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

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Obsessive - Compulsive Disorder
• Intervention / Treatment: Device: deep transcranial magnetic stimulation (dTMS); Device: Theta burst stimulation (TBS)

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20100
    • ASST Fatebenefratelli Sacco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Deep TMS; This arm includes patients classified as resistant to pharmacological treatment, clear evidence of treatment resistance (defined as the absence of a significant clinical response after at least two treatment trials with SSRIs and one trial with clomipramine each administered for a minimum of 12 weeks at the maximum recommended dose). Patients will undergo d-TMS protocol for 5 weeks of daily treatments, 5 days a week and 4 treatments during the 6th week, and a 4-week follow-up phase.	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 (RMT), defined as the coil position that elicited the minimal involuntary contractions of the feet (3 of 6 attempts). The stimulation of the area localized 4 cm anterior to the foot motor cortex targets the dorsal medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) bilaterally. Patients will receive 20 Hz d-TMS at 100% of RMT, with 2-second pulse trains and 20-second intertrain intervals, for a total of 50 trains and 2,000 pulses per session.
Experimental: TBS protocol; This arm includes patients classified as resistant to pharmacological treatment, clear evidence of treatment resistance (defined as the absence of a significant clinical response after at least two treatment trials with SSRIs and one trial with clomipramine each administered for a minimum of 12 weeks at the maximum recommended dose). Patients from this group will undergo the TBS protocol at the OCD clinic, ASST Fatebenefratelli Sacco of Milan, consisting in one week of daily treatments and a 4-weeks follow-up phase.	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 of three pulses at 50 Hz and repeated every 200 ms (at 5 Hz) for a total of 600 pulses lasting 40s (Oberman et al., 2011). A total of 1200 pulses will be delivered per day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score	The primary outcome is the change in Y-BOCS total score from baseline to the end of treatment, used to assess clinical response to TBS versus d-TMS in treatment-resistant OCD patients.	Baseline to 10 weeks (end of treatment and follow-up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response rate	Proportion of participants achieving a reduction ≥20% in Y-BOCS total score after TMS treatment.	Baseline to end of follow-up (4 weeks post-treatment)
Change in Clinical Global Impression (CGI) scores	Change in CGI-Severity and CGI-Improvement scores from baseline to post-treatment.	Baseline to 10 weeks
Change in Hamilton Depression Rating Scale (HDRS)	Change in depressive symptom severity measured by HDRS.	Baseline to end of follow-up (4 weeks post-treatment)
Change in Hamilton Anxiety Rating Scale (HARS)	Change in anxiety symptom severity measured by HARS.	Baseline to end of follow-up (4 weeks post-treatment)
Molecular and cellular characterization of patient-derived neurons	Assessment of morphological, biochemical, and transcriptomic profiles of hiPSC-derived medium spiny neurons from participants, including differential gene expression and response to stimulation.	From baseline (sample collection) to completion of laboratory analyses (up to 36 months)
Treatment response classification	Classification of participants into responders and non-responders to TBS or d-TMS based on predefined Y-BOCS thresholds.	Baseline to end of follow-up (4 weeks post-treatment)

Collaborators and Investigators

• Sponsor: ASST Fatebenefratelli Sacco
• Collaborators: Fondazione IRCCS San Gerardo dei Tintori; Istittuo ricerca carattere Sceintifico Fatenefratelli Brescia

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 (ICOCS). CNS Spectr. 2015 Oct;20(5):469-73. doi: 10.1017/S1092852915000565. Epub 2015 Sep 9.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2023
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): April 29, 2027

Study Registration Dates

• First Submitted: March 18, 2026
• First Submitted That Met QC Criteria: March 18, 2026
• First Posted (Actual): March 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 18, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: TRANSCRANIAL MAGNETIC STIMULATION; HUMAN PLURIPOTENT STEM CELLS; OBSESSIVE COMPULSIVE DISORDER
• Additional Relevant MeSH Terms: Mental Disorders; Personality Disorders; Anxiety Disorders; Compulsive Personality Disorder; Obsessive-Compulsive Disorder
• Other Study ID Numbers: RF-2021-12374133

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
• product manufactured in and exported from the U.S.: No