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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Posttraumatic Stress Disorder
• Intervention / Treatment: Drug: Methylphenidate; Drug: Reboxetine; Drug: Placebo; Drug: 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.

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Avi Avital, PhD; Phone Number: +972-4-8420-364; Email: avitalavi@hotmail.com

Study Locations

• Israel
  • Afula, Israel
    • Recruiting
    • Emek Medical Center
    • Contact: Tsipi Milman, MD; Email: tsipimi@clalit.org.il
  • Haifa, Israel
    • Recruiting
    • University of Haifa
    • Contact: Avi Avital, PhD; Phone Number: +972-4-8420-364; Email: avitalavi@hotmail.com
    • Contact: Batya Engel-Yeger, PhD; Phone Number: +972-4-828-8387; Email: bengel@univ.haifa.ac.il
    • Sub-Investigator: Janne Hoogervorst, MD
  • Netanya, Israel
    • Recruiting
    • Lev Hasharon Mental Health Center
    • Contact: Inbal Brenner, MD; Phone Number: +972 9 8981111; Email: inbalbrenner@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment with Reboxetine and Methylphenidate; 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.	Drug: Methylphenidate; Ritalin 10mg; Other Names: Ritalin; Drug: Reboxetine; Reboxetine 4mg
Placebo Comparator: Treatment with Placebo; The patients will take placebos according to the medication schedule of the treatment group.	Drug: Placebo; Placebo matched to Reboxetine; Other Names: Placebo matched to Reboxetine; Drug: Placebo; Placebo matched to Ritalin; Other Names: Placebo matched to Ritalin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1 and day 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1 and day 26
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.	Day 1 and day 26
Electroencephalography (EEG)	Electrical brain activity, measured through event-related potentials (ERP)	Day 1, day 21 and day 26
Functional near-infrared spectroscopy (fNIRS)	Cortical hemodynamic activity, measured through concentrations of oxygenated and deoxygenated hemoglobin.	Day 1, day 21 and day 26
Electrodermal Activity (EDA)	Electrodermal activity, measured through sweat secretion on digit 2 and digit 4 of right hand.	Day 1, day 21 and day 26
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.	Day 1, day 21 and day 26
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.	Day 1 and day 26
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.	Day 1 and day 26
Daily Life Questionnaire (DLQ)	Daily life limitations. Total of 59 questions. Minimum score 28, maximum score 112. A higher score reflects a worse outcome.	Day 1 and day 26
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.	Day 1 and day 26

Collaborators and Investigators

• Sponsor: University of Haifa
• Investigators: Principal Investigator: Avi Avital, PhD, University of Haifa; Principal Investigator: Batya Engel-Yeger, PhD, University of Haifa; Principal Investigator: Inbal Brenner, MD, Lev Hasharon Mental Health Center; Principal Investigator: Tsipi Milman, MD, Emek Medical Center

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Estimated): February 1, 2024
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: October 4, 2021
• First Submitted That Met QC Criteria: November 11, 2021
• First Posted (Actual): November 24, 2021

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Electroencephalogram; Emotion Regulation; Posttraumatic Stress Disorder; Methylphenidate; Attention Deficit; Sensory Processing; Reboxetine; Functional near-infrared spectroscopy
• Additional Relevant MeSH Terms: Mental Disorders; Trauma and Stressor Related Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Adrenergic Uptake Inhibitors; Methylphenidate; Reboxetine
• Other Study ID Numbers: LH9/2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No