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Research

Original Investigation

Obsessive-Compulsive Disorder as a Risk Factor


for Schizophrenia
A Nationwide Study
Sandra 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)

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and schizophrenia, little is known about the clinical and etiological relationship of these 2
disorders. Exploring the degree to which these disorders share etiological factors might
provide useful implications for clinicians, researchers, and those with the disorders.
OBJECTIVES To assess whether patients with OCD experience an enhanced risk of developing
schizophrenia and schizophrenia spectrum disorders and to determine whether a family
history of OCD constitutes a risk factor for schizophrenia and schizophrenia spectrum
disorders.
DESIGN, SETTING, AND PARTICIPANTS Using individual data from longitudinal nationwide
Danish registers, we conducted a prospective cohort study with 45 million person-years of
follow-up. All survival analyses were adjusted for sex, age, calendar year, parental age, and
place 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 December
31, 2012. During this period, 30 556 people developed schizophrenia or schizophrenia
spectrum disorders.
MAIN OUTCOMES AND MEASURES The presence of a prior diagnosis of OCD and the risk of a
first lifetime diagnosis of schizophrenia and a schizophrenia spectrum disorder assigned by a
psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate
ratios (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 of
developing schizophrenia (IRR = 6.90; 95% CI, 6.25-7.60) and schizophrenia spectrum
disorders (IRR = 5.77; 95% CI, 5.33-6.22) later in life. Similarly, offspring of parents diagnosed
as having OCD had an increased risk of schizophrenia (IRR = 4.31; 95% CI, 2.72-6.43) and
schizophrenia spectrum disorders (IRR = 3.10; 95% CI, 2.17-4.27). The results remained
significant after adjusting for family history of psychiatric disorders and the patients
psychiatric history.
CONCLUSIONS AND RELEVANCE A diagnosis of OCD was associated with higher rates of
schizophrenia and schizophrenia spectrum disorders. The observed increase in risk suggests
that OCD, schizophrenia, and schizophrenia spectrum disorders probably lay on a common
etiological pathway.

JAMA Psychiatry. 2014;71(11):1215-1221. doi:10.1001/jamapsychiatry.2014.1011


Published online September 3, 2014.

Author Affiliations: The Lundbeck


Foundation Initiative for Integrative
Psychiatric Research, iPSYCH, Aarhus,
Denmark (Meier, Petersen, Pedersen,
Nielsen, Mattheisen, Mors,
Mortensen); National Centre for
Register-Based Research, Aarhus
University, Aarhus, Denmark (Meier,
Petersen, Pedersen, Nielsen,
Mortensen); Clinic for Anxiety
Disorders, Aarhus University
Hospital, Risskov, Denmark (Arendt);
Department of Psychology and
Behavioral Sciences, Aarhus
University, Aarhus, Denmark
(Arendt); Department of
Biomedicine, Aarhus University,
Aarhus, Denmark (Mattheisen);
Research Department P, Aarhus
University Hospital, Risskov,
Denmark (Mors).
Corresponding Author: Sandra M.
Meier, PhD, National Centre for
Register-Based Research, Aarhus
University, Fuglesangs All 4, 8210
Aarhus V, Denmark
(smeier@ncrr.au.dk).

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Research Original Investigation

OCD as Risk Factor for Schizophrenia

lthough schizophrenia and obsessive-compulsive disorder (OCD) are considered distinct and infrequently
overlapping nosological entities, these disorders
apparently share some demographic and clinical characteristics. The disorders have prevalence rates of comparable magnitude, the onset of symptoms of schizophrenia and OCD
typically occurs in adolescence or early adulthood, and they
affect men and women with nearly equal frequency.1,2 Additionally, an increasing number of translational, neurophysiological, and neuroimaging studies suggest a substantial
overlap in the pathophysiology of schizophrenia and OCD.3-5
Hence, it is no surprise that obsessive-compulsive and
schizophrenic symptoms coexist in a greater proportion of patients than would be expected by chance. Although earlier studies indicated that obsessive-compulsive symptoms occur only
in a minority of patients with schizophrenia,6-9 recent studies revealed much higher comorbidity rates.10,11 In an extensive meta-analysis, the prevalence rate of comorbid OCD in
schizophrenia was estimated to be 23%12; a newer metaanalysis reported a lower prevalence rate of 12.1%.13 As the
prevalence rate of OCD in a nationally representative survey
of US adults was estimated to be 1.6%,14 OCD appears to be more
prevalent among patients with schizophrenia. This strikingly
high comorbidity is reflected in the concept of a schizoobsessive disorder.15 However, there is a lack of studies exploring the temporal relationship of these disorders in a longitudinal design.
First onset of obsessive-compulsive symptoms during the
treatment of schizophrenia with atypical antipsychotic drugs
suggested that comorbid OCD might constitute a medicationinduced state. However, obsessive-compulsive symptoms
seem to be present throughout the course of schizophrenia,
as comparable prevalence rates were reported among individuals at ultrahigh risk for psychosis, 16-18 in prodromal
phases of schizophrenia,19-21 and in drug-naive patients with
first-episode schizophrenia.17,22 In addition, obsessive-compulsive symptoms were observed across the life span in adolescent, adult, and elderly patients with schizophrenia,
further supporting a probable association of OCD and
schizophrenia.23,24 Hence, obsessive-compulsive symptoms
in schizophrenia cannot simply be considered a sequel to
chronic illness or to antipsychotic treatment. Rather, OCD
might be considered a precursor of schizophrenia, indicating
liability.
Accordingly, the etiological relationship of OCD and
schizophrenia is promising to study and might provide crucial insights for clinicians, researchers, and those with these
disorders. Therefore, we explored whether patients with an
episode of OCD were at higher risk for developing schizophrenia or schizophrenia spectrum disorders. However,
schizophrenia is highly comorbid with a broad range of psychiatric disorders,12 so we assessed the effect of a prior diagnosis of OCD in addition to the effect of a psychiatric hospital
contact per se and compared the predictive value of OCD
with that of other psychiatric disorders. Similarly, we investigated whether a parental diagnosis of OCD constitutes a risk
factor for schizophrenia or schizophrenia spectrum disorders
in offspring.
1216

Methods
Registers
The Danish Civil Registration System provides information on
sex, date of birth, and vital status (continuously updated) of
all persons living in Denmark and has been computerized
since 1968.25 In this database, all residents of Denmark are
registered by a unique personal identification number; this
identification number is also used as a personal identifier in
all other national registers, enabling accurate linkage between
registers.
Since 1969, the Danish Psychiatric Central Register has
stored data of all admissions to Danish psychiatric inpatient
facilities, including psychiatric outpatient services since 1995.
It is computerized and currently comprises data of approximately 855 000 persons and 3.91 million contacts, with allembracing coverage of the entire population of Denmark.26 As
there are no private psychiatric inpatient facilities in Denmark, this register is assumed to comprehensively represent
psychiatric hospital admissions. Since 1977, all inpatient treatments at nonpsychiatric facilities have been recorded in the
Danish National Hospital Register, which also includes outpatient and emergency department contacts since 1995.27,28
From 1969 to 1993, the clinical diagnoses were assigned
according to the Danish modification of the International
Classification of Diseases, Eighth Revision (ICD-8); since 1994,
ICD-10 has been used.
The investigators were blinded to the identity of cohort
members in the study, and as the study did not result in any
contact with the participants, no written informed consent was
required. The study was approved by the Danish Data Protection Agency.

Study Population
All individuals who were born in Denmark between January
1, 1955, and November 30, 2006, and were alive during the study
period were included in the study. The cohort was restricted
to 3 036 828 individuals with known parents. Information pertaining to the diagnosis of OCD was obtained through the Danish Psychiatric Central Register and the Danish National Hospital Register. Cohort members were linked with the Danish
Psychiatric Central Register to determine whether they were
diagnosed as having schizophrenia or a schizophrenia spectrum disorder.

Assessment of Schizophrenia and Other Mental Illness


For cohort members and their parents, data were extracted regarding diagnoses of schizophrenia (ICD-8 codes 295 except
295.7; ICD-10 code F20) or schizophrenia spectrum disorders
(ICD-8 codes 295, 297, 298.39, 301.09, 301.29, and 301.83; ICD-10
codes F20F29, F60.0-F60.1) (eTable in the Supplement). In
addition, we assessed their psychiatric history, whether they
had been admitted to a psychiatric hospital, or whether they
had received outpatient care. Date at illness onset was defined as the first contact (inpatient, outpatient, or emergency
department) that led to the diagnosis of schizophrenia or
schizophrenia spectrum disorder, irrespective of other previ-

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OCD as Risk Factor for Schizophrenia

Original Investigation Research

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

Schizophrenia Spectrum Disorder

IRR (95% CI)


Individual Diagnosis

Cases, No.

Adjustment 1a

Adjustment 2b

6.90 (6.25-7.60)

4.99 (4.53-5.48)

1 [Reference]

1 [Reference]

3.06 (2.70-3.45)

2.35 (2.08-2.64)

1 [Reference]

1 [Reference]

3.58 (3.19-4.01)

2.12 (1.89-2.37)

1 [Reference]

1 [Reference]

3.01 (2.51-3.59)

2.29 (1.90-2.72)

1 [Reference]

1 [Reference]

IRR (95% CI)


Cases, No.

Adjustment 1a

Adjustment 2b

5.77 (5.33-6.22)

5.18 (4.80-5.58)

1 [Reference]

1 [Reference]

2.64 (2.41-2.89)

2.50 (2.28-2.73)

1 [Reference]

1 [Reference]

3.06 (2.81-3.33)

2.29 (2.11-2.49)

1 [Reference]

1 [Reference]

2.46 (2.12-2.83)

2.20 (1.90-2.53)

1 [Reference]

1 [Reference]

OCD
Hospital contact
No hospital contact

447
15 784

700
29 856

Autism
Hospital contact
No hospital contact

282
15 949

509
30 047

ADHD
Hospital contact
No hospital contact

322
15 909

586
29 970

Bulimia nervosa
Hospital contact
No hospital contact

124
16 107

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; 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 at
time of birth, and the interaction of age with sex.

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

Statistical Analysis
The data were analyzed using a survival analysis approach. Cohort members were followed up from their 10th birthday or January 1, 1995 (whichever occurred latest) until the onset of schizophrenia or a schizophrenia spectrum disorder, date of death, date
of emigration from Denmark, or December 31, 2012 (whichever
occurred first). As a measure of relative risk, the incidence rate
ratio (IRR) of schizophrenia was estimated with a log-linear Poisson regression model using the GENMOD procedure in SAS version 9.3 statistical software (SAS Institute, Inc). All analyses were
adjusted for calendar year, age, maternal and paternal ages, sex,
place of residence at time of birth (as described elsewhere29), and
the interaction of age with sex. The analyses were adjusted for
first other psychiatric hospital contacts, as we aimed to explore
whether psychiatric hospital contacts per se or the more specific diagnosis of OCD increases the risk of developing schizophrenia and schizophrenia spectrum disorders. Additionally, we
compared the IRRs after a prior diagnosis of OCD with the IRRs
after a prior diagnosis of other childhood-onset disorders. The
P values and 95% confidence intervals were based on likelihood ratio tests. The IRR was calculated using log-likelihood estimation. A more detailed description of the data analysis is provided in the eAppendix in the Supplement.

Results
Relative Risk of Schizophrenia
Among the 3 036 828 persons followed up from 1995 to 2012,
16 231 developed schizophrenia during the 45 152 621 personjamapsychiatry.com

192
30 364

Estimates of relative risk were adjusted for calendar year, age, maternal and
paternal ages, sex, family history of psychiatric illness, first psychiatric hospital
contact for any other disorder, place of residence at time of birth, and the
interaction of age with sex.

years at risk, corresponding to a crude incidence rate of 3.59/


10 000 person-years. Of those 16 231 patients with schizophrenia, 447 were assigned a prior diagnosis of OCD. Hence, 2.75%
of persons diagnosed as having schizophrenia had a prior hospital contact for OCD. The overall nonspecific effect of a prior
hospital contact for OCD, relative to no prior hospital contact
for 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 psychiatric disorder to determine the specific effect of a hospital
contact for OCD in addition to the effect of a psychiatric hospital contact per se. The specific effect of a prior OCD diagnosis increased the IRR of schizophrenia to 4.99 (95% CI, 4.535.48) (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) contacts for OCD displayed an enhanced risk of developing
schizophrenia. Excluding the first months after the diagnosis,
the effect of an OCD diagnosis on the risk of schizophrenia
was relatively stable over time; the risk of developing schizophrenia 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 the
OCD diagnosis (Table 2). A prior diagnosis of OCD increased
the risk of developing schizophrenia significantly more than
a prior diagnosis of other childhood-onset disorders such as
autism (IRR = 2.35; 95% CI, 2.08-2.64), attention-deficit/hyperactivity disorder (IRR = 2.12; 95% CI, 1.89-2.37), or bulimia
nervosa (IRR = 2.29; 95% CI, 1.90-2.72) (Table 1).
A parental diagnosis of OCD increased the IRR of schizophrenia in their offspring to 4.31 (95% CI, 2.72-6.43). A prior
diagnosis 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 the
risk of developing schizophrenia (Table 3 and Figure). The risk
associated with a parental diagnosis of OCD was significantly
higher than the risk associated with a parental diagnosis of any
psychiatric disorder (IRR = 1.98; 95% CI, 1.91-2.05) other than
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Research Original Investigation

OCD as Risk Factor for Schizophrenia

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

Cases,
No.

Schizophrenia Spectrum Disorder

IRR (95% CI)


Adjustment 2b
10.27 (8.77-11.93)

305

Adjustment 2b

18.49 (16.45-20.69)

12.83 (11.43-14.34)

166

19.97 (17.04-23.24)

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)

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)

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)

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)

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)

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)

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)

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)

11

3.64 (1.89-6.24)

3.74 (1.94-6.41)

1.49 (0.68-2.78)

1.74 (0.79-3.23)

10

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

4.48 (2.15-8.08)

5.05 (2.42-9.11)

2.05 (0.88-3.96)

2.56 (1.10-4.95)

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)

1 [Reference]

1 [Reference]

1 [Reference]

1 [Reference]

No OCD

15 784

Abbreviations: IRR, incidence rate ratio; OCD, obsessive-compulsive disorder.


Estimates of relative risk were adjusted for calendar year, age, maternal and
paternal ages, sex, family history of psychiatric illness, place of residence at
time of birth, and the interaction of age with sex.

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

Relative Risk of Schizophrenia Spectrum Disorder


A total of 30 556 cohort members developed a schizophrenia
spectrum disorder during the 44 960 174 person-years at risk,
corresponding to a crude incidence rate of 6.80/10 000 personyears. Among them, 700 persons (2.29%) were diagnosed as
having OCD prior to diagnosis of a schizophrenia spectrum disorder. The overall nonspecific effect of a hospital contact for
OCD, relative to no hospital contact due to OCD, increased the
IRR 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 other
psychiatric disorder to determine the specific effect of a hospital contact for OCD in addition to the effect of a psychiatric
hospital contact per se. The specific effect of a prior OCD diagnosis increased the IRR of a schizophrenia spectrum disorder to 5.18 (95% CI, 4.80-5.58). An enhanced risk of developing a schizophrenia spectrum disorder was observed for
patients with inpatient (IRR = 6.76; 95% CI, 5.96-7.63) and outpatient (IRR = 4.99; 95% CI, 4.60-5.40) contacts for OCD. Excluding the first year after the diagnosis, the effect of an OCD
diagnosis on the risk of developing a schizophrenia spectrum
disorder was relatively stable over time; the risk of developing a schizophrenia spectrum disorder was similarly increased 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 a
schizophrenia spectrum disorder significantly more than a prior
diagnosis of other childhood-onset disorders such as autism
(IRR = 2.50; 95% CI, 2.28-2.73), attention-deficit/hyperactiv1218

IRR (95% CI)


Adjustment 1a

<1

12

Cases,
No.

Adjustment 1a

29 856

Estimates of relative risk were adjusted for calendar year, age, maternal and
paternal ages, sex, family history of psychiatric illness, first psychiatric hospital
contact for any other disorder, place of residence at time of birth, and the
interaction of age with sex.

ity disorder (IRR = 2.29; 95% CI, 2.11-2.49), or bulimia nervosa (IRR = 2.20; 95% CI, 1.90-2.53) (Table 1).
A parental diagnosis of OCD increased the IRR of a schizophrenia 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, 1.814.05) increased the risk of developing a schizophrenia spectrum disorder (Table 3 and Figure). The risk associated with a
parental diagnosis of OCD (IRR = 1.92; 95% CI, 1.87-2.01) was
higher than the risk associated with a parental diagnosis of any
psychiatric disorder (IRR = 1.92, 95% CI, 1.87-2.01) other than
schizophrenia (IRR = 4.97; 95% CI, 4.64-5.31) or schizophrenia spectrum disorders (IRR = 3.15; 95% CI, 2.96-3.35) (Table 3
and Figure).

Discussion
In this national cohort study, an elevated risk of schizophrenia and schizophrenia spectrum disorders was observed in association with a prior diagnosis of OCD in the patients and the
parents. The greater risk was observed despite controlling for
the patients psychiatric history, family history of psychiatric
disorders, degree of urbanization at place of residence, or parental age. Whereas no enhanced risk was observed in a review of 13 early follow-up studies,30 our results are in line with
a small newer study conducted in North America similarly reporting an enhanced risk of developing schizophrenia for patients with OCD.31
The strengths of this study are the prospective design and
the prediction based on the population-based nationwide registers in Denmark, ensuring a large study population in which
all exposures were recorded independently of the outcome,

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OCD as Risk Factor for Schizophrenia

Original Investigation Research

Table 3. Schizophrenia and Schizophrenia Spectrum Disorder IRRs


in Offspring of Parents With Schizophrenia, Schizophrenia Spectrum
Disorder, OCD, and Other Psychiatric Diagnosisa

Figure. Incidence Rate Ratios


7.0

IRR (95% CI)


Schizophrenia
Spectrum Disorder

Schizophrenia

5.35 (4.79-5.95)

4.57 (4.19-4.98)

Schizophrenia spectrum
disorder

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]

Maternal

Incidence Rate Ratio

Schizophrenia

Parental Diagnosis

Parental
schizophrenia

6.0

Parental
schizophrenia
spectrum
disorder

5.0
4.0

Parental
obsessivecompulsive
disorder

3.0

Other parental
psychiatric
diagnosis

2.0
1.0
0.0

Paternal

Schizophrenia

Schizophrenia

5.04 (4.42-5.72)

4.74 (4.29-5.21)

Schizophrenia spectrum
disorder

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]

Schizophrenia Spectrum
Disorder

Incidence rate ratios, with 95% confidence intervals (error bars), of


schizophrenia and schizophrenia spectrum disorder in offspring of parents with
schizophrenia, schizophrenia spectrum disorder, obsessive-compulsive
disorder, and other psychiatric diagnosis.

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 other
psychiatric disorder. Estimates of relative risk were adjusted for calendar year,
age, maternal and paternal ages, sex, place of residence at time of birth, and
the interaction of age with sex.

which minimized probable selection or recall bias effects. The


extensive Danish registers allowed us to examine the effects
of an OCD diagnosis in the patients and their parents on the
risk of developing the narrowly defined phenotype of schizophrenia and the more broadly defined phenotype of schizophrenia spectrum disorders. The consistent results observed
in the study imply that the effect of OCD does not depend on
the phenotypic definition of the disorder of interest. A major
limitation of our study is that individuals not yet diagnosed
as having schizophrenia or a schizophrenia spectrum disorder may have had nonspecific psychiatric symptoms and possible initial misclassification, which could have affected the
results. In Denmark, on average 1 year passes until patients with
schizophrenia receive an adequate treatment.32 Accordingly,
some patients might have been diagnosed solely as having OCD
even though they already had coexisting psychosis. As we observed an increased risk even 12 years after the OCD diagnosis, it is unlikely that the effect of OCD can be attributed to coexisting untreated psychosis alone. Overall, the reliance on
routinely acquired clinical information has its deficits, especially with regard to the validity and reliability of diagnoses.
However, some reassuring results do exist from studies documenting the validity of schizophrenia diagnoses acquired from
the Danish Psychiatric Central Register.33,34
We observed a specific association with OCD. Although a
psychiatric hospital contact per se increased the risk of developing schizophrenia and schizophrenia spectrum disorders,
a prior diagnosis of OCD explained some additional variation
in the diseases susceptibility. Other childhood-onset disorder such as attention-deficit/hyperactivity disorder, autism,
and bulimia nervosa did not increase the risk of developing
jamapsychiatry.com

schizophrenia and schizophrenia spectrum disorders as much


as OCD, indicating a specifically strong effect of OCD on the
diseases susceptibility.
In addition, we observed an effect of parental OCD on the
risk of developing schizophrenia and schizophrenia spectrum
disorders. This effect of parental OCD on the risk of developing schizophrenia and schizophrenia spectrum disorders was
not explained by a parental history of other mental disorders
leading to a psychiatric contact. Prior inpatient and outpatient hospital contacts for OCD increased the risk of developing schizophrenia and schizophrenia spectrum disorders. This
suggests an effect of OCD in general, not just especially severe
forms of the disorder requiring inpatient hospitalization. Unfortunately, patients with mildly or moderately severe OCD are
mostly outpatients treated by general clinicians. Hence, OCD
rates are probably underestimated in this study, as we only included patients with OCD with psychiatric hospital contacts.
Therefore, the effect of OCD on schizophrenia might not be generalizable to patients with OCD who only contact their general
clinicians. Antidepressants constitute the medication of choice
in OCD, and withdrawal symptoms and adverse effects of antidepressants can mimic psychotic symptoms.35 However, only
1% of the patients treated with antidepressants seem to develop schizophrenia,35 indicating that the results observed are
not solely due to medication effects.
Without much doubt the statistical models applied in this
study are incomplete, as they do not take into account etiological heterogeneity, which is common to complex disorders such
as schizophrenia and schizophrenia spectrum disorders. Additionally, it is reasonable to assume that the true etiological model
involves some confounding effects such as genetic variation
shared between the patients with OCD and patients with schizophrenia or a schizophrenia spectrum disorder, common environmental risk factors, or gene-by-environment interactions.
The substantial heritability estimates for OCD 36,37 and
schizophrenia38,39 along with evidence for relatively less pronounced but significant environmental effects37,39 further
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Research Original Investigation

OCD as Risk Factor for Schizophrenia

support the assumption of plausible confounding effects. Interestingly, the enhanced risk of children with parents diagnosed as having OCD developing schizophrenia or a schizophrenia spectrum disorder reported in this study can be
considered comparable to the risk of second- and third-degree
relatives of patients with OCD developing OCD.37 Despite the
fact that our results indicate putative overlapping etiological
factors of OCD and schizophrenia or schizophrenia spectrum
disorders, they do not necessarily suggest that these disorders should be aggregated into 1 global diagnosis. However,
given these findings and the fact that OCD and schizophrenia
co-occur with one another at a higher rate than would be expected in the general population, the phenotypes of these
disorders are potentially more similar than currently acknowledged. Preclinical, neuroimaging, and neurochemical studies
indicate an overlap in pathophysiological mechanisms of the
2 disorders,40-46 and several 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 are truly distinct and which
constitute putative common mechanisms underlying both
disorders.
The clinical classification systems probably rely on exemplary patients with distinct and unequivocal symptoms, but
such definitions might not prove valid and feasible in clinical
practice as many cases will display complex and mutable combinations of symptoms. Delusions and obsessions refer to irrational thoughts. However, whereas obsessions often relate
to ideas of contamination, aggressive impulses, or sexual impulses, delusions usually relate to convictions around the possession of special powers, persecution, special connections to
events or objects in the environment, or delusional explanations of other psychotic experiences. In addition, compul-

ARTICLE INFORMATION
Submitted for Publication: November 22, 2013;
final revision received February 17, 2014; accepted
April 21, 2014.
Published Online: September 3, 2014.
doi:10.1001/jamapsychiatry.2014.1011.
Author Contributions: Drs Meier and Petersen had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Meier, Pedersen, Arendt.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Meier, Arendt.
Critical revision of the manuscript for important
intellectual 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 the
Lundbeck Foundation Initiative for Integrative
Psychiatric Research, iPSYCH. Dr Mortensen was
supported by the Stanley Medical Research Institute.
1220

sions or obsessions are not consistent with the individuals


self-perception, whereas delusions are false, incorrigible convictions or judgments consistent with the self-conception. The
Diagnostic and Statistical Manual of Mental Disorders, fifth edition, enables the diagnosis of OCD with the specification with
absent insight/delusional beliefs.54 This modification further enhances the difficulty of classifying the 2 disorders. Traditionally, OCD has been found to be distinguishable from psychotic disorders by the fact that the patient recognizes the
compulsions or obsessions as products of his or her own mind.
Even if the differentiation of obsessions and delusions would
be perfectly possible, though, it is a matter of interpretation
and judgment to classify a particular cognition or behavior as
a delusion or obsession.55 Our results might indicate a marked
need of prevention in patients with OCD, especially as
comorbid OCD seems to implicate negative outcomes of
schizophrenia.10,56 Patients with schizophrenia and comorbid OCD are reported to have an earlier age at onset, more depressive symptoms and suicide attempts, higher hospitalization and unemployment rates, higher symptom severity, and
greater disability.10,22,56

Conclusions
Our findings indicate that OCD, schizophrenia, and schizophrenia spectrum disorders might share etiological risk factors. A significantly elevated risk of schizophrenia and schizophrenia spectrum disorders was observed in association with
a prior diagnosis of OCD in the patients or their parents. Future research is needed to disentangle which genetic and environmental risk factors are truly common to OCD and schizophrenia or schizophrenia spectrum disorders.

Role of the Funder/Sponsor: The funders had no


role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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