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.
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.
1. Signed written informed consent to participate in the study.
2. Age: 18 - 35
3. If female, non-pregnant, non-nursing with a negative serum pregnancy test and using
an adequate form of birth control.
4. Supine and standing blood pressure within the range 110/60 to 150/95 mmHg.
5. Heart rate, after resting for 5 minutes, within the range 46-90 beats/min.
1. Diagnosis of any psychotic disorder, bipolar disorder, severe depression, severe
anxiety, or Autism.
Subjects with mild mood, oppositional, conduct, and anxiety disorders may be
permitted to participate if considered appropriate by the investigator.
2. Scores of Baseline Scales:
Hamilton Depression Scale > 17 (out of a possible 67 on the 21-item scale)(Hamilton
1960) Beck Depression Inventory > 19 (out of a possible 63 on the 21-item
scale)(Beck, Ward et al. 1961) Hamilton Anxiety Scale > 21 (out of a possible 56 on
the 14-item scale) (Hamilton 1959)
3. Tics or Tourette's Syndrome.
4. History of head trauma with loss of consciousness, organic brain disorders, seizures,
or neurosurgical intervention.
5. Any clinically significant chronic medical condition, in the judgment of the
6. Mental impairment as evidenced by an I.Q. <75.
7. Exposure to dopamine receptor antagonists within the previous three (3) months.
8. Exposure to radiopharmaceuticals within four (4) weeks prior to PET scan.
9. Subjects receiving psychotropic medication.
10. Any clinically significant abnormality in the screening laboratory tests, vital
signs, or 11-lead ECG, outside of normal limits.
11. Any woman of childbearing potential who is seeking to become pregnant or suspects
that she may be pregnant.
12. Subjects with a known recent history (within the past six (6) months) of illicit drug
or alcohol dependence.