FUNCTIONAL CONNECTIVITY OF THE STRIATUM AS A BIOMARKER OF TREATMENT RESPONSE TO KCNQ-TARGETED AGENTS IN DEPRESSION

Purpose

MDD is a major driver of suffering and disease-related disability in the world and current treatments fail to lead to remission for many patients. Optimizing clinical trial methods to detect effective treatments and to understand patient characteristics associated with optimal response is critical to advancing treatment discovery for MDD. This talk will present new data linking brain features to positive outcomes for patients in trials of MDD that utilize novel agents to target the KCNQ channel in the brain.

Methods

We examined brain features associated with clinical response to two mechanistically novel agents that target the KCNQ channel – ezogabine (a.k.a., retigabine) and Azetukalner (previously known as XEN1101) – in separate samples of adults with MDD enriched for anhedonia. We used 3T functional MRI to measure resting-state functional connectivity (RSFC) of the ventral striatum, a key reward region, to the whole brain both at baseline and change following treatment.

Results

We report that reduced connectivity at baseline predicted improved outcomes on depression and anhedonia following treatment (p < 0.05). In addition, greater change in connectivity between the striatum and posterior cingulate cortex (PCC) was associated with greater improvement in depression and anhedonia during active treatment but not placebo in two independent data sets.

Conclusions

Across two separate, randomized, controlled trials, modulation of striatocingulate connectivity is a consistent indicator of clinical response to agents targeting the KCNQ channel. The specific correlation between this RSFC change and symptom improvement supports its potential as a pharmacodynamic marker. Future trials should assess comparative efficacy and explore utility in specific depression subtypes.

References

Costi S, Han MH, Murrough JW. The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants. CNS Drugs. 2022 Mar;36(3):207-216. Chowdhury A, Boukezzi S, Costi S, Hameed S, Jacob Y, Salas R, Iosifescu DV, Han MH, Swann A, Mathew SJ, Morris L, Murrough JW. Effects of the KCNQ (Kv7) Channel Opener Ezogabine on Resting-State Functional Connectivity of Striatal Brain Reward Regions, Depression, and Anhedonia in Major Depressive Disorder: Results From a Randomized Controlled Trial. Biol Psychiatry. 2025 Oct 1;98(7):568-577.