{"doi":"10.1016/j.brs.2025.08.022","title":"A novel home-based, combined occipital and trigeminal afferent stimulation therapy for major depressive disorder: Efficacy and safety results from a double-blind multicenter randomized sham-controlled study","abstract":"OBJECTIVE: Patients with Major Depressive Disorder (MDD) who fail to achieve satisfactory benefits with existing antidepressants have limited treatment options. This study assessed the safety and efficacy of a novel non-invasive brain neuromodulation therapy which delivers external Combined Occipital and Trigeminal Afferent Stimulation (eCOT-AS) as a therapeutic option for MDD. METHODS: 124 adults with MDD who failed to respond to antidepressants and with a baseline Hamilton Depression Rating Scale (HDRS21) score ≥20 were enrolled in a randomized, double-blind, sham-controlled, multicenter study of self-administered daily active or sham eCOT-AS (n = 62 per arm) for eight weeks. The double-blind phase was followed by an 8-week active open label phase. HDRS17 was used to assess outcomes. RESULTS: Baseline depression scores were similar for both groups and reflected moderate to very severe depression. After 8 weeks of treatment, the adjusted mean HDRS17 improvement in the active treatment group was 8.62 points versus 6.01 for sham (p = 0.0196). Compared to sham treatment, participants receiving active treatment had significantly higher remission rates (21.3 % vs 6.0 %, p = 0.027) and achieved significantly more shifts to lower HDRS17 depression severity categories. Participants further improved during the subsequent eight weeks of open-label active stimulation with a mean reduction of almost 10 points from baseline and achieved a remission rate of 32 %. The treatment was well-tolerated with generally mild and transient adverse events. CONCLUSION: This home-based brain neuromodulation system is safe and effective in treating depression. These findings support eCOT-AS as a promising new adjunct therapy for MDD patients with nonresponse to antidepressants.","journal":"Brain stimulation","year":2025,"id":524308,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":106043,"name":"Mark S. George","orcid":"0000-0003-1767-1815","position":1,"is_corresponding":false},{"id":1398359,"name":"Nancy Navarro","orcid":null,"position":2,"is_corresponding":false},{"id":1397808,"name":"Lisa Deutsch","orcid":"0000-0002-2445-7561","position":3,"is_corresponding":false},{"id":304896,"name":"Andrew F. Leuchter","orcid":"0000-0003-2402-7083","position":4,"is_corresponding":false},{"id":106038,"name":"Linda L. Carpenter","orcid":"0000-0002-9651-3307","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"40886913","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}