Guanfacine for the Treatment of PFC Disorders

The prefrontal cortex (PFC) is needed for top-down control of attention, behavior and emotion: inhibiting inappropriate impulses, controlling distractions, sustaining attention on “boring” but important information (e.g. math homework), and delaying gratification. All of these abilities can be impaired in people with Attention Deficit Hyperactivity Disorder (ADHD).

Research has shown that ADHD involves dysfunction of the PFC, including weaker PFC connections and activity, and slowed maturation of the right inferior PFC cortical areas that are especially needed for inhibiting inappropriate responses. These PFC functions are increasingly important for survival in the Information Age, when we are bombarded by stimuli, and must learn increasing amounts of information to succeed in school and in our careers.

Indeed, the ability to defer gratification as a child has been linked to a person’s ability to succeed in life 40 years later. Thus, diagnosis and treatment of ADHD is increasingly important. The Arnsten lab developed the a2A-AR agonist, guanfacine, for the treatment of ADHD, based on its ability to strengthen PFC top-down control of behavior, attention and emotion. Thus, research in monkeys has shown that guanfacine can improve working memory, calm behavior, reduce distractibility, strengthen delayed gratification, and improve behavioral flexibility. Based on these data, guanfacine was tested in ADHD patients, and an extended release formulation of guanfacine (Intuniv™) was approved by the FDA for the treatment of pediatric ADHD in 2009, and for combined therapy with stimulants in 2011.

Guanfacine has a long half-life in adults, but a very short half-life in children; thus, the extended release preparation is helpful for children. As guanfacine is a nonstimulant, it can be especially helpful in patients who cannot take stimulant medications, e.g. due to anxiety, weight loss, or abuse potential.

If you are interested:

• Casey et al. (2011) Behavioral and neural correlates of delay of gratification 40 years later. Proc Natl Acad Sci U S A108: 14998-5003.
• Rubia (2011) "Cool" inferior frontostriatal dysfunction in attention-deficit/hyperactivity disorder versus "hot" ventromedial orbitofrontal-limbic dysfunction in conduct disorder: a review. Biol Psychiatry 69: e69-87.
• Liston et al (2011) Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point? Biol Psychiatry 69: 1168-77.
• Shaw et al (2012) Development of cortical surface area and gyrification in attention-deficit/hyperactivity disorder. Biol Psychiatry 72:191-7.
• Arnsten (2010) The use of a2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother.10:1595-605.
• Sallee et al (2013) A Review of the Rationale and Clinical Utilization of a2-Adrenoceptor Agonists for the Treatment of Attention-Deficit/Hyperactivity and Related Disorders. J Child Adolesc Psychopharmacol. 23 :308-19.