case vignette

“Kelly” is an 11-year-old Caucasian female who was recently diagnosed with attention-deficit/hyperactivity disorder (ADHD). She primarily exhibited symptoms of inattention, and her problems with hyperactivity and impulsivity were minimal. She also has a history of seasonal allergies and mild asthma. She tested positive for treatment with methylphenidate, which she continues to take. At the outpatient visit, her mother asks about the potential risks of long-term treatment with medication for her ADHD. As her psychiatrist, how would you react?

There continues to be concern about the cardiovascular safety of ADHD medications.¹ A meta-analysis of randomized controlled trials (RCTs) found increases in pulse rate and blood pressure associated with both stimulant and non-stimulant treatments for ADHD.^1-3 Given the short-term nature of RCTs, it remains unclear whether these changes translate into long-term risk of clinically significant cardiovascular disease (CVD).

Previous longitudinal observational studies have yielded mixed results;^4,5 A meta-analysis of observational studies found no association.⁶ However, most of these studies had a follow-up period of less than 2 years. Given that ADHD symptoms can continue into adulthood,⁷ Trends in long-term use of ADHD medications⁸ The long-term risks of these drugs are an important area of ​​research.

current research

Zhang and his friends⁹ We used the Swedish national health registry to assess the association between cumulative use of ADHD medications (up to 14 years) and CVD risk. Diagnoses were obtained from the National Inpatient Registry. Drug information was obtained from the Swedish Prescription Drug Registry. Socioeconomic factors were obtained from the Longitudinal Integrated Database for Health Insurance and Labor Market Research. Death information was obtained from the Swedish Cause of Death Registry.

The researchers studied 6- to 64-year-olds who received an incident diagnosis of ADHD (ICD-10) or medication for ADHD (at least 18 months after no such medication) from 2007 to 2007. We conducted a nested case-control study among all individuals in Sweden. 2020. Exclusion criteria were prescription of her ADHD medication for an indication other than ADHD, individual who immigrated or died, or individual with her history of CVD before study baseline.

Cohort members were followed until the date of CVD diagnosis, death, emigration, or the end of 2020 (whichever came first). Incidental diagnoses of CVD include ischemic heart disease, cerebrovascular disease, hypertension, heart failure, arrhythmia, thromboembolic disease, arterial disease, and other cardiac diseases. For each case, up to five controls without CVD were randomly selected and matched on the basis of age, sex, and calendar time. The control group was alive, living in Sweden, and did not have CVD at the time the case was diagnosed with her CVD.

The primary exposure was cumulative duration of ADHD medication use based on free description of prescription records. To reduce reverse causality, the previous 3 months before the index date of CVD were excluded. The authors performed conditional logistic regression analysis to estimate odds ratios (OR) for the association between cumulative duration of ADHD medication and incident CVD. Analyzes were adjusted for age, gender, calendar time, country of birth, education, and physical and mental illness comorbidities.

Duration of ADHD medication use was assessed using both continuous and categorical measures. The risk of CVD was estimated for each year of increase in ADHD medication use across different dose groups categorized by mean prescribed daily dose (DDD). Subgroup analyzes examined the association between ADHD medication use and specific his CVDs and the most commonly prescribed medications (methylphenidate, lisdexamfetamine, and atomoxetine).

The study cohort consisted of 278,027 individuals with ADHD. The incidence of CVD was 7.3 per 1000 person-years. The analysis included 10,388 cases and 51,672 matched controls (median age 35 years, 59% male). Median follow-up was 4.1 years. The most common CVD types were hypertension (41%) and arrhythmia (13%). Cases had higher rates of comorbid physical and mental illness and less education compared to controls.

Longer cumulative use of ADHD medications was associated with an increased risk of CVD compared to nonuse in a dose-response manner (>5 years: aOR=1.23, 95% CI 1.12-1.36). Throughout follow-up, each 1-year increase in ADHD medication use was associated with a 4% increase in CVD risk (aOR=1.04, 95% CI 1.03-1.05).

A similar pattern of findings was observed when 1) men and women and 2) children/adolescents and adults were considered separately. Dose analysis showed that his CVD risk associated with each year of his use of ADHD medication increased with higher mean DDD and was statistically significant for individuals with mean doses of at least 1.5 DDD. got it.

Regarding specific CVDs, long-term use of ADHD medications was associated with increased risk of hypertension (>5 years: aOR=1.80, 95% CI 1.55-2.08) and arterial disease (>5 years: aOR=1.49, 95% CI 0.96) It was related to -2.32). Regarding specific drugs, methylphenidate (>5 years: aOR=1.19, 95% CI 1.08-1.31) and lisdexamfetamine (>3 years: aOR=1.17, 95% CI 10.98-1.40) were associated with CVD risk. was associated with an increase in Atomoxetine use was significant only during the first year of use (aOR = 1.07, 95% CI 1.01-1.13).

Research conclusion

The researchers concluded that long-term ADHD medication use is associated with an increased risk of developing CVD, and that this risk increases in a dose-response manner. The results were consistent regardless of age and gender. The main drivers of this association were increased risk of high blood pressure and arterial disease.

Strengths of the study include longer follow-up than previous studies and consideration of specific causes of CVD. Another strength of the study is that it uses prospective data collection, so the results are not affected by replication bias.

Limitations of the study include a possible lack of ascertainment of non-medical CVD cases, which tends to underestimate the association. Exposure misclassification may have occurred if the patient did not take the medication as prescribed. Finally, the observational nature of the study design did not allow for causal inferences.

conclusion

Findings suggest that long-term use of ADHD medications is associated with increased CVD risk, particularly hypertension and arterial disease, and with increased risk of stimulant drugs. Clinicians should closely monitor patients for signs and symptoms of CVD, especially those taking high doses.

Dr. Miller He is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the editorial board and heads the schizophrenia section. Psychiatry Times®. The authors report receiving research support from Augusta University, National Institute of Mental Health, and Stanley Medical Research Institute.

References

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2. Cortese S, Adamo N, Del Giovane C, et al. Comparing the efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: A systematic review and network meta-analysis. lancet psychiatry. 2018;5(9):727-738.

3. Mick E, McManus DD, Goldberg RJ. Meta-analysis of heart rate and blood pressure increases associated with central nervous system stimulant treatment of ADHD in adults. euro neuropsychopharmacology. 2013;23(6):534-541.

4. Cooper WO, Harvell LA, Socks CM, et al. ADHD medications and serious cardiovascular events in children and adolescents. N English J Medicine. 2011;365(20):1896-1904.

5. Habel LA, Cooper WO, Sox CM, et al. Medications for ADHD and the risk of serious cardiovascular events in young and middle-aged adults. Japan Automobile Manufacturers Association. 2011;306(24):2673-2683.

6. Zhang L, Yao H, Li L, et al. Cardiovascular disease risk associated with medications used for attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. JAMA Net Open. 2022;5(11):e2243597.

7. Faraone SV, Biederman J, Mick E. Age-dependent decline in attention-deficit hyperactivity disorder: a meta-analysis of follow-up studies. psychomed. 2006;36(2):159-165.

8. Bruno C, Harvard A, Gillies MB, et al. Patterns of attention-deficit hyperactivity disorder drug use in the new non-stimulant drug era: A population-based study of Australian children and adults (2013-2020). Australia New Zealand Psychiatry. 2023;57(5):675-685.

9. Zhang L, Li L, Andell P, et al. Attention-deficit/hyperactivity disorder drugs and long-term risk of cardiovascular disease. JAMA Psychiatry. 2024;81(2):178-187.