Meier Et Al. 2014

Copyright 2014 American Medical Association. All rights reserved.

Obsessive-Compulsive Disorder as a Risk Factorfor SchizophreniaA Nationwide StudySandra M. Meier, PhD; Liselotte Petersen, PhD; Marianne G. Pedersen, MSc; Mikkel C. B. Arendt, PhD;Philip R. Nielsen, PhD, MSc; Manuel Mattheisen, MD; Ole Mors, MD, PhD; Preben B. Mortensen, DrMedSc

IMPORTANCE Despite a remarkable co-occurrence of obsessive-compulsive disorder (OCD)and schizophrenia, little is known about the clinical and etiological relationship of these 2disorders. Exploring the degree to which these disorders share etiological factors mightprovide useful implications for clinicians, researchers, and those with the disorders.

OBJECTIVES To assess whether patients with OCD experience an enhanced risk of developingschizophrenia and schizophrenia spectrum disorders and to determine whether a familyhistory of OCD constitutes a risk factor for schizophrenia and schizophrenia spectrumdisorders.

DESIGN, SETTING, AND PARTICIPANTS Using individual data from longitudinal nationwideDanish registers, we conducted a prospective cohort study with 45 million person-years offollow-up. All survival analyses were adjusted for sex, age, calendar year, parental age, andplace of residence at the time of birth. A total of 3 million people born between January 1,1955, and November 30, 2006, were followed up from January 1, 1995, through December31, 2012. During this period, 30 556 people developed schizophrenia or schizophreniaspectrum disorders.

MAIN OUTCOMES AND MEASURES The presence of a prior diagnosis of OCD and the risk of afirst lifetime diagnosis of schizophrenia and a schizophrenia spectrum disorder assigned by apsychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rateratios (IRRs) and accompanying 95% confidence intervals are used as measures of relative risk.

RESULTS The presence of prior diagnosis of OCD was associated with an increased risk ofdeveloping schizophrenia (IRR = 6.90; 95% CI, 6.25-7.60) and schizophrenia spectrumdisorders (IRR = 5.77; 95% CI, 5.33-6.22) later in life. Similarly, offspring of parents diagnosedas having OCD had an increased risk of schizophrenia (IRR = 4.31; 95% CI, 2.72-6.43) andschizophrenia spectrum disorders (IRR = 3.10; 95% CI, 2.17-4.27). The results remainedsignificant after adjusting for family history of psychiatric disorders and the patient’spsychiatric history.

CONCLUSIONS AND RELEVANCE A diagnosis of OCD was associated with higher rates ofschizophrenia and schizophrenia spectrum disorders. The observed increase in risk suggeststhat OCD, schizophrenia, and schizophrenia spectrum disorders probably lay on a commonetiological pathway.

JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.1011Published online September 3, 2014.

Supplemental content atjamapsychiatry.com

Author Affiliations: The LundbeckFoundation Initiative for IntegrativePsychiatric Research, iPSYCH, Aarhus,Denmark (Meier, Petersen, Pedersen,Nielsen, Mattheisen, Mors,Mortensen); National Centre forRegister-Based Research, AarhusUniversity, Aarhus, Denmark (Meier,Petersen, Pedersen, Nielsen,Mortensen); Clinic for AnxietyDisorders, Aarhus UniversityHospital, Risskov, Denmark (Arendt);Department of Psychology andBehavioral Sciences, AarhusUniversity, Aarhus, Denmark(Arendt); Department ofBiomedicine, Aarhus University,Aarhus, Denmark (Mattheisen);Research Department P, AarhusUniversity Hospital, Risskov,Denmark (Mors).

Corresponding Author: Sandra M.Meier, PhD, National Centre forRegister-Based Research, AarhusUniversity, Fuglesangs Allé 4, 8210Aarhus V, Denmark ([email protected]).

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A lthough schizophrenia and obsessive-compulsive dis-order (OCD) are considered distinct and infrequentlyoverlapping nosological entities, these disorders

apparently share some demographic and clinical characteris-tics. The disorders have prevalence rates of comparable mag-nitude, the onset of symptoms of schizophrenia and OCDtypically occurs in adolescence or early adulthood, and theyaffect men and women with nearly equal frequency.1,2 Addi-tionally, an increasing number of translational, neurophysi-ological, and neuroimaging studies suggest a substantialoverlap in the pathophysiology of schizophrenia and OCD.3-5

Hence, it is no surprise that obsessive-compulsive andschizophrenic symptoms coexist in a greater proportion of pa-tients than would be expected by chance. Although earlier stud-ies indicated that obsessive-compulsive symptoms occur onlyin a minority of patients with schizophrenia,6-9 recent stud-ies revealed much higher comorbidity rates.10,11 In an exten-sive meta-analysis, the prevalence rate of comorbid OCD inschizophrenia was estimated to be 23%12; a newer meta-analysis reported a lower prevalence rate of 12.1%.13 As theprevalence rate of OCD in a nationally representative surveyof US adults was estimated to be 1.6%,14 OCD appears to be moreprevalent among patients with schizophrenia. This strikinglyhigh comorbidity is reflected in the concept of a schizo-obsessive disorder.15 However, there is a lack of studies ex-ploring the temporal relationship of these disorders in a lon-gitudinal design.

First onset of obsessive-compulsive symptoms during thetreatment of schizophrenia with atypical antipsychotic drugssuggested that comorbid OCD might constitute a medication-induced state. However, obsessive-compulsive symptomsseem to be present throughout the course of schizophrenia,as comparable prevalence rates were reported among indi-viduals at ultrahigh risk for psychosis,16-18 in prodromalphases of schizophrenia,19-21 and in drug-naive patients withfirst-episode schizophrenia.17,22 In addition, obsessive-com-pulsive symptoms were observed across the life span in ado-lescent, adult, and elderly patients with schizophrenia,further supporting a probable association of OCD andschizophrenia.23,24 Hence, obsessive-compulsive symptomsin schizophrenia cannot simply be considered a sequel tochronic illness or to antipsychotic treatment. Rather, OCDmight be considered a precursor of schizophrenia, indicatingliability.

Accordingly, the etiological relationship of OCD andschizophrenia is promising to study and might provide cru-cial insights for clinicians, researchers, and those with thesedisorders. Therefore, we explored whether patients with anepisode of OCD were at higher risk for developing schizo-phrenia or schizophrenia spectrum disorders. However,schizophrenia is highly comorbid with a broad range of psy-chiatric disorders,12 so we assessed the effect of a prior diag-nosis of OCD in addition to the effect of a psychiatric hospitalcontact per se and compared the predictive value of OCDwith that of other psychiatric disorders. Similarly, we investi-gated whether a parental diagnosis of OCD constitutes a riskfactor for schizophrenia or schizophrenia spectrum disordersin offspring.

Methods

RegistersThe Danish Civil Registration System provides information onsex, date of birth, and vital status (continuously updated) ofall persons living in Denmark and has been computerizedsince 1968.25 In this database, all residents of Denmark areregistered by a unique personal identification number; thisidentification number is also used as a personal identifier inall other national registers, enabling accurate linkage betweenregisters.

Since 1969, the Danish Psychiatric Central Register hasstored data of all admissions to Danish psychiatric inpatientfacilities, including psychiatric outpatient services since 1995.It is computerized and currently comprises data of approxi-mately 855 000 persons and 3.91 million contacts, with all-embracing coverage of the entire population of Denmark.26 Asthere are no private psychiatric inpatient facilities in Den-mark, this register is assumed to comprehensively representpsychiatric hospital admissions. Since 1977, all inpatient treat-ments at nonpsychiatric facilities have been recorded in theDanish National Hospital Register, which also includes outpa-tient and emergency department contacts since 1995.27,28

From 1969 to 1993, the clinical diagnoses were assignedaccording to the Danish modification of the InternationalClassification of Diseases, Eighth Revision (ICD-8); since 1994,ICD-10 has been used.

The investigators were blinded to the identity of cohortmembers in the study, and as the study did not result in anycontact with the participants, no written informed consent wasrequired. The study was approved by the Danish Data Protec-tion Agency.

Study PopulationAll individuals who were born in Denmark between January1, 1955, and November 30, 2006, and were alive during the studyperiod were included in the study. The cohort was restrictedto 3 036 828 individuals with known parents. Information per-taining to the diagnosis of OCD was obtained through the Dan-ish Psychiatric Central Register and the Danish National Hos-pital Register. Cohort members were linked with the DanishPsychiatric Central Register to determine whether they werediagnosed as having schizophrenia or a schizophrenia spec-trum disorder.

Assessment of Schizophrenia and Other Mental IllnessFor cohort members and their parents, data were extracted re-garding diagnoses of schizophrenia (ICD-8 codes 295 except295.7; ICD-10 code F20) or schizophrenia spectrum disorders(ICD-8 codes 295, 297, 298.39, 301.09, 301.29, and 301.83; ICD-10codes F20–F29, F60.0-F60.1) (eTable in the Supplement). Inaddition, we assessed their psychiatric history, whether theyhad been admitted to a psychiatric hospital, or whether theyhad received outpatient care. Date at illness onset was de-fined as the first contact (inpatient, outpatient, or emergencydepartment) that led to the diagnosis of schizophrenia orschizophrenia spectrum disorder, irrespective of other previ-

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ous psychiatric diagnoses in the anamnesis of the patient. Pa-rental and individual OCD diagnoses (ICD-8 code 300.39; ICD-10code F42) were identified in the Danish Psychiatric Central Reg-ister and the Danish National Hospital Register.

Statistical AnalysisThe data were analyzed using a survival analysis approach. Co-hort members were followed up from their 10th birthday or Janu-ary 1, 1995 (whichever occurred latest) until the onset of schizo-phrenia or a schizophrenia spectrum disorder, date of death, dateof emigration from Denmark, or December 31, 2012 (whicheveroccurred first). As a measure of relative risk, the incidence rateratio (IRR) of schizophrenia was estimated with a log-linear Pois-son regression model using the GENMOD procedure in SAS ver-sion 9.3 statistical software (SAS Institute, Inc). All analyses wereadjusted for calendar year, age, maternal and paternal ages, sex,place of residence at time of birth (as described elsewhere29), andthe interaction of age with sex. The analyses were adjusted forfirst other psychiatric hospital contacts, as we aimed to explorewhether psychiatric hospital contacts per se or the more spe-cific diagnosis of OCD increases the risk of developing schizo-phrenia and schizophrenia spectrum disorders. Additionally, wecompared the IRRs after a prior diagnosis of OCD with the IRRsafter a prior diagnosis of other childhood-onset disorders. TheP values and 95% confidence intervals were based on likeli-hood ratio tests. The IRR was calculated using log-likelihood es-timation. A more detailed description of the data analysis is pro-vided in the eAppendix in the Supplement.

ResultsRelative Risk of SchizophreniaAmong the 3 036 828 persons followed up from 1995 to 2012,16 231 developed schizophrenia during the 45 152 621 person-

years at risk, corresponding to a crude incidence rate of 3.59/10 000 person-years. Of those 16 231 patients with schizophre-nia, 447 were assigned a prior diagnosis of OCD. Hence, 2.75%of persons diagnosed as having schizophrenia had a prior hos-pital contact for OCD. The overall nonspecific effect of a priorhospital contact for OCD, relative to no prior hospital contactfor OCD, increased the IRR of schizophrenia to 6.90 (95% CI,6.25-7.60) (Table 1).

We adjusted for first hospital contacts for any other psy-chiatric disorder to determine the specific effect of a hospitalcontact for OCD in addition to the effect of a psychiatric hos-pital contact per se. The specific effect of a prior OCD diagno-sis increased the IRR of schizophrenia to 4.99 (95% CI, 4.53-5.48) (Table 1). Patients with inpatient (IRR = 7.39; 95% CI,6.41-8.46) and outpatient (IRR = 4.76; 95% CI, 4.30-5.26) con-tacts for OCD displayed an enhanced risk of developingschizophrenia. Excluding the first months after the diagnosis,the effect of an OCD diagnosis on the risk of schizophreniawas relatively stable over time; the risk of developing schizo-phrenia was similarly increased 1 year (IRR = 5.96; 95% CI,4.74-7.37) and 12 years (IRR = 5.77; 95% CI, 3.68-8.53) after theOCD diagnosis (Table 2). A prior diagnosis of OCD increasedthe risk of developing schizophrenia significantly more thana prior diagnosis of other childhood-onset disorders such asautism (IRR = 2.35; 95% CI, 2.08-2.64), attention-deficit/hyper-activity disorder (IRR = 2.12; 95% CI, 1.89-2.37), or bulimianervosa (IRR = 2.29; 95% CI, 1.90-2.72) (Table 1).

A parental diagnosis of OCD increased the IRR of schizo-phrenia in their offspring to 4.31 (95% CI, 2.72-6.43). A priordiagnosis of OCD in the father (IRR = 4.86; 95% CI, 2.09-9.41)and the mother (IRR = 3.57; 95% CI, 2.01-5.79) increased therisk of developing schizophrenia (Table 3 and Figure). The riskassociated with a parental diagnosis of OCD was significantlyhigher than the risk associated with a parental diagnosis of anypsychiatric disorder (IRR = 1.98; 95% CI, 1.91-2.05) other than

Table 1. Schizophrenia and Schizophrenia Spectrum Disorder IRRs in Persons With OCD, Autism, ADHD, and Bulimia Nervosa

Individual Diagnosis

Schizophrenia Schizophrenia Spectrum Disorder

Cases, No.

IRR (95% CI)

Cases, No.

IRR (95% CI)

Adjustment 1a Adjustment 2b Adjustment 1a Adjustment 2b

OCD

Hospital contact 447 6.90 (6.25-7.60) 4.99 (4.53-5.48) 700 5.77 (5.33-6.22) 5.18 (4.80-5.58)

No hospital contact 15 784 1 [Reference] 1 [Reference] 29 856 1 [Reference] 1 [Reference]

Autism



ADHD



Bulimia nervosa



Abbreviations: ADHD, attention-deficit/hyperactivity disorder; IRR, incidencerate ratio; OCD, obsessive-compulsive disorder.a Estimates of relative risk were adjusted for calendar year, age, maternal and

paternal ages, sex, family history of psychiatric illness, place of residence attime of birth, and the interaction of age with sex.

b Estimates of relative risk were adjusted for calendar year, age, maternal andpaternal ages, sex, family history of psychiatric illness, first psychiatric hospitalcontact for any other disorder, place of residence at time of birth, and theinteraction of age with sex.

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schizophrenia (IRR = 5.60; 95% CI, 5.13-6.10) or schizophre-nia spectrum disorders (IRR = 3.48; 95% CI, 3.21-3.77) (Table 3and Figure).

Relative Risk of Schizophrenia Spectrum DisorderA total of 30 556 cohort members developed a schizophreniaspectrum disorder during the 44 960 174 person-years at risk,corresponding to a crude incidence rate of 6.80/10 000 person-years. Among them, 700 persons (2.29%) were diagnosed ashaving OCD prior to diagnosis of a schizophrenia spectrum dis-order. The overall nonspecific effect of a hospital contact forOCD, relative to no hospital contact due to OCD, increased theIRR of a schizophrenia spectrum disorder diagnosis to 5.77 (95%CI, 5.33-6.22) (Table 1).

We adjusted again for first hospital contacts for any otherpsychiatric disorder to determine the specific effect of a hos-pital contact for OCD in addition to the effect of a psychiatrichospital contact per se. The specific effect of a prior OCD di-agnosis increased the IRR of a schizophrenia spectrum disor-der to 5.18 (95% CI, 4.80-5.58). An enhanced risk of develop-ing a schizophrenia spectrum disorder was observed forpatients with inpatient (IRR = 6.76; 95% CI, 5.96-7.63) and out-patient (IRR = 4.99; 95% CI, 4.60-5.40) contacts for OCD. Ex-cluding the first year after the diagnosis, the effect of an OCDdiagnosis on the risk of developing a schizophrenia spectrumdisorder was relatively stable over time; the risk of develop-ing a schizophrenia spectrum disorder was similarly in-creased 2 years (IRR = 3.95; 95% CI, 3.08-4.98) and 12 years(IRR = 3.83; 95% CI, 2.50-5.58) after the OCD diagnosis (Table 2).A prior diagnosis of OCD increased the risk of developing aschizophrenia spectrum disorder significantly more than a priordiagnosis of other childhood-onset disorders such as autism(IRR = 2.50; 95% CI, 2.28-2.73), attention-deficit/hyperactiv-

ity disorder (IRR = 2.29; 95% CI, 2.11-2.49), or bulimia ner-vosa (IRR = 2.20; 95% CI, 1.90-2.53) (Table 1).

A parental diagnosis of OCD increased the IRR of a schizo-phrenia spectrum disorder in their offspring to 3.10 (95% CI,2.17-4.27). A prior diagnosis of OCD in the father (IRR = 3.04;95% CI, 1.52-5.33) and the mother (IRR = 2.78; 95% CI, 1.81-4.05) increased the risk of developing a schizophrenia spec-trum disorder (Table 3 and Figure). The risk associated with aparental diagnosis of OCD (IRR = 1.92; 95% CI, 1.87-2.01) washigher than the risk associated with a parental diagnosis of anypsychiatric disorder (IRR = 1.92, 95% CI, 1.87-2.01) other thanschizophrenia (IRR = 4.97; 95% CI, 4.64-5.31) or schizophre-nia spectrum disorders (IRR = 3.15; 95% CI, 2.96-3.35) (Table 3and Figure).

DiscussionIn this national cohort study, an elevated risk of schizophre-nia and schizophrenia spectrum disorders was observed in as-sociation with a prior diagnosis of OCD in the patients and theparents. The greater risk was observed despite controlling forthe patient’s psychiatric history, family history of psychiatricdisorders, degree of urbanization at place of residence, or pa-rental age. Whereas no enhanced risk was observed in a re-view of 13 early follow-up studies,30 our results are in line witha small newer study conducted in North America similarly re-porting an enhanced risk of developing schizophrenia for pa-tients with OCD.31

The strengths of this study are the prospective design andthe prediction based on the population-based nationwide reg-isters in Denmark, ensuring a large study population in whichall exposures were recorded independently of the outcome,

Table 2. Schizophrenia and Schizophrenia Spectrum Disorder IRRs in Persons With a Prior Diagnosis of OCD

Time Since OCDDiagnosis, y

Schizophrenia Schizophrenia Spectrum Disorder

Cases,No.

IRR (95% CI)Cases,

No.

IRR (95% CI)

Adjustment 1a Adjustment 2b Adjustment 1a Adjustment 2b

<1 166 19.97 (17.04-23.24) 10.27 (8.77-11.93) 305 18.49 (16.45-20.69) 12.83 (11.43-14.34)

1 80 10.56 (8.40-13.07) 5.96 (4.74-7.37) 108 7.29 (5.99-8.76) 5.41 (4.45-6.50)

2 40 5.82 (4.19-7.83) 3.52 (2.54-4.73) 67 4.98 (3.87-6.27) 3.95 (3.08-4.98)

3 31 5.01 (3.44-6.99) 3.20 (2.20-4.46) 50 4.16 (3.11-5.43) 3.44 (2.57-4.49)

4 26 4.70 (3.11-6.75) 3.28 (2.17-4.71) 35 3.32 (2.34-4.55) 2.95 (2.08-4.49)

5 17 3.48 (2.08-5.42) 2.58 (1.54-4.01) 26 2.82 (1.87-4.06) 2.62 (1.74-3.76)

6 18 4.01 (2.43-6.17) 3.29 (1.99-5.06) 26 3.12 (2.07-4.48) 3.12 (2.07-4.49)

7 12 3.02 (1.62-5.07) 2.71 (1.45-4.54) 16 2.19 (1.29-3.45) 2.34 (1.37-3.68)

8 10 2.87 (1.44-5.03) 2.73 (1.37-4.79) 15 2.38 (1.37-3.80) 2.61 (1.50-4.17)

9 11 3.64 (1.89-6.24) 3.74 (1.94-6.41) 8 1.49 (0.68-2.78) 1.74 (0.79-3.23)

10 5 1.99 (0.71-4.27) 2.12 (0.76-4.56) 13 2.99 (1.65-4.93) 3.56 (1.96-5.86)

11 9 4.48 (2.15-8.08) 5.05 (2.42-9.11) 7 2.05 (0.88-3.96) 2.56 (1.10-4.95)

≥12 22 3.68 (2.35-5.45) 5.77 (3.68-8.53) 24 2.41 (1.57-3.51) 3.83 (2.50-5.58)

No OCD 15 784 1 [Reference] 1 [Reference] 29 856 1 [Reference] 1 [Reference]

Abbreviations: IRR, incidence rate ratio; OCD, obsessive-compulsive disorder.a Estimates of relative risk were adjusted for calendar year, age, maternal and

paternal ages, sex, family history of psychiatric illness, place of residence attime of birth, and the interaction of age with sex.

b Estimates of relative risk were adjusted for calendar year, age, maternal andpaternal ages, sex, family history of psychiatric illness, first psychiatric hospitalcontact for any other disorder, place of residence at time of birth, and theinteraction of age with sex.






which minimized probable selection or recall bias effects. Theextensive Danish registers allowed us to examine the effectsof an OCD diagnosis in the patients and their parents on therisk of developing the narrowly defined phenotype of schizo-phrenia and the more broadly defined phenotype of schizo-phrenia spectrum disorders. The consistent results observedin the study imply that the effect of OCD does not depend onthe phenotypic definition of the disorder of interest. A majorlimitation of our study is that individuals not yet diagnosedas having schizophrenia or a schizophrenia spectrum disor-der may have had nonspecific psychiatric symptoms and pos-

sible initial misclassification, which could have affected theresults. In Denmark, on average 1 year passes until patients withschizophrenia receive an adequate treatment.32 Accordingly,some patients might have been diagnosed solely as having OCDeven though they already had coexisting psychosis. As we ob-served an increased risk even 12 years after the OCD diagno-sis, it is unlikely that the effect of OCD can be attributed to co-existing untreated psychosis alone. Overall, the reliance onroutinely acquired clinical information has its deficits, espe-cially with regard to the validity and reliability of diagnoses.However, some reassuring results do exist from studies docu-menting the validity of schizophrenia diagnoses acquired fromthe Danish Psychiatric Central Register.33,34

We observed a specific association with OCD. Although apsychiatric hospital contact per se increased the risk of devel-oping schizophrenia and schizophrenia spectrum disorders,a prior diagnosis of OCD explained some additional variationin the disease’s susceptibility. Other childhood-onset disor-der such as attention-deficit/hyperactivity disorder, autism,and bulimia nervosa did not increase the risk of developingschizophrenia and schizophrenia spectrum disorders as muchas OCD, indicating a specifically strong effect of OCD on thedisease’s susceptibility.

In addition, we observed an effect of parental OCD on therisk of developing schizophrenia and schizophrenia spectrumdisorders. This effect of parental OCD on the risk of develop-ing schizophrenia and schizophrenia spectrum disorders wasnot explained by a parental history of other mental disordersleading to a psychiatric contact. Prior inpatient and outpa-tient hospital contacts for OCD increased the risk of develop-ing schizophrenia and schizophrenia spectrum disorders. Thissuggests an effect of OCD in general, not just especially severeforms of the disorder requiring inpatient hospitalization. Un-fortunately, patients with mildly or moderately severe OCD aremostly outpatients treated by general clinicians. Hence, OCDrates are probably underestimated in this study, as we only in-cluded patients with OCD with psychiatric hospital contacts.Therefore, the effect of OCD on schizophrenia might not be gen-eralizable to patients with OCD who only contact their generalclinicians. Antidepressants constitute the medication of choicein OCD, and withdrawal symptoms and adverse effects of an-tidepressants can mimic psychotic symptoms.35 However, only1% of the patients treated with antidepressants seem to de-velop schizophrenia,35 indicating that the results observed arenot solely due to medication effects.

Without much doubt the statistical models applied in thisstudy are incomplete, as they do not take into account etiologi-cal heterogeneity, which is common to complex disorders suchas schizophrenia and schizophrenia spectrum disorders. Addi-tionally, it is reasonable to assume that the true etiological modelinvolves some confounding effects such as genetic variationshared between the patients with OCD and patients with schizo-phrenia or a schizophrenia spectrum disorder, common envi-ronmental risk factors, or gene-by-environment interactions.The substantial heritability estimates for OCD36,37 andschizophrenia38,39 along with evidence for relatively less pro-nounced but significant environmental effects37,39 further sup-port the assumption of plausible confounding effects. Interest-

Table 3. Schizophrenia and Schizophrenia Spectrum Disorder IRRsin Offspring of Parents With Schizophrenia, Schizophrenia SpectrumDisorder, OCD, and Other Psychiatric Diagnosisa

Parental Diagnosis

IRR (95% CI)

SchizophreniaSchizophrenia

Spectrum DisorderMaternal

Schizophrenia 5.35 (4.79-5.95) 4.57 (4.19-4.98)

Schizophrenia spectrumdisorder

3.22 (2.91-3.56) 3.02 (2.80-3.26)

OCD 3.57 (2.01-5.79) 2.78 (1.81-4.05)

Other 1.93 (1.84-2.01) 1.90 (1.84-1.97)

None 1 [Reference] 1 [Reference]

Paternal

Schizophrenia 5.04 (4.42-5.72) 4.74 (4.29-5.21)

Schizophrenia spectrumdisorder

3.22 (2.83-3.63) 2.82 (2.55-3.10)

OCD 4.86 (2.09-9.41) 3.04 (1.52-5.33)

Other 1.89 (1.80-1.98) 1.84 (1.77-1.90)

None 1 [Reference] 1 [Reference]

Abbreviations: IRR, incidence rate ratio; OCD, obsessive-compulsive disorder.a Maternal and paternal diagnoses were categorized hierarchically as having a

history of OCD, schizophrenia, schizophrenia spectrum disorder, or otherpsychiatric disorder. Estimates of relative risk were adjusted for calendar year,age, maternal and paternal ages, sex, place of residence at time of birth, andthe interaction of age with sex.

Figure. Incidence Rate Ratios

Parentalschizophrenia

Parentalschizophreniaspectrumdisorder

Parentalobsessive-compulsivedisorder

Other parentalpsychiatricdiagnosis

0.0

7.0

6.0

Inci

denc

e Ra

te R

atio 5.0

4.0

3.0

2.0

1.0

Schizophrenia Schizophrenia SpectrumDisorder

Incidence rate ratios, with 95% confidence intervals (error bars), ofschizophrenia and schizophrenia spectrum disorder in offspring of parents withschizophrenia, schizophrenia spectrum disorder, obsessive-compulsivedisorder, and other psychiatric diagnosis.






ingly, the enhanced risk of children with parents diagnosed ashaving OCD developing schizophrenia or a schizophrenia spec-trum disorder reported in this study can be considered compa-rable to the risk of second- and third-degree relatives of pa-tients with OCD developing OCD.37 Despite the fact that ourresults indicate putative overlapping etiological factors of OCDand schizophrenia or schizophrenia spectrum disorders, theydo not necessarily suggest that these disorders should be ag-gregated into 1 global diagnosis. However, given these find-ings and the fact that OCD and schizophrenia co-occur with oneanother at a higher rate than would be expected in the generalpopulation, the phenotypes of these disorders are potentiallymore similar than currently acknowledged. Preclinical, neuro-imaging, and neurochemical studies indicate an overlap inpathophysiological mechanisms of the 2 disorders,40-46 and sev-eral environmental risk factors such as advanced paternal age,obstetric complications, and infections seem to be shared.47-53

Hence, it might be promising to reexamine which features aretruly distinct and which constitute putative common mecha-nisms underlying both disorders.

The clinical classification systems probably rely on exem-plary patients with distinct and unequivocal symptoms, butsuch definitions might not prove valid and feasible in clinicalpractice as many cases will display complex and mutable com-binations of symptoms. Delusions and obsessions refer to ir-rational thoughts. However, whereas obsessions often relateto ideas of contamination, aggressive impulses, or sexual im-pulses, delusions usually relate to convictions around the pos-session of special powers, persecution, special connections toevents or objects in the environment, or delusional explana-tions of other psychotic experiences. In addition, compul-sions or obsessions are not consistent with the individual’s

self-perception, whereas delusions are false, incorrigible con-victions or judgments consistent with the self-conception. TheDiagnostic and Statistical Manual of Mental Disorders, fifth edi-tion, enables the diagnosis of OCD with the specification “withabsent insight/delusional beliefs.”54 This modification fur-ther enhances the difficulty of classifying the 2 disorders. Tra-ditionally, OCD has been found to be distinguishable from psy-chotic disorders by the fact that the patient recognizes thecompulsions or obsessions as products of his or her own mind.Even if the differentiation of obsessions and delusions wouldbe perfectly possible, though, it is a matter of interpretationand judgment to classify a particular cognition or behavior asa delusion or obsession.55 Our results might indicate a markedneed of prevention in patients with OCD, especially ascomorbid OCD seems to implicate negative outcomes ofschizophrenia.10,56 Patients with schizophrenia and comor-bid OCD are reported to have an earlier age at onset, more de-pressive symptoms and suicide attempts, higher hospitaliza-tion and unemployment rates, higher symptom severity, andgreater disability.10,22,56

ConclusionsOur findings indicate that OCD, schizophrenia, and schizo-phrenia spectrum disorders might share etiological risk fac-tors. A significantly elevated risk of schizophrenia and schizo-phrenia spectrum disorders was observed in association witha prior diagnosis of OCD in the patients or their parents. Fu-ture research is needed to disentangle which genetic and en-vironmental risk factors are truly common to OCD and schizo-phrenia or schizophrenia spectrum disorders.

ARTICLE INFORMATION

Submitted for Publication: November 22, 2013;final revision received February 17, 2014; acceptedApril 21, 2014.

Published Online: September 3, 2014.doi:10.1001/jamapsychiatry.2014.1011.

Author Contributions: Drs Meier and Petersen hadfull access to all of the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis.Study concept and design: Meier, Pedersen, Arendt.Acquisition, analysis, or interpretation of data: Allauthors.Drafting of the manuscript: Meier, Arendt.Critical revision of the manuscript for importantintellectual content: Petersen, Pedersen, Arendt,Nielsen, Mattheisen, Mors, Mortensen.Statistical analysis: Meier.Obtained funding: Mortensen.Administrative, technical, or material support:Mattheisen.Study supervision: Petersen, Nielsen, Mattheisen,Mors, Mortensen.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by theLundbeck Foundation Initiative for IntegrativePsychiatric Research, iPSYCH. Dr Mortensen wassupported by the Stanley Medical Research Institute.

Role of the Funder/Sponsor: The funders had norole in the design and conduct of the study;collection, management, analysis, andinterpretation of the data; preparation, review, orapproval of the manuscript; and decision to submitthe manuscript for publication.

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