Mortality and antidepressants among individuals with autism spectrum disorder: A population-based cohort study

doi:10.21203/rs.3.rs-4722929/v1

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Research Article

Mortality and antidepressants among individuals with autism spectrum disorder: A population-based cohort study

https://doi.org/10.21203/rs.3.rs-4722929/v1

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Aim

High risk of premature mortality has been identified among individuals with autism spectrum disorder (ASD). Although possible risk factors, such as epilepsy or other comorbidities, have been described, studies investigating the association between the use of antidepressants and different causes of mortality are scarce.

Methods

This retrospective population-based cohort design used Taiwan’s National Health Insurance Research Database. 31,458 individuals with ASD between 2001 to 2017 were identified. Among them, 4,659 ASD patients with antidepressant use and 4,659 propensity score (PS)- matched ASD patients without antidepressant use were selected. Main outcomes of this study are all-cause mortality, and mortality due to accident, suicide, or natural causes.

Result

Antidepressant exposure in individuals with ASD was associated with a significantly lower all-cause mortality (aOR = 0.65, 95%CI: 0.52 ~ 0.83), as reflected in accident mortality (aOR = 0.63, 95%CI: 0.47 ~ 0.82). Among those aged 18 and above, antidepressant use was associated with a significantly decreased risk of natural cause mortality.

Conclusions

This study revealed that antidepressant use in patients with ASD was associated with a decreased risk of all-cause mortality, in particular, mortality from accidents or natural causes. These results may demonstrate the importance of early detection and treatments for comorbid psychiatric disorders in patients with ASD.

mortality

autism

psychotropic drugs

cohort study

Autism spectrum disorder (ASD) is a diverse set of neurodevelopmental conditions that affects approximately 1% of the global population. Patients with ASD often experience early onset challenges in interpersonal communications, social behaviors, task completion, or struggles with repetitive routines or changes in life [1]. Additional mental health, employment, education, independence support, and accommodation are often required to lessen lifelong disabilities [2–4].

Patients with ASD are likely to experience comorbid diseases and poor physical and mental health [5–7]. Over 70% of individuals with ASD have comorbidities involving physical disorders, developmental problems, or psychiatric illnesses [8–10]. Moreover, research suggests that patients with ASD face a more than two-fold risk of excess mortality, particularly deaths of natural cause [11], than the general population [12–16]. Differences in the leading causes of mortality between individuals with or without ASD are deaths due to neurological diseases and accidents or poisoning [14, 17]. These are also among the top causes of death in individuals with ASD [14].

Factors associated with the excess mortality in individuals with ASD include epilepsy, intellectual disability, medical, or psychiatric comorbidities [13–15, 18–20]. Concerning psychiatric comorbidities, the use of psychotropic agents by patients with ASD has also attracted recent attention [21–23]. One systematic review reported a psychotropic drug use rate of 41.9% among children with ASD [24]. Among these psychotropics, antidepressants may be prescribed to manage mood symptoms, such as depression or anxiety [25]. With prescription rates of about 7 ~ 14% in adults under age 59, antidepressants are amongst the most commonly prescribed drugs worldwide [26]. Increased trends of antidepressant prescriptions in the general population, including patients with ASD, have also been observed [25, 27]. There are many different sub-categories of antidepressants with similar efficacy profiles [28]. The choice of selection depends greatly on the potential side effects of each antidepressant. Reported side effects include an increased risk of fractures, falls, or upper gastrointestinal bleeding [17]. Some antidepressants, such as tricyclics or mirtazapine, have been reported to increase the risk of overall mortality[17]. However, increased mortality due to accidents has not been associated with antidepressant use [17]. Most evidence suggests that antidepressants may actually have protective effects against suicide, especially in countries with high suicide rates [29].

Despite the risen and widespread usage of antidepressants in the world, research regarding the safety or whether antidepressant exposures would increase or decrease all-cause or cause-specific mortality in patients with ASD is still lacking. Particularly, it takes a large sample size with long-term follow-up to detect the risk of association. Hence, using a large population-based dataset, we conducted this observational study to investigate antidepressant use and overall and cause-specific mortality risks among individuals with ASD.

Data source

Launched in 1995, the Taiwan National Health Insurance (NHI) system is a health insurance program that provides universal healthcare to the entire population in Taiwan. Residents in Taiwan pay monthly premiums set at a percentage based on their income levels and a small amount of co-payment when utilizing medical services. The National Health Insurance Research Database (NHIRD) is a comprehensive database that contains demographic information on all NHI beneficiaries, and details of medical utilizations, including diagnoses (based on the International Classification of Disease, Ninth Revision, Clinical Modification, ICD-9-CM and Tenth Revision, ICD-10), prescriptions, or procedures from hospitalizations, outpatients, or emergency visits. The NHIRD was composed for research purposes. All personal information from the NHIRD is encrypted and anonymized. Access to this database was only available to researchers approved by the National Health Insurance Administration.

Declaration of Helsinki

We confirm that we have followed ‘Declaration of Helsinki’ with our research. This research is subject to ethical standards that promote respect for all human beings and protect their health and rights. All personal information from the NHIRD is encrypted and anonymized. Access to this database was only available to researchers approved by the National Health Insurance Administration, hence, informed consents were waived. The Research Ethics Committee of China Medical University Hospital has approved this study (CMUH108-REC1-142).

Exposed and unexposed cohorts

Data sourced from the NHIRD between 2001 to 2017 was utilized. Our study subjects were individuals at least seven years of age in the year 2010, and have received the diagnosis of ASD (ICD-9-CM code 299 and ICD-10 code F84) at least twice from psychiatric or pediatric outpatient records, or once from inpatient discharge records. The exposure cohort included those prescribed antidepressants (The Anatomical Therapeutic Chemical Classification code (ATC code) N06A) for at least 28 days before January 1, 2010.

The unexposed cohort was comprised of ASD patients that did not use any antidepressants between 2001 ~ 2017(Fig. 1). To make the characteristics from the exposed and unexposed cohorts more similar for comparison, unexposed subjects with an equal propensity score calculated by logistic regression that included all covariates (as in Table 1) were selected and matched with each exposed subject [30]. The matching caliper was 0.2. The standardized mean difference (SMD) of less than 0.2 was used to evaluate the matching quality. Both the ASD and comparison cohorts were followed up until the end of the study (December 31, 2017) or until death, which was the primary outcome being investigated in this study.

Table 1

Basic Characteristics of antidepressants and non-antidepressant use cohorts after propensity score matching among ASD patients
Characteristics	Non- antidepressants drugs use (n = 4659)		Any antidepressants drugs use (n = 4659)		SMD
Age (years), mean (SD)	21.2	(12.3)	19.6	(9.7)	-0.152
Gender					0.022
Male, N (%)	3572	(76.7)	3615	(77.6)	0.022
Female, N (%)	1087	(23.3)	1044	(22.4)
Low-income, N (%)	546	(11.7)	522	(11.2)	-0.017
Psychiatric disorders
Schizophrenia, N (%)	618	(13.3)	639	(13.7)	0.014
Bipolar, N (%)	388	(8.3)	463	(9.9)	0.057
Depression, N (%)	270	(5.8)	339	(7.3)	0.043
ADHD, N (%)	2168	(46.5)	2238	(48.0)	0.030
ID, N (%)	2429	(52.1)	2331	(50.0)	-0.043
Epilepsy, N (%)	1001	(21.5)	926	(19.9)	-0.044
Physical comorbidities
Charlson comorbity index, mean (SD)	0.9	(1.6)	0.9	(1.4)	-0.051
All-cause Mortality, N (%)	178	(3.8)	118	(2.5)	-
Suicide mortality, N (%)	7	(0.2)	7	(0.2)	-
Accident mortality, N (%)	149	(3.2)	95	(2.0)	-
Natural-cause mortality, N (%)	16	(0.3)	12	(0.3)	-
ADHD: Attention-Deficit/Hyperactive Disorder; ID: Intellectual Disability, SMD: standardized mean difference.

Covariates

Covariates included in the calculation of propensity score and the primary analysis were selected in accordance with previous literature regarding ASD[14, 15, 18, 19, 31, 32]. These covariates are age, gender, low income or not, and psychiatric or physical comorbidities, such as schizophrenia, bipolar or depressive disorder, attention deficit or hyperactivity disorder, intellectual disability, or epilepsy. The Charlson comorbidity index presented physical comorbidities.

Outcome

All-cause mortality and mortality due to suicide, accident, or natural- cause from both cohorts identified by linking data from the NHIRD and the Mortality Register managed by the Office of Statistics, Ministry of Health and Welfare, Taiwan, between 2010 ~ 2017, were ascertained as the primary outcome of this study.

Statistical analysis

We compared incident mortality (all-cause, suicide, accident, or natural-cause) between the exposed and unexposed ASD cohorts using the logistic regression analysis after propensity score matching. Odds ratios (OR) and 95% confidence intervals (CI) comparing mortalities between cohorts were presented. The baseline characteristics of the two cohorts were more balanced after the propensity matching (Table 1). Further adjustments were performed adjusting for age, sex, income status, and psychiatric and physical comorbidities. To explore the impacts of antidepressants on the mortality rates of different age groups, we further conducted a sub-analysis on the mortality risk by stratifying our research subjects into those below and above 18. Statistical analyses and data management were performed using SAS (SAS Institute Inc., Cary, NC, USA).

A total of 31,458 patients diagnosed with ASD who were still alive in 2010 and aged at least seven years or above were identified from the NHIRD between 2001 ~ 2017. Among them, 8,958 patients had previous prescriptions of antidepressants. Based on the propensity scores (PS) calculation, 4,659 antidepressant-exposed ASD patients and 4,659 non-exposed ASD patients with similar PS were selected and matched (Fig. 1). Distributions of characteristics between the antidepressants exposed and PS-matched non-exposed cohorts are shown in Table 1. More ASD patients with antidepressant use have comorbid psychiatric diagnoses of schizophrenia, depression, or ADHD; while those without antidepressant use had more intellectual disability or epilepsy. However, propensity matching has controlled between-group differences on comorbidities well (all SMD < 0.1, Table 1) [33]. The mortality rates are lower in the antidepressants-exposed group than in the non-exposed group (Table 1).

Table 2 shows that ASD patients with antidepressant use were associated with a significantly lower all-cause mortality (aOR = 0.65, 95%CI: 0.52 ~ 0.83). Such lower risk in the antidepressants-exposed group was mainly found in accident mortality (aOR = 0.63, 95%CI: 0.47 ~ 0.82).

Table 2

Analysis between antidepressants use and mortality outcomes in ASD patients
		All-cause mortality aOR (95%CI)		Suicidal mortality aOR (95%CI)		Natural/Other cause mortality aOR (95% CI)		Accident mortality aOR (95% CI)
Antidepressants		0.65 (0.52 ~ 0.83)		1.00 (0.35 ~ 2.85)		0.75 (0.35 ~ 1.87)		0.63 (0.47 ~ 0.82)
Adjusted for gender, age, income status, psychiatric, and physical comorbidities

In the sub-analysis that stratified our research subjects into those under and over 18 years of age (Table 3), the all-cause mortality of those that used antidepressants was significantly lower than non-users (aOR = 0.61, 95%CI: 0.47 ~ 0.76) in those aged 18 or above. Such decreased risk was mainly reflected in the natural cause mortality (aOR = 0.58, 95%CI: 0.44 ~ 0.77). On the contrary, in the group younger than 18 years of age, antidepressants use was not associated with significant differences in all-cause mortality or mortality of different causes.

Table 3

Analysis between Antidepressants drugs and mortality outcomes in ASD patients, stratified by age groups
Age group	N	All-cause mortality aOR (95%CI)	Suicidal mortality aOR (95%CI)	Natural/Other cause mortality aOR (95% CI)	Accident mortality aOR (95% CI)
0–17	4806	0.87 (0.48 ~ 1.60)	1.35 (0.30 ~ 6.03)	1.01 (0.47 ~ 2.18)	1.01 (0.20 ~ 5.01)
18–64	4512	0.61 (0.47 ~ 0.76)	0.74 (0.17 ~ 3.32)	0.58 (0.44 ~ 0.77)	0.68 (0.29 ~ 1.60)

This is the first study to our knowledge that examined overall mortality, cause-specific mortality, and associations with antidepressant use in patients with ASD. We found that using antidepressants was associated with a reduced risk of all-cause mortality. Such a decreased risk was more prominent for accident deaths. However, from the age-stratified analysis, the decreased all-cause mortality was seen only in those aged 18 or above. In such an age subgroup, the most prominent reduction was noted in the odds ratio for other/natural causes of mortality. No significant differences in all-cause or specific-cause mortality were associated with antidepressant use among ASD patients under 18.

The most notable finding in our study is that antidepressant use is associated with a significantly decreased risk of mortality, particularly accidental deaths, in patients with ASD. To our knowledge, no previous study has investigated the association between antidepressant use and cause-specific mortality risk among ASD patients. It is not entirely known why antidepressants may help decrease overall mortality or mortality risks due to accidents in this population. Existing evidence had reported that both natural and unnatural mortality was higher in ASD patients than in the general population [19, 34, 35]. Accident mortality is classified as the unnatural cause of death, which means deaths occurred as unintended, unexpected, or unforeseeable. Literature showed that the most common accident-related deaths in ASD patients were suffocation and drowning [32, 36]. In an early sizeable population-based study with 13,111 ASD patients and 202 deaths, suffocation ranked the highest mortality cause in the subgroup with moderate or profound intellectual disability, and the rate was more than 50 times higher than the general population [32]. Causes of suffocation may include choking or hanging by self or others. In addition, drowning or poisoning due to carbon monoxide intoxication (mostly fire-related) were often causes of injuries or accidental deaths in children [37]. Selective serotonin reuptake inhibitors (SSRIs) have been shown to improve obsessive-compulsive behaviors, aggression, and anxiety [38]. It is statistically associated with decreased deaths due to suicide or poisoning in a past ecological study [39]. It may be plausible that antidepressants might have helped stabilize mood symptoms of ASD patients, making them more able to prevent unintentional injuries through behavior modification, education, or enforcements [40]. Alleviations of mood symptoms may reduce the risk of engaging in risky behaviors that might lead to accidents [32]. Maintaining the emotional stability of ASD patients might also help reduce caregiver burden. It may help prevent ASD patients, especially those with profound intellectual disability, from accidents (e.g., drowning) due to caregivers’ exhaustion- or burnout-related neglect of care [32]. Future investigations exploring the mechanisms of the beneficial effect of antidepressant use among ASD patients in preventing accidental deaths may still be warranted.

We further found from the age-stratified analysis that the use of antidepressants was associated with a decreased overall mortality in adult patients with ASD. Regarding cause-specific death in these adult ASD patients, antidepressant use has significantly reduced adult natural mortality. No previous study has explored the association between antidepressant use and natural causes of death among ASD patients. It is possible that, unlike in adolescence when accidents were often responsible for the leading cause of death, in adulthood, causes of death in both ASD or the general adult population may be more related to aging or deterioration of physical health than injuries or accidents. Hence, the potential explanation for the association between antidepressant use and decreased natural mortality may be that antidepressants were able to reduce mortality in people with long-term physical comorbidities [41–43]. Literature has described that the excess mortality in ASD patients due to natural causes may be associated with epilepsy [44, 45] or physical comorbidities, including other neurological disorders [14], diabetes, obesity, fluid or electrolyte disorders, or hypothyroidism [20]. Having physical conditions is a major risk factor for depression [46]. Depression was also associated with risks of developing physical illnesses or multimorbidity [47, 48]. Elevated all-cause mortality, and mortality, for instance, due to cardiovascular diseases, in patients with diabetes [49], have also been described. In addition to improving mental health conditions in adult ASD patients comorbid with physical illnesses, treatments of antidepressants and possible improvements in depression or anxiety may also enhance medical-seeking behaviors or comply better with preventive health measures [41–43]. They may help reduce excess natural cause mortality in adult patients with ASD.

In this study, antidepressant use did not significantly affect all-cause or different causes of mortality in ASD patients under 18 years of age, nor in suicide mortality. As mentioned earlier, the results of antidepressant use on mortality in child and adolescent ASD patients have not been studied before, and it is thus difficult to discuss the possible reasons. Past findings regarding the association between antidepressants and suicide in children and adolescents have been inconclusive [25, 29, 50]. Risks of suicidal ideation, behaviors, or committed suicide also varied between different sub-categories of antidepressants [25, 51]. There is also the possibility that suicide deaths be misclassified as accident deaths in this study. Hence, it is essential to note the possible limitations, insufficient information, or indication biases from past studies to understand better the safety and efficacy of antidepressant use in child or adolescent ASD patients [52]. Additionally, the clinical decision to use antidepressants in the child and adolescent population should still be made on a case-by-case basis in consultation with a healthcare provider considering the potential benefits and risks for each individual.

The main strengths of this study are the representativeness of its nationwide cohort design. Second, the population-based dataset provided sufficient ASD participants for evaluating the association of interest. Third, the diagnosis of ASD and antidepressant use were confirmed by clinicians rather than self-report. Significant limitations include that, first, although this study already used a vast database for investigating possible effects of antidepressants on mortality, since ASD is a psychiatric disorder with low incidence, there were still not enough samples to analyze different subcategories of antidepressants, nor interactions with other psychotropics. Second, patients with autistic spectrum disorders, such as autistic disorder, Asperger syndrome, and pervasive developmental disorder, were classified as a single entity within the ASD cohort, and could not separate by diagnoses. Second, misclassification might occur when patients need antidepressants but have never been prescribed. Third, there may still be other confounders that could not be controlled, such as further detailed sub-diagnosis, or lifestyle factors, such as diet or exercise, because the information from the database was initially collected only for insurance reimbursement purposes. Fourth, there is also the issue of external generalizability. Patterns of medical-seeking behaviors, antidepressant prescriptions, and mortality data in a population with universal healthcare coverage may not apply to society. Additional time-dependent analyses may still be needed to explore further the correlation between cause-specific mortality and antidepressants or other psychotropic drugs.

This study revealed that antidepressants use in patients with ASD was associated with a decreased risk of all-cause mortality, in particular, mortalities of accidents or natural causes. Although exact mechanisms underlying the association between antidepressant use and reduced mortality from causes other than suicide are not fully understood, our results might still demonstrate the importance of early detection of comorbid psychiatric or physical disorders in patients with ASD, including possible depression or anxiety, since adequate antidepressant treatments may significantly help reduce the associated mortality.

Ethical statement: The manuscript does not contain clinical studies or patient data.

Funding: No funding was secured for this study.

Conflicts of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.

Data and material availability: The NHIRD used in this study is held by the Taiwan Ministry of Health and Welfare. Data are available by submitting a formal proposal to Taiwan National Health Insurance Bureau. We are not permitted to share the data.

Code availability: SAS, Version 9.4 software

Authors' contributions: SI Wu wrote the first draft of the manuscript. YL Chen and VC Chen had the study concept and design, acquisition of data and. YL Chen and TY Kuo extracted the data from the database and conducted the statistical analysis and interpretation. Michael Dewey advised on analysis. All authors have participated in the writing and revision and approved the final manuscript.

Acknowledgments: The authors are grateful for support from the Health Information and Epidemiology Laboratory (CLRPG6G0043) of Chang Gung Memorial Hospital, Chiayi, Taiwan.

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No competing interests reported.

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Mortality and antidepressants among individuals with autism spectrum disorder: A population-based cohort study

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