Pharmacologically-augmented Cognitive Therapies (PACTs) for Schizophrenia.
Condition: Schizophrenia
MeSH terms: Schizophrenia
Intervention: Dextroamphetamine; Placebo
Intervention description: Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) and completes approximately 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.; Each participant receives a single pill of placebo or active drug (dextroamphetamine 10 mg) and completes approximately 6 hours of testing in the laboratory. One week later, that participant receives a single pill of the alternate comparator and is again tested in the laboratory. Thus, in total, each participant receives one placebo pill and one active pill, separated by one week.
Intervention MeSH terms: Amphetamine; Dextroamphetamine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 82.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Schizophrenia; Schizoaffective Disorder; Mental Disorders; Anti-Dyskinesia Agents; Antiparkinson Agents; Central Nervous System Agents; Dopamine Agents; Excitatory Amino Acid Agents; Excitatory Amino Acid Antagonists; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Pharmacologic Actions; Physiological Effects of Drugs; Therapeutic Uses; Prepulse inhibition; Neurocognition; Working memory; Dextroamphetamine; MATRICS Consensus Cognitive Battery; Pharmacologic Augmentation of Cognitive Therapies; Sensory discrimination learning; Targeted Cognitive Training; rs4680 polymorphism of catechol-O-methyltransferase (COMT)

Summary:

      This application seeks renewed support for MH59803, "Dopaminergic substrates of startle
      gating across species," to extend a clear path of "bench-to-bedside" progress towards a
      critical paradigm shift in therapeutic models for schizophrenia (SZ) and schizoaffective
      disorder, depressed type (SZA): the use of Pharmacologic Augmentation of Cognitive Therapies
      (PACTs). This novel therapeutic strategy for SZ/SZA directly addresses the need for more
      effective treatments for this devastating disorder. MH59803 has investigated the neural
      regulation of laboratory-based measures of deficient information processing in SZ/SZA
      patients, using rodents and healthy human subjects (HS) to explicate the biology of these
      deficits, and to establish a rational basis for developing novel therapies for SZ/SZA. In its
      first 9 years, MH59803 studies of the neural regulation of prepulse inhibition (PPI) of
      startle in rats focused on basic neurobiological and molecular mechanisms. Over the past 2
      years of support, MH59803 studies moved "from bench-to-bedside," focusing on dopamine (DA)
      agonist effects on PPI and neurocognition in HS, and their regulation by genes identified in
      cross-species studies. These studies detected biological markers that predict PPI-enhancing
      and pro-cognitive effects of the DA releaser, amphetamine (AMPH) in humans, leading to
      specific predictions of AMPH effects on PPI, neurocognition and Targeted Cognitive Training
      in SZ/SZA patients. If confirmed in the present application, these predictions could help
      transform therapeutic approaches to SZ/SZA. This renewal application of MH59803 thus reflects
      a logical progression of studies at systems and molecular levels, translated first to HS, and
      now to potentially transformative therapeutic models in SZ/SZA patients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  18-55 years old:

          -  Drug Free (No recreational/street drugs)

          -  Diagnosis of Schizophrenia or Schizoaffective Disorder, Depressed Type

          -  Must be stable on antipsychotic medication for at least 1 month

          -  Any medications other than antipsychotic medications need to be stable for at least 1
             week

        Exclusion Criteria:

          -  Dominant hand injury

          -  Hearing impairment at 40 dB

          -  Irregular menstrual cycle or cycle is no within in 25-35 days (menopausal is eligible)

          -  EKG, conduction abnormalities confirmed by cardiologist

          -  Reading component of Wide Range Achievement Test 4 (WRAT4) Score less than 70

          -  Any serious illness, including: Insulin-dependent diabetes, HIV, AIDS, cancer, stroke,
             heart attack, uncontrolled hypothyroidism

          -  Sleep apnea

          -  A diagnosis of epilepsy or history of seizures with loss of consciousness

          -  Open/closed head injury with loss of consciousness greater than 1 minute at any time
             in the lifetime

          -  Blood pressure: Systolic Blood Pressure < 90 or > 160, Diastolic Blood Pressure < 45
             or > 95

          -  Heart Rate < 55 or > 110

          -  Current use of Dexatrim or drugs containing phenylephrine (eligible if not used for at
             least 72 hours prior to participation)

          -  Current use of St. John's Wort, Milk Thistle (eligible if for at least 1 month)

          -  Self report of any illicit drug use within the last 30 days

          -  Positive urine toxicology

          -  Self-report of any use of ecstasy, lysergic acid diethylamide (LSD), mushrooms, gamma
             hydroxybutyrate (GHB), ketamine, phencyclidine (PCP), heroin or any intravenous-drugs
             within past year

          -  If there is a history of substance abuse/addiction, participant must be in remission
             for at least 6 months

          -  Within 1 month of recent psychiatric hospitalization

          -  Current mania

          -  Dementia/Alzheimer's diagnosis

          -  Mania episode meeting criteria outlined in the MINI-International Neuropsychiatric
             Interview Plus 6.0 (M.I.N.I. plus 6.0) anytime in the lifetime (hypomania/Bipolar II
             eligible)