Psychiatric Comorbidities and Schizophrenia in Youths With Attention-Deficit/Hyperactivity Disorder

This cohort study evaluates the association between psychiatric comorbidities and schizophrenia in children and adolescents with attention-deficit/hyperactivity disorder.


Introduction
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children and adolescents, characterized by impulsivity, hyperactivity, and poor attention. 13][4][5][6] One previous systematic review and meta-analysis 5 of observational studies demonstrated that ADHD is statistically significantly associated with the incidence of subsequent schizophrenia, with a relative risk of 4.74 (95% CI, 4.11-5.46).Since schizophrenia negatively influences quality of life, including academic functioning, social functioning, and mortality, 7 early detection and intervention for schizophrenia for children and adolescents with ADHD have long been considered important. 5 control the risk of developing subsequent schizophrenia among patients with ADHD, understanding the mechanisms and risk factors associated with these 2 disorders is essential.0][11] However, studies investigating the influence of psychiatric comorbidity on diagnosis of schizophrenia in patients with ADHD are limited.
Psychiatric comorbidity is commonly observed in patients with ADHD. 12,135][16][17][18] The presence of psychiatric comorbidity in patients with ADHD has significant implications for symptom severity, functional impairment, and treatment outcomes. 130][21][22] Moreover, most patients exhibited several clinical symptoms of other psychiatric disorders before schizophrenia occurrence.Therefore, the notion that the presence of psychiatric comorbidity may further be associated with being diagnosed with schizophrenia in this population is plausible.Thus, we aimed to explore the association between ADHD and subsequent schizophrenia and patterns of diagnosis of schizophrenia in children and adolescents with ADHD, focusing on comorbidity.

Data Sources
We conducted a nationwide population-based retrospective cohort study using the Health Insurance Review and Assessment Service (HIRA) database of South Korea (from January 1, 2007, to December 31, 2019).HIRA is a government-operated agency that evaluates the reimbursement system, which is mandatory for all Korean populations.In this study, we used information about pediatric patients with psychiatric disorders from the HIRA database from 2007 to 2019.The HIRA database contains individual characteristics, including age, sex, and economic vulnerability (ie, approximately 2.8% of the total population who qualify for medical insurance advantage beneficiaries).Clinical data include information billed by health care practitioners, including diagnoses (according to the International

Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]),
prescriptions, procedures, and devices.This study was approved by the institutional review board of Jeju National University, and the requirement for informed consent was waived as the HIRA database was anonymized.This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort study.

JAMA Network Open | Psychiatry
Psychiatric Comorbidities in Youths With Attention-Deficit/Hyperactivity Disorder

Study Participants
Initially, we identified patients aged 5 to 19 years with at least 1 diagnosis record of ADHD (ICD-10: F90) between January 1, 2010, and December 31, 2018.The index date for individual patients was defined as the first date of ADHD diagnosis.We excluded patients with a history of ADHD diagnosis or prescription of stimulants and nonstimulants for ADHD for at least 3 years before the index date to restrict the cohort for new incident cases of ADHD.We subsequently only included those who had no diagnosis record of schizophrenia or psychosis for at least 3 years before the index date.4][25] The detailed codes of diagnosis and medications were summarized in eTable 1 in Supplement 1.
All study populations were followed up from the index date to the first diagnosis date of schizophrenia or end of follow-up (December 31, 2019), whichever occurred earlier.Schizophrenia development was defined according to the ICD-10 code of F2 following ADHD diagnosis.

Association of Being Diagnosed With Schizophrenia With the Psychiatric Comorbidity of ADHD
We defined depression, anxiety disorder, intellectual disability, nonorganic sleep disorder, tic disorder, bipolar disorder, ASD, conduct disorder, obsessive-compulsive disorder, and substance use disorder (SUD) as psychiatric comorbid disorders of ADHD.The detailed ICD-10 codes of psychiatric comorbidities are shown in eTable 2 in Supplement 1.These psychiatric comorbid disorders were selected according to previous studies. 12,17,26,27 this study, we classified patients into 2 groups according to the presence of psychiatric comorbidity within 1 year before the index date.Patients who had at least 1 diagnosis record of these psychiatric disorders within 1 year before the index date belonged to the group with psychiatric comorbidities, and others were categorized into the group without psychiatric disorders.Among those with underlying psychiatric comorbidities, further categorization was conducted according to the number of psychiatric comorbidities and specific psychiatric disorders.The number of psychiatric comorbidities was divided into the following 3 groups: 1 comorbidity, 2 comorbidities, and 3 or more comorbidities.For each psychiatric disorder, patients who had at least 1 diagnostic record of that specific disorder were considered as having that particular disorder.To simultaneously investigate the outcomes of both multiple comorbidities and a specific disorder, patients were additionally categorized into the following 3 groups: 1 comorbidity for each psychiatric disorder, 2 comorbidities, and 3 or more comorbidities.
To estimate hazard ratios (HRs) along with 95% CIs for the association of being diagnosed with schizophrenia with psychiatric comorbidity in patients with ADHD, Cox proportional hazard models (Cox PH models) were used.We considered several potential confounders in schizophrenia development, including sex, age (categorized as 5-9, 10-14, and 15-19 years), insurance type (health insurance or Medicaid), psychiatric hospitalization, and psychotropic medication use.Age, sex, insurance type, and psychiatric hospitalization were assessed at the index date.The use of psychotropic medications (ie, antipsychotics, antidepressants, anxiolytics, anticholinergics, antiepileptics, and lithium) was assessed during the 1-year period before the index date (eTable 3 in Supplement 1).We used 2 models adjusting different potential confounders.Model 1 adjusted sex, age, insurance type, and psychiatric hospitalization as covariates.Model 2 further adjusted for psychotropic medication use as a covariate.
Moreover, we conducted various sensitivity analyses to examine the robustness of main finings.
First, to evaluate whether increasing age is associated with the diagnosis of schizophrenia, we performed a subgroup analysis by age group.Second, we performed a subgroup analysis according to the use of methylphenidate (the only approved stimulant for ADHD in South Korea) during the follow-up period.Additionally, we conducted subgroup analyses according to presence of bipolar disorder, ASD, and intellectual disability at baseline period.Third, to further address uncontrolled confounding effects, we performed an analysis using a propensity score (PS)-matched cohort.We

Patterns of Psychiatric Comorbid Diagnosis of Schizophrenia Following ADHD
During the follow-up period, individuals with ADHD might experience various psychiatric comorbidities before the subsequent incidence of schizophrenia.However, in the association analysis, it is difficult to capture the comprehensive longitudinal diagnosis pattern from ADHD to schizophrenia due to the complex trajectories of these disorders.To address this, we used trajectory analysis to examine the progression of psychotic disorders to a schizophrenia diagnosis in patients with ADHD.
We assessed the occurrence of psychiatric comorbid disorders during the period between the index date of ADHD and subsequent schizophrenia to explore the patterns of diagnosis from ADHD to schizophrenia.This analysis exclusively focused on patients who received schizophrenia diagnoses without any preexisting psychiatric comorbidities (patients belonging to the group without psychiatric comorbidities), ensuring that the diagnostic progression was not influenced by prior cumulative diagnoses.During the follow-up period, the first date of diagnosis record for each psychiatric disorder was considered the occurrence of psychiatric comorbidities.The investigation of diagnostic patterns from ADHD to schizophrenia was presented as frequency and incidence rate per 100 person-years.When 2 or more psychiatric disorders occurred simultaneously on the same day, we adjusted weight of incidence by dividing the number of psychiatric comorbid disorders.The diagnostic flow was depicted using a Sankey diagram.

Statistical Analysis
SAS Enterprise Guide 6.1 (SAS Institute) and R software V.3.6.1 (R Project for Statistical Computing) were used for data analyses.The baseline demographics of the patients were presented as numbers and proportions for the 2 groups according to the presence of psychiatric comorbidities.The comparison between these groups was performed using 2-sided χ 2 tests with significance set at less than .05.Data were analyzed from January 2010 to December 2019.

Results
We identified a total of 211 705 patients to be involved in our study cohort.

Discussion
To our knowledge, this is the first study to investigate schizophrenia risk among children and adolescents with ADHD, with a particular focus on psychiatric comorbidities.Our findings suggested that patients with ADHD with psychiatric comorbidities had a higher risk of being diagnosed with schizophrenia than those without comorbidities.Furthermore, we observed a stepwise increase in schizophrenia risk with an increasing number of comorbidities.Regarding individual psychiatric comorbidities, ASD, intellectual disability, tic disorders, depression, and bipolar disorder showed relatively higher association with the increased schizophrenia risk in patients with ADHD.
Additionally, to gain a better understanding of the progression toward schizophrenia in patients without psychiatric comorbidities at baseline, we constructed diagnosis trajectories.
Our results are consistent with previous studies that identified several psychiatric disorders as risk factors for schizophrenia development. 28For example, Maibing et al 28 examined schizophrenia risk in pediatrics with a broad range of psychiatric disorders and reported an increased schizophrenia risk in short-and long-term periods.However, since this study primarily focused on the incidence  rates of patients with overall psychiatric disorders, it did not address the impact of psychiatric comorbidities in patients with ADHD.Another study 2 conducted in Taiwan used the Taiwan national claims database to estimate the risk of psychosis in patients with ADHD and reported approximately 2-to 3-fold higher risk in patients with other psychiatric disorders than those without other disorders.
Nevertheless, they did not account for common psychiatric comorbidities, including depression and anxiety, which are frequently observed in patients with ADHD.Furthermore, as most studies focused on the risk factors at baseline, evidence regarding the diagnosis pattern from ADHD to schizophrenia is lacking.Therefore, our study contributes additional evidence regarding the association between several psychiatric comorbidities and subsequent schizophrenia development among children and adolescents with ADHD.
We observed that patients with ADHD with psychiatric comorbidities were without psychiatric comorbidities.Provided that schizophrenia frequently occurs between 10 and 25 years in male patients and between 25 and 35 years in female patients, 29 the higher schizophrenia incidence in patients with psychiatric comorbidities seems to be associated with age.However, various models using Cox PH models with age adjustment and subgroup analysis by age group suggested that the presence of psychiatric comorbidities was independently associated with schizophrenia development.
Regarding individual psychiatric comorbidities, ASD, intellectual disability, tic disorder, depression, and bipolar disorder were the top 5 comorbid disorders associated with an increased risk

Figure . SCZ
Figure.Sankey Diagram Illustrating the Incidence of Psychiatric Comorbidities in the Diagnostic Pattern From Attention-Deficit/Hyperactivity Disorder (ADHD) to Schizophrenia (SCZ) Psychiatric Comorbidities in Youths With Attention-Deficit/Hyperactivity Disorder JAMA Network Open.2023;6(11):e2345793. doi:10.1001/jamanetworkopen.2023.45793(Reprinted) November 30, 2023 3/14 Downloaded from jamanetwork.comby guest on 12/16/2023 used logistic regression to estimate the PS for the probability of having psychiatric comorbidities by including sex, age, health insurance, and health care utilization (overall visit frequency, psychiatric visit frequency, nonpsychiatric hospital visit frequency).Patients with psychiatric comorbidities and those without were matched 1:1 using the estimated PS with a caliper width of 0.2 on the PS scale.

Table 1 .
Demographics of Patients With Attention-Deficit/Hyperactivity Disorder (ADHD) According to the Presence of Psychiatric Comorbidities a History of psychiatric hospitalization, psychiatric comorbidities, and the use of psychotropic medications were evaluated within 1 year before the index date.bPatients with at least 1 diagnosis record of each disorder were considered to have each disorder.JAMA Network Open | Psychiatry Psychiatric Comorbidities in Youths With Attention-Deficit/Hyperactivity Disorder JAMA Network Open.2023;6(11):e2345793. doi:10.1001/jamanetworkopen.2023.45793(Reprinted)November 30, 2023 5/14 Downloaded from jamanetwork.combyguest on 12/16/2023The association between being diagnosed with schizophrenia and psychiatric comorbidities according to several studies is depicted in

Table 3 .
With the increasing number of psychiatric comorbidities, patients with psychiatric comorbidities had an increased schizophrenia risk compared with those without psychiatric comorbidities.In model 2, the risk of being diagnosed with schizophrenia was approximately 1.91-fold for 1 comorbidity, 2.94-fold for 2 comorbidities, and 4.26- the magnitude of this association exhibited an increasing tendency with multiple comorbidities and a wide variety of individual comorbidity (eTable 4, eTable 5, and eTable 6 in Supplement 1).After 1:1 PS matching, we identified 70 590 patients in each group with well-balanced baseline characteristics (eTable 7 and eTable 8 in Supplement 1).Results of analyses using the PS-matched cohort also showed the largely consistent result with our main findings (eTable 9, eTable 10, eTable 11, and eTable 12 in Supplement 1).Patients who did not have any psychiatric comorbidity still encountered various psychiatric comorbidities before being diagnosed with schizophrenia, as shown in Table4.Notably, 3244 patients (73.8%) experienced at least 1 psychiatric comorbidity before schizophrenia onset, and this trend was consistently observed across all age groups (5-9 years, 1804 patients [71.8%]; 10-14 years, 1045 patients [77.2%]; 15-19 years, 395 patients [74.3%]).Although the specific comorbidities varied among different age groups, depression emerged as the most common incident psychiatric comorbidity, found in 2023 patients (46.0%), followed by anxiety disorders, found in 1326 patients

Table 2 .
Association Between Being Diagnosed With Schizophrenia and Psychiatric Comorbidities in Patients With Attention-Deficit/Hyperactivity Disorder (ADHD) 2%).The longitudinal association between ADHD and schizophrenia, including the occurrence of psychiatric comorbidities, is further illustrated in the Sankey diagram in the Figure; eFigure 2 in Supplement 1; and eTable 13, eTable 14, eTable 15, and eTable 16 in Supplement 2.

Table 3 .
Association Between Being Diagnosed With Schizophrenia and Psychiatric Comorbidities According to Several Studies a Model 1 adjusted sex, age, health insurance, and psychiatric hospitalization as covariates.bModel 2 adjusted sex, age, health insurance, psychiatric hospitalization, and psychotropic medication use as covariates.

Table 4 .
Incidence of Psychiatric Comorbidities in the Trajectories From Attention-Deficit/Hyperactivity Disorder to Schizophrenia a a This analysis is conducted only in patients who received a schizophrenia diagnosis without psychiatric comorbidity at baseline.