Measurement of psychological state changes at low dopamine transporter occupancy following a clinical dose of mazindol

Rationale: The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. Objectives: The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. Methods: Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [¹⁸F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [¹¹C]raclopride binding. Results: Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24–25 %, and the binding potential of [¹¹C]raclopride was reduced by 2.8–4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [¹¹C]raclopride binding in the limbic striatum. Conclusions: A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [¹¹C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. Trial registration <ref-website><ce_e-address>https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009703</ce_e-address><RefTarget Address="https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009703"