August 2026

What if patients with treatment-resistant depression (TRD) could be treated at home, with a ketamine tablet? A 12-week international trial tested this possibility using a new extended-release ketamine formulation (R-107) in outpatient settings (Glue et al, 2024). Here’s the complete breakdown of the study and how it could shape safer, more scalable treatment options for patients who don’t respond to standard antidepressants. 231 adults with treatment-resistant depression (TRD) entered a 5-day open-label phase. Those who responded continued twice-weekly tablet treatment for 12 weeks, primarily at home. The goal: test efficacy, safety, and real-world feasibility of oral ketamine. Does the dose matter? Absolutely. Only the 180 mg dose showed statistically significant and sustained improvement in depressive symptoms. Lower doses were comparable to placebo, indicating a clear dose-response threshold. Relapse rates over 12 weeks were lower in the 180 mg group, suggesting potential for maintenance treatment. This adds weight to the case for ketamine as both an acute and continuation-phase option in TRD. This was the first ketamine trial to permit home administration during the treatment phase. Adherence was high. No serious adverse events occurred.  This marks a turning point in how we might deliver care for TRD. Across all dose groups: ● Adverse events were predominantly mild ● Headache, dizziness, and anxiety were the most common ● No cases of hypertension, dissociation, or sedation requiring intervention Safety was unexpectedly strong for a glutamatergic agent. R-107 Differs from Esketamine in Formulation and Mechanism, this is not esketamine. R-107 is a racemic ketamine tablet designed to deliver gradual absorption and prolonged exposure, minimizing peaks that may cause dissociation or misuse. A pharmacokinetic shift with clinical relevance. Can this be used broadly? Not yet. Participants were enriched, only those with a rapid initial response continued in the trial. This limits generalisability. It remains unclear how unselected TRD populations would respond to this intervention. Compared to intranasal esketamine or ECT, oral ketamine may offer: ● Greater scalability ● Less intensive monitoring ● Potential for community-based protocols But only if larger trials replicate these findings. If replicated, this approach could reduce: ● Clinical burden ● Logistical barriers ● Patient disengagement due to complexity Home-based options offer a new paradigm for sustained care. What remains unknown? ● Durability beyond 12 weeks ● Long-term neurocognitive effects ● Effectiveness in broader clinical populations This is a promising proof of concept, not yet a clinical standard. Clinical Importance For patients unresponsive to multiple antidepressants, options are limited. If further validated, oral ketamine may represent a viable outpatient pathway, extending care access while reducing infrastructure demands. Could this be the future of TRD care? A well-tolerated, at-home intervention for a complex psychiatric condition. This study opens the door, but the field must proceed cautiously, grounded in replication and long-term outcome data.

Memantine and ketamine are not the same. Yes, they are both NMDA receptor antagonists. But that shared label often obscures major differences in affinity, binding duration, receptor specificity, and clinical effects. The key point here is that receptor labels can be too broad. Two drugs can act at the same receptor system and still behave very differently. Memantine modulates excessive NMDA activity while preserving normal signalling. Ketamine produces a broader NMDA blockade with a different clinical profile. Let’s start with memantine’s receptor behaviour. Memantine is a low-affinity, voltage-dependent, non-competitive NMDA receptor antagonist. That combination matters because memantine is not designed to erase glutamate signalling. It is designed to limit excessive NMDA activity. Glutamate is essential for the brain. It supports: The problem is not glutamate itself. The problem is prolonged NMDA receptor activation and sustained calcium influx. Memantine works at that point of excess. When glutamatergic activity is excessive, memantine antagonises prolonged calcium influx through the NMDA channel. But during normal physiological signalling, it can dissociate, normal transmission can continue, location sharpens the mechanism. Synaptic NMDA receptor activation is linked with neuronal health. Chronic extrasynaptic NMDA receptor activation is linked with neurotoxicity. Memantine preferentially inhibits extrasynaptic NMDA receptors. That is the key memantine profile: This is why its mechanism is closer to selective modulation than blunt blockade. Ketamine behaves differently. It inhibits both synaptic and extrasynaptic NMDA receptors. It is also less selective for NMDA receptors, with activity at muscarinic, monoaminergic, and opioid receptors. That broader receptor footprint changes the clinical picture. Binding duration adds the final distinction. Memantine has a favourable off-rate from the NMDA receptor channel. Too slow, and it could accumulate and interfere with normal neurotransmission. Too fast, and it may be ineffective. Ketamine binds to NMDA receptors for longer periods than memantine. That longer binding is linked with more persistent effects on pain and antidepressant activity. It may also help explain ketamine’s higher sedative and psychotomimetic effects. Memantine is not simply a ‘weaker’ ketamine. Its profile depends on: Same receptor label. Different pharmacology. For more evidence-based psychiatry insights like this, join the Psych Scene newsletter. We share clinical frameworks, research updates, diagnostic explainers, and practical resources designed to support mental health professionals in practice.

A real-world 2025 EEG study in bipolar depression patients reveals a cascade of changes across brain rhythms, complexity, and excitation-inhibition (E/I) balance. Let’s break it down: Ketamine, a dissociative compound, shows promise in treating mood disorders, including treatment-resistant depression (TRD) and bipolar disorder (BD). Despite its therapeutic potential, the neurophysiological mechanisms underlying ketamine’s effects are not fully understood. (Agnorelli, C., et al, 2025). Oscillatory activity: Ketamine reduced theta (θ), alpha (α), and low beta (β) power while increasing low gamma (γ), consistent with cortical disinhibition via NMDA antagonism on GABAergic interneurons. Translation: The brain’s usual slow, calming rhythms were dampened and fast, stimulating activity ramped up. This likely reflects a release of inhibitory control. Spectral slope flattening The slope of the EEG power spectrum above 20 Hz flattened, indicating a shift in E/I balance toward excitation. Translation: The brain’s rhythm becomes less steady and more noisy. High-frequency activity dominates, indicating a more chaotic state. Entropy and complexity Global signal entropy increased, especially in high beta and gamma bands suggesting heightened informational complexity. It decreased in slower frequencies. Translation: The brain became more unpredictable and dynamic-especially in fast-processing regions. Rhythms, slope, and entropy are linked These three metrics shift together, pointing to a shared underlying mechanism. Translation: Ketamine doesn’t just tweak one system, it rewires the whole pattern of brain communication. Dissociation effects unclear: EEG changes did not consistently correlate with CADSS-measured dissociation; some weak associations (e.g., δ power and derealisation) were not robust. Translation: While the brain clearly shifts, our current dissociation scales may miss what patients are actually experiencing under ketamine. Ketamine pushes the brain into a globally excited, complex, high-frequency state. This may be key to both its antidepressant effects and its strange, dissociative experience, but our tools to measure the latter might need rethinking. Time course matters: The acute, transient excitatory shift may support antidepressant effects, but sustained over-excitation is not adaptive (insomnia, anxiety, mood elevation). In bipolar depression, activation risk is higher. Monitor for hypomania/mania, agitation, and sleep reduction; consider spacing doses and ensuring mood-stabiliser cover. Buy Ketamine | Ketamine dissociation mechanism | Buy Spravato