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Efficacy of Reboxetine and Methylphenidate Treatment on Attentional, Sensory and Emotional Dysregulation in Adults With PTSD

Primary Purpose

Posttraumatic Stress Disorder

Status
Recruiting
Phase
Phase 2
Locations
Israel
Study Type
Interventional
Intervention
Methylphenidate
Reboxetine
Placebo
Placebo
Sponsored by
University of Haifa
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Posttraumatic Stress Disorder focused on measuring Posttraumatic Stress Disorder, Attention Deficit, Sensory Processing, Emotion Regulation, Methylphenidate, Reboxetine, Randomized Controlled Trial, Electroencephalogram, Functional near-infrared spectroscopy

Eligibility Criteria

20 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • diagnosed with PTSD according to DSM-IV or DSM-5 criteria
  • current treatment at the outpatient facilities of Lev HaSharon Netanya Adult Clin
  • age between 20 and 60 years
  • PTSD diagnosis at least one month prior to study inclusion
  • no present-day re-exposure to the traumatic event
  • any psychotropic drug therapy that is being administered must be at a fixed dose for at least one month prior to the study conductance

Exclusion Criteria:

  1. comorbid major psychiatric disorder, e.g. psychotic disorder, unipolar or bipolar disorder, borderline personality disorder, or active suicidal ideation,
  2. ADHD diagnosis,
  3. significant or severe systematic disease that limits normal activity, e.g. autoimmune disease, AIDS or renal failure,
  4. cardiovascular disease, e.g. hypertension, atrioventricular (AV) block, bradycardia, or conduction disorder,
  5. severe disease that is a threat to life, e.g. acute myocardial infarction, respiratory failure, or cancer,
  6. nervous system impairment, e.g. multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, or stroke,
  7. previous or current severe traumatic brain injury,
  8. glaucoma,
  9. impaired hearing,
  10. pregnancy or breastfeeding during study inclusion,
  11. active substance dependency including regular use of medical cannabis,
  12. use of steroid medication in the two months prior to study conductance,
  13. use of medication that may affect the function of the central nervous system,
  14. failure to complete all research steps

Sites / Locations

  • Emek Medical CenterRecruiting
  • University of HaifaRecruiting
  • Lev HaSharon Mental Health CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Treatment with Reboxetine and Methylphenidate

Treatment with Placebo

Arm Description

During the first 3 weeks of the study, subjects in the active treatment group will take reboxetine at a dose of 4mgper day, with the instructions to start at 2mg per day for 3 days and then increase the dosage to 4mg per day for 26 days, i.e. until completion of the study. On day 22 of the study, the patients will take the first dosage of10mg Ritalin or a placebo, and remain in the clinic for 2 hours to guard safety and guidance during possible occurrence of side effects such as anxiety, palpitations, etc. During the observation time in the clinic, 6 Ritalin IR 10mg and 3 Reboxetine 4mg pills will be handed out to the participants. These pills will be taken at the responsibility of the subject at8:00 AM (Ritalin and Reboxetine) and at noon (Ritalin only) at the following three days.

The patients will take placebos according to the medication schedule of the treatment group.

Outcomes

Primary Outcome Measures

Change in Clinician-Administered Posttraumatic Stress Disorder Scale for the Diagnostic and Statistical Manual (DSM)-5 (CAPS-5) between baseline score (before treatment) and score on day 26 (after treatment)
PTSD symptom severity score. Total of 56 questions. Minimum score 0, maximum score 80. A higher score reflects a worse outcome.

Secondary Outcome Measures

Posttraumatic Stress Disorder Symptom Scale (PSS-SR5)
PTSD symptom severity score. Total of 24 questions. Minimum score 0, maximum score 80. A higher score reflects a worse outcome.
Conner's Adult ADHD Rating Scales - Self Report: short version (CAARS-S:S)
ADHD index score. Total of 26 questions. Minimum score 26, maximum score 78. A higher score reflects a worse outcome.
Electroencephalography (EEG)
Electrical brain activity, measured through event-related potentials (ERP)
Functional near-infrared spectroscopy (fNIRS)
Cortical hemodynamic activity, measured through concentrations of oxygenated and deoxygenated hemoglobin.
Electrodermal Activity (EDA)
Electrodermal activity, measured through sweat secretion on digit 2 and digit 4 of right hand.
Auditory Sustained Attention Test (ASAT)
Pre-pulse inhibition, measured through the eyeblink reflex at the level of the musculus orbicularis oculi 1cm below the pupil.
Adolescent/Adult Sensory Profile Questionnaire (AASP)
Sensory profile. Total of 60 questions. Minimum score 60, maximum score 300. A higher score reflects a worse outcome.
Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A)
Global executive composite. Total of 75 questions. Minimum score 75, maximum score 225. A higher score reflects a worse outcome.
Daily Life Questionnaire (DLQ)
Daily life limitations. Total of 59 questions. Minimum score 28, maximum score 112. A higher score reflects a worse outcome.
World Health Organization Quality of Life Questionnaire - BREF (WHOQOL-BREF)
Quality of Life. Total of 26 questions. Minimum score 24, maximum score 120. A higher score reflects a better outcome.

Full Information

First Posted
October 4, 2021
Last Updated
October 5, 2023
Sponsor
University of Haifa
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1. Study Identification

Unique Protocol Identification Number
NCT05133804
Brief Title
Efficacy of Reboxetine and Methylphenidate Treatment on Attentional, Sensory and Emotional Dysregulation in Adults With PTSD
Official Title
The Relation Between Attentional, Sensory and Emotional Dysregulation in Adults With Posttraumatic Stress Disorder: a Double-blind, Placebo-controlled Randomized Controlled Trial of the Combined Treatment With Reboxetine and Methylphenidate
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2022 (Actual)
Primary Completion Date
February 1, 2024 (Anticipated)
Study Completion Date
March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Haifa

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Up-to-date, no studies have examined the attentional, sensory and emotional processing (difficulties) among patients diagnosed with Posttraumatic Stress Disorder (PTSD). In addition, the efficiency of drug treatments that focus on the noradrenergic and dopaminergic, and thus influence attention processing and PTSD symptoms through these pathways, have only briefly been investigated. There is well-established and long-standing evidence for the involvement of dopamine and noradrenaline in attentional function. This previously led to an investigation by the investigator's research lab in which the investigators hypothesized the involvement of an attentional disorder would influence PTSD symptoms in a rat model. Based on these results, the current study aims to characterize attentional deficits in patients with PTSD, as well as the correlation between attention, emotional regulation and sensory processing. The investigators do this partially by conducting a case-control study and through a subsequent double-blind RCT (with only the cases). The patients will be either treated with reboxetine + methylphenidate or placebo.
Detailed Description
Posttraumatic stress disorder (PTSD) is a highly impairing psychiatric disorder, characterized by re-experiencing, avoidance behaviour, emotional numbing, and hyperarousal after traumatic exposure. Current treatments mainly focus on non-cognitive symptoms and are only partially effective: one third of PTSD patients will find symptoms to be chronic and progressive; highly impacting daily function and quality of life. Arising evidence suggests a correlation between impaired attention, sensory dysfunction, and PTSD symptoms. Thus, the importance of combined treatment, focused on concentration difficulties as often found PTSD, has been suggested. Two suggested leads are reboxetine and methylphenidate. Hypothesising that impaired attentional and sensory processing induces re-experiencing with avoidance and hyperarousal as coping strategies, the investigators aim to elucidate the neuro-dysregulation characteristics of each of the PTSD symptoms, with focus on attention, executive function and sensory processing, and relate to their implications on daily life function, following a novel combined treatment strategy of reboxetine and methylphenidate (Ritalin). A case-control study will be conducted, including 53adult patients with PTSD and 53 matched healthy controls. First, a baseline measure will be performed amongst all participants to create a population profile. Then, patients will be randomised into an active treatment group (n=27) and a placebo group (n=26) for a double-blind randomized controlled trial, investigating the effect of a 3-week treatment with reboxetine 4mg per day and a one-week addition of Ritalin 10mg twice a day. This research will include established and innovative neurophysiological measures and questionnaires. A PTSD symptom profile will be created combining the Clinician-Administered Posttraumatic Stress Disorder Scale and Posttraumatic Stress Disorder Symptom Scale. Brain activity will be measured using functional near-infrared spectroscopy (fNIR) or electroencephalography, with the Auditory Sustained Attention Test (ASAT) and Electrodermal Activity (EDA). Together with the Conners' Adult Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale - Short Version, the ASAT and EDA will create an attentional profile. Furthermore, a sensory profile consisting of the Adolescent/Adult Sensory Profile Questionnaire, and an executive function profile measured with the Behavior Rating Inventory of Executive Function will be created. Finally, in order to relate to individual experiences in real-life context, this research measures activities through the Daily Living Questionnaire and quality of life with the World Health Organization Quality of Life Instrument. Using a translational research paradigm, this research is one of the first to investigate neuro-dysregulation in PTSD with a focus on sensory processing and executive function, with emphasis on attention and behaviour. It is also the first research to integrate the fNIR with the ASAT and EDA, thus contributing to the technological advancing of clinical research. This research will gather innovative data that may offer new explanations of PTSD symptoms and allow for further development of treatment interventions needed to reduce the burden of disease and optimise quality of life.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Posttraumatic Stress Disorder
Keywords
Posttraumatic Stress Disorder, Attention Deficit, Sensory Processing, Emotion Regulation, Methylphenidate, Reboxetine, Randomized Controlled Trial, Electroencephalogram, Functional near-infrared spectroscopy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Patients will be randomized into two groups: either treatment with medication or treatment with placebo. In addition, within each group patients will be randomized into a group for EEG recording and a group for fNIRS recording. This is a non-interventional randomization.
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
53 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment with Reboxetine and Methylphenidate
Arm Type
Experimental
Arm Description
During the first 3 weeks of the study, subjects in the active treatment group will take reboxetine at a dose of 4mgper day, with the instructions to start at 2mg per day for 3 days and then increase the dosage to 4mg per day for 26 days, i.e. until completion of the study. On day 22 of the study, the patients will take the first dosage of10mg Ritalin or a placebo, and remain in the clinic for 2 hours to guard safety and guidance during possible occurrence of side effects such as anxiety, palpitations, etc. During the observation time in the clinic, 6 Ritalin IR 10mg and 3 Reboxetine 4mg pills will be handed out to the participants. These pills will be taken at the responsibility of the subject at8:00 AM (Ritalin and Reboxetine) and at noon (Ritalin only) at the following three days.
Arm Title
Treatment with Placebo
Arm Type
Placebo Comparator
Arm Description
The patients will take placebos according to the medication schedule of the treatment group.
Intervention Type
Drug
Intervention Name(s)
Methylphenidate
Other Intervention Name(s)
Ritalin
Intervention Description
Ritalin 10mg
Intervention Type
Drug
Intervention Name(s)
Reboxetine
Intervention Description
Reboxetine 4mg
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo matched to Reboxetine
Intervention Description
Placebo matched to Reboxetine
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo matched to Ritalin
Intervention Description
Placebo matched to Ritalin
Primary Outcome Measure Information:
Title
Change in Clinician-Administered Posttraumatic Stress Disorder Scale for the Diagnostic and Statistical Manual (DSM)-5 (CAPS-5) between baseline score (before treatment) and score on day 26 (after treatment)
Description
PTSD symptom severity score. Total of 56 questions. Minimum score 0, maximum score 80. A higher score reflects a worse outcome.
Time Frame
Day 1 and day 26
Secondary Outcome Measure Information:
Title
Posttraumatic Stress Disorder Symptom Scale (PSS-SR5)
Description
PTSD symptom severity score. Total of 24 questions. Minimum score 0, maximum score 80. A higher score reflects a worse outcome.
Time Frame
Day 1 and day 26
Title
Conner's Adult ADHD Rating Scales - Self Report: short version (CAARS-S:S)
Description
ADHD index score. Total of 26 questions. Minimum score 26, maximum score 78. A higher score reflects a worse outcome.
Time Frame
Day 1 and day 26
Title
Electroencephalography (EEG)
Description
Electrical brain activity, measured through event-related potentials (ERP)
Time Frame
Day 1, day 21 and day 26
Title
Functional near-infrared spectroscopy (fNIRS)
Description
Cortical hemodynamic activity, measured through concentrations of oxygenated and deoxygenated hemoglobin.
Time Frame
Day 1, day 21 and day 26
Title
Electrodermal Activity (EDA)
Description
Electrodermal activity, measured through sweat secretion on digit 2 and digit 4 of right hand.
Time Frame
Day 1, day 21 and day 26
Title
Auditory Sustained Attention Test (ASAT)
Description
Pre-pulse inhibition, measured through the eyeblink reflex at the level of the musculus orbicularis oculi 1cm below the pupil.
Time Frame
Day 1, day 21 and day 26
Title
Adolescent/Adult Sensory Profile Questionnaire (AASP)
Description
Sensory profile. Total of 60 questions. Minimum score 60, maximum score 300. A higher score reflects a worse outcome.
Time Frame
Day 1 and day 26
Title
Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A)
Description
Global executive composite. Total of 75 questions. Minimum score 75, maximum score 225. A higher score reflects a worse outcome.
Time Frame
Day 1 and day 26
Title
Daily Life Questionnaire (DLQ)
Description
Daily life limitations. Total of 59 questions. Minimum score 28, maximum score 112. A higher score reflects a worse outcome.
Time Frame
Day 1 and day 26
Title
World Health Organization Quality of Life Questionnaire - BREF (WHOQOL-BREF)
Description
Quality of Life. Total of 26 questions. Minimum score 24, maximum score 120. A higher score reflects a better outcome.
Time Frame
Day 1 and day 26

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: diagnosed with PTSD according to DSM-IV or DSM-5 criteria current treatment at the outpatient facilities of Lev HaSharon Netanya Adult Clin age between 20 and 60 years PTSD diagnosis at least one month prior to study inclusion no present-day re-exposure to the traumatic event any psychotropic drug therapy that is being administered must be at a fixed dose for at least one month prior to the study conductance Exclusion Criteria: comorbid major psychiatric disorder, e.g. psychotic disorder, unipolar or bipolar disorder, borderline personality disorder, or active suicidal ideation, ADHD diagnosis, significant or severe systematic disease that limits normal activity, e.g. autoimmune disease, AIDS or renal failure, cardiovascular disease, e.g. hypertension, atrioventricular (AV) block, bradycardia, or conduction disorder, severe disease that is a threat to life, e.g. acute myocardial infarction, respiratory failure, or cancer, nervous system impairment, e.g. multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, or stroke, previous or current severe traumatic brain injury, glaucoma, impaired hearing, pregnancy or breastfeeding during study inclusion, active substance dependency including regular use of medical cannabis, use of steroid medication in the two months prior to study conductance, use of medication that may affect the function of the central nervous system, failure to complete all research steps
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Avi Avital, PhD
Phone
+972-4-8420-364
Email
avitalavi@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Avi Avital, PhD
Organizational Affiliation
University of Haifa
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Batya Engel-Yeger, PhD
Organizational Affiliation
University of Haifa
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Inbal Brenner, MD
Organizational Affiliation
Lev HaSharon Mental Health Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Tsipi Milman, MD
Organizational Affiliation
Emek Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emek Medical Center
City
Afula
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tsipi Milman, MD
Email
tsipimi@clalit.org.il
Facility Name
University of Haifa
City
Haifa
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Avi Avital, PhD
Phone
+972-4-8420-364
Email
avitalavi@hotmail.com
First Name & Middle Initial & Last Name & Degree
Batya Engel-Yeger, PhD
Phone
+972-4-828-8387
Email
bengel@univ.haifa.ac.il
First Name & Middle Initial & Last Name & Degree
Janne Hoogervorst, MD
Facility Name
Lev HaSharon Mental Health Center
City
Netanya
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inbal Brenner, MD
Phone
+972 9 8981111
Email
inbalbrenner@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
25247592
Citation
Aga-Mizrachi S, Cymerblit-Sabba A, Gurman O, Balan A, Shwam G, Deshe R, Miller L, Gorodetsky N, Heinrich N, Tzezana O, Zubedat S, Grinstein D, Avital A. Methylphenidate and desipramine combined treatment improves PTSD symptomatology in a rat model. Transl Psychiatry. 2014 Sep 23;4(9):e447. doi: 10.1038/tp.2014.82.
Results Reference
background
PubMed Identifier
26361060
Citation
McAllister TW, Zafonte R, Jain S, Flashman LA, George MS, Grant GA, He F, Lohr JB, Andaluz N, Summerall L, Paulus MP, Raman R, Stein MB. Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury. Neuropsychopharmacology. 2016 Apr;41(5):1191-8. doi: 10.1038/npp.2015.282. Epub 2015 Sep 11.
Results Reference
background

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Efficacy of Reboxetine and Methylphenidate Treatment on Attentional, Sensory and Emotional Dysregulation in Adults With PTSD

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