Cognitive vs. Emotional Psychopharmacological Manipulations of Fear vs. Anxiety
Condition: Anxiety Disorder
MeSH terms: Anxiety Disorders
Intervention: Propranolol; Methylphenidate; Placebo
Intervention description: Propranolol 40 mg was given orally during study visit; Methylphenidate 20mg was given orally during study visit; Placebo was given orally during study visit
Intervention MeSH terms: Propranolol; Methylphenidate
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 142.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: No
Keywords: Startle; Induced-Threat; Memory; Stimulant; Cognitive Interference

Summary:

      Objective:

      The overall aim of this protocol is to examine the effect of pharmacological manipulations of
      affective and cognitive processes on anxiety and task performance. Ultimately, the goal is 1)
      to provide insight into the relative influence of cognitive and affective states on anxiety,
      2) generate theoretical models that can be applied to a better understanding of the
      interaction between cognition and emotion, 3) develop a better screening approach to
      candidate anxiolytics, and 4) help formulate novel therapeutic interventions for clinical
      anxiety.

      Excessive or inappropriately sustained anxiety and fear lead to the most common group of
      psychiatric disorders. A number of theoretical models have been proposed to understand the
      mechanisms engaged in these maladaptive behaviors. Most recent emphasis has focused on the
      synergistic contribution of cognitive and emotional processes. Our laboratory has been
      instrumental in delineating aspects of behavioral and neural processes that are associated
      with fear and anxiety, using psychophysiological and neuroimaging measures of fear and
      anxiety. Evidence shows that levels of anxiety modulate cognitive performance, such as
      working memory or perceptual discrimination, and that, conversely, cognitive engagement
      influences severity of experimentally induced anxiety. The exact contribution of emotional
      processes vs. cognitive processes to the experience of anxiety is not clear, similarly to the
      neural mechanisms underlying these interactions.

      In this protocol, we propose to manipulate pharmacologically separately cognitive and
      emotional processes to dissociate their contribution to fear/anxiety, while using
      state-of-the-art measures of anxiety derived from translational work. Indeed, we already
      developed integrative experimental models of fear and anxiety via the manipulation of
      predictable and unpredictable shock, respectively. We already employed successfully these
      models to measure anxiolytic and anxiogenic effects of various compounds such as alprazolam,
      citalopram, hydrocortisone, and oxytocin in healthy participants.

      We propose in a first step (step-1) to start with a simple proof-of-concept study, using two
      pharmacological compounds in a double-blind randomized parallel design, each preferentially
      acting respectively on the cognitive (methylphenidate) or affective (propranolol) domain, and
      using a single cognitive process (working memory). In a second step (step-2), we propose to
      extend this work to the fMRI to examine the cognitive correlates of the effects seen in the
      step-1 behavioral study, specifically with methylphenidate. Whereas the comparison among
      three drugs is planned for the electrophysiology study, we plan to study only the drug that
      improves cognition in the fMRI. The reason we will focus on methylphenidate in step 2 is that
      our overall goal is to study the effect of improving cognitive functions on anxiety using
      neuroimaging. To reach this goal, we plan to use different approaches to boost cognitive
      functions in the coming years, including psychopharmacology, direct current stimulation,
      mindfulness. Methylphenidate is our first psychopharmacological study towards this objective.
      Future work will also expand to other compounds and cognitive processes, as well as vary the
      strategy to induce anxiety. Presently, anxiety will be induced using the threat of shock,
      while participants perform the task. We will examine in step-1 whether 1) the reduction of
      induced-anxiety with propranolol improves cognitive performance, and 2) the facilitation of
      cognitive performance with methylphenidate reduces induced-anxiety. In step-2, we will
      identify the neural mechanisms underlying the effects of methylphenidate, the drug having
      beneficial effects on cognitive function.

      Study population:

      Medically and psychiatrically healthy adult males and females, aged 18 to 50 years.

      Design:

      The study is a double-blind design. For step-1, three groups of healthy participants will
      come for one experimental session. During this session, they will be asked to perform a
      working memory task under the threat of shock, i.e., while anticipating unpleasant electric
      shocks. Each group will receive one drug challenge, either placebo, propranolol (40 g) or
      methylphenidate (20 mg). For step-2, the study tasks will be conducted in a 3T fMRI scanner.
      In this step, only methylphenidate and placebo will be compared. Two groups will come for one
      experimental session, one will receive placebo and the other one will receive methylphenidate
      (20 mg). In a follow-up study for the step-2 fMRI the two groups will come for one
      experimental fMRI session one will receive methylphenidate (60 mg).

      Outcome measures:

      In step-1, the primary outcome measures are the startle reflex and performance on the working
      memory task. In step-2, the primary outcome measures are the startle reflex and the cerebral
      fMRI blood-oxygen-level ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Ages 18-50

          -  Males and females

          -  Subjects give their own consent

        EXCLUSION CRITERIA:

          -  Clinically significant prior exposure to medications, that based on the investigator s
             judgment, may impact the study, such as Ritalin (MPH).

          -  Any significant medical or neurological problems (e.g. cardiovascular illness,
             respiratory illness, neurologic illness, seizure, etc.)

          -  Raynaud syndrome

          -  IQ < 80

          -  Sinus bradycardia (P<45), or tachycardia (P>90)

          -  Significant ECG abnormality (i.e., greater than first-degree block etc.) as determined
             by investigators judgement

          -  High or low blood pressure (SBP>140 or SBP<90; SDP<50 or SDP>90)

          -  A first-degree family history of mania, schizophrenia, or other psychoses based on
             verbal reports

          -  Significant past psychopathology (e.g., hospitalization for psychiatric disorders,
             recurrent depression, suicide attempt, psychoses)

          -  Current psychiatric disorders according to Diagnostic and Statistical Manual (DSM)-V

          -  Current alcohol or substance use disorder

          -  Current use of psychotropic medication

          -  Impaired hearing (clinic study only)

          -  Pregnancy or positive pregnancy test

          -  Neurological syndrome of the wrist (e.g., carpal tunnel syndrome) for shocks to be
             delivered on affected arm.

          -  Breastfeeding

          -  Significant lab abnormalities (i.e., complete blood count (CBC) with differential,
             acute care and mineral panel, hepatic panel, TSH)

          -  Positive urine toxicology screen

          -  You have been in another study with an experimental medication within the previous
             month

          -  For physiological/clinic participants: small startle reactivity (a change in EMG
             activity that is less than 3 times the baseline EMG activity)

          -  Current daily use of anti-acid -medication or within 5 half-lives of study visit if
             taken on pro re nata (PRN) basis

          -  Employee of National Institute of Mental Health (NIMH) or an immediate family member
             who is a NIMH employee.

          -  For functional magnetic resonance imaging (fMRI) participants: Any medical condition
             that increases risk for fMRI:

               -  Any metal implants (clips, screws, plates, pins, etc.) that are not safe for MRI
                  or metal fragments cause by injuries or metal working. Metal implants that are
                  deemed MRI safe are allowable (i.e. certain screws).

               -  Any sort of medical implants that are not safe for the MRI (aneurysm clips,
                  pacemaker, insulin pump, Hickman line, etc.). Medical implants that are MRI safe
                  (Nexplanon implant, certain intrauterine device (IUDs), etc.) are allowable.

               -  Permanent eye liner and tattoos above the neck

               -  Patients who have difficulty lying flat on their back for up to 90 min in the
                  scanner

               -  Participants who are uncomfortable in small closed spaces (have claustrophobia)
                  and would feel uncomfortable in the MRI machine