AbbVie Acquires Gilgamesh Pharmaceuticals' Bretisilocin for Major Depressive Disorder
Breakthrough Clinical Results
AbbVie announced the acquisition of Gilgamesh Pharmaceuticals' bretisilocin, a novel Phase 2 psychedelic compound for treating moderate-to-severe major depressive disorder (MDD). Bretisilocin is a short-acting serotonin 2A receptor agonist and 5-HT releaser, offering a shorter duration of psychoactive effects compared to existing agents. Positive Phase 2a results showed a significant reduction in depressive symptoms. The acquisition is valued at up to $1.2 billion, including upfront payment and milestones. Gilgamesh will spin off a new entity to continue other programs. This builds upon a 2024 collaboration between the two companies.
Key Highlights
- AbbVie acquires Gilgamesh Pharmaceuticals' bretisilocin for up to $1.2 billion.
- Bretisilocin is a novel, short-acting psychedelic compound for treating MDD.
- Positive Phase 2a results demonstrated a significant reduction in depressive symptoms.
- Gilgamesh will spin off a new entity to continue its other research programs.
Incidence and Prevalence
Global Estimates of Major Depressive Disorder
Based on the available data, there are several important findings regarding depression rates in specific populations, though comprehensive global estimates are limited:
In a 2021 study from China involving 598 MDD patients and 467 healthy controls, the severity distribution showed: - 29.5% (260 patients) had mild depression - 50.2% (443 patients) had moderate depression - 20.3% (179 patients) had severe depression
A 2014 study in the United States found that 11.6% of US adults met criteria for lifetime subsyndromal depression (SD): - The majority (9.3%) had fewer than 5 total symptoms required for major depression diagnosis - A smaller proportion (2.3%) reported 5 or more symptoms but denied clinically significant distress or functional impairment - Importantly, SD was associated with increased likelihood of developing incident major depression (odds ratios 1.72-2.05) - SD also increased risk for dysthymia, social phobia, and generalized anxiety disorder (GAD)
In patients with psoriasis, depression rates were notably higher: - 28% prevalence of depressive symptoms using questionnaires - 12% prevalence using International Classification of Diseases codes - 19% prevalence using Diagnostic and Statistical Manual of Mental Disorders IV - 9% prevalence based on antidepressant use - Psoriasis patients were at least one and a half times more likely to experience depression (OR 1.57; 95% CI 1.40-1.76) - They also used more antidepressants than controls (OR 4.24, 95% CI 1.53-11.76)
These findings highlight the significant burden of depression in specific populations, though they do not provide a comprehensive global epidemiological picture of Major Depressive Disorder.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Major Depressive Disorder
Neurotransmitter-Based Mechanisms
- Serotonin plays a predominant role in depression pathophysiology
- 5-HT receptor antagonists (5-HTRA) produce anti-depressant-like effects by increasing serotonin availability to other receptors
- Glutamate receptor antagonists like ketamine show promise for treatment-resistant depression
- Hyperactivity of serotonin neurons, especially in the dorsal raphe nucleus, is commonly induced by various antidepressants
Lipid-Based Mechanisms
- Increased ceramide levels in blood plasma correlate with MDD severity
- Anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD
- Ceramide inhibits phospholipase D (PLD) activity, decreasing phosphatidic acid in the hippocampus
Anti-Inflammatory Approaches
- EPO-derived helix-B peptide ARA290 ameliorates depression-like behavior in mouse models
- ARA290 and fluoxetine reverse chronic stress-induced increases in neutrophils and monocytes in bone marrow and meninges
- Both drugs reversed chronic stress-induced microglia activation
Novel Molecular Targets
- SUMO specific peptidase 3 (SENP3) in the hippocampus leads to depression-like behavior by impairing the CREB-BDNF signaling cascade
- GPR158, an orphan G-protein-coupled receptor in the medial prefrontal cortex, has been identified as a novel therapeutic target
- Trilobatin alleviates depressive-like behavior by targeting GPR158 and promoting mitophagy
- 5-O-methylvisammioside exerts antidepressant effects by inhibiting Src-mediated activation of the nuclear factor kappa B signaling pathway
Non-Pharmacological Approaches
- Non-invasive brain stimulation significantly increases expression of neurotrophic factors (NTFs)
- Eye movement desensitization and reprocessing (EMDR) therapy is being studied for MDD
- Physical activity improves mental status with positive effects on cognitive function, sleep, and brain plasticity
- Mindfulness-based interventions decrease activation in the right dorsolateral prefrontal cortex in response to angry faces
- Mindfulness-based cognitive therapy leads to decreased salience network connectivity to the lingual gyrus during rumination
Biomarkers and Diagnostic Approaches
- EEG neural oscillations show abnormalities in first-episode and drug-naïve MDD patients
- Relative power of the alpha band in the left parietal region is a potential objective electrophysiological indicator
- Machine learning analysis of EEG data achieved 88.2% accuracy in identifying MDD patients
Future Directions
- Combining pharmacotherapy with behavioral therapy or deep brain stimulation could potentially cause desired changes in specific neural circuits
- RNA binding proteins and epitranscriptomic mechanisms represent a new frontier for rapidly altering protein synthesis
- Correcting aberrant synaptic plasticity offers long-lasting therapeutic effects even after treatment has ended
Drug used in other indications
Bretisilocin Clinical Trials Beyond Major Depressive Disorder
Based on the information available, I cannot provide details about clinical trials of bretisilocin for indications other than Major Depressive Disorder. The medication "bretisilocin" does not appear in the provided information sources.
The available data mentions several other antidepressants that have been studied and used clinically, including duloxetine, escitalopram, venlafaxine, fluoxetine, sertraline, desvenlafaxine, quetiapine XR, and vortioxetine, but contains no references to bretisilocin, its clinical trials, or intervention models.
Without specific information about bretisilocin trials, I cannot detail which indications beyond Major Depressive Disorder it might be investigated for, nor can I describe the intervention models employed in such trials.
