This prospective, open-label trial in children with PDD accompanied by hyperactivity and impulsive behavior showed that, despite highly significant decreases of 41% (total SNAP scores) and 42% (ABC–Hyperactivity) in parent ratings of ADHD symptoms during guanfacine administration, exploratory analyses of MDR1 gene variants showed prominent differences in response by genotype. The magnitude of the difference between the two genotype groups was greater than 1 SD in the final week-8 ratings, indicative of a large influence on treatment response. This is one of few observations of the influence of MDR1 on psychotropic treatment response.
MDR1 is a member of the ABC family of membrane-bound drug transporter proteins that are present at the blood–brain barrier. Besides MDR1 (ABCB1), the group includes multidrug resistance (-associated) protein 1 (MRP1, ABCC1), MRP2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4), MRP5 (ABCC5), and the breast cancer resistance protein (BRCP, ABCG2) (Wang et al. 2007
). The substrates and inhibitors of each of these transporters vary widely, but psychotropic drugs have been found to bind to many of these proteins. In the case of the best-studied member of the family, MDR1, 29 SNPs have been identified. The MDR1
variant we chose to examine has previously been shown to influence gene expression (Hoffmeyer et al. 2000
) and substrate specificity (Kimchi-Sarfaty et al. 2007
). Indeed, one report described a reduction of nearly 50% in MDR1 protein concentration between the C/C versus the T/T genotype; however, not all reports have observed effects on expression (Sakaeda 2005
). The effects of such reductions in MDR1 can be complex. Reduced MDR1 has been associated with increased brain concentrations of drugs known to be transported by MDR1; however, reduced MDR1 can also reduce absorption and increase renal excretion of some substrates, defying straightforward attempts to explain differences in clinical effects by genotype.
Our report should be viewed as exploratory, given the small sample composed only of individuals previously shown to be unresponsive to or intolerant to MPH, with a restricted age range, predominance of males and Caucasian subjects, a lack of treatment blinding, and short observation period. Data from much larger clinical trial samples are needed to confirm or refute this observation and to better estimate the magnitude of the difference, if any, associated with the MDR1 genotype. Another limitation is the absence at present of definitive in vitro data confirming that guanfacine is a major substrate for MDR1 transport. If confirmed that guanfacine transport is influenced by MDR1, it would also be critical to examine in a controlled system the precise impact of MDR1 gene variants on guanfacine absorption, distribution, blood–brain levels, and excretion. Our ability to examine MDR1 genotype effects on adverse events is also limited in this pilot study. However, a large clinical trial sample could examine whether more commonly observed adverse events, such as sedation or mood liability, adverse events that we observed often mandated dose reduction or predicted intolerance, may also be associated with the MDR1 genotype. Such observations hold obvious potential clinical importance if applicable at the level of the individual patient.
Clinically, additional trials are needed to determine the benefits and safety of the α agonists as common treatments for pediatric neuropsychiatric disorders, especially in individuals with PDD with ADHD symptoms. More data are needed on the durability of benefits, as some reports suggest waning effects over time (Jaselskis et al. 1992
), effects of sedation and fatigue on adherence (Biederman et al. 2008b
), and to confirm the apparent acceptable cardiovascular safety profile from larger, recent reports (Biederman et al. 2008a
; Daviss et al. 2008
). As clinical support for guanfacine is growing, given the modest benefits of stimulants in subgroups of children such as PDD (Aman et al. 2003
; Research Units on Pediatric Psychopharmacology [RUPP] Autism Network 2005
), it is important to attempt to identify possible predictors of treatment benefit. Accumulated findings from initial guanfacine trials in children for the management of ADHD behaviors have varied, perhaps due to differences in clinical populations sampled. Although our data support MDR1
gene variants as significant moderators to guanfacine response, there yet may be other important variants in other genes that further contribute to variability in guanfacine response. Examination of other relevant target genes thought to play a role in guanfacine distribution, neurochemical effect, or metabolism, including α2A (ADRA2A
), other noradrenergic system genes, CYP450
genes, and others could well reveal more robust genetic influences on clinical response to guanfacine.
In conclusion, the results of this study suggest that gene variants of MDR1 may serve as a potent moderator of the benefits of guanfacine as a treatment for hyperactivity in children with PDD who do not show improvement with MPH. Besides encouraging efforts for replication, the results should also stimulate a greater awareness in child psychopharmacology of the potential importance of the family of drug transporters as key components in drug distribution and clinical effect.