Familial Risks in OCD, Psychosis, and Bipolarity
Following approval from the Regional Ethics Committee in Stockholm, we linked 4 Swedish national registers, using the individual personal identification numbers assigned at birth or, for resident immigrants, upon arrival to the country. The Total Population Register contains demographic information on all individuals registered as Swedish inhabitants since 1968 and is extended by the Multi-Generation Register, which contains information about the identity of biological parents of all individuals born in Sweden since 1932 and living in Sweden since 1961. The latter register allows the reconstruction of family pedigrees for all individuals with relatives at increasing genetic and environmental distances from each index person. The Swedish National Patient Register covers psychiatric inpatient care since 1969 and outpatient care since 2001. The Swedish Prescribed Drug Register contains data on all dispensed prescribed drugs since July 2005. Using the codes from the Anatomical Therapeutic Chemical Classification System, we identified all dispensed prescriptions of atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole) in patients with schizophrenia and schizoaffective disorder and of antidepressants (selective serotonin reuptake inhibitors [SSRI], serotonin and norepinephrine reuptake inhibitors [SNRI], and other antidepressants [including clomipramine]) in persons with OCD. The study period spans 40 years (January 1969–December 2009).
OCD probands were defined as individuals identified in the National Patient Register with at least one International Classification of Diseases (ICD)-10 diagnosis of OCD (F42). The ICD codes for OCD have been recently subject to validation (Rück et al, in preparation). Briefly, we obtained a random sample of patient records from 3 Swedish counties (N = 68). Each file was carefully reviewed and blindly rated by 2 independent clinicians specialized in OCD. The ICD-10 codes, which represent approximately 80% of the OCD cases in the Register, had excellent validity, with a positive predictive value (true positives/true positives + false positives) of 91% (rater 1) and 98% (rater 2). The inter-rater agreement between the 2 raters was outstanding (κ = 0.98, P < .001). ICD-8 and ICD-9 patients were not included in this study because the validation study suggested relatively high rates of false positives.
Schizophrenia was defined as at least one inpatient episode with a discharge diagnosis of schizophrenia (ICD-8: 295.0–295.6, 295.8, 295.9; ICD-9: 295A-295G, 295W, 295X; ICD-10: F20). Inpatient diagnoses of schizophrenia have a 94% agreement when compared with research diagnoses based on semi-structured interviews and medical records.
Bipolar disorder was defined according to a validated algorithm based on the following codes in the National Patient Register: ICD-8/9: 296 and ICD-10: F30–F31, with the exclusion of individuals whose identification relied solely on ICD-8: 296.2 or ICD-9: 296B. This algorithm, which requires at least 2 discharge diagnoses of bipolar disorder, showed 92% agreement when compared with reassessed diagnostic status based on medical records.
Schizoaffective disorder was defined as at least one inpatient or outpatient diagnosis of the disorder (ICD-8: 295.7, ICD-9: 295H, and ICD-10: F25).
We first examined the risks of schizophrenia, bipolar disorder, and schizoaffective disorder in individuals with OCD (index persons) compared with individuals without OCD at the time of the first diagnosis of the index persons. For each individual with OCD, 10 individuals matched by birth year, sex, and county of residence at the time of the first OCD diagnosis of the index person were randomly selected from the general population. They had to be alive, living in Sweden, and not diagnosed with OCD at the time of the first OCD diagnosis of the index person.
In longitudinal analyses, we estimated the risk that individuals with OCD would receive a later diagnosis of schizophrenia, bipolar disorder, or schizoaffective disorder compared with individuals without an OCD diagnosis during the follow-up period. Conversely, we also examined the risk that individuals first diagnosed with each of these 3 disorders would later receive a diagnosis of OCD compared with individuals without such diagnoses during the follow-up period. We also calculated the median number of years (plus interquartile range [IR]) between the first diagnosis (eg, OCD) and the subsequent diagnoses (eg, schizophrenia). These longitudinal analyses were only done for patients first diagnosed in ICD-10 to ensure equal follow-up periods for all disorders. For patients first diagnosed after July 2005 (the start date of the Swedish Prescribed Drug Register), we further examined whether these sequential risks were maintained after adjusting for the dispensation of atypical antipsychotics in persons first diagnosed with schizophrenia or schizoaffective disorder and for the dispensation of antidepressants in persons first diagnosed with OCD.
Finally, we used the family design to examine the possible etiological overlap between OCD and the other disorders of interest. Specifically, the risks of schizophrenia, bipolar disorder, and schizoaffective disorder in relatives of individuals with OCD who did not have a lifetime diagnosis of any of the 3 disorders were compared with the risks in relatives of individuals without a diagnosis of OCD, schizophrenia, bipolar disorder, or schizoaffective disorder. For each index person-relative pair, 10 randomly selected unexposed-relative pairs were matched by birth year and gender, and they had to be alive, living in Sweden, and without a diagnosis of OCD at the time of the first diagnosis of the index person. This method reduces potential bias introduced by individuals in the population registers entering the study at different times. OCD-affected relatives of individuals with OCD were excluded in order to control for the effect of independent transmission of these conditions. Shared familial (genetic and environmental) risk factors are assumed when individuals with the index disorder (ie, OCD) have relatives with the other disorder (ie, schizophrenia) but not the index disorder. First-, second-, and third-degree relatives were analyzed separately to examine the extent to which the familial associations were influenced by genetic and shared environmental factors. These analyses were based on the following assumptions: (1) first-degree relatives are more genetically similar than second-degree relatives, who in turn are more genetically similar than third-degree relatives and (2) maternal half-siblings are more similar in shared environmental exposures than paternal half-siblings because Swedish children continue to live predominantly (90%) with their mother following parental separation.
To estimate the concurrent and longitudinal risks of schizophrenia, bipolar disorder, and schizoaffective disorder in individuals with OCD (and vice versa), we calculated risk ratios (RR) and corresponding 95% CIs using conditional logistic regressions. When assessing risks within families, CIs were obtained with a robust sandwich estimator function to adjust for the correlated data structure. All analyses were conducted in SAS version 9.3 (SAS Institute).
Methods
National Registers
Following approval from the Regional Ethics Committee in Stockholm, we linked 4 Swedish national registers, using the individual personal identification numbers assigned at birth or, for resident immigrants, upon arrival to the country. The Total Population Register contains demographic information on all individuals registered as Swedish inhabitants since 1968 and is extended by the Multi-Generation Register, which contains information about the identity of biological parents of all individuals born in Sweden since 1932 and living in Sweden since 1961. The latter register allows the reconstruction of family pedigrees for all individuals with relatives at increasing genetic and environmental distances from each index person. The Swedish National Patient Register covers psychiatric inpatient care since 1969 and outpatient care since 2001. The Swedish Prescribed Drug Register contains data on all dispensed prescribed drugs since July 2005. Using the codes from the Anatomical Therapeutic Chemical Classification System, we identified all dispensed prescriptions of atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole) in patients with schizophrenia and schizoaffective disorder and of antidepressants (selective serotonin reuptake inhibitors [SSRI], serotonin and norepinephrine reuptake inhibitors [SNRI], and other antidepressants [including clomipramine]) in persons with OCD. The study period spans 40 years (January 1969–December 2009).
Validity of International Classification of Diseases Codes for OCD
OCD probands were defined as individuals identified in the National Patient Register with at least one International Classification of Diseases (ICD)-10 diagnosis of OCD (F42). The ICD codes for OCD have been recently subject to validation (Rück et al, in preparation). Briefly, we obtained a random sample of patient records from 3 Swedish counties (N = 68). Each file was carefully reviewed and blindly rated by 2 independent clinicians specialized in OCD. The ICD-10 codes, which represent approximately 80% of the OCD cases in the Register, had excellent validity, with a positive predictive value (true positives/true positives + false positives) of 91% (rater 1) and 98% (rater 2). The inter-rater agreement between the 2 raters was outstanding (κ = 0.98, P < .001). ICD-8 and ICD-9 patients were not included in this study because the validation study suggested relatively high rates of false positives.
Classification of Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder
Schizophrenia was defined as at least one inpatient episode with a discharge diagnosis of schizophrenia (ICD-8: 295.0–295.6, 295.8, 295.9; ICD-9: 295A-295G, 295W, 295X; ICD-10: F20). Inpatient diagnoses of schizophrenia have a 94% agreement when compared with research diagnoses based on semi-structured interviews and medical records.
Bipolar disorder was defined according to a validated algorithm based on the following codes in the National Patient Register: ICD-8/9: 296 and ICD-10: F30–F31, with the exclusion of individuals whose identification relied solely on ICD-8: 296.2 or ICD-9: 296B. This algorithm, which requires at least 2 discharge diagnoses of bipolar disorder, showed 92% agreement when compared with reassessed diagnostic status based on medical records.
Schizoaffective disorder was defined as at least one inpatient or outpatient diagnosis of the disorder (ICD-8: 295.7, ICD-9: 295H, and ICD-10: F25).
Statistical Analysis
We first examined the risks of schizophrenia, bipolar disorder, and schizoaffective disorder in individuals with OCD (index persons) compared with individuals without OCD at the time of the first diagnosis of the index persons. For each individual with OCD, 10 individuals matched by birth year, sex, and county of residence at the time of the first OCD diagnosis of the index person were randomly selected from the general population. They had to be alive, living in Sweden, and not diagnosed with OCD at the time of the first OCD diagnosis of the index person.
In longitudinal analyses, we estimated the risk that individuals with OCD would receive a later diagnosis of schizophrenia, bipolar disorder, or schizoaffective disorder compared with individuals without an OCD diagnosis during the follow-up period. Conversely, we also examined the risk that individuals first diagnosed with each of these 3 disorders would later receive a diagnosis of OCD compared with individuals without such diagnoses during the follow-up period. We also calculated the median number of years (plus interquartile range [IR]) between the first diagnosis (eg, OCD) and the subsequent diagnoses (eg, schizophrenia). These longitudinal analyses were only done for patients first diagnosed in ICD-10 to ensure equal follow-up periods for all disorders. For patients first diagnosed after July 2005 (the start date of the Swedish Prescribed Drug Register), we further examined whether these sequential risks were maintained after adjusting for the dispensation of atypical antipsychotics in persons first diagnosed with schizophrenia or schizoaffective disorder and for the dispensation of antidepressants in persons first diagnosed with OCD.
Finally, we used the family design to examine the possible etiological overlap between OCD and the other disorders of interest. Specifically, the risks of schizophrenia, bipolar disorder, and schizoaffective disorder in relatives of individuals with OCD who did not have a lifetime diagnosis of any of the 3 disorders were compared with the risks in relatives of individuals without a diagnosis of OCD, schizophrenia, bipolar disorder, or schizoaffective disorder. For each index person-relative pair, 10 randomly selected unexposed-relative pairs were matched by birth year and gender, and they had to be alive, living in Sweden, and without a diagnosis of OCD at the time of the first diagnosis of the index person. This method reduces potential bias introduced by individuals in the population registers entering the study at different times. OCD-affected relatives of individuals with OCD were excluded in order to control for the effect of independent transmission of these conditions. Shared familial (genetic and environmental) risk factors are assumed when individuals with the index disorder (ie, OCD) have relatives with the other disorder (ie, schizophrenia) but not the index disorder. First-, second-, and third-degree relatives were analyzed separately to examine the extent to which the familial associations were influenced by genetic and shared environmental factors. These analyses were based on the following assumptions: (1) first-degree relatives are more genetically similar than second-degree relatives, who in turn are more genetically similar than third-degree relatives and (2) maternal half-siblings are more similar in shared environmental exposures than paternal half-siblings because Swedish children continue to live predominantly (90%) with their mother following parental separation.
To estimate the concurrent and longitudinal risks of schizophrenia, bipolar disorder, and schizoaffective disorder in individuals with OCD (and vice versa), we calculated risk ratios (RR) and corresponding 95% CIs using conditional logistic regressions. When assessing risks within families, CIs were obtained with a robust sandwich estimator function to adjust for the correlated data structure. All analyses were conducted in SAS version 9.3 (SAS Institute).
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