Journal of Psychosomatic Research 67 (2009) 515–523

Tourette syndrome and comorbid early-onset schizophrenia

Jacob Kerbeshiana,c, Chun-Zi Pengb, Larry Burdb,c,⁎

aDepartment of Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202-9037, USAbDepartment of Pediatrics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202-9037, USA

cAltru Health System, Grand Forks, ND, USA

Received 6 August 2009; accepted 6 August 2009

Abstract

Objective: A study of the shared phenomenology betweenTourette syndrome (TS) and schizophrenia. Method: An illus-trative case report is presented. We used a chart review of 399clinically ascertained patients with TS to identify 10 cases meetingcriteria for schizophrenia. From our 10 patients, salient clinicalcharacteristics were then tabulated. We then extracted similarclinical characteristics from a previously published series ofpatients with comorbid TS and schizophrenia in order to combinecases and allow for a comparison between childhood-onsetschizophrenia (COS), adolescent-onset schizophrenia (AdolOS),and adult-onset schizophrenia (AduOS) cases in these groups.Results: We found 10 cases of schizophrenia (all were males) inthe 399 TS patients for a prevalence rate of 2.5% (95% CI 0.96–4.04). Mean age of tic onset for TS diagnostic criteria ranged from2-14 years with a mean of 8.2 years. The mean age of diagnosis forschizophrenia was 14.2 (range 9–23 years). We found six cases ofschizophrenia with onset of positive psychotic symptoms by 13years of age, two cases with onset after 13 years of age and before

⁎ Corresponding author. Department of Pediatrics, University of NorthDakota, School of Medicine and Health Sciences, 501 N. Columbia Road,Grand Forks, ND 58202-9037, USA. Tel.: +1 701 777 3683; fax: +1 701777 4474.

E-mail address: laburd@medicine.nodak.edu (L. Burd).

0022-3999/09/$ – see front matter © 2009 Published by Elsevier Inc.doi:10.1016/j.jpsychores.2009.08.002

18 years of age, and two cases with onset after 18 years of age.Attention deficit hyperactivity disorder was present at a higher rate(70%) than one would expect in a clinically ascertained group ofpatients with TS. Comparison between COS, AdolOS and AduOSin our pooled cases noted a sex bias skewed toward males.Catatonic symptoms may be more likely in child or adolescentonset cases and negative symptoms more likely in AduOS cases.Conclusions: The 2.5% prevalence of schizophrenia in our TSsample exceeds the 1% expected rate of schizophrenia in thegeneral population (chi-square=9.14; P=.0025). The six cases ofCOS (before 13 years of age) exceeds the expected rate of 1–2 per100,000 (chi-square=4499; P=.0001). The 752-fold increase inobserved rates of comorbid TS and COS over expected ratessuggests a role for unknown common underlying etiologic factors.Based on clinical features, patients with TS and comorbid COS,AdolOS, or AduOS do not have different conditions. We concludewith suggestions for further research.© 2009 Published by Elsevier Inc.

Keywords: Tourette syndrome; Schizophrenia; Children; Comorbidity; Phenomenology

Introduction

Tourette syndrome (TS) is a neuropsychiatric develop-mental disorder, the hallmarks of which are multiple motorand vocal tics of at least a year's duration [1]. TS is thoughtto represent a genetically mediated condition with a broadrange of severity, much of which may be attributable to theneuropsychiatric comorbidities with which it commonlyoccurs [2]. Comorbid disorders including attention deficit-

hyperactivity disorder (ADHD) and obsessive–compulsivedisorder (OCD) are common [3]. We have previously notedadditional patterns of comorbidity between TS and autisticdisorder, Asperger syndrome, and bipolar disorder [4–8].We have also have examined the comorbidity between TSand schizophreniform symptomatology, and TS and child-hood-onset schizophrenia (COS) [8,9].

As conceptualized in the Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, Text Revision(DSM-IV-TR), specific symptom criteria for schizophreniaencompass positive symptoms such as delusions, hallucina-tions, disordered thinking, and disorganized behavior. Thenegative symptoms include flat affect, poverty of speech, andlack of ability and persistence in goal directed activity [1].

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Although commonly cited in the literature, age of onsetcriteria for COS vary widely. Prevalence rates of schizophre-nia suggest that a childhood onset (based on age 14 or 13years and younger) is very rare [10,11]. Studies in Swedenreported a rate of COS of 1.6 per 100,000 [12,13]. Anotherstudy in North Dakota found a prevalence rate of 1.9 per100,000 [4,14]. In New Zealand, only two cases with an onsetunder age 12 years were identified in a population of 130,000[15]. Thus, current prevalence estimates suggest a rate of 1 to2 cases per 100,000 for COS (onset by 13 years of age).

In our clinical work, we have been struck by thephenomenologic overlap in symptoms of our TS patientsand our schizophrenia patients. Our patients with schizo-phrenia, particularly of the catatonic and disorganized(hebephrenic) subtypes often exhibit motor or vocal tics,including complex echophenomena, and palilalia. Similarly,some of our patients with TS have engaged in complexposturing reminiscent of catatonia, or in mirror gazingreminiscent of disorganized schizophrenia. Many of our TSpatients report brief and fragmentary auditory hallucinations.The vivid, eidetic imaging of echolalia and palilalia thatsome patients with TS describe has considerable overlapwith the auditorization of thought, or “echo des pensees” ofSchneider's so-called first rank symptoms, which oftenpresent with schizophrenia, but not exclusively so [16]. Oneof our TS patients interpreted his echokinesis in response tothe movement of others as those people having control overhis bodily movements, reminiscent of a delusion of somaticpassivity, another so called first rank symptom of schizo-phrenia. These clinical similarities have caused us and othersto question just what the relationship between TS andschizophrenia might be [9,17–24].

The onset of DSM-IV-TR Tourette's disorder, or TS, bycriterion definition is during the childhood or adolescentyears with a peak age of tic onset at 6–7 years of age [1].Schizophrenia has a broader range of age of onset [1]. COS isthought to be symptomatically similar to and appears to becontinuous with adolescent-onset schizophrenia (AdolOS)and adult-onset schizophrenia (AduOS), according toNicolson and Rapoport [25]. However, their cohort of COSpatients had more premorbid developmental abnormalities,more cytogenetic abnormalities, and a greater burden offamily history of paranoid and schizotypal personalitydisorders than later onset cases, pointing to perhaps a greaterdevelopmental neurobiologic vulnerability. Their findingthat an earlier age of onset of schizophrenia is associated withmore severe psychopathology and neurocognitive deficitshas been supported by others [26,27]. It has been hypothe-sized that the typical age of onset of schizophrenia in lateradolescence to early adulthood is a manifestation ofneurotransmitter ontogeny interacting with neurobiologicalvulnerability [25]. An earlier age of onset would be consistentwith a developmental period of increased vulnerability toneurobiological and genetic risk factors.

In 1946, the venerableMargaret Mahler described the caseof G.K., a boy with “the tic syndrome” who later went on to

develop schizophrenia [28]. In more recent decades, therehave been multiple case reports and small case series ofpatients with comorbid TS and schizophrenia [9,17–21,23,24]. From an epidemiologically defined sample inNorth Dakota, we have published a prevalence rate ofschizophrenia in boys aged 2–12 years old with TS of 8.7%[9]. In a recent paper, Cavanna et al. [29] also noted that 15%of patients in their clinical population with TS also metcriteria for schizotypal personality. They found increasedrates of obessionality and anxiety in this group with comorbidTS and schizotypal personality [29]. Muller et al. [20] alsohave reported on 5 adults with comorbid TS and schizophre-nia. All of their patients first showed symptoms of TS,followed by symptoms of schizophrenia. Four of these had anadult onset of their schizophrenia, and one had an onset inlater adolescence. The course of the tic disorder was chronicor worsening over time. They speculated that TS andschizophrenia might co-occur at a rate greater than expectedby chance. In their review of the clinical and pathophysio-logic similarities between TS and schizophrenia, they positedthat common biological mechanisms likely play a key role inthe shared phenomology between these clinical syndromes.

To date, the majority of case series reports of comorbidityfor TS and schizophrenia have focused on patients withprimarily later AdolOS/AduOS. In this study, we estimatethe prevalence rate for schizophrenia and shared phenomol-ogy in a clinical population of primarily child and adolescentpatients with TS.

Case illustration from subjects of study

U.T. is a 14-year-old boy who has been in our care sinceage 7. He was first seen for treatment of hyperactivity,inattentiveness, and learning difficulties, not responsive tostimulants. His pervasive hyperactivity dated back to hisearliest years. His tics preexisted the use of mixed salts ofamphetamine, but seemed to worsen following the start ofthat medication. The patient's pattern of waxing and waningmultiple motor and vocal tics dates back to 5 years of age.They have included the blinking of his eyes and pursing ofhis lips. He would repeatedly clear his throat, causing theparents often to wonder if he had allergies and wascongested. He had difficulties with swearing, usually inanger, as well as episodic sexual exhibitionism. At age 7years, his learning disability included a pattern of attemptingto read from right to left and letter and number reversals. Hewould have rapid shifts in mood and sleep onset insomnia.U.T. was treated with clonidine 0.05 mg qam and 0.2 mgqhs, with some improvement in attention and tics. Due toperiods of brief blanking of consciousness, he had aneurological evaluation and was diagnosed with epilepsy,for which he was successfully treated with carbamazepine.He admitted that since age 5 years, he has had 2 “imaginaryfriends.” They had names, but he did not hear them or seethem. At age 8 years, the patient indicated that he washearing voices in his head when no one else was about. At

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times, he would hear two voices in his head yelling at eachother. He noted at times he smelled odors that others did notsmell. At times, he would have “bad thoughts” that wouldcompel him to do things such a jumping from a movingautomobile. These thoughts did not feel as if they were his.He discovered that if he hit his head with his fist, thesethoughts would dissipate. Risperidone 1 mg qhs was addedto U.T.'s treatment regimen. Subsequently, with theemergence of depressive affect, citalopram 20 mg qd wasadded. At age 11 years, U.T. had a psychiatric hospitaliza-tion with symptoms of sleep disturbance, night terrors, fairlyrapid shifts in mood with explosive and unpredictablelaughter, and violence directed against his mother. There wasa resurgence of his psychotic ideation. Ziprasidone was

Table 1Data from 10 TS case reports in ascending order age of onset of schizophrenia

U.T. D.N. N.T. K.Q.

Age eval 7 7 11 9Age motor tics 5 7 4 7Age vocal tics 5 7 4 7ADHD + + + +Meds before TS – Stim – –

Age-positive psychotic sx 8 9 10 7Age dx schiz 9 9 11 12Catatonic sx's – + – –Schiz-negative psychotic sx + + – +Meds before Schiz Stim Stim Halo Pheno

Clon Li+ TrifluCBZ Desip

Stim

OC sx's + – + –Learning disorder + – + +Drug abuse – – + –EtOH abuse – – – +Knives – – + +Comorbidities Klein – Dep Enur

Levin Enco

Medical hx Obese – Otitis OtitisAsthma

Seizures + – – +Family hx ADHD Dep ADHD ADHD

Tics Tics TSSchiz EtOH

Sequence comorbidities ADHD ADHD ADHD ADHDTS TS TS TSSchiz Schiz Dep Schiz

Schiz EtOH

Klein, Klein Levin syndrome; Dep, depression; Enur, enuresis; Enco, encopresis; Malcohol abuse; Drugs, drug abuse; Degen CNS, degenerative disorders (progressivsx's, obsessive compulsive disorders; Otitis, otitis media; Stim, stimulant; MephClon, clonidine; Li+, lithium; Triflu, trifluoperazine; CBZ, carbamazepine; DesipAll 10 were males. All 10 were of average intelligence (+, present; −, absent).

substituted for risperidone with good effect. The patientcontinued with occasional facial grimacing and subtleblinking of his left eye. During the subsequent 3 years, thepatient remained fairly stable, although he was markedlywithdrawn and shy at times. U.T. gained a considerableamount of weight. He also developed a waxing and waningpattern of hyperphagia, hypersomnolence, and irritabilityconsistent with Klein-Levin syndrome. Past medical historyis positive for complex partial seizures.

Family history is positive for ADHD on the part of anolder brother. Mother's father was diagnosed with paranoidschizophrenia. Mother can recall her father driving along inan automobile repetitively twitching his arm while staring,and at the same time engaging in a guttural throat clearing

T.T. S.H. D.R. U.M. E.I. Q.N.

7 13 15 9 17 66 13 14 11 13 36 13 14 11 13 2+ – – + + –– – – Stim Meph –

Stim

11 10 15 15 18 2212 13 15 16 22 23– + + – + –– + + – + +Halo – – Stim Stim PimPim Halo HaloFlu Pim

Clon

+ – – – + –– + – + + +– – + – – –– – – – + –+ + – – + –Enur Meige – – Dep EnurEnco Dep Gambl

TDysGambl

– Web – – – –Toes

– – – – + –OCD EtOH Drugs Tics Degen CNS TicsTics WebEtOH Toes

Seizure

ADHD Schiz Drugs ADHD ADHD TSTS TS TS TS TS SchizSchiz Dep Schiz Schiz OCD

DelusSchiz

eige, Meige syndrome; Gambl, gambling; TDys, tardive dyskinesia; EtOH,e supranuclear palsy); Schiz, schizophrenia; Delus, delusional disorder; OC, mephobarbital; Halo, haloperidol; Pheno, phenobarbital; Pim, pimozide;, desipramine; Flu, fluphenazine; sx, symtoms; hx, history; dx, diagnosis.

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sound. Since childhood, mother had had a pattern ofrepetitively rolling her eyes, spasmodically closing hereyes, pursing her lips, and making a slight vocalization.Mother's brother at age 13 had recurrent suicide attempts.Mother states that father may have some odd mannerisms,which father denies.

U.T.'s diagnoses are schizophrenia, paranoid type, withchildhood-onset, TS, ADHD combined type, learningdisorder, and epilepsy.

Method

For the purposes of our study, we adopted the age rangedefinitions of Kumra [30]. COS was defined by an onset ofpsychotic symptoms by 13 years of age. AdolOS wasdefined as an onset of psychotic symptoms after age 13 yearsand by age 18 years. AduOS had an age of onset of psychoticsymptoms after age 18 years.

We reviewed the charts of all 399 patients in our practicewith TS for cases meeting DSM-IV-TR criteria for schizo-phrenia [1]. This cohort was comprised of consecutive casescollected over a 30-year time span. We examined age-relatedvariables for onset of tics, ADHD, psychotic symptoms, ageof onset and of diagnosis for TS and schizophrenia, rates ofcomorbidities, and family history variables (Table 1). Wealso reviewed phenomenology.

We then compared our patients with comorbid TS andschizophrenia with the five patients reported by Muller et al.[20] Of these, one had AdolOS and 4 had AduOS. Weabstracted data from these cases using the same format weused for our cases. We excluded those data points for whichthere was no mention in the Muller et al. cases. We inferredthat if no mention was made of use of medication prior to theonset of TS, none had been used; that the use of psychoactive

Table 2Case data from Muller et al. [20] in ascending order of age of diagnosis of schizo

3 5 4

Age in report 25 25 2Gender M M MMeds before TS N N NMeds before Schiz N N N

Age motor tics 14 11 1Age vocal tics ? 14 1Age-positive psychotic sx 17 25 2Age dx schiz 17 25 2Catatonic sx's Y N NSchiz-negative sx's Y Y YOC sx's Y N YIntelligence MR Avg AFamily hx Schiz Schiz D

SeizuresSequence comorbidities TS TS O

Schiz Schiz TS

MR, Mental retardation; Avg, average intelligence; Y, present; N, absent; see foo

medication prior to onset of schizophrenia would bementioned in the report (neuroleptic use was reported incase number 2); that the age of onset of psychotic symptomswas the same as the age of onset of schizophrenia; that ifcatatonic symptoms were not reported that they were notpresent; and that major neurologic events such as a seizuresand mental retardation were reported if they were present(Table 2).

We then combined data which allowed for contrast andcomparison between our cases and the cases of Muller et al.and filtered the data points as a function of whether theonset of schizophrenia for the 15 subjects with TS wasduring childhood/adolescence (n=9) or adulthood (n=6)(Tables 1 and 2).

Results

Our results are in tabular form in Tables 1 through 4.From our clinical cohort of 399 TS patients, we identified 10cases (all were males) with comorbid DSM-IV-TR schizo-phrenia, six of whom had COS, two of whom had AdolOS,and two of whom had AduOS (Table 1). The prevalence rateof schizophrenia in subjects with TS was 10/399=2.5% (95%CI 0.96–4.039). The rate of comorbidity is 2.5 times thepopulation base rate for schizophrenia in adults which is 1%(chi square=9.14; P=.0025) [1,31]. Previous prevalenceestimates suggest that the expected rate of COS to be 1–2 per100,000 [4,10,12,13,15,32]. The finding of six cases of COS(by 13 years of age) in 399 patients with TS exceedsexpected rates of 1–2 per 100,000 (chi square=4499;P=.0001). The expected male to female preponderance forCOS was as would be expected. That all 6 of our COS caseswere males likely further increases the discrepancy betweenthe observed and expected rates for schizophrenia.

phrenia

2 1 Summary

7 30 41 29.6M F 80% MN N 0Tiapride N 20%Flupentixol

7 School age 187 Adolescent 187 30 33 26.47 30 33 26.4

N N 20%Y Y 100%Y Y 80%

vg ? ?ep EtOH Negative

CD TS TSS OCD OC sx'schiz Schiz Schiz

tnote to Table 1.

Table 3Summary data from 10 subjects with TS and schizophrenia

Age at evaluation under 18 years 10

Male gender 10Onset of motor and vocal tics at same age 9Comorbid ADHD 7Use of stimulants before TS 3Use of stimulants before schizophrenia 5Use of antipsychotics before schizophrenia 6Tics precede onset psychotic symptoms 9Positive psychotic symptoms before age 18 8Diagnosis of schizophrenia before age 18 8Catatonic symptoms 4Negative symptoms of schizophrenia 7Obsessive compulsive symptoms 4Learning disabilities 7Drug abuse 2Alcohol abuse 2Preoccupation with knives 5Seizures 3Average intelligence 10Family history of tics/TS 6Family history of schizophrenia 1Family history of ADHD 3Family history of OCD 1Family history of drugs/alcoholism 4Developmental sequence of ADHD:TS:depression/OCD:schizophrenia 9

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Seven of our 10 cases were comorbid for ADHD a ratesomewhat greater than the 55% concordance rated expectedfor TS and ADHD in clinical samples [2].

We found that 3 of our patients with comorbid ADHDhad exposure to stimulants prior to the onset of their TS. In 9of the 10 cases, tics preceded the onset of psychoticsymptoms, perhaps reflective of age associated general riskfactors for the two conditions. Five of our 10 patients withcomorbid TS and schizophrenia had been exposed tostimulants prior to the onset of their psychotic symptoms.Exposure to stimulants may modify risk for psychoticsymptomatology [33]. We also found 6 patients who hadbeen exposed to antipsychotic medications for treatment oftheir TS prior to the onset of psychotic symptoms.

Table 4Comparison of combined patient groups from this study and Muller et al. [20] (n=

No. of patientsMale genderOnset of motor and vocal tics at same ageUse of antipsychotics before schizophreniaTics precede onset psychotic symptomsCatatonic symptomsNegative symptoms of schizophreniaObsessive compulsive symptomsSeizuresFamily history of schizophreniaFamily history of drugs/alcoholismDevelopmental sequence (if present) of ADHD:TS:depression/OCD:schizophrenia

Four of our 10 patients exhibited catatonic symptoms.This is not surprising as typical catatonic symptoms such asposturing, the automatic compliance of echokinesis, echo-lalia, and palilalia, when seen in TS are often categorized ascomplex tics. Four patients exhibited obsessive compulsivesymptoms. We found that 5 of our 10 patients had anunexpected preoccupation with knives.

Three of our patients had comorbid epilepsy. U.T. wasdiagnosed with epilepsy at age 8 years, after the onset of histics and about the time of and possibly preceding the onset offormal psychotic symptoms. His seizures were characterizedby brief blanking of consciousness, and he also endorsedolfactory hallucinations. K.Q., at age 16, years complainedof blanking-out spells and was diagnosed with a generalizedseizure disorder with nonconvulsive epilepsy. His electro-encephalography (EEG) disclosed a photoparoxysmal re-sponse. TS and schizophrenia diagnoses preceded thediagnosis of his epilepsy. E.I. was diagnosed with epilepsyat age 4 years, prior to the onset of his tics and of hisschizophrenia. His first seizure followed a bout withpneumonia and high fever. Repeated EEGs disclosedpolyspike activity. He was treated with mephobarbital.After a few years of remaining seizure-free, his anticonvul-sant was discontinued, and he has remained seizure-freesince then.

From our case studies, we have abstracted examples ofSchneiderian first-rank symptoms, or symptoms indicativeof so called nuclear schizophrenia, and specific ticsymptoms that may share a phenomenologic overlap withschizophrenic symptoms, including catatonic symptoms,and/or temporal lobe phenomena [34,35]. U.T.'s case studyis noted above. He auditorized two voices yelling at eachother, olfactory hallucinations, and a belief that his behaviorwas controlled by thoughts that were not his. D.N. hadcommand auditory hallucinations causing a sense of externalcontrol, and a belief that his body was externally controlledby and was turning into a robotic toy called a “transformer.”This was a manifestation of a delusion of somatic passivity,was on a spectrum with catatonia, and may have reflected asensory precursor to a motor tic phenomenon. N.T. had a tic

5) by age of onset: COS+AdolOS=EOS vs. AduOS

EOS AduOS

9 69=100% 5=83%8=88% 3=50%4=44% 3=50%8=88% 6=100%4=44% 1=17%6=67% 6=100%4=44% 4=67%2=22% 1=17%2=22% 1=17%3=33% 1=17%8=88% 5=83%

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of significant palilalia, a symptom often present inindividuals with catatonia. He would engage in the complexmotor behavior of hitting his head in order to relieve thesensory phenomenon of his command auditory hallucina-tions, behavior perhaps on the spectrum with his TS. He hadolfactory hallucinations, and the delusion of somaticpassivity that contact with water would melt away hisbody. K.Q. had auditory hallucinations commenting on hisactions. Prior to the onset of formal psychotic symptoms, hehad a delayed mental echolalia as a “mental tic,” more asintense eidetic imagery. This preceded the onset ofcommand auditory hallucinations, voices referring to himin the third person, and a sense of transmitting his thoughtsinto the heads of others. T.T. believed he was beingmagically externally controlled by a specific other student.His vocal tic (or catatonic) behavior of echoing obscenitiesuttered by this other student was perceived by him as beingcontrolled by an external agency. He also experiencedvoices in conflict talking to each other in his head. S.H.complained of uncomfortable somatic sensations interpretedas small creatures crawling over his body, reminiscent ofsensory phenomena preceding motor tics. He had behaviorsreflecting a phenomenologic overlap between complexmotor tics and catatonia in which he would posture, holdinghis right arm flexed and intermittently dragging his leg whilewalking. He also had command auditory hallucinations.D.R. complained that God was a “buzz-box” in his head. Heclaimed powers of clairvoyance and was bizarrely silly. Histhought blocking was reminiscent of vocal tics manifestedby interruptive silences. He claimed he could not stophimself from automatically whistling in the classroom. U.M.had command hallucinations to harm others with a knife.His making loud noises to drown out the auditoryhallucinations in his head had all the outward appearanceand function of a vocal tic. He had the sensation that otherswere reading his mind, prior to his expressing those thoughtsin words. E.I. had complex sustained posturing involving hisupper extremities, again pointing to a phenomenologicoverlap between catatonia and complex motor tics. He haderotic delusions of reference and that others were monitoringhis comings and goings. Q.N. had religious delusions andwas preoccupied with the belief that all his family memberswere homosexual.

None of our patients met criteria for a pervasivedevelopmental disorder. Although patients with a pervasivedevelopmental disorder may present with symptomaticcatatonia, the catatonic symptoms in our patients werefellow travelers with more specific schizophrenic or TSsymptoms [36,37]. In addition, we have noted that, inpatients with TS and other developmental disorders,schizophreniform symptoms may also be present [7,38].

Our profile of the patients of Muller et al. [20] is noted onTable 2. Data from our clinical cohort of 10 TS+schizophreniapatients are summarized in Table 3. A comparison of COSand AdolOS cases with AduOS utilizing a pooling of our 10cases with Muller et al.'s 5 cases is noted on Table 4 [20].

Discussion

Our clinical population of 399 TS patients is one thelargest reported to date to examine the rate of comorbidity ofschizophrenia in patients with TS. The prevalence rate of2.5% exceeds the expected rate of schizophrenia in a generalpopulation where it is typically reported to be 1% [1].

Of the 10 cases with TS and comorbid DSM-IV-TRschizophrenia, six had a childhood onset by 13 years of age,two had an adolescent onset by 18 years of age, and two hadan adult onset after 18 years of age. This suggests that therate of COS in subjects with TS is increased 752-fold. Inprevious reports we have discussed increased rates ofschizophreniform symptomatology in TS patients who werechildren [4]. We found an 8.7% rate for schizophreniaamong TS boys aged 2–12 years, and 0% among girls withTS [9]. In our current study, all 10 cases were males, andthis supports an increase in risk for schizophrenia in maleswith TS.

In Table 3, we summarized the data for the 10 subjectswith TS and comorbid schizophrenia. Seven of our caseswere comorbid for ADHD, somewhat greater than the 55%concordance rated expected for TS and ADHD in clinicalsamples [3]. Perhaps ADHD in the presence of TS confers asomewhat greater risk for schizophrenia. With the exceptionof one case, tics preceded the onset of psychotic symptoms,suggesting periods of developmental vulnerability for thetwo conditions. Due to the presence of comorbid ADHD, it isnot surprising that three of our patients had exposure tostimulants prior to the onset of their TS. Five patients wereexposed to stimulants prior to the onset of their psychoticsymptoms, raising the question of kindling of thosesymptoms [33]. It is also not surprising that six patientswere exposed to antipsychotic medications for treatment oftheir TS prior to the onset of psychotic symptoms. One mighthave predicted a protective effect against the advent ofpsychotic symptoms. This was not observed in our cases, butmight be operative in other cases of antipsychotic treated TSpatients, who do not go on to develop schizophrenia. Four ofour patients developed catatonic symptoms. This is ofinterest since typical catatonic symptoms such as posturing,the automatic compliance of echokinesis, echolalia, andpalilalia, when seen in TS are often categorized as complextics [37]. Further research is required to define thephenotypic boundaries of catatonia and complex tics inchildren, as well as other aspects of shared phenomenologybetween TS and schizophrenia. As catalogued in our results,we selectively abstracted examples of Schneiderian first ranksymptoms, of catatonic symptoms, of possible temporal lobephenomena, of specific tic symptoms which may portendtransmutation to schizophrenic symptomatology, and ofschizophrenic symptoms which share a structural similaritywith complex tics. Command auditory hallucinations werefrequent, as were two or more voices, often in conflict,talking to each other and referring to the patient in the thirdperson. Delusions of somatic passivity and a belief of being

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controlled by an external agent were also prominent. Themesof somatosensory phenomena interfering with volition orresulting in bizarre motor behavior or vocalizations were alsopresent. Some of our patients had a distinct intense eideticimagery phase as a precursor to their experiencing formalhallucinations. “Mental tics” were also present. Reflexbizarre motor or vocal behaviors were interpreted by patientsas terminating disturbing hallucinatory experiences. Themesof thought broadcasting were also present. Our patients alsoexperienced olfactory hallucinations, raising the question oftemporal lobe phenomena.

Four patients exhibited obsessive compulsive symptoms,which has been reported in both TS and in schizophrenia[39,40]. The presence of learning disabilities in individualswith TS and/or ADHD is also not surprising, nor is it sowith schizophrenia, especially in light of recent researchinto the neurocognitive impairments present in that disorder[41,42]. We found the 50% prevalence of preoccupationwith knives in our patients to be a most interesting clinicaltidbit. We know not what it means in its specificity, but itcould be related in general to the compelling disinhibitionnoted in some patients with TS [43]. It may also be aprecursor to or early manifestation of paranoid behavior.Young people likely have greater access to knives thanother weapons.

The presence of three patients with seizures in ourcohort may reflect a greater neurobiologic risk for sameassociated with the presence of schizophrenia and alsopossibly by the concordance with TS [44]. Two of thesethree patients had the onset of their seizures contempora-neous with or following the onset of their psychosis andone prior to the onset of psychosis and of tics. One hadolfactory hallucinations, a phenomenon often associatedwith temporal lobe abnormality. None of our three patientshad major motor seizures or lateralization of EEGpolyspike activity. Awareness of the greater risk forschizophrenia or at least schizophrenia-like psychoses inpatients with epilepsy dates prior to the seminal work ofSlater et. al. [45]. Typically patients with comorbidepilepsy and schizophrenia have an earlier onset ofseizures, with seizures typically and often by yearspreceding the onset of psychotic symptoms; more severeseizures; vegetative seizure symptoms; frequently temporallobe discharges; and a likelihood of Schneiderian first ranksymptoms, fitting a picture of so-called nuclear schizo-phrenia [34,35,46]. With the exception of the presence ofSchneiderian first rank symptoms in all three, the presenceof olfactory hallucinations in one, and an early age of onsetfollowed by psychosis in another, our patients did notstrongly fit the epilepsy/schizophrenia profile. Schneiderianfirst-rank symptoms are often present in patients withschizophrenic psychoses and with non-schizophrenic psy-choses. Our patient with a preschool age onset of epilepsywas treated with mephobarbital. It is tempting to speculatewhether that anticonvulsant may have played a part inkindling a vulnerability for tics [38].

Our patients' family histories are not unexpected for theconditions studied [1]. The developmental sequence of onsetof comorbidities in nine of our patients is consistent withage-related risk factors for these conditions.

Pooling our cases with those of Muller et al. [20], wefound the gender balance continues to be skewed towardmales even in adults with comorbid TS and schizophrenia(Table 4). Exposure to antipsychotics prior to onset ofschizophrenia appears to be comparable, as does theonset of tics preceding that of psychotic symptoms.Catatonic symptoms may be more likely in COS andAdolOS cases and negative schizophrenic symptomsmore likely in the AduOS group. A history of obsessivecompulsive symptoms may be more likely in the AduOSgroup. The presence of seizures and a family history ofschizophrenia may be similar. As expected, the develop-mental sequence of syndrome ontogenesis also appears tobe similar.

The relationship between TS and schizophrenia is allthe more intriguing and elusive in light of our study. Theprevalence rate of schizophrenia in our clinic ascertainedsample of TS is at least suggestive of common underlyingetiologic factors. Assuming a shared underlying etiology,by way of a chemistry analogy, TS might be seen as acation and schizophrenia as an anion in a neuropsychiatricphenomenological solution, which is more than just thesum of its constituent parts. Assuming an absence ofshared underlying etiology, an alternate chemistry analogywould be of a mixture of the TS and the schizophreniaphenotype emerging from a phenomenologic and neurobi-ological final common pathway, with each conditionmaintaining its overlapping but categorical integrity. Atleast, in our TS patients, there appears to be no indicationbased on symptomatic comparisons across studies thatconcordant COS, AdolOS, and AduOS are differentconditions. Whatever the etiologic relationship might bebetween TS and schizophrenia, it is likely similar for boththe COS and AdolOS type [early onset (EOS)] and theAduOS type (Table 4).

Limitations

With our admittedly small and clinically ascertainedpopulation and resulting data set, we suggest a cautiousand conservative appraisal of our findings and conclusions.Nonetheless, given the large caseload from which ourcases were extracted, and given the limited state of theliterature in regard to our topic, we believe that ourfindings are worthy of consideration, at least from thestandpoint of clinical description and of hypothesisgeneration. The generous proportion of child and adoles-cent compared to adult TS cases in our cohort is notunexpected as our practice has a referral bias towardchildren and adolescents.

The agenda for marshalling additional epidemiologicstudies regarding the nature of concordance for TS and

522 J. Kerbeshian et al. / Journal of Psychosomatic Research 67 (2009) 515–523

schizophrenia will be hampered by logistic obstacles,especially for the case of COS for which the populationbase rate is so low. It took our clinical center over 30 years tocollect this case series from North Dakota and surroundingareas. Other approaches, such as genetic studies, or dynamicimaging studies may point toward subgroups in which therelevance of the concordance may be clarified, but thatwould still leave open the question for the population atlarge. In the meantime, we can only hope that our study hasadded additional data to pique interest in future studies toexamine the role of the syndromal overlap between TS andschizophrenia with its age-related subtypes.

Reference

[1] American Psychiatric Association. Diagnostic and Statistical Manualof Mental Disorders. 4th ed. Text Rev. Washington, DC: AmericanPsychiatric Association, 2000.

[2] Freeman RD. Tic disorders and ADHD: answers from a world-wideclinical dataset on Tourette syndrome. Eur Child Adolesc Psychiatry2007;16(Suppl 1):15–23.

[3] Freeman RD, Fast DK, Burd L, Kerbeshian J, Robertson MM, SandorP. An international perspective on Tourette syndrome: selectedfindings from 3,500 individuals in 22 countries. Dev Med ChildNeurol 2007;42:436–47.

[4] Burd L, Kerbeshian J. A North Dakota prevalence study ofschizophrenia presenting in childhood. J Am Acad Child AdolescPsychiatry 1987;26:347–50.

[5] Kerbeshian J, Burd L, Klug MG. Comorbid Tourette's disorder andbipolar disorder: an etiologic perspective. Am J Psychiatry 1995;152:1646–51.

[6] Kerbeshian J, Burd L. Case study: comorbidity among Tourette'ssyndrome, autistic disorder, and bipolar disorder. J Am Acad ChildAdolesc Psychiatry 1996;35:681–5.

[7] Kerbeshian J, Burd L. Are schizophreniform symptoms present inattenuated form in children with Tourette disorder and otherdevelopmental disorders. Can J Psychiatry 1987;32:123–35.

[8] Kerbeshian J, Burd L. Asperger's syndrome and Tourettesyndrome: the case of the pinball wizard. Br J Psychiatry 1986;148:731–6.

[9] Kerbeshian J, Burd L. Tourette disorder and schizophrenia in children.Neurosci Biobehav Rev 1988;12:267–70.

[10] Remschmidt H, Theisen FM. Schizophrenia and related disorders inchildren and adolescents. J Neural Transm Suppl 2005:121–41.

[11] Eggers C, Bunk D, Volberg G, Ropcke B. The ESSEN study ofchildhood-onset schizophrenia: selected results. Eur Child AdolescPsychiatry 1999;8(Suppl 1):I21–8.

[12] Gillberg C. Infantile autism and other childhood psychoses in aSwedish urban region. Epidemiological aspects. J Child PsycholPsychiatry 1984;25:35–43.

[13] Gillberg C, Steffenburg S. Outcome and prognostic factors ininfantile autism and similar conditions: a population-based study of46 cases followed through puberty. J Autism Dev Disord 1987;17:273–87.

[14] Burd L, Fisher W, Kerbeshian J. A prevalence study of pervasivedevelopmental disorders in North Dakota. J Am Acad Child AdolescPsychiatry 1987;26:700–3.

[15] Werry JS. Child and adolescent (early onset) schizophrenia: a review inlight of DSM-III-R. J Autism Dev Disord 1992;22:601–24.

[16] Nordgaard J, Arnfred SM, Handest P, Parnas J. The diagnostic status offirst-rank symptoms. Schizophr Bull 2008;34:137–54.

[17] Becker T, Laux G, Sofic E, Riederer P, Beckmann H. Schizophrenicpsychosis in a patient with Gilles de la Tourette syndrome. Nervenarzt1988;59:616–20.

[18] Escobar R, Bernardo M. Schizophrenia, obsessive-compulsive disor-der, and Tourette's syndrome: a case of triple comorbidity. JNeuropsychiatry Clin Neurosci 1993;5:108.

[19] Fennig S, Fennig S, Pomeroy J, Calev A. Developmental disorder,Tourette disorder and schizophrenia: a case study. Isr J PsychiatryRelat Sci 1997;34:239–43.

[20] Muller N, Riedel M, Zawta P, Gunther W, Straube A. Comorbidity ofTourette's syndrome and schizophrenia—biological and physiologicalparallels. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:1245–52.

[21] Sandyk R, Bamford CR. Gilles de la Tourette's syndrome associatedwith chronic schizophrenia. Int J Neurosci 1988;41:83–6.

[22] Sverd J, Montero G, Gurevich N. Brief report: cases for an associationbetween Tourette syndrome, autistic disorder, and schizophrenia-likedisorder. J Autism Dev Disord 1993;23:407–13.

[23] Takeuchi K, Yamashita M, Morikiyo M, Takeda N, Morita K, TamuraT, et al. Gilles de la Tourette's syndrome and schizophrenia. J NervMent Dis 1986;174:247–8.

[24] Wagle AC, Staley CJ. Gilles de la Tourette syndrome withschizophrenia and obsessive-compulsive disorder: a case report. JNeuropsychiatry Clin Neurosci 1999;11:517.

[25] Nicolson R, Rapoport JL. Childhood-onset schizophrenia: rare butworth studying. Biol Psychiatry 1999;46:1418–28.

[26] Bellino S, Rocca P, Patria L, Marchiaro L, Rasetti R, Di Lorenzo R,et al. Relationships of age at onset with clinical features and cognitivefunctions in a sample of schizophrenia patients. J Clin Psychiatry 2004;65:908–14.

[27] Luoma S, Hakko H, Ollinen T, Jarvelin MR, Lindeman S. Associationbetween age at onset and clinical features of schizophrenia: theNorthernFinland 1966 birth cohort study. Eur Psychiatry 2008;23:331–5.

[28] Mahler MS, Luke JA. Outcome of the tic syndrome. J Nerv Ment Dis1946;103:433–45 Ref Type: Generic.

[29] Cavanna AE, Robertson MM, Critchley HD. Schizotypal personalitytraits in Gilles de la Tourette syndrome. Acta Neurol Scand 2007;116:385–91.

[30] Kumra S. Digging deeper: using neuroimaging tools reveals importantclues to early-onset schizophrenia. J Am Acad Child AdolescPsychiatry 2008;47:1103–4.

[31] American Academy of Child and Adolescent Psychiatry. Practiceparameter for the assessment and treatment of children and adolescentswith schizophrenia. J Am Acad Child Adolesc Psychiatry 2001;40(7Suppl):4S–23S.

[32] Burd L, Fisher WW, Kerbeshian J, Arnold ME. Is development ofTourette disorder a marker for improvement in patients with autism andother pervasive developmental disorders? J Am Acad Child AdolescPsychiatry 1987;26:162–5.

[33] Post RM, Kopanda RT. Cocaine, kindling, and psychosis. Am JPsychiatry 1976;133:627–34.

[34] Trimble MR. First-rank symptoms of Schneider. A new perspective?Br J Psychiatry 1990;156:195–200.

[35] Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity ofepilepsy. Acta Neurol Scand 2004;110:207–20.

[36] Kakooza-Mwesige A, Wachtel LE, Dhossche DM. Catatonia inautism: implications across the life span. Eur Child Adolesc Psychiatry2008;17:327–35.

[37] Cavanna AE, Robertson MM, Critchley HD. Catatonic signs in Gillesde la Tourette syndrome. Cogn Behav Neurol 2008;21:34–7.

[38] Burd L, Kerbeshian J, Fisher W, Gascon G. Anticonvulsantmedications: an iatrogenic cause of tic disorders. Can J Psychiatry1986;31:419–23.

[39] BlochMH, Peterson BS, Scahill L, Otka J, Katsovich L, Zhang H, et al.Adulthood outcome of tic and obsessive-compulsive symptom severityin children with Tourette syndrome. Arch Pediatr Adolesc Med 2006;160:65–9.

[40] Nechmad A, Ratzoni G, Poyurovsky M, Meged S, Avidan G, Fuchs C,et al. Obsessive-compulsive disorder in adolescent schizophreniapatients. Am J Psychiatry 2003;160:1002–4.

523J. Kerbeshian et al. / Journal of Psychosomatic Research 67 (2009) 515–523

[41] Burd L, Freeman RD, Klug MG, Kerbeshian J. Tourette Syndrome andlearning disabilities. BMC Pediatr 2005;5:34.

[42] Fisher M, McCoy K, Poole JH, Vinogradov S. Self and Other inSchizophrenia: a Cognitive Neuroscience Perspective. Am J Psychiatry2008;165:1465–72.

[43] Cohen AJ, Leckman JF. Sensory phenomena associated with Gilles dela Tourette's syndrome. J Clin Psychiatry 1992;53:319–23.

[44] Sachdev PS. Alternating and postictal psychoses: review and aunifying hypothesis. Schizophr Bull 2007;33:1029–37.

[45] Slater E, Beard A, Glithero E. The schizophrenialike psychoses ofepilepsy. Br J Psychiatry 1963;109:95–150.

[46] Schmitz EB, Robertson MM, Trimble MR. Depression and schizo-phrenia in epilepsy: social and biological risk factors. Epilepsy Res1999;35:59–68.