The development of Spravato (esketamine) by Johnson & Johnson (J&J) marked a turning point in depression treatment, offering a novel mechanism of action and faster relief compared to traditional selective serotonin reuptake inhibitors (SSRIs). Approved by the FDA in 2019, Spravato paved the way for a resurgence in psychiatric drug development, with researchers now exploring a range of new targets beyond serotonin.
Psychiatric Drug Development Renaissance
After a period of relative stagnation, psychiatric drug development is experiencing a renaissance. According to a report by PhRMA, over 160 medications for mental health conditions are currently in clinical development, including approximately 50 candidates specifically for depression. This renewed interest is driven by a shift towards more precise diagnoses and targeted treatments.
"The more we can refine our population and target them with a precise mechanism, that is the best way," said Dr. Husseini Manji, adjunct professor of psychiatry at Yale University and former global therapeutic head of neuroscience at J&J.
While there have been setbacks, such as Alto Neurosciences' ALTO-100 failing to beat placebo in a mid-stage trial for major depressive disorder (MDD), optimism remains high for other emerging strategies.
Targeting Orexin Receptors
Orexins, neurotransmitters involved in mood, appetite, reward, and wakefulness, are gaining attention as potential therapeutic targets. J&J is investigating seltorexant, a selective orexin-2 receptor antagonist, as an adjunctive treatment for insomnia in patients with MDD. Phase 3 trial results showed that seltorexant improved both depression and insomnia symptoms compared to placebo. J&J forecasts potential peak sales of up to $5 billion for seltorexant, despite shelving it as an Alzheimer's disease candidate.
Exploring New Receptor Targets
Beyond serotonin and orexin, drugmakers are exploring other receptors linked to depression symptoms. Neurocrine Biosciences reported positive Phase 2 data for NBI-1065845, a drug candidate that modulates AMPA, which has been linked to depression symptoms. Patients taking NBI-1065845 showed statistically significant improvements on a common depression scale compared to placebo. Neurocrine acquired the candidate from Takeda Pharmaceuticals in 2020 in a deal worth up to $2 billion.
The kappa opioid receptor (KOR) is another promising target, with emerging treatments aiming to modulate the receptor and improve the regulation of neurotransmitters like dopamine. Neumora Therapeutics is currently in Phase 3 development with its KOR antagonist, navacaprant, after positive Phase 2 results in patients with moderate to severe depression. Initial results from the first of three late-stage trials are expected in the fourth quarter of this year. J&J is also in Phase 3 with its KOR antagonist, aticaprant, which has shown symptom improvement in MDD patients. J&J has identified aticaprant as a potential blockbuster.
The Role of Inflammation
Mounting evidence suggests that inflammation plays a significant role in neurological disorders, including depression. Research co-authored by Manji in 2022 indicated that immune activation could be driving depression symptoms. Analysis of clinical trial datasets for drugs tested in autoimmune diseases revealed improvements in depression symptoms, even among non-responders for the autoimmune disease.
While clinical testing of anti-inflammatory agents in psychiatry is still in early stages, researchers have identified the P2X7 receptor as a potential therapeutic target for reducing inflammation and combating depression. J&J previously tested a P2X7 antagonist in a Phase 2 trial for bipolar disorder, but the drug is no longer in their pipeline.
