Clinical trial NCT04029740: Exosomal microRNAs as a Biomarker in Panic Disorder and in Response to CBT
Official title: Searching for Exosomal microRNAs and Cellular Biomarkers and Mechanisms Underlying the Differences Between Panic Disorder Patients Who Are Responders and Non-responders to Cognitive Behavior Therapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Panic Disorder
Lead sponsor: Hebrew University of Jerusalem
Sponsor class: OTHER
Collaborators: name: Hadassah Medical Organization
First posted: 2019-07-23
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All patients will be treated with either internet or face to face CBT according to their preference. Circulating exosomal microRNAs will be measured pretreatment and post-treatment.
Primary purpose: BASIC_SCIENCE

Brief summary: Cognitive behavior therapy (CBT) has long been known as an effective treatment for anxiety disorders, either when given by a therapist or when self-administered through a computer program. However, the biological effect of CBT remained largely unexplored. Most studies focused on genomic differences and pursued differences in methylation patterns following CBT, but the findings were very limited in scope, especially when comparing responders and non-responders to CBT. In the currently proposed study, the investigators plan to go one step further and look for changes in exosomal microRNAs (miRs) from serum samples taken before and after CBT from Panic Disorder (PD) patients. Notably, miR changes show a much faster biological response than methylation patterns yet had never been used before in PD research. The primary benefit of this work will be in providing biological validation to psychological treatments. PD is a heavy public health burden, associated with significant market potential for both therapeutic and diagnostic uses.

Detailed description: Cognitive Behavior Therapy (CBT) is an evidence-based treatment, commonly used for treating anxiety disorders. Patients with anxiety disorders are characterized by having cognitive distortions regarding evaluations of threat, which results in safety behaviors to avoid them thereby causing impairment in the patient's quality of life. CBT focuses on changing those "false beliefs" and "maladaptive behaviors" by exposing the patients to their anxiety source in a gradual way, supervised by the therapist.

Anxiety disorders are relatively common, and many people have difficulty accessing treatment due to a variety of obstacles. Researchers have therefore explored the possibility of using different methods to administer CBT, resulting in the making of internet-delivered CBT (iCBT). iCBT programs can involve therapist guidance through emails or can be entirely unguided. These programs are typically comprised of 6-15 modules, which are text chapters corresponding to sessions in face-to-face therapy. These programs require little therapist involvement other than guidance and feedback on homework assignments. Current meta-analyses suggest that iCBT does not differ from regular CBT in its efficacy, conducted through a guided program.

In this study, the investigators plan to examine whether iCBT and regular CBT can cause biological changes as well as cognitive ones. Few previous studies have shown epigenetic changes in different directions for CBT responders and non-responders. Those studies used methylation patterns as biomarkers, showing that Panic Disorder (PD) patients had lower methylation in specific genes than the control group at the baseline point. After going through CBT the responders showed higher methylation and the non-responders showed even lower methylation than at the baseline point. In addition, a more recent study showed that in comparison to healthy controls, PD patients showed changes in immune system activities. Microglial acid sensing G-protein coupled receptor and T cell death-associated gene-8 (TDAG8), which was found was found higher in PD patients.

The investigators wish to take these findings one step forward by using micro-RNAs (miRs) content of circulation exosomes as our biomarker. Exosomes are a type of extracellular vesicles of endocytic origin, used in signaling and cell to cell communication, by transferring proteins, lipids, and variety of RNAs between cells. miRs are short single-stranded RNA molecules that bind to complementary sequences of target mRNAs, causing inhibition of their translation and/or inducing target degradation and affecting brain functioning and mental processes.

The investigators will base their work on the hypothesis that the brain's state is reflected, to a certain extent in the miR contents of circulating exosomes. Therefore, the aim of the study will be to test the difference between patients and controls as well as between responders and non-responders by profiling miRs content of circulation exosomes from their plasma samples and seeking association with their clinical data. Whole blood samples will also be collected, in order to serve as secondary outcome measurement, checking for changes in expression of other small non-coding circulating RNAs as well.

The investigators will use a cohort of 40 panic disorder patients, comparing them with matching 40 mentally healthy controls. This approach has never been used before in the field of anxiety biomarkers, although miR changes show a much faster biological response than methylation patterns. Therefore, the investigators believe it will provide many new insights on the biological changes following PD and its treatment using CBT/iCBT, especially regarding the biological difference between respondents and non-respondents.

The investigators anticipate big benefits for psychologists and psychiatrists who could in the future use simple blood samples to determine which kind of therapy will be most suitable for their patients, or rather to check if the therapy has given the desirable outcomes. Biotech firms may be interested in developing this method as a commercial diagnostic tool that could easily be used by health maintenance organizations just as a simple blood test. PD is a big public health burden, leading the market potential both for therapeutics as well as diagnostics to be large in dollar terms.

This study received two ethics approvals that act together. The mentioned ethics approval given by the Hebrew university ethics committee was given for the psychological part of the experiment and include the CBT, using a psychologist or computer program. A second approval, Helsinki approval by the Hadassah hospital committee, covers the biological part of the experiment - including the blood drawing and further analysis.

Eligibility criteria: Inclusion Criteria:

* Principal DSM-5 primary diagnosis of panic disorder and/or agoraphobia.
* Aged 18 years or older.
* PD duration of at least 3 months.
* If participant is on on medications for PD, the dosage has to remain constant for 3 months prior to the start of treatment and cannot be increased during treatment.
* The participant must have access to the internet and be willing to use it.

Exclusion Criteria:

* Substance abuse or dependence within the last 6 months.
* Active suicide potential within the last 6 months.
* Any current or history of psychosis or bipolar I disorder.
* Currently in weekly or biweekly psychotherapy.
* History of a complete course of panic focused CBT

Primary outcomes:
measure: Differntial expression of plasma exosomal microRNAs
timeFrame: Pre and post treatment, up to 6 months apart.
Secondary outcomes:
measure: Change in Panic Disorder Severity Scale (PDSS)
timeFrame: Weekly during treatment and at pre and post treatment evaluations, up to 6 months apart.
measure: Change in Anxiety Sensitivity Index-3 (ASI-3)
timeFrame: Weekly during treatment and at pre and post treatment evaluations, up to 6 months apart.
measure: Change in Mobility Inventory
timeFrame: Weekly during treatment and at pre and post treatment evaluations, up to 6 months apart.
measure: Differntial expression of whole Blood short non-coding RNAs
timeFrame: Pre and post treatment, up to 6 months apart.
measure: Change in the Five-Dimensional Curiosity Scale (DCS-5)
timeFrame: Pre and post treatment, up to 6 months apart.
measure: Changes in Experiences in Close Relationship Scale-Short (ECR-s)
timeFrame: Pre and post treatment, up to 6 months apart.
measure: Changes in Sexual Functioning Questionnaire
timeFrame: Pre and post treatment, up to 6 months apart.
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Hebrew University of Jerusalem
Study officials:
affiliation: Hebrew University of Jerusalem
name: Hermona Soreq, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hadassah Hebrew University Hospital
name: Ronen Segman, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hebrew University of Jerusalem
name: Salomon Israel, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, Seabra MC, Round JL, Ward DM, O'Connell RM. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 2015 Jun 18;6:7321. doi: 10.1038/ncomms8321.
citation: Andersson G, Cuijpers P, Carlbring P, Riper H, Hedman E. Guided Internet-based vs. face-to-face cognitive behavior therapy for psychiatric and somatic disorders: a systematic review and meta-analysis. World Psychiatry. 2014 Oct;13(3):288-95. doi: 10.1002/wps.20151.
citation: Bekenstein U, Mishra N, Milikovsky DZ, Hanin G, Zelig D, Sheintuch L, Berson A, Greenberg DS, Friedman A, Soreq H. Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity. Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E4996-E5005. doi: 10.1073/pnas.1701201114. Epub 2017 Jun 5.
citation: Barlow DH. Cognitive-behavioral therapy for panic disorder: current status. J Clin Psychiatry. 1997;58 Suppl 2:32-6; discussion 36-7.
citation: Fruhbeis C, Helmig S, Tug S, Simon P, Kramer-Albers EM. Physical exercise induces rapid release of small extracellular vesicles into the circulation. J Extracell Vesicles. 2015 Jul 2;4:28239. doi: 10.3402/jev.v4.28239. eCollection 2015.
citation: Huppert, J. D., & Baker-Morissette, S. L. (2003). Beyond the manual: The insider's guide to panic control treatment. Cognitive and Behavioral Practice, 10(1), 2-13.
citation: Meunier J, Lemoine F, Soumillon M, Liechti A, Weier M, Guschanski K, Hu H, Khaitovich P, Kaessmann H. Birth and expression evolution of mammalian microRNA genes. Genome Res. 2013 Jan;23(1):34-45. doi: 10.1101/gr.140269.112. Epub 2012 Oct 3.
citation: Olthuis JV, Watt MC, Bailey K, Hayden JA, Stewart SH. Therapist-supported Internet cognitive behavioural therapy for anxiety disorders in adults. Cochrane Database Syst Rev. 2016 Mar 12;3(3):CD011565. doi: 10.1002/14651858.CD011565.pub2.
citation: Roberts S, Lester KJ, Hudson JL, Rapee RM, Creswell C, Cooper PJ, Thirlwall KJ, Coleman JR, Breen G, Wong CC, Eley TC. Serotonin transporter [corrected] methylation and response to cognitive behaviour therapy in children with anxiety disorders. Transl Psychiatry. 2014 Sep 16;4(9):e444. doi: 10.1038/tp.2014.83.
citation: Ziegler C, Richter J, Mahr M, Gajewska A, Schiele MA, Gehrmann A, Schmidt B, Lesch KP, Lang T, Helbig-Lang S, Pauli P, Kircher T, Reif A, Rief W, Vossbeck-Elsebusch AN, Arolt V, Wittchen HU, Hamm AO, Deckert J, Domschke K. MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Transl Psychiatry. 2016 Apr 5;6(4):e773. doi: 10.1038/tp.2016.41.
citation: Strawn JR, Mills JA, Sauley BA, Welge JA. The Impact of Antidepressant Dose and Class on Treatment Response in Pediatric Anxiety Disorders: A Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2018 Apr;57(4):235-244.e2. doi: 10.1016/j.jaac.2018.01.015. Epub 2018 Feb 8.