Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder

Abstract

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [(11)C]raclopride (D(2)/D(3) receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D(2)/D(3) receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.

Figure 1.

Averaged DA D₂/D₃ receptor availability (BP_ND) images for the [¹¹C]raclopride scans done after intravenous placebo and after intravenous MP (iv-MP) for the treatment-naive and long-term treatment conditions. Intravenous MP reduced DA D₂/D₃ receptor availability in striatum in both conditions, reflecting the DA increases elicited by the drug.

Figure 2.

SPM results for the effects of intravenous MP on DA D₂/D₃ receptor availability (BP_ND) for the measures made for the treatment-naive and long-term treatment conditions and SPM results for the comparisons between treatment-naive and long-term treatment. MP reduced DA D₂/D₃ receptor availability in striatal regions and also in frontal and temporal cortices. The reductions in DA D₂/D₃ receptor availability induced by intravenous MP were significantly greater for the treatment-naive than for the long-term treatment condition in striatal regions but did not differ in cortical regions.

Figure 3.

SPM results for the voxelwise correlation between intravenous MP-induced changes in DA D₂/D₃ receptor availability (BP_ND) (measures taken after long-term MP treatment) and the changes in scores of symptoms of inattention (CAARS A; Δtreatment-naive > long-term treatment) shown in an axial and a sagittal plane at the levels where the VS (A) and the prefrontal cortex (B) are located along with the respective regression slopes for the ROIs identified from SPM.