PET Study Examining the Dopaminergic Activity of Armodafinil in Adults
Condition: Healthy
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The specific aims of this study are 1) to document the Dopamine Transporter (DAT) receptor
      occupancy of armodafinil using positron emission tomography (PET) scanning with C-11
      altropane as the ligand and 2) to document the increased intrasynaptic dopamine produced by
      armodafinil using PET scanning with C-11 raclopride as the ligand. We hypothesize that DAT
      occupancy will be low with armodafinil; less than the DAT occupancy produced by therapeutic
      doses of methylphenidate. We also hypothesize that increases in intrasynaptic dopamine will
      be relatively low with armodafinil.
    

Detailed description: 
      Modafinil produces a unique spectrum of pharmacological effects including enhanced vigilance,
      arousal, and wakefulness in human subjects (Bastuji and Jouvet 1988). The drug is widely used
      to treat narcolepsy (Banerjee, Vitiello et al. 2004), but is also effective in Attention
      Deficit Hyperactivity Disorder (ADHD) (Biederman, Swanson et al. 2005). Notwithstanding the
      expanding clinical indications for modafinil, the neurochemical mechanisms that produce
      therapeutic improvement remain unresolved. Pre-clinically, modafinil is a weak inhibitor of
      the DAT, and displays no affinity for dopamine receptor subtypes (Mignot, Nishino et al.
      1994). Further evidence supporting low dopaminergic activity is the low abuse potential of
      modafinil (Jasinski 2000). Various theories have been proposed as alternative modes of action
      including enhancement of glutamate release and inhibition of Gamma-aminobutyric acid (GABA)
      release in various brain regions (Ferraro, Antonelli et al. 1997; Ferraro, Antonelli et al.
      1997; Ferraro, Antonelli et al. 1999). However, the exact mechanisms of action of modafinil
      and the principle active metabolite, armodafinil, are unknown. Understanding these mechanisms
      of action is important in assessing the potential therapeutic role of armodafinil. We will
      test to see if there are differences in the degree of DAT occupancy and D2 binding of
      armodafinil compared with that of traditional stimulants.

      The main target of typical stimulants in the brain is the dopamine transporter (DAT) (Volkow,
      Wang et al. 1998). We have an exquisitely sensitive methodology to measure DAT occupancy
      using C-11 altropane and Positron Emission Tomography (PET) (Fischman, Bonab et al. 2001).
      Our group has previously documented the central nervous system pharmacokinetics of several
      psychiatric drugs (including methylphenidate) using similar techniques. (Christian, Livni et
      al. 1996; Fischman, Bonab et al. 1996; Fischman, Alpert et al. 1997; Salazar and Fischman
      1999; Fischman, Alpert et al. 2002; Spencer, Biederman et al. 2006).

      Increases in intrasynaptic (extracellular) dopamine concentrations associated with
      medications are routinely measured by changes in C-11 raclopride binding in PET scans. C-11
      raclopride binds to postsynaptic D-2 receptors. If the intrasynaptic concentration of
      dopamine increases, it competes with raclopride leading to a weaker signal (i.e. decreased
      raclopride binding to D-2 receptors). After administration of a stimulant, associated
      increases in intrasynaptic dopamine compete with C-11 raclopride binding in this manner
      (Volkow, Wang et al. 2002). By using this technology we can document the change in D-2
      binding in the intrasynaptic space achieved by armodafinil, and compare it to that achieved
      by a typical stimulant.

      To this end, using two PET ligands (C-11 altropane and C-11 raclopride), this protocol seeks
      to compare the DAT receptor occupancy and the increased intrasynaptic dopamine produced by
      armodafinil to previous studies of methylphenidate. This research will provide novel and
      unique information toward better understanding the mechanisms of action of armodafinil in
      comparison to those of typical stimulants.
    

Intervention name(s): armodafinil
Intervention type(s): Drug
Intervention description(s): tablet, taken by mouth, once each study day
Other intervention name(s): Nuvigil
Intervention MeSH terms: Modafinil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Adults; Healthy Volunteers; Nuvigil; Armodafinil; DAT occupancy in healthy volunteers