Obsessive - Compulsive Disorder
Conditions
Keywords
TRANSCRANIAL MAGNETIC STIMULATION, HUMAN PLURIPOTENT STEM CELLS, OBSESSIVE COMPULSIVE DISORDER
Brief summary
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
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.
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.
Sponsors
ASST Fatebenefratelli Sacco
Fondazione IRCCS San Gerardo dei Tintori
Istittuo ricerca carattere Sceintifico Fatenefratelli Brescia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study with no masking. Participants, care providers, and investigators are aware of the assigned intervention (TBS or d-TMS), as the procedures differ in administration and cannot be feasibly blinded. No independent blinded outcome assessors are used.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score | Baseline to 10 weeks (end of treatment and follow-up) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical response rate | Baseline to end of follow-up (4 weeks post-treatment) | Proportion of participants achieving a reduction ≥20% in Y-BOCS total score after TMS treatment. |
| Change in Clinical Global Impression (CGI) scores | Baseline to 10 weeks | Change in CGI-Severity and CGI-Improvement scores from baseline to post-treatment. |
| Change in Hamilton Depression Rating Scale (HDRS) | Baseline to end of follow-up (4 weeks post-treatment) | Change in depressive symptom severity measured by HDRS. |
| Change in Hamilton Anxiety Rating Scale (HARS) | Baseline to end of follow-up (4 weeks post-treatment) | Change in anxiety symptom severity measured by HARS. |
| Molecular and cellular characterization of patient-derived neurons | From baseline (sample collection) to completion of laboratory analyses (up to 36 months) | Assessment of morphological, biochemical, and transcriptomic profiles of hiPSC-derived medium spiny neurons from participants, including differential gene expression and response to stimulation. |
| Treatment response classification | Baseline to end of follow-up (4 weeks post-treatment) | Classification of participants into responders and non-responders to TBS or d-TMS based on predefined Y-BOCS thresholds. |
Countries
Italy
Outcome results
None listed