Why methylphenidate is not successful in cocaine-dependent ADHD patients: A SPECT
study comparing DAT before and after methylphenidate treatment in ADHD patients
with and without cocaine dependence.

Attention deficit hyperactivity disorder (ADHD) may play a role in the etiology and pathogenesis of substance use disorders (SUD) although its relationship to substance abuse is not fully understood.

The dopamine transporter (DAT) plays a fundamental role in both ADHD and SUD. Dopamine transporter (DAT)-selective medications, such as methylphenidate (MPH), have been shown to successfully block the DAT in ADHD patients (Krause et al., 2000; Dresel et al., 2000), and DAT occupancy has been associated with clinical effectiveness (Vles et al., 2003; van Dyck et al., 2002). In ADHD patients with SUD, however, these medications are not very effective, neither for
treating ADHD nor SUD.

Thus, ADHD patients with SUD are often not responsive to MPH. This raises two important questions: why are patients with ADHD with SUD not responsive to adequate doses of MPH and how does this relate to SUD?

This study is an attempt to investigate one of the most plausible reasons for the difference in effectiveness of MPH in the treatment of adult ADHD patients with and without SUD. It
is hypothesized that adult ADHD patients with SUD generally have higher baseline DAT availability in the basal ganglia (Jacobsen et al., 2000; Little et al., 1998, 1999; Malison et al., 1998), and that similar doses of MPH result in lower occupancy rates in adult ADHD patients with SUD compared to adult ADHD patients without SUD. It remains unclear whether baseline DAT density and DAT
occupancy following MPH treatment differs between ADHD patients with and without SUD. These are relevant concerns since answers to these questions may shed light on the lack of efficacy of MPH for the treatment of ADHD symptoms and drug use in ADHD patients with comorbid SUD.

1. Does baseline dopamine transporter (DAT) binding differ in ADHD patients with (ADHD+SUD) and without substance use disorders (ADHD-SUD)?
A possible explanation for the difference in treatment response is that ADHD patients with
and without comorbid SUD differ in their baseline DAT density. We expect higher baseline
striatal DAT expression in patients with cocaine dependence compared to patient without
comorbid cocaine dependence;

2. Does methylphenidate (MPH) affect DAT binding differently in ADHD+SUD and ADHD-SUD patients?
Another possible explanation for the difference in treatment response between ADHD patients
with and without comorbid SUD is that MPH differentially affects striatal DAT binding in
ADHD+SUD compared to ADHD-SUD patients. We expect 10-20% lower occupancy in
ADHD patients with cocaine addiction compared to those without addiction following
treatment with identical dosages of MPH;

3. Does MPH differentially affect ADHD symptoms and ADHD associated cognitive functions in
ADHD patients with and without cocaine dependence?
We expect that identical dosages of MPH are less effective in the reduction of ADHD
symptoms and associated cognitive functions in ADHD patients with cocaine addiction
compared to patients without cocaine addiction;

4. Does DAT occupancy affect drug craving and drug use in ADHD+SUD patients?
We expect MPH to increase striatal DAT occupancy and possibly reduce drug craving in
ADHD patients with cocaine dependence compared to their baseline measures.

All outcome measurements (questionaires and 123I-FP-CIT single photon emmision computed tomography (SPECT) scans) are assessed at baseline, and following two weeks treatment with methylphenidate.

Patients with ADHD with and without cocaine dependence will be treated with a fixed dose of methylphenidate for 2 weeks (slow-release methylphenidate, 54 mg tablets). Patients will be scanned using 123I-FP-CIT single photon emmision computed tomography (SPECT) to assess possible differences in dopamine transporter availability at baseline, and differences in dopamine transporter occupancy following fixed-dose methylphenidate treatment.