Clinical trial NCT05133804: 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
Overall status: RECRUITING
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder
Keywords: Posttraumatic Stress Disorder
Attention Deficit
Sensory Processing
Emotion Regulation
Methylphenidate
Reboxetine
Randomized Controlled Trial
Electroencephalogram
Functional near-infrared spectroscopy
Lead sponsor: University of Haifa
Sponsor class: OTHER
First posted: 2021-11-24
Enrollment: 53
Sex: ALL
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

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:

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

Primary outcomes:
measure: 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)
timeFrame: Day 1 and day 26
Secondary outcomes:
measure: Posttraumatic Stress Disorder Symptom Scale (PSS-SR5)
timeFrame: Day 1 and day 26
measure: Conner's Adult ADHD Rating Scales - Self Report: short version (CAARS-S:S)
timeFrame: Day 1 and day 26
measure: Electroencephalography (EEG)
timeFrame: Day 1, day 21 and day 26
measure: Functional near-infrared spectroscopy (fNIRS)
timeFrame: Day 1, day 21 and day 26
measure: Electrodermal Activity (EDA)
timeFrame: Day 1, day 21 and day 26
measure: Auditory Sustained Attention Test (ASAT)
timeFrame: Day 1, day 21 and day 26
measure: Adolescent/Adult Sensory Profile Questionnaire (AASP)
timeFrame: Day 1 and day 26
measure: Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A)
timeFrame: Day 1 and day 26
measure: Daily Life Questionnaire (DLQ)
timeFrame: Day 1 and day 26
measure: World Health Organization Quality of Life Questionnaire - BREF (WHOQOL-BREF)
timeFrame: Day 1 and day 26
Other outcomes:
Locations:
city: Afula
country: Israel
facility: Emek Medical Center
city: Haifa
country: Israel
facility: University of Haifa
city: Netanya
country: Israel
facility: Lev HaSharon Mental Health Center
Study officials:
affiliation: University of Haifa
name: Avi Avital, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Haifa
name: Batya Engel-Yeger, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lev HaSharon Mental Health Center
name: Inbal Brenner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emek Medical Center
name: Tsipi Milman, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.