MODELING OBSESSIVE COMPULSIVE DISORDER AND EXPLORING TREATMENT RESPONSE USING INNOVATIVE THERAPIES AND STEM CELLS

Official title

FROM DISEASE MODELING TO THE MOLECULAR BASES OF TREATMENT RESPONSE FOR OBSESSIVE-COMPULSIVE DISORDER USING INNOVATIVE THERAPIES AND PATIENT-DERIVED PLURIPOTENT STEM CELLS

Overview

This study focuses on people with obsessive-compulsive disorder (OCD) who do not respond well to standard treatments. Researchers aim to understand why some patients respond to medications or brain stimulation therapies, while others do not. The study will include 60 patients grouped by their treatment response: 1. Those who respond to medications 2. Those who respond to transcranial magnetic stimulation (TMS) 3. Those who do not respond to either Blood samples will be used to create nerve cells in the lab, allowing scientists to study how these cells react to treatments and brain stimulation. By combining clinical information with lab findings, the goal is to discover biological markers that predict which therapy will work best for each person. This research hopes to improve personalized treatment options for OCD.

Detailed description

Adults (18-65 years old) with obsessive-compulsive disorder (OCD) recruited at two specialized clinics in Milan (Luigi Sacco Hospital) and Monza (IRCCS Fondazione San Gerardo Monza). After a complete explanation of the study, everyone will provide written informed consent and have a diagnostic interview to confirm OCD. People with seizures/epilepsy or certain implanted devices (e.g., pacemaker, intracranial metal clips) will not be enrolled.

Procedures:

1. Initial assessments: Participants complete standard questionnaires and tests about OCD symptoms, mood, anxiety, and thinking (e.g., Y-BOCS, HDRS, HARS, MMSE, CANTAB, CGI). Basic information (age, sex, education, medical history, current medications) is collected in an anonymized electronic form. 2. Grouping by medication response:

Responders (20 people): OCD symptoms improve with serotonin reuptake inhibitors (SRIs).

Treatment-resistant (40 people): OCD symptoms did not improve after multiple SRI trials (including SSRIs and clomipramine at recommended doses). 3. Randomized brain stimulation for treatment-resistant OCD:

The 40 treatment-resistant participants are randomly assigned (1:1) to Theta-Burst TMS (TBS) or Deep TMS (d-TMS), following established safety guidelines.

Medications remain stable during TMS. Symptom changes are measured with the Y-BOCS at baseline and follow-up. Participants are classified as responders or non-responders to TBS or d-TMS.

After treatment, people fall into five subgroups: SRI Responders, d-TMS Responders, TBS Responders, d-TMS Non-Responders, TBS Non-Responders. 4. Blood samples and lab modeling:

A small blood sample is used to create patient-derived stem cells (hiPSCs) and then striatal neurons (medium spiny neurons, MSNs) in the lab.

These neurons help us study how brain cells from different patient groups respond to medicines and stimulation. 5. Mimicking brain stimulation in the lab:

Researchers use optogenetics (safe light pulses) to activate the lab-grown neurons, mirroring the effects of TMS.

They also use well-known medicines that turn up or down dopamine signaling (e.g., D1/D2 agonists/antagonists) to see how neurons react.

Changes in synaptic proteins and cell activity are measured with standard lab techniques. 6. Gene activity (transcriptomics):

Using RNA sequencing, the team looks at which genes are "on" or "off" in neurons from different patient groups-before and after light stimulation-to discover molecular signatures linked to treatment response or resistance.

Findings are checked and confirmed with additional lab tests.

Study results analysis

The study includes 60 participants in total. Data are analyzed with standard statistical methods to compare groups and treatments. Lab experiments use multiple independent preparations to ensure reliable results.

Study outcomes:

By combining careful clinical assessments with cutting-edge cell models, this study aims to discover biological markers that can predict who will benefit from medicines and from innovative TMS protocols (TBS or d-TMS)-helping move toward more personalized care for OCD.

Interventions

• Device deep transcranial magnetic stimulation (dTMS)
  The d-TMS protocol will be performed at the treatment-resistant disorders clinic, IRCCS San Gerardo Monza, and will consist of 5 weeks of daily treatments, 5 days a week and 4 treatments during the 6th week, and a 4-week follow-up phase, following most recent clinical studies. d-TMS will be administered using a TMS stimulator equipped with an H-shaped coil (Harmelech et al., 2021). The coil will be placed 4 cm anterior to the foot motor cortex and used at 100% of the leg resting motor threshold
• Device Theta burst stimulation (TBS)
  TBS will be administered using a Magstim Rapid2 stimulator. 3-pulse 50-Hz bursts will be given to patients' left orbitofrontal cortex every 200 ms (at 5 Hz) at an intensity of 80% of the active motor threshold, defined as the coil position that elicited a right thumb movement while stimulating the left primary motor cortex. The treatment will consist of 2 sessions per day, thirty minutes apart, for 5 days in a week. Following the parameters of previous studies, each session will deliver a burst

Primary outcome measures

• Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score [Time frame: Baseline to 10 weeks (end of treatment and follow-up)]

Secondary outcome measures (6)

• Clinical response rate [Time frame: Baseline to end of follow-up (4 weeks post-treatment)]
• Change in Clinical Global Impression (CGI) scores [Time frame: Baseline to 10 weeks]
• Change in Hamilton Depression Rating Scale (HDRS) [Time frame: Baseline to end of follow-up (4 weeks post-treatment)]
• Change in Hamilton Anxiety Rating Scale (HARS) [Time frame: Baseline to end of follow-up (4 weeks post-treatment)]
• Molecular and cellular characterization of patient-derived neurons [Time frame: From baseline (sample collection) to completion of laboratory analyses (up to 36 months)]
• Treatment response classification [Time frame: Baseline to end of follow-up (4 weeks post-treatment)]

Eligibility criteria

Inclusion criteria

• diagnosis of Obsessive-Compulsive Disorder (according to DSM-5; APA, 2013); both sexes; age ≥ 18 years and ≤ 65 years, ability to provide valid written informed consent; for patients classified as responders to pharmacological treatment, a clinical history of at least one pharmacological trial with an SRI for a minimum of 6 weeks and evidence of treatment response, defined as a 30% reduction in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score (Goodman et al., 1989) relative to the patient's baseline; for patients classified as resistant to pharmacological treatment \[TR\], clear evidence of treatment resistance, defined as the absence of a significant clinical response after at least two treatment trials with selective serotonin reuptake inhibitors (SSRIs) and one trial with clomipramine, each administered for a minimum of 12 weeks at the maximum recommended dose (Pallanti et al., 2002).

Exclusion criteria

• inability to provide informed consent; no clinical history of treatment with SRI medications; clinical history of epilepsy or seizures; presence of a pacemaker, removable metal prostheses, implanted medical pumps, or intracranial metal clips.

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

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• Asst Fatebenefratelli Sacco — Milan

Publications

• Vadodaria KC, Ji Y, Skime M, Paquola A, Nelson T, Hall-Flavin D, Fredlender C, Heard KJ, Deng Y, Le AT, Dave S, Fung L, Li X, Marchetto MC, Weinshilboum R, Gage FH. Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry. 2019 Jun;24(6):795-807. doi: 10.1038/s41380-019-0363-y. Epub 2019 Jan 30. PMID 30700803
• Shoaib M, Giacopuzzi E, Pain O, Fabbri C, Magri C, Minelli A, Lewis CM, Gennarelli M. Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression. Pharmacogenomics J. 2021 Feb;21(1):85-93. doi: 10.1038/s41397-020-00186-5. Epub 2020 Sep 17. PMID 32943772
• Burguiere E, Monteiro P, Feng G, Graybiel AM. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science. 2013 Jun 7;340(6137):1243-6. doi: 10.1126/science.1232380. PMID 23744950
• Marcatili M, Marsoner F, D'Agostino A, Karnavas T, Bottai D, Scarone S, Conti L. Establishment of an induced pluripotent stem cell (iPSC) line from a patient with Clozapine-responder Schizophrenia. Stem Cell Res. 2016 Nov;17(3):630-633. doi: 10.1016/j.scr.2016.11.009. Epub 2016 Nov 9. PMID 27934596
• Marcatili M, Sala C, Dakanalis A, Colmegna F, D'Agostino A, Gambini O, Dell'Osso B, Benatti B, Conti L, Clerici M. Human induced pluripotent stem cells technology in treatment resistant depression: novel strategies and opportunities to unravel ketamine's fast-acting antidepressant mechanisms. Ther Adv Psychopharmacol. 2020 Nov 2;10:2045125320968331. doi: 10.1177/2045125320968331. eCollection 2020. PMID 33224469
• Dell'Osso B, Mundo E, D'Urso N, Pozzoli S, Buoli M, Ciabatti M, Rosanova M, Massimini M, Bellina V, Mariotti M, Altamura AC. Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression. Bipolar Disord. 2009 Feb;11(1):76-81. doi: 10.1111/j.1399-5618.2008.00651.x. PMID 19133969
• Arici C, Benatti B, Cafaro R, Cremaschi L, Degoni L, Pozzoli S, Oldani L, Molteni L, Giorgetti F, Priori A, Vigano C, Dell'Osso B. A 6-month follow-up study on response and relapse rates following an acute trial of repetitive transcranial magnetic stimulation in patients with major depression. CNS Spectr. 2022 Feb;27(1):93-98. doi: 10.1017/S1092852920001807. Epub 2020 Sep 4. PMID 32883389
• Dell'Osso B, Nicolini H, Lanzagorta N, Benatti B, Spagnolin G, Palazzo MC, Marazziti D, Hollander E, Fineberg N, Stein DJ, Pallanti S, Van Ameringen M, Lochner C, Hranov G, Karamustafalioglu O, Hranov L, Zohar J, Denys D, Altamura AC, Menchon JM. Cigarette smoking in patients with obsessive compulsive disorder: a report from the International College of Obsessive Compulsive Spectrum Disorders (ICO PMID 26349811

Identifiers

NCT: NCT07488663 · RF-2021-12374133

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗