ipRGC as a Potential Biomarker for Predicting Transcranial Magnetic Stimulation Treatment Response in Major Depressive Disorder

Official title

Illuminating Depression: ipRGC as a Potential Biomarker for Predicting Transcranial Magnetic Stimulation Treatment Response in Major Depressive Disorder

Overview

This research explores the potential of retinal ganglion cells (RGCs), particularly intrinsically photosensitive RGCs (ipRGCs), as biomarkers for predicting response to transcranial magnetic stimulation (TMS) in treatment-resistant depression (TRD). We also aim to assess the impact of TMS treatment on RGCs and ipRGCs in TRD patients, investigating associations with clinical improvements and cognitive status. A clinical trial involving 44 patients with treatment-resistant depression (TRD) will be conducted. All participants will receive rTMS targeting the dorsolateral prefrontal cortex (DLPFC). Data will be collected pre- and post-intervention, as well as at a 2-month follow-up, using multiple outcome measures, including the post-illumination pupil response (PIPR). The project seeks to confirm the effectiveness of TMS and the potential of RGCs/ipRGCs as predictors of treatment response, thereby facilitating the development of personalized treatment strategies for TRD patients undergoing rTMS therapy.

Interventions

• Device Repetitive transcranial magnetic stimulation (rTMS)
  Each participant's resting motor threshold (RMT) will be determined by visual observation in accordance with standard clinical practice. Intermittent theta-burst stimulation (iTBS) will be delivered over the left dorsolateral prefrontal cortex (DLPFC) using these parameters: stimulation intensity 120% RMT; bursts at 50 Hz; 2 s on and 8 s off; 600 pulses per session; total stimulation time approximately 3 minutes per session. Stimulation will be delivered using a MagPro X100 stimulator with MagOp

Primary outcome measures

• Chromatic pupillometry [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]

Secondary outcome measures (10)

• Optical Coherence Tomography (OCT) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Pattern Electroretinogram (PERG) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Contrast sensitivity test [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Montgomery-Åsberg Depression Rating Scale (MADRS) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Maudsley Staging Depression [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• California Verbal Learning Test-II (CVLT-II) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Reading Mind in Eyes Test (RMET) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Symbol Digit Modalities Test (SDMT) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• Brief Visuospatial Memory Test-Revised (BVMT-R) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]
• WHODAS 12-item (Self-report) [Time frame: Baseline (pre-intervention), Post-intervention (a day immediately after the end of intervention) and Follow-up (2 months after the end of intervention)]

Eligibility criteria

Inclusion criteria

• Diagnosis of MDD, confirmed via the structured clinical interview;
• TRD type;
• Age between 18-65 years;
• Visual acuity of 20/32 or better.

Exclusion criteria

• Prior rTMS treatment;
• Contraindications for TMS;
• Psychiatric disorders other than MDD;
• Systemic diseases affecting the eyes (e.g., diabetes mellitus);
• Ocular conditions;
• Head injuries causing loss of consciousness;
• Current or past alcohol/substance dependence within 6 months;
• Neurodegenerative diseases;
• Major neurological illnesses;
• Use of medications affecting iris mechanics or the autonomic nervous system.

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Portugal · 1 center

• RISE-Health, Center for Translational Health and Medical Biotechnology Research (TBIO), Sc — Porto

Publications

• Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26. PMID 29726344
• Laurenzo SA, Kardon R, Ledolter J, Poolman P, Schumacher AM, Potash JB, Full JM, Rice O, Ketcham A, Starkey C, Fiedorowicz JG. Pupillary response abnormalities in depressive disorders. Psychiatry Res. 2016 Dec 30;246:492-499. doi: 10.1016/j.psychres.2016.10.039. Epub 2016 Oct 21. PMID 27821359
• Jung KI, Hong SY, Shin DY, Lee NY, Kim TS, Park CK. Attenuated Visual Function in Patients with Major Depressive Disorder. J Clin Med. 2020 Jun 22;9(6):1951. doi: 10.3390/jcm9061951. PMID 32580488
• Kalenderoglu A, Celik M, Sevgi-Karadag A, Egilmez OB. Optic coherence tomography shows inflammation and degeneration in major depressive disorder patients correlated with disease severity. J Affect Disord. 2016 Nov 1;204:159-65. doi: 10.1016/j.jad.2016.06.039. Epub 2016 Jun 17. PMID 27344626
• Yildiz M, Alim S, Batmaz S, Demir S, Songur E, Ortak H, Demirci K. Duration of the depressive episode is correlated with ganglion cell inner plexifrom layer and nasal retinal fiber layer thicknesses: Optical coherence tomography findings in major depression. Psychiatry Res Neuroimaging. 2016 May 30;251:60-6. doi: 10.1016/j.pscychresns.2016.04.011. Epub 2016 Apr 18. PMID 27124425
• De Risio L, Borgi M, Pettorruso M, Miuli A, Ottomana AM, Sociali A, Martinotti G, Nicolo G, Macri S, di Giannantonio M, Zoratto F. Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies. Transl Psychiatry. 2020 Nov 10;10(1):393. doi: 10.1038/s41398-020-01055-2. PMID 33173042
• Maruani J, Geoffroy PA. Multi-Level Processes and Retina-Brain Pathways of Photic Regulation of Mood. J Clin Med. 2022 Jan 16;11(2):448. doi: 10.3390/jcm11020448. PMID 35054142
• Benarroch EE. The melanopsin system: Phototransduction, projections, functions, and clinical implications. Neurology. 2011 Apr 19;76(16):1422-7. doi: 10.1212/WNL.0b013e31821671a5. No abstract available. PMID 21502603

Identifiers

NCT: NCT07474974 · ORT-2026-001 · 2024.06665.BD · CE0085E

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗