A new pharmacological approach for treating ADHD

UCL neuroscientists have opened up a new line of research for medication of Attention Deficit Hyperactivity Disorder (ADHD). The research team has developed a vital new animal model for investigation of this disorder, which has led to the discovery of a genetic locus in humans that increases vulnerability to ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) has a worldwide prevalence in children of about 5% but persists in adulthood in over 60% of cases. Its core diagnostic features - 'hyperactivity', 'inattentiveness' and 'impulsivity' -disrupt academic development and can lead to complex social problems in adulthood.

The majority of adult patients also experience serious co-morbidity, including: substance misuse (especially alcohol), emotional lability, bipolar disorder, criminality, suicidality, motor tics and other repetitive behaviours ('perseveration'). All these problems impair the quality of life of the patient and their family. They can also reduce life‑expectancy, as can an unexplained increased risk among ADHD patients of other medical conditions such as obesity and asthma.

In combination with a greater incidence of accidents and social problems, these factors make the cost of care for ADHD patients around twice that for the average patient, with about £78 million spent on medicating ADHD in 2012. The psychostimulants, d‑amphetamine and methylphenidate, are the first-choice treatments for ADHD, but only two other drugs (atomoxetine and guanfacine) have confirmed benefits in ADHD patients. There is a pressing need for new ways of treating this disorder, not least because all four drugs can have harmful cardiovascular side‑effects and there is concern about the risk of misuse of psychostimulants after their long-term use. Another problem is that more than 25% of patients do not respond to any of these medications

Since 2004, researchers at UCL have been studying mice, which have been genetically altered to prevent activation of their neurokinin-1 receptors: the so-called 'NK1R-/-' mice, which turned out to be a more valid animal analogue of ADHD than any other studied so far.

They discovered that the mice were hyperactive and that this abnormal behaviour was prevented by amphetamine and methylphenidate. They also determined that this hyperactivity arose directly from the lack of functional NK1R, implying that it could be reduced by drugs that augment activation of NK1R. Follow-on work by the UCL team confirmed that guanfacine prevented inattentiveness of NK1R-/- mice, while guanfacine, atomoxetine and methylphenidate reduced their impulsivity. By contrast, only their repetitive behaviour (perseveration) was diminished by d-amphetamine, which could help explain why not all ADHD patients respond to this psychostimulant.

This work prompted a human genetic study by the team at UCL, which found a strong association between four genetic markers in the TACR1 gene (the human equivalent of the NK1R gene) and ADHD. Since then, polymorphism(s) of the TACR1 gene have also been found to be associated with bipolar affective disorder, suicidal behaviour and alcoholism.

The discovery that disruption of NK1 receptor function causes deficits in cognitive performance and response control, similar to those seen in ADHD patients, has opened up new directions for investigating the causes of ADHD and its treatment. These include the development of NK1R as a new drug target and also a new use for drugs that are already used in the clinic to treat patients with other illnesses. The NK1R-/- mouse model of ADHD, which is protected by an EU patent, will continue to provide researchers around the world with a vital animal research resource for those investigations.

These UCL discoveries have already had major significance for both clinical psychiatrists and the health and wellbeing of ADHD patients in their care. A key impact has been that drug treatment could now begin to be tailored for maximum efficacy, according to the genetic subtype of the disorder that specific individuals have inherited. Furthermore, the UCL research has challenged traditional clinical diagnostic categories by identifying a molecular pathophysiology for ADHD that cuts across traditional diagnostic boundaries. Again, this has important implications for clinicians, by suggesting that biomarkers, which identify genetic effects on subcategories of mental illness, or specific symptoms/signs of this disorder, may be more powerful and useful than the traditional diagnostic categories that are used at present.