Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity.
OBJECTIVE
Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs.


METHODS
Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype.


RESULTS
The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56).


CONCLUSIONS
In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response.
Szobot
Claudia M
CM
ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brasil. cmszobot@terra.com.br
Roman
Tatiana
T
Hutz
Mara H
MH
Genro
Júlia P
JP
Shih
Ming Chi
MC
Hoexter
Marcelo Q
MQ
Júnior
Neivo
N
Pechansky
Flávio
F
Bressan
Rodrigo A
RA
Rohde
Luis A P
LA
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D001931:Brain Mapping; D015897:Comorbidity; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology / Q000627:therapeutic use*; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D019966:Substance-Related Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014326:Tropanes / Q000493:pharmacokinetics; D055815:Young Adult
C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C493214:SLC6A3 protein, human; D014326:Tropanes; C104196:technetium Tc 99m TRODAT-1; D050638:Receptors, Dopamine D4; D008774:Methylphenidate