Circuit-Guided Approach for Identifying Synergistic Drug Combinations for Treatment-Resistant Depression

Background & Unmet Need

• Depression is a leading cause of global disability with a lifetime prevalence of ~17%
• Selective serotonin reuptake inhibitors (SSRIs) and monoamine-targeting drugs only achieve full remission in one-third of depression patients, leaving two-thirds with partial or no response
• Ketamine provides rapid antidepressant effects within hours of treatment, unlike traditional antidepressants that take weeks to work
• Despite ketamine's effectiveness, its unclear mechanism of action contributes to significant limitations, including transient benefits and side effects that require controlled administration settings
• Unmet Need: Development of mechanistically-driven antidepressant treatments that can provide rapid and effective relief for treatment-resistant depression with reduced side effects

Technology Overview

• The Technology: A therapeutic strategy targeting multiple GPCRs to achieve synergistic antidepressant effects
• The Discovery: Ketamine’s antidepressant effects are initiated through Gi/o signaling via mu-opioid receptors within somatostatin (Sst) interneurons
• RNA-seq identified several GPCRs enriched in Sst+ interneurons after chronic unpredictable stress (CUS)
• The inventors developed a drug cocktail that synergistically targets three Sst+ interneuron-enriched GPCRs
• PoC Data: The drug cocktail produced rapid antidepressant effects within 60 minutes that persisted for at least 24 hours in stress-treated mice
• The drug cocktail demonstrated superior safety compared to ketamine, showing no impairment in motor coordination, normal locomotion, and anxiolytic effects

Technology Applications

• Development of synergistic drug cocktails for depression
• Combination with low-dose ketamine to maximize benefits and minimize side effects
• Screening platform for identifying GPCR targets in specific cell types, applicable to depression, anxiety, PTSD, and OCD treatment

Technology Advantages

• Superior therapeutic effects through strategic targeting of multiple complementary pathways at lower doses
• Faster clinical translation through repurposing existing FDA-approved GPCR-targeting compounds
• Enables precision medicine approach by matching specific drug combinations to individual symptom profiles

Figure: Screening tool is based on distinct patterns of brain connectivity associated with depression symptoms: anhedonia1 (A) and anxiety (B)