Tolerance to the dopaminergic effects of methylphenidate in adults with ADHD after one-year treatment with methylphenidate

Objectives Stimulant medications (methylphenidate and amphetamine) are the treatments of choice in ADHD and are believed to acutely compensate for a chronic dopamine (DA) deficit in this disorder. However the effects of long-term (ie, one year) stimulant medication on brain DA activity in ADHD have not been evaluated.

Methods To measure dopaminergic responsivity before and after long-term treatment with stimulant medication we assessed dopamine D2 receptor availability (D2R) with placebo (PL) and with intravenous methylphenidate (iv, 0.5 mg/kg) in 18 never-medicated ADHD subjects (31±9 yrs of age) twice, prior to treatment initiation (BL) and after 1 year of treatment with oral MP (FU). D2R availability (Binding PotentialND) was computed from manually drawn ROIs using Logan plots. Dopaminergic responsivity was assessed as changes in D2R availability between iv MP and PL at BL and FU.

Results Prior to treatment, D2R availability in caudate-CA was: 3.0±0.4, in putamen-PU: 3.6±0.3 and in ventral striatum-VS: 3.1±0.5. Long-term MP treatment decreased D2R availability in CA (-10±14%, p < 0.005) and PU (-7±10%, p < 0.006). Dopaminergic responsivity corresponded in CA to -12±11%, p<0.0001; in PU to -26±8%, p<2x10-10; and in VS to -18±15%, p<0.0001 for the evaluation performed at BL. Long-term MP treatment significantly attenuated the dopaminergic responsivity to iv MP in PU (-18±9%) when compared with BL (p<0.005).

Conclusions This study reveals that long-term MP treatment of naïve, adults with ADHD reduced striatal D2R availability and attenuated the responses to iv MP. The attenuated DA responses to iv MP after long-term treatment could underlie the decreases in MP’s efficacy (tolerance). Further study will assess whether the attenuated dopaminergic responsivity is associated therapeutic efficacy.

Research Support NIMH/NIAAA/GCRC & DOE (infrastructure support)