ADHD: Comorbidity kills

New study: Undiagnosed ADHD in childhood gives a 10-fold increase in the risk of suffering “an early death due to unnatural causes”. 82% of all deaths are deemed to be related to unnatural causes. Unintentional injury accounts for 36% and suicide for 31%.

Psychiatric comorbidity appears to play an important role in all-cause and cause-specific mortality risks in ADHD. In adulthood, early-onset psychiatric comorbidity contributed primarily to the association with death due to natural causes, whereas later-onset psychiatric comorbidity mainly influenced death due to unnatural causes, including suicide and unintentional injury.

Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown.

A previous register-based study reported elevated all-cause mortality in attention-deficit/hyperactivity disorder (ADHD), but cause-specific risks and the potential associations of psychiatric comorbidities remain unknown.

[…] ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents. […] Dalsgaard et al. (2015)

Key Points

Question

Is attention-deficit/hyperactivitydisorder (ADHD) associated with premature death, and what is the role of psychiatric comorbidity?

Findings

This cohort study of Swedish register data of 86,670 individuals with ADHD found that ADHD was associated with elevated risk of premature death, and psychiatric comorbidity played an important role for the all-cause and cause-specific associations in adults.

Early-onset psychiatric comorbidity was mainly associated with the risk of natural deaths whereas later-onset psychiatric comorbidity was mainly associated with death due to unnatural causes, including suicide and unintentional injury.

Meaning

These findings suggest that healthcare professionals should closely monitor specific psychiatric comorbidities in individuals with ADHD to identify high-risk groups and implement prevention efforts.

Background

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting approximately 5% of children and adolescents and 2.5% of adults worldwide.

Individuals with ADHD show impairments in psychosocial functioning. Several large observational studies have reported that ADHD is associated with factors that increase the risk for premature death, such as conduct disorder, substance use disorders (SUD), and incidence of unintentional injuries and suicidal behaviors, but little is known about how ADHD is directly associated with premature death and the potential role of psychiatric comorbidities.

A Danish register-based study found a 2-fold increased risk of all-cause mortality in ADHD, with unintentional injury as the leading cause of death.

The association was stronger when ADHD was diagnosed in adulthood than in childhood, and the mortality rates were higher among individuals with co-occurring conduct disorder, oppositional defiant disorder, and/or SUD.

One important limitation in the Danish study was the lack of statistical power to clarify cause-specific mortality risks associated with ADHD, especially death due to unintentional injuries and suicide.

Furthermore, the study did not explore in detail the role of psychiatric comorbidity, such as early-onset disorders that include autism spectrum disorders and intellectual disability (ID),as well as psychiatric disorders with a later age at onset, including mood and personality disorders and eating disorders.

Improved understanding of the potential contributions by psychiatric comorbidity for associations between ADHD and premature death could substantially facilitate surveillance, intervention, and prevention efforts.

In the present cohort study based on the Swedish national registers, we investigated associations between ADHD and all-cause as well as cause-specific mortality risks and explored the potential effects of number and type of psychiatric comorbidities (ie, early-onset vs later-onset comorbid psychiatric disorders).

Results

Cohort Description and Overall Mortality

We followed up 2,675,615 individuals in the cohort (1,374,790 [51.4%] male and 1,300,825 [48.6%] female), with a mean (SD) age at study entry of 6.4 (5.6) years and a mean (SD) follow-up of 11.1 (3.1) years with a total 29,237,993 person-years at risk.

In the cohort, 86,670 individuals (3.2%; 57,919 male and 28,751 female) were diagnosed with ADHD (Table 1), among whom 12,246 (14.1%) were only identified by medication use records from the Prescribed Drug Register.

The mean (SD) age at ADHD diagnosis was 14.3 (5.7 years (13.5 [5.5] years for male and 16.0 [5.6] for female individuals).

Significantly higher incidences of all comorbid psychiatric disorders were present in the ADHD group compared with the non-ADHD group (eg, 11,518 [13.3%] diagnosed with substance use disorder in the ADHD group vs 68,187 [2.5%] in the non-ADHD group). Diagnosis of psychiatric disorders in male and female individuals is shown in Table 2.

The overall mortality rate during follow-up was 2.28 per 10,000 person-years (Table 3), because 6,655 cohort members (0.3%) died.

Mortality rates were much higher in individuals diagnosed with psychiatric disorders (range, 9.52 to 45.09 per 10 000 person-years) and higher in adulthood than in childhood (4.36 vs 1.26 per 10 000 person- years).

ADHD and Risk of Premature Death

In total, 424 individuals with ADHD died during follow-up (all-cause mortality rate, 11.57 per 10,000 person-years) compared with 6,231 deaths (2.16 per 10 000 person-years) in the non-ADHD group.

Overall, ADHD was associated with a significantly increased risk of all-cause premature death (adjusted HR, 3.94; 95% CI, 3.51-4.43).

The adjusted HR in adulthood (4.64; 95% CI, 4.11-5.25) was substantially higher than the HR in childhood (1.41; 95% CI, 0.97-2.04) (Table 2).

Causes of Death

Unnatural causes

Individuals with ADHD primarily died due to unnatural causes (346 [81.6%]), with unintentional injury (152 [35.8%]) and suicide (133 [31.4%]) as the leading causes of death.

The all-cause mortality risks significantly increased with the age at first ADHD diagnosis (HRs for ≤12 years, 1.50 [95% CI, 10.4-2.17]; 13-17 years, 2.69 [95% CI, 2.20-3.31]; ≥18 years, 10.34 [95% CI, 8.94-11.96]).

Natural causes

Neoplasms (15 [3.5%]), diseases of the nervous system (12 [2.8%]), and circulatory system diseases (12 [2.8%]) accounted for the most deaths due to natural causes in the ADHD group.

ADHD vs. Non-ADHD groups

Compared with the non-ADHD group, the ADHD group had significantly higher risks of death due to natural (adjusted HR, 2.47; 95% CI, 1.66-4 3.68) and unnatural (adjusted HR, 6.48; 95% CI, 5.12-8.21) causes.

Specifically among unnatural causes, ADHD was associated with an 8.63 (95% CI, 6.27-11.88) times higher risk of dying due to suicide and a 3.94 (95% CI, 2.49-6.25) times higher risk of dying due to unintentional injuries.

Sun et al., JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.1944

Psychiatric Comorbidity With ADHD and Risk of Premature Death in Adults

First, when stratifying by the number of comorbid psychiatric conditions, the diagnosis of ADHD without comorbidity conferred a 40% higher risk of all-cause mortality (adjusted HR, 1.41; 95% CI, 1.01-1.97).

The association increased substantially with the number of comorbidities in a dose-response pattern (adjusted HR for 1 comorbidity, 3.71 [95% CI, 2.88-4.78]; adjusted HR for ≥4 comorbidities, 25.22 [95% CI,19.60-32.46]), indicating a cumulative contribution of psychiatric comorbidity to premature death, including an independent contribution due to being diagnosed with ADHD (Table 3).

Second, most of the specific comorbid disorders except autism spectrum disorder (adjusted HR, 0.89; 95% CI, 0.64-1.25) and ID (adjusted HR, 0.36; 95% CI, 0.18-0.70) were associated with increased risk for all-cause mortality among individuals with ADHD (Table 4).

The strongest association was found for SUD, with an adjusted HR of 8.01 (95% CI, 6.16-10.41), when compared with individuals with only ADHD.

Third, when adjusting for early-onset psychiatric comorbidity (model 3), the associations between ADHD and unnatural cause-specific mortality risks were partly attenuated, whereas death due to natural causes (HR, 1.32; 95% CI, 0.94-1.85) was no longer statistically associated with ADHD (Table 5). When adjusting for later-onset disorders (model 4), all associations were attenuated. The association became statistically nonsignificant for death due to suicide (HR, 1.13; 95% CI, 0.88-1.45) but remained statistically significant for death due to unintentional injury (HR, 2.14; 95% CI, 1.71-2.68) or other external causes (HR, 1.75; 95% CI, 1.23-2.48).

Finally, when analyzing specific psychiatric comorbidities among individuals with ADHD, associations were not significant for most of the early-onset disorders with cause-specific mortalities.

However, ADHD and comorbid ID presented a substantially lower risk of death due to unintentional injury (adjusted HR, 0.20; 95% CI, 0.05-0.80) compared with individuals with ADHD only.

Among later-onset psychiatric comorbidities, SUD presented the strongest associations with death due to natural causes (adjusted HR, 3.23; 95% CI, 1.72-6.07), suicide (adjusted HR, 6.61; 95% CI, 4.13-10.57), and unintentional injury (adjusted HR, 10.02; 95% CI, 6.49-15.49).

Associations between most later-onset disorders other than SUD were stronger with death due to suicide than death due to unintentional injury or natural causes.

Discussion

In a national register-based cohort study with more than 2.6 million individuals, we found that ADHD was associated with elevated all-cause and cause-specific mortality risks.

The association was stronger in adulthood than in childhood, with increased risks when ADHD was diagnosed later.

In adulthood, the all-cause mortality risk increased substantially with the number of psychiatric comorbidities with ADHD.

Early-onset psychiatric comorbidity was associated with a substantial part of the mortality risks due to natural causes such as neoplasms.

Later-onset psychiatric comorbidity, on the other hand, contributed substantially to the ADHD-associated mortality risks due to unnatural causes, such as suicide and unintentional injuries.

Assessment of the risk and intervention focusing on different psychiatric comorbidities might help with not only improving general quality of life for individuals with ADHD but also preventing premature deaths due to various causes.

In line with the previous Danish register based study and other studies, we found that unnatural causes, including suicide and unintentional injuries, accounted for the most deaths among individuals with ADHD.

The association between ADHD and the risk of dying due to suicide or unintentional injuries in adulthood was largely explained by later-onset psychiatric comorbidity.

A survey of school-age children from Taiwan reported that mood disorders and conduct disorders mediated about 20% and 8%, respectively, of the suicidality risk associated with ADHD, whereas our results suggested more pronounced associations in adulthood from later-onset psychiatric comorbidity, in particular SUD and mood disorders.

Inattention and impulsivity in ADHD increase the proneness to risky behaviors and the risk of severe unintentional injuries, suggesting a direct association of ADHD with death due to unintentional injuries.

This theory was supported by our results with a 2-fold increased risk of death due to unintentional injuries after adjusting for psychiatric comorbidities, although the association was much stronger before the adjustment for later-onset psychiatric comorbidity.

The association between ADHD and risk of death due to natural causes in adulthood might be explained to a large extent by co-occurring early-onset disorders, including conduct disorder/oppositional defiant disorder, autism spectrum disorder, and ID.

For example, individuals with ADHD and co-occurring ID had increased mortality risks compared with those with ADHD only, and most deaths in this group were due to natural causes.

This finding is consistent with those of studies demonstrating that adults with mild to severe ID showed increased risk of premature death and mainly died due to somatic conditions other than external causes.

Intellectual disability–related poor self-care may increase the risk of preventable health conditions such as respiratory infections and digestive diseases.

Management of early-onset psychiatric comorbidities such as intellectual disability with ADHD needs to focus also on somatic conditions.

We analyzed the association of ADHD with and without specific psychiatric comorbidities with all-cause and cause- specific mortality risks in adulthood.

Consistent with previous research, comorbid conduct disorder and SUD further increased the all-cause mortality risks in ADHD.

Substance use disorder was also associated with elevated risk of death due to suicide, unintentional injuries, and natural causes in individuals with ADHD.

Common risk factors for suicide, including depression, anxiety, and bipolar disorders, were consistently associated with significantly higher risk of suicide death in ADHD..

On the other hand, individuals with ADHD and comorbid ID had a lower risk of death due to unintentional injuries compared with individuals with ADHD only, possibly owing to the fact that individuals with both disorders have lower possibility of experiencing severe traffic crashes because of difficulty obtaining a driving license.

Such findings could guide clinical treatment and facilitate development of risk evaluation and prediction tools when different psychiatric comorbidities are identified with ADHD.

Conclusions

By using a longitudinal design based on national register data, our results suggest an elevated risk in ADHD for all-cause and cause-specific premature death, which may increase with the number of psychiatric comorbidities present.

Among adults, early-onset psychiatric comorbidity contributed substantially to the premature mortality risks due to natural causes.

On the other hand, later-onset psychiatric comorbidity, especially SUD, explained a substantial part of the risk for unnatural deaths, including all the risk of suicide deaths and most of the deaths due to unintentional injuries.

These results suggest that overall health conditions and risk of psychiatric comorbidity should be evaluated clinically to identify high-risk groups among individuals with ADHD.

Reference

Sun S, Kuja-Halkola R, Faraone SV, et al. Association of Psychiatric Comorbidity With the Risk of Premature Death Among Children and Adults With Attention-Deficit/Hyperactivity Disorder [published online ahead of print, 2019 Aug 7]. JAMA Psychiatry. 2019;e191944. doi:10.1001/jamapsychiatry.2019.1944

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