Treatment of Pediatric Post-traumatic Stress Disorder With Memory Reactivation Under the Influence of Propranolol

Official title

Treatment of Pediatric Post-traumatic Stress Disorder With Memory Reactivation Under the Influence of Propranolol: A Randomized Placebo-controlled Trial. PPP

Overview

By age 18, roughly 8% of traumatized youth have met criteria for a diagnosis of PTSD, with numbers rising up to 40% in cases of sexual abuse and assault. To date there is no empirical support for the use of psychopharmacological interventions as treatment of pediatric PTSD. Trauma-focused psychotherapeutic/TFP approaches should be favored in childhood PTSD. However, when compared to active control conditions, TFP produced a mean effect size on child and adolescents population (g=0.83). Moreover, in therapies with a substantial exposure component, the intense and lengthy reexperiencing of the traumatic event results in a substantial proportion of participants dropping out. The reactivation of a previously consolidated memory can make it labile, subsequently requiring a re-stabilization of it called reconsolidation of the memory. Acting on these reconsolidation processes makes possible to interfere with the subsequent storage of this memory.

Detailed description

By age 18, roughly 8% of traumatized youth have met criteria for a diagnosis of PTSD, with numbers rising up to 40% in cases of sexual abuse and assault. To date there is no empirical support for the use of psychopharmacological interventions as treatment of pediatric PTSD. Trauma-focused psychotherapeutic/TFP approaches should be favored in childhood PTSD. However, when compared to active control conditions, TFP produced a mean effect size on child and adolescents population (g=0.83). Moreover, in therapies with a substantial exposure component, the intense and lengthy reexperiencing of the traumatic event results in a substantial proportion of participants dropping out.

The reactivation of a previously consolidated memory can make it labile, subsequently requiring a re-stabilization of it called reconsolidation of the memory.

Acting on these reconsolidation processes makes possible to interfere with the subsequent storage of this memory.

The combination of the targeted reactivation of the traumatic memory and the intake of an agent that decreases the reconsolidation can thus disrupt the recall of unwanted memories and thus serve as a treatment for people suffering from traumatic memories, such as in PTSD.

Since stimulation of β-noradrenergic receptors facilitates the consolidation of memories as well as their re-consolidation, an antagonist of these receptors, propranolol, has generated considerable interest as a treatment to alleviate emotional and traumatic memories in individuals with PTSD.

In adults diagnosed with long-standing PTSD two 6-week, double-blind, placebocontrolled, randomised clinical trials, one in 60 subjects and the other in 67 have shown promising results. PTSD participants who actively recalled their traumatic event under the influence of propranolol once a week for up to 6 weeks showed a substantial decrease in symptom ratings compared with placebo. Thus, all of this data led the team to propose a comparable design study in children with PTSD

Interventions

• Drug Propranolol Oral Product
  Child will receive oral propranolol (syrup). The dose of propranolol will increase gradually over the first 3 treatment sessions in order to assess tolerance.
• Drug Placebo
  Child will receive oral placebo (syrup). The dose of placebo will increase gradually over the first 3 treatment sessions in order to match propranolol intervention.
• Other memory reactivation
  90 minutes after the propranolol take, a trained psychologist will ask the child to recount his trauma.

Primary outcome measures

• Child Post-Traumatic Stress Reaction Index/CPTS-RI [Time frame: week 8]

Secondary outcome measures (12)

• Child Post-Traumatic Stress Reaction - Week 32 Index/CPTS-RI [Time frame: week 32]
• Child Post-Traumatic Stress Reaction - Week 60 Index/CPTS-RI [Time frame: week 60]
• Child PTSD Checklist-Child version/CPC-C total score [Time frame: Week 8]
• Child PTSD Checklist-Child version/CPC-C total score - Week 32 [Time frame: Week 32]
• Child PTSD Checklist-Child version/CPC-C total score - Week 60 [Time frame: Week 60]
• Child PTSD Checklist-Parent version/CPC-P total score - Week 32 [Time frame: Week 32]
• Child PTSD Checklist-Parent version/CPC-P total score - Week 60 [Time frame: Week 60]
• Child PTSD Checklist-Parent version/CPC-P total score [Time frame: Week 8]
• Kiddie-SADS-Present and Lifetime Version DSM-5/K-SADS-PL-DSM5 [Time frame: week 8]
• Current diagnosis of PTSD at Week 32 [Time frame: week 32]
• Children Depression Inventory/CDI total score [Time frame: week 8]
• Children Depression Inventory/CDI total score - Week 32 [Time frame: week 32]

Eligibility criteria

Inclusion criteria

• Children aged 7-12 years
• CPTS-RI total score ≥40
• Primary diagnosis of PTSD (6 months or more after the traumatic event)
• Heart rate ≥ 55 bpm
• Systolic blood pressure ≥ 95 mm Hg
• Affiliation to a social security scheme
• Written consent signed by the parents/holders of parental authority and the investigator
• Acceptance of the protocol by the child-Child and Parents/Holders of parental authority fluent in French

Exclusion criteria

• Age<7 years or ≥13 years
• Children whose parents have been deprived of their authority
• Contraindication to propranolol (cardiogenic shock, sinus bradycardia, hypotension (< fifth percentile oscillometric or <2SD) (Banker et al., 2016 - see APPENDIX 1), greater than first-degree heart block, heart failure, bronchial asthma and hypersensitivity to propranolol hydrochloride)
• Concurrent medication with possible interactions with propranolol (cf 8.2)
• Concurrent psychotropic drugs that have been shown to be effective in improving symptoms of PTSD (Antidepressants, atypical antipsychotics, mood stabilizers)
• Concurrent psychotherapy (>1 structured session/month declared by the clinician who follows the child)
• Current active psychosis, anorexia nervosa, bulimia nervosa, binge-eating disorder, attention-deficit hyperactivity disorder, autism spectrum disorder
• Children with psoriasis
• Children with a predisposition to hypoglycemia
• Obsessive-compulsive disorders
• Bipolar Disorders
• Mental retardation,
• Traumatic brain injury (loss of consciousness > 10 minutes)
• Currently treated with a bradycardic drug
• Concurrent participation to another interventional study
• Renal or Hepatic Impairment
• Pregnancy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

France · 1 center

• Toulouse University Hospital — Toulouse

Publications

• Olliac B, Birmes P, Bui E, Allenou C, Brunet A, Claudet I, Sales de Gauzy J, Grandjean H, Raynaud JP. Validation of the French version of the Child Post-Traumatic Stress Reaction Index: psychometric properties in French speaking school-aged children. PLoS One. 2014 Dec 2;9(12):e112603. doi: 10.1371/journal.pone.0112603. eCollection 2014. PMID 25460912
• Roullet P, Vaiva G, Very E, Bourcier A, Yrondi A, Dupuch L, Lamy P, Thalamas C, Jasse L, El Hage W, Birmes P. Traumatic memory reactivation with or without propranolol for PTSD and comorbid MD symptoms: a randomised clinical trial. Neuropsychopharmacology. 2021 Aug;46(9):1643-1649. doi: 10.1038/s41386-021-00984-w. Epub 2021 Feb 21. PMID 33612830
• Birmes P, Raynaud JP, Daubisse L, Brunet A, Arbus C, Klein R, Cailhol L, Allenou C, Hazane F, Grandjean H, Schmitt L. Children's enduring PTSD symptoms are related to their family's adaptability and cohesion. Community Ment Health J. 2009 Aug;45(4):290-9. doi: 10.1007/s10597-008-9166-3. Epub 2009 Jul 21. PMID 19621258

Identifiers

NCT: NCT04985344 · RC31/18/0471 · 2020-005956-39

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗