Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in published reports. In addition, the Fusar-Poli meta-analysis has come under strong criticism because of methodological errors with improper patient inclusion and characterization of treatment status,37 calling into question the investigators’ conclusions.
Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
• an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
• absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.38-40
Dresel et al38 evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with controls, at baseline. After treatment, the researchers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.
Study: SPECT in 18 adults with ADHD given methylphenidate. Krause39 used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.
Study: 22 Adult ADHD patients evaluated with 99m-technetium TRODAT SPECT. The same group of investigators40 presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at baseline; none had a good clinical response to methylphenidate.
The positive clinical response to methylphenidate in 67%37 and 77%40 of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.41 Improvement might be related to an increase in functioning of the frontostriatal dopaminergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake transporter, produces increased dopamine neurotransmission and increased activation of frontostriatal circuits.
In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.42
Will imaging pave the way for therapeutic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symptom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to distinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.
Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminergic neurons in the striatum, where it is decarboxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased values are thought to indicate increased density of dopaminergic neurons.43
Ernst et al44 reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.43 They hypothesized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine synthesis due to low synaptic dopamine concentrations that might result from increased dopamine reuptake.
Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.
The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and prefrontal cerebral cortex. D1 receptor knockout mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.45 D1 has been imaged using C-11 SCH 23390 PET46 in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.13