Response

The study by O’Nions et al in the most recent issue of the British Journal of Psychiatry showed an alarming reduction in life expectancy in both men and women who had been diagnosed with attention-deficit hyperactivity disorder (ADHD) in the UK. ^{Reference O’Nions, El Baou, John, Lewer, Mandy and McKechnie1} The authors noted the more stringent diagnostic criteria applied at the time of the study, and identified the effects of social disadvantage and higher rates of comorbid physical and especially mental health conditions found in samples of ADHD patients among the potential causes of premature death. However, the authors did not mention the possible effect of treatment with stimulant medications as a contributing factor to both mortality and to the very high rates of comorbid mental and physical conditions.

Meeting the accepted criteria for a diagnosis of ADHD is typically followed by a trial of treatment with stimulant drugs, despite the high rate of comorbid neurodevelopmental, behavioural and emotional disorders and the recommendation that medication should never be the sole intervention in children. ² Despite the evidence for combined biological, psychological and social interventions, little emphasis is given to treatments other than medication, especially in low socioeconomic families, and there has been a significant increase in prescriptions in the UK in the last 5 years, particularly in those who are socioeconomically disadvantaged or ethnically diverse. ^{Reference Khan and Hasan3}

The medications most commonly prescribed for ADHD are dextroamphetamine and methylphenidate, and longer acting variants, which act by inhibiting the reuptake and stimulating the release of dopamine. Recognised adverse effects of both the abuse of stimulant drugs and long-term treatment with amphetamine-like drugs such as modafinil and phentermine include increased blood pressure, tachycardia, insomnia, anxiety, depression, psychosis and movement disorders. ^{Reference Elliott, Johnston, Husereau, Kelly, Eagles and Charach4} All of those could contribute on their own or together to premature mortality. There is limited information and few trials reporting the long-term adverse effects of treatment with stimulant drugs for ADHD, ^{Reference Elliott, Johnston, Husereau, Kelly, Eagles and Charach4} including controlled trials examining the potential for tolerance, addiction and whether the medication should be taken continuously or intermittently. However, there is evidence of an increased risk of cardiovascular disease with long-term use of ADHD medication, ^{Reference Tadrous, Shakeri, Chu, Watt, Mamdani and Juurlink5} a risk that is greatest in the elderly, where even 30 days’ use of stimulants increases the risk of ventricular arrhythmias, cardiovascular accidents and transient ischaemic attacks. ^{Reference Zhang, Li, Andell, Garcia-Argibay, Quinn and D’Onofrio6} Methylphenidate in particular has been associated with a four-fold increase in developing prehypertension in otherwise healthy young adults, and significant increases in heart rate and systolic blood pressure in children and adolescents. ^{Reference Liang, Lim, Tam, Ho, Zhang and McIntyre7}

There is also evidence of a direct neurotoxic effect of ADHD medication, from a study of adults aged between 21 and 49 who had a 2.4-fold increased risk of basal ganglia and cerebellum diseases, of which Parkinson’s disease is the most common, whereas the subgroup of the overall sample diagnosed with ADHD who were treated with ADHD medications have been found to have an 8.6-fold increased risk. ^{Reference Curtin, Fleckenstein, Keeshin, Yurgelun-Todd, Renshaw and Smith8} Noting that this was a single, albeit large, study, this is an area that surely warrants further research.

O’Nions et al suggested that ADHD might have contributed to lower socioeconomic status and that modifiable risk factors and unmet support and treatment needs associated with socioeconomic disadvantage in turn contributed to premature death, especially deaths from suicide and substance use. However, early life adversity is itself a predictor of a child being diagnosed with ADHD by the age of seven, with financial disadvantage being the single strongest predictor. ^{Reference Khan and Hasan3} Another possible explanation is that the comorbid psychiatric disorders of anxiety, depression, psychosis and substance use contributed to the presence of symptoms amounting to the syndrome of ADHD. Of particular concern is the possibility that long-term treatment with stimulant drugs actually exacerbate the comorbid psychiatric conditions reported in the ADHD sample.

Additional information on the causes of death, the rate of prescription of stimulant drugs, the doses used and the likely adherence to those treatments might help estimate how much of the premature mortality is due to trait impulsivity, neglect of physical and mental health, and lifestyle factors such as smoking and obesity, and how much might be attributed to the neurological and other physical effects of stimulant medications prescribed to treat ADHD. We note the higher mortality rate found in a population-wide study of people diagnosed with ADHD who were not receiving medication, ^{Reference Vasiliadis, Lunghi, Rahme, Rochette, Gignac and Massamba9} which confirms the need for a higher level of support and measures to address lifestyle factors that might contribute to premature mortality. However, from the information that is now available, adults prescribed ADHD medications should be warned about the possible increased risk of developing basal ganglia and cerebellum diseases and the risks associated with an increased rate of cardiovascular disease, particularly when psychosocial treatment modalities have been overlooked or underutilised.