attenuation of the polygenetic signal by 35%, despite the increase in sample size of 30%. This is evidence for differences in the genetic architecture between OCD and OCD + TD. Unfortunately, sample size of the TS sample impeded the authors to conduct a polygenic risk analysis with comorbid TS patients to see whether that would also lead to signal changes. In an earlier analysis of this sample that included fewer case numbers, it was found that the genetic correlation of OCD and TD changed from r = 0.41 to 0.50 when OCD + TD cases were excluded, i.e. genetic overlap increased when cases were removed that are considered main carriers of common genetic architecture (Davis et al., 2013). 3.5.1. Summary genetics Increased cross-disorder rates in first-degree relatives of OCD/ TD patients are consistently found but numbers vary across studies. Twin studies showed that the phenotypic correlation of OCD and tics was 0.25 – 0.34, indicating moderate genetic overlap, and that genetic and environmental factors contribute to the co-occurrence of OCD and TD. Genetic studies so far were unable to detect genes or polymorphisms that are linked to OCD+TD. Evidence for genetic heterogeneity between tic-free OCD and OCD+TD comes from a GWAS. Whether this genetic heterogenetic means that OCD+TD is an alternate expression of genes related to TD remains unclear. 3.6. Neurochemistry Three studies examined markers of dopaminergic dysfunction, namely concentration of dopamine metabolite homovanillic acid and properties of D2 receptors and dopamine release (Table 14). In patients with TD, these markers were altered in comparison with normal controls but mostly unremarkable compared with concomitant OCD (Leckman et al., 1995; Wong et al., 2008). An exception was a trend significant result for increased dopamine release in the TS + OCD group compared to TS-only and healthy controls. Critically, there were only two TS-only patients in this study. Comparing comparatively larger sample sizes of matched OCD and OCD + TD patients revealed a higher concentration of CSF HVA in the latter (Leonard et al., 1993). This study needs replication though. Altered mechanisms in the serotonergic system are implicated in OCD, mainly due to the effectiveness of SRIs to reduce symptoms (Westenberg et al., 2007). Several studies examined whether differences exist between OCD patients with or without TD but results provide an inconsistent picture. Two studies suggest serotonergic hyperactivity of OCD + TD compared to OCD by showing increased capacity of 5-HT precursor tryptophan and a higher concentration of 5-HIAA (Leckman et al., 1995; Leonard et al., 1993). Conversely, reduced serotonergic transmission for OCD + TD is suggested by reduced serotonin 294

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

L. Kloft et al.

Fig. 3. Forest plot showing male-to-female odds ratio in patients with obsessive-compulsive disorder plus comorbid tic disorders and patients with obsessivecompulsive disorder only.

3.7.2. Structural and functional mri studies Peterson et al. (2003) conducted volume studies of the basal ganglia in pediatric and adult TS patients and found that in pediatric patients, BG nuclei were smaller in patients comorbid with OCD than TS alone (Table 14). They also observed regional specificity of volume reduction indicating that the presence of comorbid OCD was associated with smaller putamen volume while the absence of OCD was linked to smaller volume of caudate and pallidus. In adults, no correlation was found between volume of the basal ganglia and Y-BOCS measures in a sample including TS and TS + OCD patients (Worbe et al., 2015). Two studies found evidence for increased volume of the cerebrum of pediatric TS + OCD compared to TS (Peterson et al., 2001b; Tobe et al., 2010). Connectivity analyses of cortico-basal ganglia pathways and within basal ganglia pathways in a sample of TS patients +/−OCD found that OCD symptom severity measured by the Y-BOCS was positively correlated with structural connectivity of the striatum with the orbito-frontal cortex and the left thalamo-putaminal tract (Worbe et al., 2015). The severity of tics as indexed by the YGTSS was also positively correlated with the thalamo-putaminal tract, but bilateral, and also with cortico-striatal and thalamo-cortical pathways that included the inferior frontal gyrus, the primary motor cortex, the supplementary motor area, and the cingulate. The same authors also used resting state functional connectivity analysis to examine differences between TS +/−OCD in a priori selected regions of sensory-motor, associative and limbic networks (Worbe et al., 2012). The authors conducted correlational analysis between connectivity measures of the YGTSS and YBOCS and found that more complex tics were associated with altered connectivity in sensory-motor, posterior cingulate, parietal, and insula cortex. More OCD symptoms were linked with abnormal connectivity in medial OFC and DLPFC. Two studies conducted cortical thickness analysis of adult TS patients +/−OCD, of these, Worbe et al. (2010) found overlapping volume alterations between these groups which included the motor cortex, superior frontal cortex, and middle frontal gyrus in the left hemisphere, and inferior frontal cortex in the right hemisphere. There was also a trend towards reduced thickness of left ventral ACC and posterior OFC in patients with TS + OCD. Conversely, no effect of OCD was found by (Draganski et al., 2010) although similar regions were examined. A functional magnetic resonance imaging study also indicates differences between TS and TS + OCD. Worbe et al. (2011) observed that patients with simple and complex tics show intact reward processing in terms of functional activation but in patients with TS + OCD, activation

capacity of whole blood 5-HT and MAO platelet (Cath et al., 2001b). Binding potential of serotonin transporter in the midbrain was also negatively correlated with obsessive-compulsive behavior in TS patients (Muller-Vahl et al., 2005). Finally, no differences between patients with OCD and OCD + TS but reduced binding potential compared to healthy controls was found by (Wong et al., 2008). Only one study (Cath et al., 2001b) included matched samples of patients groups and normal controls while all others performed posthoc comparisons of small, unmatched samples. Furthermore, replication is warranted before firm conclusions can be drawn. 3.6.1. Summary neurochemistry There is preliminary evidence for increased dopamine neurotransmission and reduced serotonergic transmission in comorbid OCD and TD compared to OCD/ TD. Studies of serotonin parameters are inconsistent. 3.7. Neural dysfunctions 3.7.1. Transcranial magnetic resonance (TMS) studies Three studies probed excitability of the motor cortex to test the hypothesis of reduced motor impulse control in patients with OCD, TD, and both (Table 14). Of these, two included patients with a primary diagnosis of TS and one included those with a primary diagnosis of OCD. According to these studies, patients with pure OCD/ TD have similar active and resting motor thresholds compared to patients with OCD + TD. Independent of comorbidity, motor thresholds in patients with OCD were reduced compared to controls (Greenberg et al., 2000) while for TD they were either increased (Orth and Rothwell, 2009) or not different (Ziemann et al., 1997). Two of the studies that examined intracortical inhibition did not find differences between pure and complicated conditions (Orth and Rothwell, 2009; Ziemann et al., 1997), whereas one found reduced intracortical inhibition of OCD + TD compared to OCD (Greenberg et al., 2000). Independent of comorbidity, intracortical inhibition in these studies was reduced in TS compared to HC. Sensory afferent inhibition of TS patients was reduced compared to healthy subjects and patients with co-existing OCD (Orth and Rothwell, 2009). This may indicate altered sensory motor integration or altered cholinergic activity in TS compared to TS + OCD (Di Lazzaro et al., 2000; Tokimura et al., 2000). Interpretations must be taken cautiously since all studies examined case-case differences posthoc, patients were not matched, and only a small number of case numbers was included. 295

270 with OCD, 170 with OCD + TD

29 pediatric OCD + TD, 29 pediatric OCD

50 OCD, 12 OCD + TD

89 with OCD, 21 CD + TD Pediatric sample

124 OCD partial responders (n = 66 with TD)

1001 with OCD patients (28.4% cooccurring TD)

577 with OCD, 236 with TD

50 TS patients (13 with TS + OCD, 15 TS + ADHD, 11 TS + OCD + ADHD); adolescent sample 239 with early-onset OCD, 91 with earlyonset OCD + TD

de Vries et al. (2016a)

Bennett et al. (2015)

Skarphedinsson et al. (2015)

Tanidir et al. (2015)

Conelea et al. (2014)

de Mathis et al. (2013)

de Alvarenga et al. (2012)

Eddy et al. (2012)

296

50 with OCD + TD, 141 with OCD

98 with OCD, 31 with OCD + CMVT, 31 with OCD + TS

50 with OCD, 19 with OCD + TS, 18 with TS, 30 normal controls

32 with pediatric OCD + TD, 48 with OCD

45 with pediatric OCD, 15 with OCD + TD

32 with TS, 10 with OCD + TS, 21 with OCD, 29 normal controls

13 OCD + TS, 13 OCD

Jaisoorya et al. (2008)

Diniz et al. (2006)

Anholt et al. (2006)

Scahill et al. (2003)

Hanna et al. (2002)

Cath et al. (2001c)

Petter et al. (1998)

de Mathis et al. (2008)

N

First author, year

Table 8 Symptom Dimensions.

Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case/case-control Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Cross-sectional; outpatients from specialized treatment site; matched casecase

Prospective study; uncontrolled case-case; The Netherlands Obsessive-Compulsive Association (NOCDA) study 14 sessions of CBT program; matched casecase; outpatients from specialized treatment site; cross-sectional 16 weeks of sertraline treatment; crosssectional; unmatched case-case; outpatients; NordLOTS Cross-sectional; Outpatients from specialized treatment center; uncontrolled case-case CBT augmentation to SRI; cross-sectional; matched case-case; outpatients in three specialized treatment sites Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment centers; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case/ case-control

Study design

Clinical interview according to DSM-III-R; Y-BOCS TSURS

Leiden GTS/OCD semistructured interview; Y-BOCS

Clinical interview according to DSM-III-R; CY-BOCS

Y-BOCS

Y-BOCS

CY-BOCS

CY-BOCS

Padua-R scores

Padua-R

CY-BOCS; CBCL

Y-BOCS

Y-BOCS

DY-BOCS

CY-BOCS

DY-BOCS

DY-BOCS

CY-BOCS score

OCD supplement of K-SADS-PL-T

CY-BOCS score

CY-BOCS

Y-BOCS

Outcome measure

SCID-I; Y-BOCS; YGTSS; USPHARVARD Repetitive Behaviors Interview

Y-BOCS; CY-BOCS; SCID-I; STOBS

SCID-I; DY-BOCS; Y-BOCS; YGTSS

YGTSS; CBCL; CY-BOCS

SCID-I; Y-BOCS; DY-BOCS; USP-SPS YGTSS

SCID-I; Y-BOCS; DY-BOCS; USP-SPS; YGTSS

ADIC-C/P; YGTSS; CY-BOCS; NIHM-GOCS

KSADS-PL-T

K-SADS-PL; CY-BOCS

Clinical interview according to ICD-10; CY-BOCS; ChOCI

SCID-I; Y-BOCS; ten items tic screener; YGTSS

OCD and Tic assessment

(continued on next page)

obsessions involving nonviolent images, excessive concern with appearance, and need for symmetry: OCD + TS > OCD; touching, blinking or staring, and counting compulsions: OCD + TS > OCD

More echophenomena (p = .03) and fewer counting behaviors (p = .03), no difference on others

OCD + tics > OCD: symmetry (p = .009); aggressive (p = .005) and religious (p = .052); obsessions, and cleaning (p = .014); ordering/arranging (p = .054); hoarding (p = .054) compulsions OCD + TS, OCD + CMVT > OCD repeating behavior (p = .023), intrusive sounds (p = .025), counting (p = .054), tic-like (p = .003), OCD + TS > OCD somatic (p = .023), hoarding (p = .004) Padua-R scores: OCD > TS, HC, OCD + tic; OCD > TS Padua-R subscales: checking (p < .01), washing (p < .001) and rumination (p < .05); OCD > OCD + tic Padua-R washing subscale (p < .001) OCD > OCD + tics contamination (p = .001), washing (p = .006), compulsive requests for reassurance (p = .04 by Fisher’s exact test); OCD + tics > OCD repetition of routines (p = .002) OCD > OCD + TD (F = 6.01, p = .02) lifetime obsessions and lifetime compulsions (F = 7.14, p = .01).

OCD + TD > OCD contamination cleaning (p = .04); OCD + TD > OCD Global score (p = .04)

TS < TS + OCD (p = .021) and TS < TS + OCD + ADHD (p = .038)

OCD < OCD + TD: "aggressive" p = .027; "sexual/religious" p = .03; "hoarding" p = .005; “Others” p = .007

OCD = OCD + TD

OCD > OCD + TD religious obsessions, washing compulsions, ordering compulsions

OCD = OCD + TD

OCD + TD > OCD repeating and ordering compulsions

No difference

OCD + TD > OCD p = .002

Result

L. Kloft et al.

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

121 OCD, 56 OCD + tic

TS + OCS, OCD

Leckman et al. (1994a)

de Groot et al. (1994)

Abbreviations: ADHD Attention Deficit Hyperactivity Disorder; CBCL Child Behavior Checklist; CMVT Chronic Motor and Vocal Tic Disorder; CY-BOCS Children’s Yale-Brown Obsessive Compulsive Scale; DY-BOCS Dimensional Yale-Brown Obsessive Compulsive Scale; DSM-III-R Diagnostic and Statistical Manual for Mental Disorders; KSADS-PL-T Kiddie Schedule for Affective Disorders and Schizophrenia for School Age ChildrenPresent and Lifetime Version – Turkish Version; OCD Obsessive-Compulsive Disorder; SCID-I Structured Clinical Interview for DSM-IV; STOBS Schedule for Tourette and Other Behavioral Syndromes; TD Tourette Disorder; TS Tourette Syndrome; TSURS Tourette Syndrome Association Unified Tic Rating Scale; USP-SPS University of São Paulo Sensory Phenomena Scale; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

Y-BOCS

Y-BOCS

Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS Clinical interview according to DSM-III; Y-BOCS; YGTSS

35 with OCD, 35 with OCD + tics Holzer et al. (1994)

Cross-sectional; outpatients from specialized treatment site; unmatched case-case Cross-sectional; outpatients from specialized treatment site; unmatched case-case

Y-BOCS STOBS; Y-BOCS Cross-sectional; outpatients from specialized treatment site; matched casecase

OCD + TS > OCD: violent or horrific images (p = .03), concern with illness or diseases (p = .001), concern with body part or appearance (p < .001); need to know or remember (p = .005); fear of saying certain things (p = .01); intrusive images (p = .001); intrusive sounds (p < .001); touching (p = .02); trichotillomania (p = .05) eyeblinking and other simple tics (p = 0.001) touching, tapping, rubbing, blinking and staring rituals: OCD + TD > OCD, F = 5.44, p = .02; cleaning rituals: OCD + TD < OCD, F = 4.03, p = .05; obsessions: OCD + TD = OCD OCD + tic > OCD: aggressive, religious, and sexual obsessions as well as checking, counting, ordering, touching, and hoarding compulsions OCD > TS + OCS: contamination obsessions and cleaning compulsions; TS + OCS > OCD: more somatic, sexual and symmetry obsessions and more checking, counting and touching/ blinking compulsions Y-BOCS; YGTSS; USPHARVARD Repetitive Behaviours Interview Cross-sectional; outpatients from specialized treatment site; matched casecase 20 with OCD, 21 with TS 20 with OCD + TS Miguel et al. (1997)

Y-BOCS

OCD and Tic assessment Study design N First author, year

Table 8 (continued)

Outcome measure

Result

L. Kloft et al.

was reduced compared to normal controls in vmPFC and posterior cingulate cortex. Critically, most of the reported studies were conducted by the same working group and were based on the same sample of TS patients. It is therefore highly necessary to replicate these findings in independent samples and by independent researchers. Also, none of the studies compared patients with OCD to OCD + TD. Such studies are critically needed, if possible these should follow a 2 × 2 design (OCD yes/ no, TD yes/ no). A big plus of the imaging studies reviewed here is that they included large sample sizes. 3.7.3. EEG studies Further evidence for brain functional differences between diagnostic groups stems from event-related potential studies (Table 14). Hanna et al. (2012) examined the error-related negativity (ERN), a negative deflection that peaks over frontocentral electrodes shortly after erroneous reactions in response-conflict tasks, reflecting performance monitoring. They found increased ERN amplitudes in tic-free OCD whereas ERN amplitudes were unaffected in OCD + TD. This is an interesting result, especially when compared with results from studies examining uncomplicated OCD and TS. In OCD, increased ERN amplitudes are one of the most consistent results (Riesel et al., 2011) whereas in patients with TS ERN amplitudes are frequently unimpaired (Eichele et al., 2016; Shephard et al., 2016). These differences in performance monitoring were further corroborated by an own study which compared inhibition-related P3 between carefully matched samples of ticfree and tic-related OCD. We found hyperactivity and inflexibility of P3 amplitudes in OCD patients whereas the P3 was unaffected in OCD + TD (Kloft et al., Unpublished results). Thibault et al. (2008) examined the P3 in the context of attention allocation and working memory in patients with OCD, TD, and OCD + TD and found that in this case, OCD and co-occurring OCD + TD patients were similar as they both showed reduced allocation of resources. However, the opposite was found for TD patients. 3.7.3.1. Summary psychobiological and neural dysfunctions. TMS studies show largely similar functioning of the motor cortex of TD/ OCD and OCD+TD but there is some weak evidence for reduced sensory afferent inhibition of TS compared to TS+OCD. In structural imaging studies, tics were associated with sensory-motor and associate networks, while OCS relate to associative and limbic networks including the OFC, DLPFC. In children with TD+OCD, smaller BG nuclei and a larger cerebrum were found. There is preliminary evidence for differential brain functioning in reward processing, performance monitoring, and attention allocation. 3.8. Neuropsychological dysfunctions Neuropsychological dysfunctions appear intact in pure TD patients (Eddy and Cavanna, 2014) whereas OCD is associated with neuropsychological dysfunctions like response inhibition and planning and also, but rather inconsistently, for tasks measuring set shifting, interference control, fluency, and working memory (Abramovitch and Cooperman, 2015). Of the three studies that examined interference control in comorbid patients, two found impaired performance of patients compared to normal controls (Muller et al., 2003; Rankins et al., 2006) while the third did not find a difference (Silverstein et al., 1995) (Table 15). Studies further point to deficits in cognitive flexibility (Muller et al., 2003), and intermodal integration (Muller et al., 2003) whereas other cognitive functions appeared normal (e.g. response inhibition, planning, verbal and non-verbal fluency, working memory, verbal and nonverbal learning, motor speed) (Muller et al., 2003). Four studies examined different components of attention and found performance of TS + OCD patients compared to normal control to be unremarkable in visual selective and sustained attention (Muller et al., 2003) but 297

298

121 OCD, 56 OCD + TS

92 with TS (36.5 % with OCD)

Leckman et al. (1994a)

Santangelo et al. (1994)

Cross-sectional; outpatients from specialized treatment site; unmatched case-case

Cross-sectional; Outpatients from specialized treatment sites and through advertisement in the community; unmatched case-case Cross-sectional; outpatients from specialized treatment site; unmatched case-case

Cross-sectional; Outpatient study in specialized unit; unmatched case-case Cross-sectional; outpatients from specialized treatment centers; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case; Brazilian Research Consortium (C-TOC) Cross-sectional; outpatients from specialized treatment site; uncontrolled case-case

Cross-sectional; Outpatient study in specialized unit; unmatched case-case

Study design

Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS Modified Yale schedule for Tourette and other behavioral disorders; TSGS; Y-BOCS Clinical interview according to DSM-III-R; SADS-K; DIS

SCID-I; Y-BOCS; YGTSS; USPHARVARD Repetitive Behaviors Interview SCID-I; Y-BOCS; YGTSS; USPHARVARD Repetitive

NHIS; NJRE-QR; MOVES; OCIR; GTS-QoL; YGTSS SCID-I; Y-BOCS; DY-BOCS; YGTSS; USP-SPS

Clinical interview according to DSM-III-R and DSM-IV-TR

OCD and Tic assessment

Question regarding the precursors of tics

“just-right” phenomena

Prevalence of Sensory tics according to Yale schedule

the University of Sao Paulo –Harvard Repetitive Behaviors Interview the University of Sao Paulo –Harvard Repetitive Behaviors Interview

The University of Sao PauloSensory Phenomena Scale

Premonitory urges; assessed by a question regarding the presence yes/ no NJRE-QR

Outcome measure

No difference

No difference

Bodily sensations, mental urges, sense of inner tension OCD + TS, TS > OCD; Feelings of incompleteness, need for things to be "just right" OCD + TS > TS, OCD; OCD + TS > OCD, t = -3.67, df = 38, p = .001; no difference in autonomic and cognitive phenomena OCD + TS = TS > OCD, p < .05

OCD + TS > OCD: energy release (p = .009), NJRE (p = .029), bodily sensations (p = .048)

OCD + TD > OCD, p = .001

TS + OCD > TS, Mann–Whitney U test = 438.00, p = .043

no significant association between PU and OCD; significant positive association between PU and OCB (X2 = 15.379; p < .001)

Result

Abbreviations: ADHD Attention Deficit Hyperactivity Disorder; DSM-III-R Diagnostic and Statistical Manual for Mental Disorders; CMVT Chronic Motor and Vocal Tics; GSR Global Severity Ratings; GTS-QoL Gilles de la Tourette Syndrome – Quality of Life scale; MOVES Motor tic Obsession and compulsion and Vocal tic Evaluation Survey; OCB Obsessive-Compulsive Behavior; OCD Obsessive-Compulsive Disorder; OCI-R Obsessive Compulsive Inventory-Revised; NHIS National Hospital Interview Schedule for the Assessment of tics and related Behaviours; NJRE-QR Not Just Right Experiences-Questionnaire Revised; SIB Self-injurious Behavior; SCID-I Structured Clinical Interview for DSM-IV; SADS Schedule for Affective Disorders and Schizophrenia; STSS Shapiro Tourette-Syndrome Severity Scale; TS Tourette Syndrome; TSGS Tourette syndrome global scale; USP-SPS University of São Paulo Sensory Phenomena Scale; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

50 with TS, 50 with OCD, 50 normal controls

Chee and Sachdev (1997)

Miguel et al. (1997)

Diniz et al. (2006)

98 with OCD, 31 with OCD + CMVT, 31 with OCD + TS 20 OCD, 20 OCD + TS, 21 TS

782 children and adolescents with TS and 250 with OCD/ OCB 42 with TS + OCD, 29 with TS 577 with OCD, 236 with TD

Sambrani et al. (2016)

Neal and Cavanna (2013) de Alvarenga et al. (2012)

N

First author, year

Table 9 Sensory Phenomena in OCD, TD, and OCD + TD.

L. Kloft et al.

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

299

82 youth with OCD (n = 37 with TD)

Storch et al. (2005) Mataix-Cols et al. (1999)

outpatients from specialized treatment site; cross sectional outpatients from specialized treatment site; cross sectional; unmatched case-case

cross-sectional; outpatients and subjects from the community; multicenter; matched casecase

outpatients from specialized treatment site; cross sectional; unmatched case-case; the OCD collaborative genetics study (OCGS)

cross-sectional; outpatients from specialized treatment site; unmatched case-case

cross-sectional; outpatients from specialized treatment site; unmatched case-case; the OCD collaborative genetics study (OCGS)

cross-sectional; outpatients from specialized treatment site; unmatched case-case

cross-sectional; outpatients from specialized treatment site; unmatched case-case; the Tourette Syndrome Association International Consortium for Genetics (TSAICG) (sample overlaps with Scharf et al., 2012) cross-sectional; outpatients from specialized treatment site; unmatched case-case

cross-sectional; outpatients from specialized treatment site; unmatched case-case; the Tourette Syndrome Association International Consortium for Genetics (TSAICG)

Study design

Clinical interview according to DSM-IV; Y-BOCS; NIHM OCD scale

SADS-LA-P; TODS-PR

STOBS; YGTSS; DCI, Y-BOCS

SCID-I; SADS-LA-R; YBOCS

Factor analysis of Y-BOCS scales; regression analysis

Cluster analysis of tic symptoms and relationship with tic severity, global impairment, number of oc symptoms, presence of comorbid OCD or ADHD, family history of tics, age of onset, history of medication treatment and IQ Factor analysis of the CY-BOCS

Factor analysis on seven obsession categories and six compulsion categories (all excluding miscellaneous symptoms)

Diagnostic categories of TD, OCD/ OCS, ADHD; Latent class analysis and heritability analysis

Latent class of subclasses based on presence of co-morbid disorders

SCID-I; SADS-LA-R; YBOCS K-SADS; SCID-I, YGTSS

Factor analysis of DCI, YGTSS, and NIHS informed tic symptoms

Item-level factor analysis of 26-tic items; heritability analysis

Confirmatory factor analysis of TD, OCD, and ADHD symptom scales

Exploratory factor analysis of tic, OCD and ADHD items; latent class based on presence of tics, OCD and ADHD; heritability analysis and polygenic burden analysis

Outcome measure

DCI; YGTSS

STOBS; YGTSS; DCI; Y-BOCS

YGTSS; Y-BOCS; SCIDI

TICS; SCID-I/N, SADSLA; K-SADS-P

OCD and TD assessment

The CY-BOCS factors were not significantly related to tic symptoms 5-factor solution of OCD symptoms and patients with OCD + TD scored higher on symmetry/ ordering factor (F = 7.52, df = 1, 171, p = 0.006)

4-class solution (heritability): 1) “TS + OCD + ADHD” (0.63); 2) “OCD symmetry symptoms” (0.38); 3) “TD + ADHD” (0.47), 4) “Tics only” (0.28); 4-factor solution (heritability): 1) tics (0.25); 2) obsessivecompulsive factor (0.46); 3) disinhibited symptoms (0.35); 4) symmetry symptoms (0.39) 5-factor solution: tic/hyperactivity/aggressive OC symptom factor; 2) a “repetitive” OC symptom factor; 3) an ADHD symptom factor; 4) an autism-related symptom factor; 5) a hoarding/inattention symptom factor 3-factor solution (heritability, significance): 1) complex vocal tics & obscene behaviour (0.21, p > 0.0006); 2) body tics (0.004, ns); and 3) head/neck tics (0.25, p > 0.02) Factor 1 “complex motor tics and echopaliphenomena”, Factor 2 “ADHD symptoms and aggressive behaviours”; OCD symptoms loaded significantly on factors one and two, Factor 3 “complex vocal tics and coprophenomena” Two- and a more descriptive three-class solution with “OCD simplex + MDD” (Class 1), “OCD + tics” (Class 2), OCD with personality disorders and affective syndromes “(Class 3) 5-class solution (heritability, significance): 1) minimal symptoms (NA, ns); 2) “chronic tics + OCD” (0.49, ns); 3) “GTS only” (0.0, ns), 4) “GTS + OCD” (0.18, p < 0.02); “GTS + OCD + ADHD combined” (0.65, p < 0.000002) 4-factor solution with Factor I (religious, aggressive, sexual, checking, and somatic obsessions) being positively related to affective disorders, certain anxiety disorders, body dysmorphic disorder, and tic disorder, OR 95 % CI 1.6 (1.2, 2.2) Two primary clusters: simple tic cluster and complex symptom cluster (increased tic severity, rate of comorbid OCD and ADHD, of tic family history, and an earlier age of onset)

Result

Abbreviations: ADHD Attention Deficit Hyperactivity Disorder; ADIS Anxiety Disorder Interview Schedule for DSM-IV; OCD Obsessive-Compulsive Disorders; K-SADS-P Kiddies Schedule for Affective Disorders and Schizophrenia Parents Version; DCI Diagnostic Confidence Interview; NHIM National Health Institute for Mental Disorders; MDD Major Depressive Disorder; SADS Schedule for Affective Disorders and Schizophrenia; SCID I Structured Clinical Interview for DSM-IV; STOBS Schedule for Tourette and Other Behavioral Syndromes; TD Tic Disorders; TICS Tic and Comorbid Symptom Inventory; TSAICG Tourette Syndrome Association International Consortium for Genetics; TBI Thoughts and Behavior Inventory; TS Tourette Syndrome; TSS Tourette Syndrom Symptom List; TODS Tourette Disorder Scale-Parent Rated; Y-BOCS Yale-Brown ObsessiveCompulsive Scale; YGTSS Yale Global Tic Severity Scale.

354 with OCD (26.6 % TD)

254 pediatric and adult TS patients (n = 121 TS patients from Costa Rica, 4.1 % with OCD; n = 133 patients of Ashkenazi Jew descent, 61.4%)

624 patients and family members with OCD, 82 probable (26.2 % Tics)

Nestadt et al. (2003, 2009)

Mathews et al. (2007)

639 with TS (36.4 % OCD)

Cavanna et al. (2011)

418 subjects from families containing a proband with OCD and at least one sibling with OCD (5.9 % TD)

437 with TS (n = 145 OCD), 351 family members of TS (4.5 % OCD)

de Haan et al. (2015)

Hasler et al. (2007)

225 with TS (35.9 % OCD), 321 of their family members (3.3 % OCD)

Huisman-van Dijk et al. (2016)

72 TD and 596 TS children and adolescents from Tourette sib pair families (46 % OCD, 18 % subclinical OCD)

1191 with TD (50.2 % OCD) and 2303 family members

Darrow et al. (2017)

Grados and Mathews (2008)

N

First author, year

Table 10 Latent class analyses, factor analyses, and cluster analyses of OCD and TD symptoms.

L. Kloft et al.

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

92 pediatric and adult TS Santangelo et al. (1994)

Abbreviations: CTD Chronic Tic Disorders; CI Confidence Interval; CY-BOCS Children’s Yale-Brown Obsessive Compulsive Scale; DSM-IV Diagnostic and Statistical Manual for Mental Disorders; HC Healthy Controls; OCD Obsessive-Compulsive Disorder; OR Odds ratio; PANDAS Pediatric Autoimmune Neuropsychiatric Disorders; TS Tourette Syndrome; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

No difference between TS + OCD and OCD in composite variables but TS + OCD was more often associated with forceps delivery (Chi = 9.92, p < .01, OR = 7.9, 95 % CI = 3.2, 19.5) Composite variables; pregnancy complications, delivery complications, medications and procedures, coffee, cigarette and alcohol consumption

13 OCD, 20 OCD + PANDAS, 23 OCD + TD, 29 HC Gause et al. (2009)

Cross-sectional; outpatients from specialized treatment site; unmatched case-case

Clinical interview according to DSM-IV and to the Tourette Syndrome Classification Group CY-BOCS Clinical interview according to DSM-III-R; SADS-K; DIS

236 CTD/TS patients, 518 unaffected family members Abdulkadir et al. (2016)

Cross-sectional; outpatients from specialized treatment centers; matched case-case; TIC Genetic Study Cross-sectional; outpatients from specialized treatment centers; unmatched case-case/ case-control

YGTSS; Y-BOCS; clinical interview according to DSM-IVTR

Modified Schedule for Risk and Protective Factors Early in Development: clusters of pregnancy, delivery, and neonatal complications Antibrain antibody profiles

Patients with OCD, TD and comorbidity of OCD and TD had similar comorbidity and familial risks of autoimmune disease (i.e. increased comorbidity with any and individual autoimmune diseases and increased familiarity of autoimmune disease) TS + OCD > TS at least one pregnancy (t = 1.96, p < 0.05, Beta 2.70, 95 % Beta -0.13- -5.54) and one neonatal complications (t = 2.34, p < 0.05, Beta 2.27, 95 % Beta 0.024.52) OCD + PANDAS > all other bands against antigens and peak height Comorbidity and familial clustering of autoimmune disease 30,082 with OCD, 7279 with TD (1276 had both) Mataix-Cols et al. (2017)

longitudinal, population based family clustering study

Register-based according to ICD8, ICD-9 Or ICD-10

Result N First author, year

Table 11 Pre-, peri- and postnatal complications.

Study design

OCD and Tic assessment

Outcome measure

L. Kloft et al.

impaired in attention shift (Rankins et al., 2005; Yuen et al., 2005). In another study, sustained attention was reduced and distractibility was increased, which also supports attentional dysfunctions (Lucke et al., 2015). There is preliminary evidence to indicate a right-left hemisphere dissociation between patients with TD + OCD + ADHD and OCD only. (Rankins et al., 2005; Yuen et al., 2005). A further dissociation is indicated by results from cognitive oculomotor studies that report increased cognitive control of TD + ADHD + OCD patients compared to normal controls (TajikParvinchi and Sandor, 2013), a finding that was also reported for pure TD patients (Mueller et al., 2006) but that stands in contrast to deficient cognitive control in pure OCD patients (Kloft et al., 2011, 2013). This may indicate that cognitive control processes of comorbid OCD + TD are more similar to pure TD than pure OCD patients. Alternatively, diagnosis of comorbid ADHD might have influenced this pattern of result. 3.8.1. Summary neuropsychological findings Preliminary evidence indicates that OCD+TD seems to be associated with neuropsychological dysfunctions like interference control, cognitive flexibility, intermodal integration, and attentional shift. As TD alone is not reliably associated with cognitive dysfunctions, these results indicate similarity between OCD and OCD+TD on a neuropsychological level although there is preliminary evidence that some functions (e.g. intermodal integration, attention dysfunctions) might dissociated these OCD phenotypes. 3.9. Treatment Serotonin reuptake inhibitors (SRIs) are considered the most effective psychopharmacological treatment for OCD. Yet, up to 60% of patients do not or not fully respond to this treatment (Fineberg et al., 2004). An initial report by McDougle et al. (1993) reported a greater response in tic-free OCD to fluvoxamine than in patients with OCD + TD (Table 16). Of the four studies that later on examined the effect of SRIs like Fluvoxamine and Fluoxetine, two found support for this finding (March et al., 2007; McDougle et al., 1993), whereas two others did not (Husted et al., 2007; Skarphedinsson et al., 2015). Further research is clearly needed as reflected by this inconsistency and as none of these studies followed a double-blind, placebo-controlled protocol and none included matched groups of OCD and OCD + TD patients. Also, a meta-analysis would be helpful to examine this effect. On the contrary to a potentially reduced reaction of patients with OCD + TD in response to SRI, there is evidence to support a greater benefit to neuroleptic medication. Four studies examined differences between OCD patients with or without TD in neuroleptic trials. Of these, one study found that the number of responders was larger in the group of patients with co-occurring OCD than in tic-free OCD (McDougle et al., 2000). Only one study found a greater reduction in OCD symptoms in the tic-related group while the remaining three failed to find a difference (Bogetto et al., 2000; Carey et al., 2005; Shapira et al., 2004). Moreover, when compared to placebo, no benefit was found for neuropleptic augmentation in refractory OCD patients. The case numbers of comorbid tic patients were generally small which limits conclusions drawn from single studies. In a meta-analysis of these studies that examined the absolute risk difference between proportion of treatment responders compared to placebo group, Bloch et al. (2006a) found a positive effect for comorbid OCD patients when treated with antipsychotics. A number of studies compared the effectiveness of CBT in pediatric OCD patients with or without TD and consistently found symptom reduction is equally well in both groups (Bennett et al., 2015; Conelea et al., 2014; Himle et al., 2003; March et al., 2007; Piacentini et al., 2002); (Table 16). Thus, in contrast to pharmacological studies, psychotherapy delivered as CBT seems to target comparable processes in both groups. 300

301

106 with EO-OCD, 325 FDR, 44 normal controls, 140 control relatives

199 FDR of EO-OCD, 34 FDR of LO-OCD

72 with OCD patients, 263 FDR, 32 normal controls, 154 case FDR

Chabane et al. (2005)

Fyer et al. (2005)

205 relatives of 75 with TD + ADHD, 219 relatives of 74 with TD-only (n = 126 with OCD), 114 relatives of ADHD-only, 154 control relatives

O’Rourke et al. (2011)

do Rosario-Campos et al. (2005)

314 children with TS (77.4% with genetic predisposition) and their relatives 382 with OCD, 974 FDR of OCD, 73 normal controls, 233 control relatives

Eysturoy et al. (2015) Bienvenu et al. (2012)

35 EO-OCD patients, 411 case relatives, 17 normal controls, 189 control relatives

198 families of EO-OCD patients

Nissen et al. (2016)

Hanna et al. (2005)

5167 with OCS, 5297 with probable TD, 5,221with Hoarding sympoms

Zilhao et al. (2016)

1708 twins (n = 136 with sub-threshold OCD, n = 124 with TD, n = 57 OCD lifetime)

1411 with Tics, 793 with Tics + OCS, 52 with OCS + ADHD, 19 with Tics + OCS + ADHD

Pinto et al. (2016)

Bolton et al. (2007)

N

First author, year

family study; cross-sectional; out- or inpatients from specialized clinics; unmatched case-control

family study; cross-sectional; outpatients from specialized clinic; matched case-control

family study; cross-sectional; outpatients from specialized clinic; matched case-control

cross-sectional; family study; outpatients from specialized clinics; matched casecontrol; sample overlaps with Hanna et al., 2002; Dickel et al., 2007

cross-sectional; population based study; twin study

longitudinal study; outpatients from specialized clinic; Nordic OCD treatment study (NordLOTS) family study; cross-sectional; outpatients from specialized clinic family association study; matched casecontrol; cross-sectional; outpatients from specialized clinics; sample overlaps with Johns Hopkins OCD Family Study & OCD Collaborative Genetics Study family association study; matched casecontrol; cross-sectional; outpatients from specialized clinic; sample overlaps with Stewart et al., 2007

cross-sectional; population –based; Netherlands Twin Register; twin study

cross sectional; population-based Swedish Twin Registry: twin study

Study design

Table 12 Family prevalence rate of comorbid OCD and TD (including prevalences of case patients).

DSM-IV; SADS-LA-R

K-SADS-E; DIGS

Current OCD diagnosis, no information if current or lifetime TD diagnosis

No information if current or lifetime diagnosis

No information if current or lifetime diagnosis

Current OCD and lifetime TD diagnosis

DSM-III-R; STOBS; K-SADS-E

STOBS, K-SADS, SCID

heritability of OCD and familial aggregation of OCD and tics

Impact of OCD on familial association between TS and ADHD; odds ratio

No information if current or lifetime diagnosis Lifetime prevalence rate

No information if current or lifetime diagnosis

Covariation of tics, OCS, and hoarding

covariation of tics and OCS

Outcome variables

ADIS/C-P; tic interview from the Yale Child Study Center

YGTSS; Y-BOCS; SCID-Non-Patient edition; KSADS; DSM-IV-TR

Clinical interview according to DSM-IV-TR SADS-LA; Kiddie-SADS; SKID

K-SADS-PL; CY-BOCS

Padua Inventory; STOBS

Tics: checklist of 15 lifetime motor tics and 11 lifetime vocal tics; OCS: seven-item scale; ADHS: 18 DSM-IV based items

OCD and TD assessment

(continued on next page)

Rates in FDR of TD Only: OCD/ OCS Only 10.0%, OCD/ OCS + ADHD + TD 8.2 %, OCD/ OCS + TD 5.9 % (Total 24.1 %) Rates in FDR of TD + ADHD: OCD/ OCS Only 8.8 %, OCD/ OCS + ADHD + TD 6.9 %, OCD + TD 6.8 % (Total 22.5 %) cases: TD + ADHD (53.7 % OCD), TD-only (61.5 % OCD) Phenotypic correlation OCD-tic = 0.31 (95 % CI 0.18-0.44); Cross-twin cross-trait correlation MZ = 0.19 (95 % CI –0.06-0.42); DZ = 0.28 (95 % CI 0.10-0.43) FDR: case vs. control: OCD: 22.5% vs. 2.6%, OR = 11.06 (1.44, 85.01), p = 0.021; OCS: 27.4% vs. 2.6%, OR = 14.38 (1.88, 109.77), p = 0.010; TS, TD: 4.1% vs. 2.5%, OR = 1.57 (0.20, ∞), p = 0.570; Any tic disorder: 7.1 vs.5.3%, OR = 1.38 (0.24, 7.83) cases: 40 % TD FDR: case vs. control: OCD syndrome: 22.7 % vs. 0.9 %, CI 95 % = 32.5 (4.5 %-230.8), p < 0.0005; OCD subthreshold: 29.2 % vs. 2.4 %, CI 95 % 15.4 (3.567.3), p = 0.0003; TD/TS: 11.7 % vs. 1.7 %, CI 95 % 7.9 (1.9-3.1), p = 0.005 cases: 33 % TS, 13.2 % TD FDR of EO-OCD vs. FDR of LO-OCD: OCD = 16.1% vs. 2.9%, Fischer exact test, p = .058; TS = 7.1% vs. 0%, Fischer´s exact test, p = 1; TD = 14.7% vs.0%, Fischer´s exact test, p = .031 cases: EO-OCD with 43.9 % TD (including 31.6 % TS) FDR: OCD vs. control: OCD or OCS 12.2 % vs. 1.8 %, hazard ratio 8.2, p < 0.005, 95 % CI 2-35; TS: 1 % vs. 0 %, ns cases: 7 % TD

cross-twin within-trait correlation OCS MZ = 0.48 (95 % CI 0.48-0.52); DZ = 0.15 (95 % CI 0.10-0.18); tics MZ = 0.35 (95 % CI 0.30-0.38); DZ = 0.11 (95 % CI 0.08-0.14); cross-twin cross-trait correlation OCS-Tics = 0.18 (95 % CI 0.14-0.22); broad-sense genetic correlation between tics and OCS = 0.45 cross-twin cross-trait correlation of OCS –tics = 0.25, genetic correlation between OCS and tics = 0.37 FDR: OCD 3.5 %,OR = 0.84 (0.22, 3.30), p = .807, Tics 1.5 %, OR = 3.35 (1.11, 10.13), p = 0.032 cases: 18.7 % TD TS + genetic vs TS-genetic: ADHD + OCD: 86.8 % vs. 13.2 %, ns; OCD:75.4 % vs. 24.6 %, ns FDR: OCD Relatives: 14 % (n = 137) any tic disorder; Control relatives: 2 % (n = 5). OR = 7.5 % (95 % CI:3.0-18), p < 0.0005 cases: 17.8 % any TD

Result

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Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

N

24 parents of TS (n = 4 with OCS), 31 normal controls

34 children of TD parents (with/without OCD), 13 children of normal controls

106 FDR of 35 pediatric OCD patients, 94 FDR of normal controls

77 with OCD, 66 matched controls, 323 case relatives, 289 control relatives

107 with OCD, 1539 OCD relatives

51 with TS, 20 normal controls, 102 FDR of TS probands, 40 FDR of normal controls

100 with OCD, 466 FDR, 113 normal controls

86 with TS, 338 case FDR, 43 control FDR

54 children and adolescents with OCD, 171 FDR of OCD

First author, year

Kano et al. (2004)

McMahon et al. (2003)

Reddy et al. (2001)

Grados et al. (2001)

Cavallini et al. (1999)

Hanna et al. (1999)

Pauls et al. (1995)

Pauls et al. (1986,1991)

Leonard et al. (1993)

Table 12 (continued)

302 Follow-up; no information regarding patient recruitment

family study; cross-sectional; no matching information patients were members of local chapter of the Tourette Syndrome Association

family study; cross-sectional; unmatched case-control; patients were members of local chapter of the Tourette Syndrome Association

cross-sectional; no matching information; outpatients from specialized treatment department family transmission study; no matching information cross-sectional; consecutive patients

family study (the HOPKINS OCD family study); unmatched case-case/ control crosssectional; outpatients from specialized clinics

family study; cross-sectional; patients from specialized treatment services

family association study; matched casecontrol; cross-sectional; outpatients from specialized clinic prospective study; subjects from a large, multi-generational family; unmatched casecontrol

Study design

DICA; SADS; STOBS

DSM-III-R; Tic diagnosis according to clinical interview

DSM-III-R; KIDDIE-SADS-E; DIS; tics were evaluated according to an interview according to Pauls et al. (1991)

DIS-R; Y-BOCS; tic-diagnoses based on questionnaire derived by Black et al., 1992 TSRS; OCD Inventory; TS Global Disability Rating Scale; MOVES; YBOCS

SADS-LA-R IV; K-SADS-PL

DSM-III-R; DICA-R; the Questionnaire for tic disorders; CYBOCS; CY-BOCS; SCAN

SADS, K-SADS;

Clinical interview according to DSM-IV

OCD and TD assessment

Current and lifetime prevalence rates

Lifetime prevalence rates

Lifetime prevalence rates

No information if current or lifetime diagnose

No information if current or lifetime diagnoses

Lifetime prevalence rate

Lifetime prevalence rates

Prevalence rates (not reported whether current or lifetime) Lifetime prevalence rate

Outcome variables

(continued on next page)

FDR: Prevalence in fathers and mothers in TS vs. HC families: tics: 31.4 % and 15.7 % vs. 0 % and 0 %; p < 0.00; OCB: 15.7 % and 33.3 % vs. 0 % and 0 %, p < 0.00 cases: 64 % OCB FDR: sig. difference between prevalence of TD (TS and CMT) in OCD FDR (4.6 %) and HC (1 %); sig. difference of TD diagnosis between FDR of OCD + TD (10.6 %) and OCD-TD (3.2) case probands; no case age-of-onset effect for tic diagnosis in relatives FDR: prevalence for TS FDR and HC for TS (8.7 % vs. 0 %), TD (17.3 % vs. 2.7 %), and OCD (11.5 % vs. 2.5 %); all differences sig.; prevalence for FDR of TS + OCD case probands vs. TS case probands for TS (9.0 % vs. 8.1 %), TD (17.6 % vs. 17.0 %), and OCD (10.4 % vs. 13.6 %), not sig.; male relatives are significantly more likely (P < .0003) to have TS than female relatives, while female relatives are more likely (P < .04) to have OCD without tics than male relatives cases: 36 % OCD FDR: 1.8 % with TS, 14 % with TD; illness was unrelated to sex but men had a higher risk of developing TD and/ or OCD cases: 59% lifetime rate of any TD (15 % TS)

At-risk children vs. control children for any tic disorder 29.4 % vs. 0 %, Fisher´s exact test, p = 0.045; any OCD diagnosis 32.4 % vs 0 %, Fisher´s exact test, p = 0.021 FDR: case vs. control: OCD = 3.7 % vs. 0 % (Z = 2.4, p < 0.05); TD/TS = 0.9 % vs. 0 % (ns); no association between EO-OCD and TD/TS in case relatives cases: 14.3 % TD, 2.9 % TS FDR: case vs. control TS = 0.6 % vs. 0.0 %; TD 4.3 % vs. 1.4 %, p = .05 (Fischer’s exact); any Tic disorder 6.2 % vs. 1.7 %, p = .01 (Pearson chi-square = 7.7030, p = .006); younger age of onset of OCD case patients of relatives with OCD + TD vs OCD, χ2 = 13.58, p = .0002, hazard ratio 3.7 (1.5, 9.1); bidirectional relationship OCD and TD: TD in case relatives with OCD vs.no OCD: 16 % vs. 4.4 % (Pearson χ2 = 9.8, p = .002). cases: 6.5 % TD FDR: OCD = 2.72 %; CMT/TS = 1.49 % cases: 27.1 % TD / TS

1 FDR with tics and OCS; 1 with OCS

Result

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Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

Abbreviations: ADHD Attention Deficit Hyperactivity Disorder; ADIS-C/P Anxiety Disorders Interview Schedule for Children and Parents; CI Confidence Interval; DICA-R Diagnostic Interview for Children and AdolescentsRevised; DIS Diagnostic Interview Schedule; DIGS Diagnostic Interview for Genetic Studie; DIGS Diagnostic Interview for Genetic Studies; DZ Dizygotic; FDR First-degree relatives; DSM-III Diagnostic and Statistical Manual for Mental Disorders; EO Early Onset; HSR-SR Hoarding Rating Scale-Self-Report; KIDDIE-SADS-E Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version; MOCI Maudsley Obsessive Compulsive Inventory; MOVES The Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey; MZ Monozygotic; LO Late onset; OCD Obsessive-Compulsive Disorder; OCS ObsessiveCompulsive Symptoms; OLIG Gene for oligodendrocyte lineage transcription factor; OR Odds ratio; REL Relatives; SCAN Schedule for Clinical Assessment in Neuropsychiatry; SADS-LA- Schedule for Affective Disorders and Schizophrenia - Lifetime Anxiety Version; SCID Structured Clinical Interview for DSM-IV; STOBS Schedule for Tourette syndrome and Other Behavioral Syndromes; TD Tic Disorders; TS Tourette Syndrome; TSRS Tourette Syndrome Rating Scale; Y-BOCS Yale-Brown Obsessive-Compulsive Scale; Yale Global Tic Severity Scale.

no difference in OCD prevalence rates; no difference in TD/TS prevalence rates No information whether lifetime or current prevalence rates 32 OCD FDR, 33 normal controls FDR Black et al. (1992)

Cross-sectional; matched case-control; outpatients from specialized treatment site; unmatched case-control

DIS; questionnaire for tic disorders; DSM-III

Result N First author, year

Table 12 (continued)

Study design

OCD and TD assessment

Outcome variables

L. Kloft et al.

Two of three studies that compared the efficacy of SSRIs and CBT in the presence of tics found differences between OCD patient groups. In one study, the treatment consisted of CBT, sertraline, combination of both, or placebo. The efficacy of CBT was not differential between groups but if a comorbid TD diagnosis is present, patients treated with CBT either alone or in combination with SRI will show a greater response than will patients treated with medication alone (March et al., 2007). Another study compared efficacy of different treatment strategies in patients that are non-responders to CBT. It was shown that patients with OCD + TD, who did not respond to CBT, will benefit more from SSRIs than from continued CBT, while tic-free patients respond equally to both treatments. This shows that the presence of comorbid TD in OCD moderates the response to SSRIs but not CBT and should therefore be considered in treatment decisions. Limitations to these studies include the small number of comorbid patients compared to “only” patients and that cases were not controlled for matching criteria. Another treatment strategy that might be considered for refractory cases of severe comorbid OCD and TD is deep brain stimulation (DBS) (Scalone et al., 2017). However, none of the studies conducted on DSB in these patients fulfilled our inclusion criteria. Controlled studies with larger sample sizes are thus needed to make any conclusions in this area. 3.9.1. Summary treatment There is evidence to suggest reduced response to SSRI and increased response to neuroleptics in OCD+TD. CBT appears similar effective in comorbid and pure patients. Tics moderate response to SSRIs but not CBT. 4. Discussion The current work is the first systematic review of co-occurring OCD and TD and is an attempt to summarize a large and broad literature and to examine the nature of co-occurring OCD and TD. The review shows that a large body of literature exists that covers all relevant areas in psychopathological research, from genetic over psychobiological to clinical features and environmental risk research. So far, research has clearly focused on uncovering genetic factors and describing clinical features, which is reflected in the higher numbers of conducted studies, which also allows investigation of replicability of findings. Conversely, the research dedicated to uncover psychobiological (e.g. neurochemical, neural, and cognitive) pathways that translate between genetic and phenotypic expressions is rather unsystematic. For each construct that is investigated exist hardly more than two studies that target the same construct and often these apply different methods making it impossible to draw valid conclusions. In addition, the methodological quality of most studies is low, further limiting conclusions. This regards especially post-hoc analyses of mostly small, unmatched samples, the fact that most studies only include two diagnostic groups, and the lack of control groups. Therefore, it cannot be excluded that results are affected by sample differences like medication, symptom severity, gender, age etc. This review could also be limited by a selection bias since the majority of the studies that are published and were reviewed here examined outpatients from specialized treatment centers that probably have a longer illness and treatment history, more severe symptoms and additional disorders than patients in others settings. Publication bias may also affect the results as those studies that report differences between pure and complicated phenotypes are more likely to be published. Keeping the above mentioned limitations in mind, what can be summarized from the present review regarding acknowledged and possible further correlates of OCD + TD? We substantiate some of the most often cited clinical features associated with comorbid OCD + TD: earlier age-of-onset, higher frequency of sensory phenomena, higher male preponderance (by factor 1.6), and familiality. Evidence was found to suggest reduced response to SSRI and increased response to neuroleptics in OCD + TD, that CBT appears similar effective in 303

N

617 with TD (233 with OCD), 1,061 with OCD (83 with TD), 8352 normal controls

304

289 TS trios (126 OCD + TD + trios)

373 with OCD (46.6 % tics)

25 families with TD + OCD, 41 with OCD, 31 with TD

54 parent-child trios of early onset OCD patients (15 case probands with OCD-only, 11 with OCD + TD; 85 relatives (47 with OCD syndrome lifetime, 6 with subthreshold OCD lifetime, 11 any TD lifetime)

Katerberg et al. (2009)

Stewart et al. (2007)

Dickel et al. (2007)

96 with TD, 41 with TS + ADHD, 33 with TS + OCD, 36 with TS + ADHD + OCD, 450 with normal controls HC 200 with OCD (n = 11 with tic), 403 normal controls

Crane et al. (2011)

Liu et al. (2011)

Bertelsen et al. (2015)

Candidate gene study Huertas112 nuclear TD families (42 % with OCD), Fernandez 253 unaffected families et al. (2015)

Rare copy number variants 260 with OCD, 454 with TD patients and Moya et al. (2013) relatives, 447 normal controls

Davis et al. (2013)

Genome wide association studies Yu et al. (2015) 834 with TD, 1310 with OCD (77 % with comorbid TS/TD), 5667 normal controls

First author, year

Table 13 Genetic studies.

cross-sectional; no matching information; outpatients from specialized clinics; the Tourette Syndrome Association International Consortium for Genetics (TSAICG) cross-sectional; no matching information provided; outpatients from specialized treatment site cross-sectional; family base genetic study: outpatients from specialized clinic; matched case-case Cross-sectional; no matching information; outpatients from specialized treatment site; sample overlaps with Hanna et al., 2002, 2005

cross-sectional; matched case-control; outpatients from specialized clinics

cross-sectional; no matching information

cross-sectional; family based genetic study; no information regarding matching; outpatients from specialized institution

cross-sectional; no information regarding patient recruitment

cross-sectional; population based study; genome-wide complex trait analysis; no information provided to examine matching; the Tourette Syndrome Association International Consortium for Genetics (TSAICG)

cross-sectional; population based study; genome-wide complex; no information provided to examine matching; the Tourette Syndrome Association International Consortium for Genetics (TSAICG)

Study design

K-SADS-E-5; SCID; Schedule for Tourette´s Syndrome and Other Behavioral Syndromes

Tic diagnosis according to structured clinical interview according to Pauls et al. (1991); OCD according to DSM-IV-TR MINI; SCID-I; for tics, clinical interview according to DSMIV; Y-BOCS-SS; Y-BOCS-CL SCID-I; KIDDIE-SADS; YBOCS; YGTSS

MINI; Y-BOCS

Clinical interview according to DSM IV-TR

semi-structured interview according to DSM-IV; DYBOCS; YGTSS

semi-structured interview according to DSM-IV; DYBOCS, YGTSS

Clinical interview according to the TS Classification Study Group (TSCSG) diagnosis and DSM-IV-TR criteria

Clinical interview according to the TS Classification Study Group (TSCSG) diagnosis and DSM-IV-TR criteria

OCD AND TD assessment

Transmission-disequlibrium test; SLC6A4, HTR1B, HTR2A, BDNF

genetic association study with OLIG-2

COMT Val158 Met polymorphism <

22 SNP´s in the DLGAP3 region were analyzed

Genetic association study of COMT-287 A/ G

Genetic association study of GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRIA1-4, GRM1, GRM5, CACNG2, CAMK2A, DRD1-5, SLC6A3, BDNF, GDNF, COMT, CNR1, NTRK2 Genetic association of CHRNA7

rare missense neuronal cadherin gene (CDH2) variants

Univariate and bivariate correlation of hereditary of OCD and TD

Genetic association; enrichment analysis; polygenic risk scores

Outcome measure

(continued on next page)

3 single nucleotide polymorpphism were associated with OCD-only but none were associated with OCD + TD or TD-only No association found with EO-OCD or OCD + TS

All p > 0.05

No difference between subgroups OCD with tic and without tic in the observed genotypic (χ2 = 2.87, DF = 2; P = 0.24) and allelic (χ2 = 0.19, DF = 1; P = 0.66) frequencies of 287 A/G polymorphism No association with OCD or OCD + TD

Trend for significant association between −86 T and OCD (TS/OCD and TS/OCD/ADHD), p = 0.0.18; OR = 3.96; 95 % CI 1.27-12.32

no significant association with OCD + TD

Difference in N845S: of the 12 OCDs with this variant, 333% had comorbid TD in contrast to only 7.7% of OCD without this variant (Fisher´s exact test P = 0.014, OR = 6.03). For TD patients, this difference was not significant.

No SNP reached the genome-wide sig threshold (p < 5 × 10−8); risk scores derived from the TS discovery sample did not predict case-control status in the OCD target sample (p = 0.66), nor did OCD-associated risk scores predict into the TS target sample; combination of OCD and TD samples led to attenuated (R 2 = 3.2 % vs. R 2 = 2.1%) Genetic correlation between OCD and TD = 0.41 (se = 0.15; LRT = 7.98; p = 0.002). After removing comorbid cases, genetic correlation was 0.50 (se = 0.29; LRT = 4.08; p = 0.02)

Result

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Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

32 with OCD and TD, 60 normal controls

52 with TS (54 % comorbid OCD), 63 normal controls

73 with OCD (26.5 % with tics), 148 normal controls

de Carvalho Aguiar et al. (2004) Cavallini et al. (2000)

Karayiorgou et al. (1997)

305

50 with TS, 30 with TS + OCD, 35 with TS + OCD + ADHD, 50 with OCD, 72 Alcohol Dependence

cross-sectional; outpatients from specialized treatment site; no matching information

cross-sectional; no matching information; outpatients from specialized treatment department

cross-sectional; no matching information

cross-sectional; no matching information provided; outpatients from specialized treatment site

cross-sectional; no information regarding patient recruitment; no matching information provided cross-sectional; unmatched case-case; outpatients from specialized treatment site

Study design

DIS

DIS-R; Y-BOCS; Tic-diagnoses based on questionnaire derived by Black et al., 1992

Clinical interview according to DSM IV-TR

SADS-L (DSM-III-R)

Clinical interview according to DSM-IV; Yale-Brown Tourette syndrome scale

Clinical interview according to DSM-IV

OCD AND TD assessment

Mutation screening in dopamine D1

Complex segregation analysis

genetic association of ADORA polymorphisms

COMT gene

COMT gene (codon 158); 5-HTTLPR typing

SGCE

Outcome measure

No SSCP band shifts were noted in any of the groups

OCD phenotype = dominant model of transmission; OCD + TD phenotype = unrestricted model of transmission

GG of ADORA1 rs2228079 significantly associated with OCD/OCB (OR 2.86, 95 % CI: 1.14–7.21, p = 0.021)

No association was found between the COMT polymorphism and TS (genotypic: χ2 = 0.261, df = 2, P = 0.878; allelic: χ2 = 0.145, df = 1, P = 0.704) and no association with OCD (genotypic: χ2 = 2.679, df = 2, P = 0.261; allelic: χ2 = 2.329, df = 1, P = 0.127); no association was found between 5-HTTLPR and TS (genotypic: χ2 = 0.522, df = 2, P = 0.77; allelic: χ2 = 0.008, df = 1, P = 0.929) or OCD. no association with COMT (OR = 2.24 (0.56, 8.91)

No significant difference (p = 0.83)

Result

Abbreviations: AD Affective Disorder; ADHD Attention Deficit Hyperactivity Disorder; ADORA Adenosine Receptor; ANX Anxiety Disorders; BDNF Brain-derived neurotrophic factor; CACNG2 Calcium voltage-gated channel auxiliary subunit gamma 2; CAMK2A Calcium/Calmodulin Dependent Protein Kinase II Alpha; CHRNA7 Cholinergic Receptor Nicotinic Alpha 7 Subunit; COMT Catechol-O-methyltransferase; CY-BOCS Children’s version of the Yale-Brown Obsessive-Compulsive Scale; CV-LOI Children’s version of Leyton’s Obsessional Inventory; CNR1 Cannabinoid Receptor 1; DIS Diagnostic Interview Schedule; DSM Diagnostic and Statistical Manual for Mental Disorders; DRD dopamine receptor; DLGAP3 Discs Large Homolog Associated Protein 3; FISC family Informant Schedule and Criteria; GRIN Glutamat Receptor Ionotropic; GRIA Glutamate Ionotropic Receptor AMPA type subunit; GRM Glutamate Metabotropic Receptor; GDNF Glial cell-derived neurotrophic factor; K-SADS-E-5 Schedule for Affective Disorders and Schizophrenia for School Age Children – Epidemiologic Version-5; LOCI Leyton Obsessive-Compulsive inventory; LRT likelihood ratio test; MINI Mini International Neuropsychiatric Interview; NTRK2 Neurotrophic Receptor Tyrosine Kinase 2; OCD ObsessiveCompulsive Disorder; OCI-CV Obsessive–Compulsive Inventory Child Version; OLIG Oligodendrocyte transcription factor; SIB = Self Injurious Behavior; SGCE Epsilon-sarcoglycan gene; SLC6A3 Solute Carrier Family 6 Member 3; SSCP single strand conformation polymorphis; Y-BOCS Yale-Brown Obsessive Compulsive Scale; YGTSS Yale Global Tic Severity Scale; TD Tic Disorders; TS Tourette syndrome; 5-HTTLPR serotonin transporter polymorphism.

Mutation analysis Thompson et al. (1998)

Segregation analysis Cavallini et al. 1539 relatives of 107 families of OCD (1999) patients (27.1 % with TD)

Genetic linkage study Janik et al. 162 with TD (42.3 % with OCD/OCB), 270 (2015) normal controls

N

First author, year

Table 13 (continued)

L. Kloft et al.

Neuroscience and Biobehavioral Reviews 95 (2018) 280–314

22 OCD, 12 OCD + TD

Kloft et al. (Unpublished results) Lucke et al. (2015)

306

6 with TS, 10 with OCD, 6 with TS + OCD, 16 normal controls

6 with TS, 10 with OCD, 6 with TS + OCD, 16 normal controls

15 children with TS, 11 with TS and cooccurring conditions (ADHD±OCD), 11/12 normal controls 14 with TS/OCD, 14 normal controls

Rankins et al. (2006)

Rankins et al. (2005)

Yuen et al. (2005)

cross-sectional; matched casecontrol; outpatients from neurology institute

cross-sectional; matched casecontrol; same sample as Rankins et al., 2006 cross-sectional; outpatients; case-control; unmatched casecase/control cross-sectional; matched casecontrol

cross-sectional; outpatients; unmatched case-case/control; same sample as Tajik-Parvinchi and Sandor (2012) cross-sectional; matched casecontrol; same sample as Rankins et al., 2005

cross-sectional; outpatients from specialized treatment unit; matched case-case cross-sectional; outpatients from specialized treatment unit; matched case-case cross-sectional; outpatients; unmatched case-case/control; same sample as Tajik-Parvinchi and Sandor (2013)

Study design

Clinical interview according to DSM-III; LOCI

TSGS; Padua inventory; Clinical interview according to DSM-IV Padua inventory; Clinical interview according to DSM-IV Expert interview according to DSM-IV criteria; TSGC; LOCI Structured psychiatric interviews

Expert interview according to DSM-III-R

Clinical interview according to DSM-IVTR; CY-BOCS Expert interview according to DSM-III-R

SCID I, DCI; YGTSS; YBOCS

OCD and Tic assessment

Reaction times and error rates in neuropsychological test battery (Colour Word Interference Test, CBAA, Ruff figural fluency test, d2, verbal learning test, finger tapping test) Span of apprehension (SOA) and neuropsychological test battery (TMT, Perceptual speed test, Stroop, WAIS-R)

Inhibition of return task

Reaction times in local-global paradigm

Reaction times and error rates in semantic Simon task

Reaction times and error rates in prosaccade and antisaccade tasks (varying gap and overlap)

Reaction times and error rates in prosaccade and antisaccade tasks

Errors and reaction time in the continuous performance test

Stop-Signal Reaction Time, Inhibition-Related N2 and P3

Outcome measure

TS + OCS vs. normal controls had slower RT in SOA test

TS + ADHD + OCD vs normal controls showed loss of facilitatory and inhibitory effects for right sided stimuli (F(1,9) = 5.78, p > 0.05) normal controls > TS/OCD in interference control (p < 0.01) and cognitive flexibility (p < 0.05)

OCD + TS patients vs. normal controls trended towards impaired interference control under conditions of conditionality (F(110) = 3.71, p = 0.08, F(110) = 3.77, p = 0.08) OCD + TS > normal controls in responding to local stimuli (F(110) = 5.79, p > 0.05)

OCD + TD > OCD/ TD in omission errors (t = -2.04, p 0 0.047) and hit RT block change rate (F82) = 7.74, p = 0.001) TS + ADHD + OCD showed shorter prosaccade latencies than normal controls and both ADHD groups, longer antisaccade latencies compared to normal controls and shorter antisaccade compared to other TS groups TS + ADHD + OCD had faster reaction times than all other groups

OCD > OCD + TD inhibition-related P3 amplitudes

Result (cases vs. controls)

Abbreviations: ACC anterior cingulate cortex; ADHD Attention Deficit Hyperactivity Disorder; BP binding potential; TSGC Tourette Syndrome Global Scale; CY-BOCS Children´s Yale Obsessive-Compulsive Disorders Scale; DA-REL dopamine release; DAT dopamine transporter; DICA Diagnostic Interview for Children and Adolescents-Revised; DSM Diagnostic and Statistical Manual for Mental Disorders; HVA homovanillic acid; LOCI Leyton Obsessive-Compulsive Inventory; MAO monoamine oxidase activity; MHPG Methoxy-4-hydroxyphenylglycol; MOFC medial orbitofrontal cortex; mCPP meta-chlorophenylpiperazine; OCD Obsessive-Compulsive Disorder, OFC orbitofrontal cortex; PR−OCCS Patient Rated Obsessive-Compulsive Challenge Scale; PCC posterior cingulate cortex; REL relative; SERT serotonin transporter; SMA supplementary motor area; TMT Trail Making Test; TD Tic Disorders; TS Tourette Syndrome; vmPFC ventromedial prefrontal cortex; WAIS Wechsler Adult Intelligence Scale; 5-HIAA 5-Hydroxyindoleacetic acid; 5-HT2AR serotonin receptors.

Silverstein et al. (1995)

17 with TS (12 including OCsymptoms), 17 normal controls

6 children with TS, 9 children with TS + ADHD, 7 children with TS + ADHD + OCD, 10 normal controls

Tajik-Parvinchi and Sandor (2012)

Muller et al. (2003)

6 children with TS, 9 children with TS + ADHD, 7 children with TS + ADHD + OCD, 10 normal controls

Tajik-Parvinchi and Sandor (2013)

20 pediatrics with OCD, 15 pediatrics with TD, 15 pediatrics with OCD + TD

N

First author, year

Table 14 Cognitive dysfunctions in TD + OCD.

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307

60 with TS (n = 13 with OCD), 30 normal controls

22 OCD (n = 3 tic-related), 22 normal controls

59 with TS (n = 22 with OCS), 27 normal controls

60 with TS (n = 22 with OCS), 50 normal controls

163 children and adolescents with TS (n = 43 with OCD), 147 normal controls

60 with TS (n = 17 with OCD), 30 normal controls

40 with TS (n = 14 with OCD, n = 8 with OCD + ADHD), 40 normal controls

29 with TS (n = 5 with OCD), 24 normal controls

11 with TS (n = 9 OCD), 10 normal controls

14 with TS, 12 with TS + OCD, 15 OCD, 14 normal controls 12 with TS + OCB, 16 normal controls

Worbe et al. (2015)

Ahmari et al. (2012)

Worbe et al. (2012)

Worbe et al. (2011)

Tobe et al. (2010)

Worbe et al. (2010)

Draganski et al. (2010)

Orth et al. (2005, 2008)

Wong et al. (2008)

Thibault et al. (2008)

Muller-Vahl et al. (2005)

N

First author, year

Table 15 Psychobiological and neural dysfunctions.

cross-sectional; outpatients from specialized treatment site; unmatched case-control

cross-sectional; outpatients; matched case-case/control

cross-sectional; outpatients from specialized treatment site; matched case-control

cross-sectional; outpatients from specialized treatment site; unmatched case-case/control

cross-sectional; outpatients from specialized treatment site; matched case-case; same sample as Worbe et al., 2010, 2012, 2015 cross-sectional; outpatients from specialized treatment site; matched case-control; sample overlaps with Peterson et al. (2001a,b) cross-sectional; outpatients from specialized treatment site; matched case-case; same sample as Worbe et al., 2011, 2012; 2015 cross-sectional; outpatients from specialized treatment site; matched case-control

cross-sectional; outpatients from specialized treatment site; matched case-control cross-sectional; outpatients from specialized treatment site; matched case-case

cross-sectional; outpatients from specialized treatment site; matched case-case; same sample as Worbe et al., 2010, 2011, 2015

Study design

TSGS, structured questionnaire assessing OCB

Clinical interview according to DSM-IV-TR; TSGS; Y-BOCS

Clinical interview according to DSM-IV-TM for TS, SCID-I for OCD, Y-BOCS, YGTSS

NHIS; SCID-I; YGTSS; DCI

NHIS; YGTSS

YGTSS; Y-BOCS; Clinical interview according to DSMIV-TR; MINI (for OCD)

STOBS, YGTSS, Y-BOCS

Clinical interview according to DSM-IV; YGTSS; Y-BOCS; MINI (for OCD)

Clinical interview according to DSM-IV; YGTSS; Y-BOCS; MINI (for OCD)

SCID-I, Y-BOCS, YGTSS

YGTSS; Y-BOCS; Clinical interview according to DSMIV-TR; MINI (for OCD)

OCD and Tic assessment

SERT BP in midbrain

Comparison between TS + OCD and TS-OCD for binding potential of 5-HT and dopaminergic neurotransmission (dopamine measures were DA release and BP of DAT) P200 and P300 in a visual oddball paradigm; EEG

TMS: active and resting motor threshold, intracortical inhibition and facilitation, short latency afferent inhibition

cortical thickness estimation and voxel-based analysis

Cortical thickness, whole brain

Region-of-interest (cerebrum); structural imaging

Functional MRI of ROIs in a reward-based learning task

Functional connectivity of ROIs in sensori-motor, associative and limbic networks

Prepulse inhibition; EMG

Connectivity of cortico-striata-pallido-thalamocortical structures; volume of the basal ganglia and thalamus

Outcome measure

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No effect of OCD; adult normal controls > TS: GM volume in MOFC, rostral cingulate, VLPFC, operculum; adult TS > normal controls: putamen normal controls > TS: amygdala and hippocampus; OFC; VLPFC, Operculum; TS > normal controls: primary somatosensory cortex and right dorsal premotor cortex Patients > normal controls active and resting motor threshold (F(151) = 4.6, p = 0.037) and (F1,51) = 4.0, p = 0.051), respectively; and intracortical facilitation (F(1204) = 7.64, p = 0.006); normal controls > patients short-interval cortical inhibition (F(1204) = 5.5, p = 0.02) and sensory afferent inhibition normal controls = TS + OCD > TS, TS + ADHD shortlatency sensory afferent inhibition TS + OCD > sensory afferent inhibition normal controls > TS + OCD, TS-OCD SERT BP in midbrain (p < 0.05); TS + OCD > TS-OCD, normal controls ; 5-HT2A BP in prefrontal, temporal and cingulate cortices and of dopamine release (trend significance) Anterior P3 amplitudes of TS > OCD = TS + OCD Posterior amplitudes of TS > normal controls, OCD = TS + OCD Trend for a negative correlation between SERT binding capacity and OCB (r=-0.78, p = 0.023)

TS > TS + OCD: left ventral ACC, left middle frontal gyrus, left motor cortex, superior parietal, bilateral occipital lobe, right hippocampus, posterior right orbital lobe

TS + OCD > TS in crus I and lobules VI, VIIB, and VIIIA compared with those who have TS without OCD

Positive correlation of Y-BOCS scores with connection parameters in right MOFC and local efficiency of information transfer was correlated positively with right prefrontal dorsolateral cortex (p = 0.0081) and negatively with right prefrontal dorso-lateral cortex (p = 0.0008) Reduced reward-related activation in vmPFC and posterior cingulate cortex compared to normal controls and TS patients with simple tics (t = 2.146, p = 0.04)

OCD symptom severity measured by the Y-BOCS was positively correlated with structural connectivity of the striatum with the orbito-frontal (r = 0.204, z = 2.43, p < 0.007) cortex and the left thalamo-putaminal tract (r = 0.378, z = 4.09, p < 0.0001); no significant correlation between volume of the basal ganglia and Y-BOCS scores OCD > OCD with tics percent prepulse inhibition

Result

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154 children and adolescents with TS (n = 62 with OCD), 130 normal controls 155 children and adolescents with TS (n = 62 with OCD), 131 normal controls

15 with TS, 14 with TD + OCD, 15 with OCD, 26 normal controls 16 with OCD (n = 5 with tics), 11 normal controls

Peterson et al. (2003)

Cath et al. (2001b)

308

20 with TS (n = 12 with OCD), 21 normal controls

39 OCD (n = 7 TD), 30 TS (n = 18 OCD), 44 normal controls

54 children and adolescents with OCD (n = 32 tics) 16 pediatric OCD (n = 5 TD), 14 normal controls

Ziemann et al. (1997)

Leckman et al. (1995)

Leonard et al. (1993) Hanna et al. (1999)

CSF 5-HIAA, HVA Whole blood 5-HT

DICA-C/P; GOCS; CY

TMS; Resting and active motor thresholds; duration of the cortical silent period; intracortical inhibition and facilitation Concentration of tyrosine, norepinephrine, MHPG, HVA, tryptophan, 5-Hydroxyindoleacetic acid

Whole blood 5-HT

TMS: resting motor threshold, active motor threshold, the MEP “recruitment curve, cortical silent period, intracortical inhibition and facilitation

Region-of-interest (dorsal prefrontal, OFC, premotor, subgenual, sensorimotor, parietooccipital, midtemporal, inferior occipital) and cerebrum; structural imaging Whole blood 5-HT, platelet MAO

Region-of-interest (basal ganglia); structural imaging

Outcome measure

DICA; SADS; STOBS

Clinical interview according to DSM-III-R; YGTSS

cross-sectional; outpatients; matched case-control/ case

Follow-up; no information regarding patient recruitment cross-sectional; outpatients from specialized treatment site; unmatched case-control

Expert interview according to DSM-III-R

DICA-C/P; GOCS; CY

SCID-I; YGTSS; Y-BOCS

CIDI (for OCD), Shapiro symptom checklist for TD

STOBS; YGTSS; Y-BOCS

STOBS; YGTSS; Y-BOCS

OCD and Tic assessment

cross-sectional; outpatients from specialized treatment site; unmatched case-control cross-sectional; outpatients; matched case-control

cross-sectional; outpatients from specialized treatment site; unmatched case-case/control

cross-sectional; outpatients from specialized treatment site; unmatched case-control

cross-sectional; outpatients from specialized treatment site; matched case-control cross-sectional; outpatients from specialized treatment site; matched case-control

Study design

No difference between groups

TS patients showed shortened cortical silent period and reduced intracortical inhibition compared to controls, no effect of OCD Tyrosine: OCD > normal controls; Norephinedrine: TS, TS + OCD > normal controls; MHPG: OCD, normal controls > OCD + TS; HVA: TS > OCD + TS > OCD; Tryptophane: OCD + TS > all other groups; 5-HIAA: no difference; tic-related but not tic-free OCD show negative correlation between Y-BOCS scores and tyrosine (r=-.40, p = .01) and HVA (r=-.40, p = .01) OCD + TD > OCD

normal controls > OCD active and resting motor threshold (t = 3.09, p = 0.007 and t = 3.05, p = 0.006, respectively) and intracortical inhibition (F = 18.8, df = 1, p = 0.0002); normal controls > OCD-TD (F = 10.5, df = 1, p = 0.004) and OCD-TD > OCD + TD reduced intracortical inhibition (F = 4.8, df = 1, p = 0.045) No difference between groups

Platelet MAO: OCD > OCD + TD (p = 0.01), normal controls (p = 0.04) Whole blood: OCD > OCD + TD (p = 0.04)

Pediatric TS > TS + OCD volume of BG (p = 0.006); regional specifity of reduced putamen, (TS > TS + OCD, (F(1245) = 4.1, p = 0.04)) Trend for larger volume of cerebrum for TS + OCD compared to TS (F = 2.91, p = 0.09)

Result

Abbreviations: CY-BOCS Children’s Yale-Brown Obsessive-Compulsive Scale; DICA Diagnostic Interview for Children and Adolescents; DCI Diagnostic Confidence Interview; DSM Diagnostic and Statistical Manual for Mental Disorders; MINI Neuropsychiatric Interview; OCD Obsessive-Compulsive Disorder; NHIS National Hospital Interview Schedule for the Assessment of Tics and Related Behaviours; SADS Schedule for Affective Disorders and Schizophrenia; STOBS Yale-Schedule for Tourette and Other Behavioral Syndromes; SCID Structured Clinical Interview for DSM; Y-BOCS Yale-Brown Obsessive-Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

16 pediatric OCD (n = 5 TD), 14 normal controls

Hanna et al. (1999)

Greenberg et al. (2000)

Peterson et al. (2001b)

N

First author, year

Table 15 (continued)

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309

69 pediatric OCD

112 pediatric OCD, 15 OCD + CTD/TS

61 OCD, 13 OCD + TD

41 OCD non-responder (n = 11 tics)

Storch et al. (2008)

March et al. (2007)

Husted et al. (2007)

Carey et al. (2005)

33 with OCD + TD, 33 with OCD

17 OCD non-responder to fluvoxamine with or without lithium

McDougle et al. (1993)

McDougle et al. (1990)

Controlled study of neuroleptic augmentation to fluvoxamine plus lithium; cross-sectional; outpatients; unmatched case-case

Double-blind, randomized placebo-controlled study of risperidone augmentation to SRI (six weeks); matched case-case; outpatients from specialized treatment site Retrospective; fluvoxamine treatment study; outpatients; matched case-case

Prospective, eight week open-label fluoxetine treatment study; cross-sectional; community and outpatients; matched case-case Double-blind, randomized placebo-controlled study of quetiapine augmentation to SRI (six weeks); crosssectional; unmatched case-case; outpatients; multicenter study Double-blind, randomized placebo-controlled augmentation of olanzapine to fluoxetine; crosssectional; unmatched case-case; outpatients 7 sessions of group CBT; outpatients; unmatched casecase Open-trial; 10 sessions of CBT; outpatients; unmatched case-case 3-month open-label trial of augmentation with olanzapine; cross-sectional; unmatched case-case

14 sessions of CBT program; matched case-case; outpatients from specialized treatment site; crosssectional CBT augmentation to SRI; cross-sectional; matched case-case; outpatients in three specialized treatment sites 14 sessions of CBT program; matched case-case; outpatients from specialized treatment site; crosssectional 12 weeks randomized, controlled trial with sertraline or CBT; cross-sectional; unmatched case-case; outpatients

16 weeks of sertraline treatment; cross-sectional; unmatched case-case; outpatients; NordLOTS

Study design

SADS; Clinical interview according to DSM-III-R for tics Clinical interview according to DSM-III-R; CGI

ADIS; CY-BOCS; NIHMGOCS Clinical interview according to DSM-IVTR; Y-BOCS SADS; Y-BOCS; YGTSS

KSADS-E; CY-BOCS

Clinical interview according to DSM-IV

Improvement of Y-BOCS scores and CGI rating

Clinical interview according to DSM-IV; YBOCS; YGTSS MINI; Y-BOCS

Improvement of Y-BOCS scores and CGI rating

Improvement of Y-BOCS scores and CGI rating

Improvement of Y-BOCS scores and CGI rating

Improvement of NIHM Global Scale and CGI score Improvement of Y-BOCS scores and CGI rating

CY-BOCS score

Improvement of Y-BOCS scores and CGI rating

Improvement of Y-BOCS und YGTSS scores and CGI rating

CY-BOCS score

CY-BOCS score

CY-BOCS score

CY-BOCS

CY-BOCS score

Outcome measure

ADIC-C; CY-BOCS; YGTSS

ADIS-IV-P; CY-BOCS; YGTSS

Clinical interview according to ICD-10; CY-BOCS; ChOCI ADIC-C/P; YGTSS; CYBOCS; NIHM-GOCS

K-SADS-PL; CY-BOCS

OCD and Tic assessment

OCD + TD > OCD treatment response to neuroleptic therapy

OCD > OCD + TD improvement of Y-BOCS (t = 2.3, df = 64, p < 0.03) and CGI (t = 3.0, df = 64, p < 0.004)

No difference between diagnostic groups (Fisher exact test, p = 1.0)

No difference between diagnostic groups

No difference between diagnostic groups (F = 1.32, df = 1, 17, p = .27) No difference between diagnostic groups

No difference in treatment response between olanzapine and placebo in OCD + TD

No difference in treatment response between quetiapine and placebo in OCD + TD (p = 0.66)

Tic disorder treatment interaction showing that response in OCD + TD/TS did not differ between sertraline and placebo whereas in OCD there was a greater response to sertraline (Chi2 = 12.32, p < 0.006); no difference in response to CBT No difference between diagnostic groups

No difference

No difference between diagnostic groups (F1,36) = 0.15, p = 0.90)

No difference between CBT and sertraline in patients with OCD but increased response of OCD + TD to sertraline compared to CBT Both groups responded equally to intervention (F(156) = 1.54, p = 0.22)

Result

Abbreviations: ADIS Anxiety Disorders Interview Schedule; CBT = Cognitive Behavioral Therapy; CGI Clinical Global Impression Scale; ChOCI Children´s Obsessive-Compulsive Inventory; COIS = Children´s OCD Impact Scale; CY-BOCS Children´s Yale-Brown Obsessive-Compulsive Scale; DSM Diagnostic and Statistical Manual for Mental Disorders; NIHM-GOCS = National Institutes of Mental Healthy – Global Obsessive Compulsive Scale; OCD Obsessive-Compulsive Disorder; K-SADS-PL Kiddie Schedule for Affective Disorders and Schizophrenia Parent version Lifetime; MINI Neuropsychiatric Interview; SRI Serotonin Reuptake Inhibitor; SADS Schedule for Affective Disorders and Schizophrenia; TD Tic Disorders; Y-BOCS Yale-Brown Obsessive-Compulsive Scale; YGTSS Yale Global Tic Severity Scale.

33 OCD non-responder (n = 12 TD/TS)

McDougle et al. (2000)

Bogetto et al. (2000)

Piacentini et al. (2002)

19 adolescents with OCD (n = 8 with OCD) 42 youngsters with OCD (n = 12 with TD) 23 OCD non-responder (n = 3 TD)

124 OCD partial responders (n = 66 with TD)

Conelea et al. (2014)

Himle et al. (2003)

29 pediatric OCD + TD, 29 pediatric OCD

Bennett et al. (2015)

44 OCD non-responder (n = 9 CTD/TS)

50 OCD, 12 OCD + TD

Skarphedinsson et al. (2015)

Shapira et al. (2004)

N

First author, year

Table 16 Psychopharmacological and psychological treatment studies in OCD + TD.

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comorbid and pure patients, and that tics moderate response to SSRIs but not CBT. In contrast, our review does not find clear support for differences in symptom dimensions, comorbidity patterns, or symptom severity. In terms of possible further features associated with OCD + TD, there is preliminary evidence for increased dopamine neurotransmission and reduced serotonergic transmission in comorbid cases (Cath et al., 2001b; Leonard et al., 1993) and reduced volume of the putamen (Peterson et al., 2003). There is a lack of functional imaging studies since studies exclusively examined comorbidity of OCD in TD. On a neuropsychological level, OCD + TD and OCD appear similar but there is preliminary evidence pointing to a dissociation in performance monitoring with comorbid patients showing intact performance monitoring or intermodal integration (Hanna et al., 2012, Kloft et al., Unpublished results). What conclusions can be drawn from the existing literature about the relationship between OCD, TD, and their co-occurrence as to whether the question of subtype, hybrid combination or unique disorder? The genetic studies conducted so far are equivocal regarding the subtype/ variant expression hypothesis. As Yu et al. (2015) showed in their combined GWAS of TS and OCD data the inclusion of OCD + TS patients reduced the polygenetic signal by 35%, despite the increase in sample size of 30%. This shows that - although there are common genetic components underlying OCD and OCD + TD – there are also genetic differences between diagnostic groups and that these are compatible with the variant genetic expression hypothesis. In line with that, several research areas were identified where patients with OCD + TD were more similar to TD than OCD, e.g. enhanced cognitive control (Tajik-Parvinchi and Sandor, 2013), comparable dopaminergic dysfunctions (Leckman et al., 1995; Wong et al., 2008), normal ERN amplitudes (Hanna et al., 2012). What the current review also shows is that there is no domain indicating that OCD + TD is an alternative expression of OCD. However, if OCD + TD were a variant expression of TD, one would expect increased rates of TD in family members of co-morbid patients compared to OCD-TD patients. This was not found in any of the studies that examined this question; yet, only a minority of studies investigated this question and these relied on rather small sample sizes. Also, in an earlier analysis of the Yu et al. (2015) sample, the genetic correlation of OCD and TD changed from r = 0.41 to r = 0.50 when OCD + TD cases were excluded, i.e. genetic overlap increased when cases were removed that are considered main carriers of common genetic architecture. These results do not disprove the subtype hypothesis but they are difficult to integrate within a model of alternate expression. Results from imaging studies add little to our understanding in this regard due to the inconsistency between studies, the lack of metaanalysis in TS, and the high number of TS subjects that present with OCS making it impossible to infer whether differences relate to tics, OCS, or both. Also, so far no imaging studies exist that compared OCD with OCD + TD. The few studies that explicitly looked at differences between TS and TS + OCD showed a large overlap between TS and TS + OCD but found that TD + OCD seems to be associated with cortical thinning in ventral ACC and posterior OFC (Worbe et al., 2010) and increased cortical thickness in the cerebrum (Tobe et al., 2010). Interestingly, in OCD similar alterations were found in a recent megaanalysis (de Vries et al., 2016b) which suggests that (some) neural dysfunctions are compatible with an additive model. Results from neuropsychological studies showing impaired cognitive flexibility and interference control could also be taken as evidence for the additive model as no such dysfunction is found in TS but is found in OCD (Muller et al., 2003; Rankins et al., 2006). However, there are also results that are in line with the hypothesis of a unique entity associated with specific correlates like regional specific alterations in the BG (i.e. smaller putamen in TS + OCD and smaller caudate in TS) that are not found in OCD (de Wit et al., 2014) or results from functional neuroimaging indicating unaffected reward processing in TS, but hypoactivity in TS + OCD (Worbe et al., 2011)

and hyperactivity in OCD (Kaufmann et al., 2009; Stern et al., 2011). Some evidence also supports specific attentional dysfunctions (Yuen et al., 2005). Taken together, there is evidence against and in favor for the subtype/ alternate expression hypothesis, the additive model, and the idea of unique syndrome. This seemingly inconsistency could either indicate the existence of a stepwise model of co-morbidity, that is, OCD + TD must be specified at different levels within the psychopathological pathways from genetics to symptoms. From alternate expression on a genetic and structural brain level (in some areas) to the additive combination of pathogenic processes in other genetic and brain systems and/ or the development of specific cognitive and functional dysfunctions. Alternatively, inconsistency could be an artefact to the low methodological quality of studies. To overcome these limitations, we recommend some aspects which could direct next steps in future research. The field needs a (semi-)structured interview of good validity and reliability for diagnosing TD in adults. This could also help to direct the attention of researchers and clinicians to the comorbidity of OCD and TD. The assessment and report of lifetime TD and OCD should become standard in all studies examining these patient groups. Comorbidity should be assessed a priori and cases should be carefully matched. Together these factors might help to reduce variance due to differences in assessment methods, which is one possible factor leading to inconsistency between studies. To gain further understanding of the relationship between OCD and TD, sufficiently large epidemiological and clinical studies of different age groups are needed to estimate the prevalence rates of OCD in TD and of TD in OCD and how these differ with age. These should be combined with prospective and longitudinal studies to better understand the natural and clinical course of comorbidity between OCD and TD and how the occurrence of one disorder might affect occurrence of another. Studies of variable assessment areas (e.g. self-report, cognition, neural) are needed that include ticfree OCD patients, OCD-free TD patients and comorbid patients (if possible even both, OCD + TD and TD + OCD). This research strategy should be combined with the parallel assessment of different variables (e.g. fMRI and cognitive tasks). The comparison of the profiles of each of these diagnostic groups would allow conclusions regarding the nature of comorbidity. In accordance with the variant expression theory would be the finding of similar profiles between OCD, TD, and their comorbid patients. In favor for the model of additive combination would be a profile of the comorbid cases where characteristics of both, OCD and TD, are additively combined. Finally, the unique syndrome model would be supported if comorbid cases showed a profile that is not only the additive combination of TD and OCD-related factors but specific for the occurrence of comorbidity. This approach was successful in elucidating comorbidity of TD and ADHD (Banaschewski et al., 2007). Finally, controlled randomized treatment studies of large numbers of comorbid patients are needed to validate differences in efficacy of psychopharmacological compared to cognitive-behavioral treatment. 5. Conclusions The bulk of studies reviewed here did not examine the co-occurrence of OCD and TD in a systematic way with severe consequences for interpretation and conclusions drawn. The exploratory and post-hoc nature of most of the analyses and the variable assessment level of tics between studies strongly hampers interpretation. The field certainly needs more studies that include sufficiently powered, a priori defined and matched samples, and the development and use of well validated assessment instruments for TD in adults. Almost all domains lack replication. Despite these limitations, the reviewed studies provide further evidence that, in contrast with OCD, OCD + TD is associated with an earlier age-of-onset, a 1.6. times higher number of males, is more familial and presents with more sensory phenomena. Regarding age-ofonset and gender, however, studies are heterogeneous and an earlier 310

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age-of-onset may more reliable be found in larger sample sizes (n > 100). The nature of OCD + TD is still unresolved as the current review provides evidence against and in favor for the hypotheses of variant expression or tic-related OCD subtype, a hybrid combination, or a unique syndrome, the current review provides evidence against and in favor of all of these hypothesis.

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