New England Journal of Medicine
October 4, 2023
Andreas Reif, Istvan Bitter, Jozefien Buyze et al.
197 citations
In treatment-resistant depression, esketamine nasal spray combined with an SSRI or SNRI led to remission in 27.1% of patients at week 8, compared to 17.6% for extended-release quetiapine plus an SSRI or SNRI. Over 32 weeks, 21.7% of patients on esketamine had no relapse after remission versus 14.1% on quetiapine. The open-label, single-blind, randomized trial included 676 patients. Adverse events matched known safety profiles. Esketamine was superior to quetiapine for achieving remission and preventing relapse.
Neuropharmacology
January 6, 2023
Nicolas Singewald, Simone B. Sartori, Andreas Reif et al.
57 citations
Anxiety disorders and PTSD are common and increasing worldwide. Current medications help some patients but have side effects and do not address underlying brain changes. After a period of stagnation, there is renewed interest in developing new drug treatments. This review describes currently available drugs and summarizes recent and ongoing clinical trials of novel medicines, grouped by their neurochemical targets: monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic, and neuropeptide systems. The authors emphasize designing treatments based on an understanding of neurobiology and harnessing neuroplasticity to produce lasting beneficial changes, for example by combining psychotropic drugs with psychotherapy. Emerging trends in this new phase of drug development are noted.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
August 1, 2024
Roger S McIntyre, Istvan Bitter, Jozefien Buyze et al.
30 citations
In the ESCAPE-TRD trial, esketamine nasal spray caused treatment-emergent adverse events more often than quetiapine extended release (91.9% versus 78.0%), but these events were typically mild or moderate and transient: 92.0% resolved the same day, and only 4.2% of patients discontinued esketamine due to adverse events compared with 11.0% for quetiapine. The median proportion of days with adverse events was lower with esketamine (11.9% versus 21.3%). Along with greater efficacy, esketamine's tolerability profile supports its use for treatment-resistant depression.
European archives of psychiatry and clinical neuroscience
August 29, 2024
Florian Freudenberg, Christine Reif-Leonhard, Andreas Reif
10 citations
Changes in glutamate-related brain plasticity may underlie depression, leading researchers to explore components of the glutamate synapse as targets for faster-acting antidepressants. The NMDA receptor blocker ketamine and its S-enantiomer esketamine already show rapid antidepressant effects. This review examines other glutamatergic rapid-acting antidepressants beyond (es)ketamine that have meaningful clinical trial data, including arketamine, esmethadone, nitrous oxide, and other glutamate receptor modulators. Substances successful only in preclinical studies or case reports are discussed marginally. The authors aim to highlight glutamatergic modulation's critical role in advancing antidepressant therapy, potentially improving clinical outcomes and reducing depression's burden through faster therapeutic effects.
Biological Psychiatry
March 8, 2025
Jonathan Repple, Maximilian Bayas, Chiara Möser et al.
8 citations
Rapid-acting antidepressants (RAADs) such as ketamine show promise for bipolar depression, but research remains limited compared to major depressive disorder. This review covers RAAD classes under investigation for bipolar depression, including NMDA antagonists (ketamine, esketamine, riluzole, felbamate), GABAA activators (zuranolone, pregnenolone, PEA), psychedelics (psilocybin, 5-MeO-DMT), muscarine receptor antagonists (scopolamine), and kappa opioid receptor antagonists (navacaprant). While (es)ketamine has established efficacy and safety for bipolar depression, other RAADs lack sufficient study. Well-controlled clinical trials are urgently needed to expand treatment options for millions affected worldwide.
The British journal of psychiatry : the journal of mental science
February 1, 2025
Allan H Young, Pierre-Michel Llorca, Andrea Fagiolini et al.
7 citations
In people with treatment-resistant depression, esketamine nasal spray outperformed quetiapine extended release across multiple measures. Sensitivity analyses using different definitions of remission and relapse consistently favored esketamine, with relative risks for the primary endpoint ranging from 1.462 to 1.737 and for the key secondary endpoint from 1.417 to 1.838. Esketamine also shortened time to first remission by 71% and confirmed remission by 66%. The robustness of the original ESCAPE-TRD trial findings was confirmed.
JAMA Psychiatry
March 25, 2026
Wiesław Jerzy Cubała, Malek Bajbouj, Michael Bauer et al.
3 citations
A single day of treatment with an inhaled synthetic formulation of mebufotenin (GH001) significantly reduced depression symptoms in adults with treatment-resistant depression compared to placebo. In a randomized, double-blind trial of 81 patients, those receiving up to three escalating doses of GH001 showed an average 15.5-point greater improvement on the Montgomery-Åsberg Depression Rating Scale by day 8 than those on placebo. Remission rates were 57.5% for GH001 and 0% for placebo. No severe or serious adverse events occurred. The findings suggest GH001 may be a rapid-acting, well-tolerated treatment option for treatment-resistant depression.
The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry
January 1, 2025
Christine Reif-Leonhard, Shannon N Millard, Dorsa Ferdowssian et al.
3 citations
Repeated intravenous esketamine infusions improved emotion recognition for all emotions except sadness, where accuracy decreased, particularly for low-intensity expressions. Misclassifications of other emotions as sad also decreased, indicating a reduced response bias towards sadness. This shift emerged after the first infusion and consolidated over time. Participants showed significant reductions in feelings of sadness and irritability, and cognitive functioning improved. Among those receiving at least five infusions, 66.7% showed significant improvement. The findings suggest that esketamine's antidepressant effects may involve changes in emotion processing and cognition, with acute mood-lifting effects distinguishable from longer-lasting responses that consolidate after repeated administration.
Eur Neuropsychopharmacol
June 5, 2026
Andreas Reif, A. Elif Anıl Yağcıoğlu, Istvan Bitter et al.
No Summary
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
July 17, 2026
Allan H Young, Bernhard T Baune, Beatrice Benatti et al.
A panel of 30 European psychiatrists with expertise in treatment-resistant depression (TRD) reached consensus on strategies for using esketamine nasal spray across treatment phases. During the acute phase (4-12 weeks), even modest reductions in core symptoms support continuing esketamine, especially for patients with long disease course or resistance to multiple therapies. Dose and frequency maximization (84 mg weekly) was recommended to improve acute outcomes. In the continuation phase (6-9 months), monitoring should focus on residual symptoms, functional recovery, and comorbidities. Prolonging maintenance treatment (≥12 months) depends on the degree of worsening when tapering, relapse risk, and recurrence history. Across all phases, integrating psychotherapy, optimizing antidepressants, managing comorbidities, and strengthening support networks were recommended.
Pharmacological research
October 1, 2025
Florian Freudenberg, Christine Reif-Leonhard, Gerard R Dawson et al.
Treatment-resistant depression (TRD) affects about 30% of patients with major depressive disorder. While antidepressant development has long focused on monoamine targets, research over the past 35 years has increasingly explored glutamatergic mechanisms. This review discusses developments in glutamatergic drug discovery, emphasizing convergent mechanisms between NMDA and AMPA receptor signaling. Beyond established rapid-acting antidepressants like (es)ketamine and dextromethorphan/bupropion, novel directions include esmethadone, nitrous oxide, and NMDA receptor positive allosteric modulators (rapastinel, zelquistinel, apimostinel), as well as AMPA receptor PAMs (osavampator, tulrampator). The convergent mechanism involves increased AMPA receptor activation, triggering BDNF release and mTOR signaling, promoting synaptic strengthening. Glutamatergic agents represent a transformative path for TRD treatment.