A Pilot Dose-Response Biomarker Study of Brexpiprazole Treatment in PTSD
Condition: Post Traumatic Stress Disorder
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Intervention: Brexpiprazole
Intervention description: Comparison of brexpiprazole 2mg to placebo Comparison of brexpiprazole 4mg to placebo
Intervention MeSH terms: Brexpiprazole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      Determine if brexpiprazole treatment will be associated with a dose-dependent reduction in
      resting pupil diameter as a reflection of locus coeruleus (LC) norepinephrine (NE) neuron
      target engagement in a group of subjects with PTSD. All subjects will be evaluated by
      physical examination, ECG, standard blood chemistry, hematologic labs, toxicology testing,
      and urinalysis. Results of these studies must demonstrate a lack of clinically significant
      abnormalities prior to enrollment. Subjects will need to satisfy DSM-5 criteria for PTSD and
      receive a CAPS-5 score of 40 or greater on testing for study enrollment. Resting pupil
      diameter during pupillometric evaluation after two weeks on each treatment will serve as the
      primary outcome measure. This will be compared in the treatment groups using mixed effects
      repeated measures models to evaluate if there is a significant difference in pupil size among
      the treatments studied. As a secondary analysis this approach will be used to evaluate
      whether there is treatment effect on total CAPS-5 score. Lastly, the investigators will
      compute correlations between pupil size and CAPS-5 scores.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants will be 18-65 years of age.

          -  All subjects will be evaluated by physical examination, ECG, standard blood chemistry,
             hematologic labs, toxicology testing, and urinalysis at baseline and end of study.
             Results of these studies must demonstrate a lack of clinically significant
             abnormalities prior to enrollment. If results are outside of the normal reference
             range the study physician will be consulted to assess if clinically significant.

          -  Subjects will need to satisfy DSM-5 criteria for PTSD and receive a CAPS-5 score of 40
             or greater on testing for study enrollment.

          -  Subjects will need to be free of psychotropic medications or treatments that could
             impact results of this study as deemed by the PI for at least 1 week.

          -  If the subject's primary psychiatrist or treating primary care physician are providing
             the subject with psychotropic medications they will be notified and a discussion about
             tapering current psychotropic medications prior to study enrollment will occur.

        Exclusion Criteria:

          1. Subjects will be excluded if they have significant medical or neurologic conditions
             (other than mild to moderate TBI), specifically seizures, or movement disorders,

          2. have substance abuse within 12 months of study enrollment, substance dependence within
             past three months, per DSM-5 criteria (excluding caffeine and nicotine). The absence
             of substance use will be determined by self-report and confirmed by the results of
             urine toxicology at screening.

          3. Women who are pregnant, breast-feeding, or planning to become pregnant while enrolled
             in this study will also be excluded.

          4. Subjects with a history of severe drug allergy or hypersensitivity, or known
             hypersensitivity to the Brexpiprazole or its ingredients.

          5. The subject has a history of tardive dyskinesia.

          6. The subject has clinically significant extrapyramidal symptoms (EPS) including
             akathisia.

          7. The subject has epilepsy or a history of seizures, except for a single seizure episode
             (e.g., childhood febrile seizure, post traumatic, or alcohol withdrawal).

          8. The subject has chronic, uncontrolled, or unstable clinically relevant medical
             conditions Including:

               -  Uncontrolled hypertension defined as blood pressure greater than 180/90

               -  Hypotension defined as a blood pressure less than 90/60

               -  Moderate to severe hepatic impairment (Child-Pugh score ≥7)

               -  Moderate, Severe or End-Stage Renal Impairment (CrCL <60ml/min)

               -  Known CYP2DG Poor Metabolizers

               -  Heart failure NYHA Class III or IV

               -  Diabetes mellitus or HbA1c greater than 5.7% (which defines pre-diabetes)

               -  Hypertriglyceridemia defined as triglycerides greater than 200mg/dL

               -  Low white blood cell count (below lower range of normal)

               -  History of leukopenia or neutropenia

               -  Arrhythmia with heart rate greater than 100bpm

               -  Myocardial infarction in the past 6 months

               -  Cerebrovascular accident in the past 6 months

               -  Recurrent syncope

               -  Seizure disorder

               -  Currently receiving treatment for malignancy

               -  QTc interval of greater than 450ms on electrocardiogram

          9. The subject has a neurodegenerative disorder (Alzheimer disease, Parkinson's disease,
             multiple sclerosis, Huntington disease, etc.).