American Journal of Psychiatry
May 21, 2019
Vanina Popova, Ella J. Daly, Madhukar Trivedi et al.
879 citations
Switching to esketamine nasal spray plus a new antidepressant led to a significantly greater reduction in depression severity after 28 days than switching to a new antidepressant alone in adults with treatment-resistant depression. The average improvement on the Montgomery-Åsberg Depression Rating Scale was 4 points greater with esketamine (95% CI -7.31 to -0.64). Earlier improvements were also seen. Common side effects included dissociation, nausea, vertigo, dysgeusia, and dizziness, which typically appeared shortly after dosing and resolved within 1.5 hours. Seven percent of esketamine patients discontinued due to adverse events versus 0.9% in the comparator group. The findings support esketamine as a rapidly acting option for this difficult-to-treat population.
World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
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.
Eur Neuropsychopharmacol
November 7, 2025
Mikkel Højlund, Helin Y. Kafali, Begüm Kırmızı et al.
12 citations
A living systematic review with meta-analysis examined the efficacy, safety, and all-cause discontinuation of serotonergic psychedelics and MDMA for treating mental disorders. The review found that these substances show promise in reducing symptoms of conditions such as depression, anxiety, and post-traumatic stress disorder, with some evidence supporting their therapeutic potential. However, the authors note that the overall quality of evidence is limited by small sample sizes, short follow-up periods, and methodological concerns. Safety profiles varied, with most adverse events being mild to moderate, though serious adverse events were reported in some studies. The review emphasizes the need for larger, more rigorous trials to confirm these findings.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
April 1, 2025
Eduard Vieta, Nahida Ahmed, Celso Arango et al.
12 citations
Patients with treatment-resistant depression who received esketamine nasal spray experienced 43.2% more weeks with functional remission over 32 weeks compared to those taking quetiapine extended release, a difference of 2.0 weeks. Esketamine also led to an 11.9% reduction in productivity loss due to absenteeism and a 14.2% reduction in overall work productivity loss. Both treatments were taken alongside an ongoing SSRI or SNRI. The findings suggest that esketamine provides greater improvements in daily functioning and workplace productivity for this patient group.
Lancet Reg Health Eur
November 20, 2025
Santiago Madero, Oscar Soto-Angona, Genís Ona et al.
9 citations
Psychedelic-assisted therapy in Europe is gaining momentum through recent initiatives in Switzerland, Germany, and the Czech Republic, though access remains limited. The authors argue for an integrative framework that considers neurobiological mechanisms, subjective experience, and contextual factors, emphasizing how effects involving neuroplasticity and critical periods may interact with psychotherapeutic processes. Context and psychological support are highlighted as crucial for shaping outcomes. Regulatory fragmentation and methodological complexities hinder progress, but publicly funded trials such as EPIsoDE and PsyPal offer promising examples of ethical and effective approaches. The future of psychedelic therapy lies in embracing its complexity.
The European Journal of Psychiatry
May 2, 2025
Josep Antoni Ramos‐quiroga, Fernando Mora, Silvia Arostegui et al.
4 citations
Treatment-resistant depression (TRD) patients have often been excluded from antidepressant drug trials, leaving unclear clinical guidance. Intranasal esketamine, a non-monoaminergic treatment that modulates the glutamatergic system to improve neuroplasticity, offers a new option. A Spanish committee of nine psychiatrists expert in TRD reviewed literature from 2014 to 2024 and developed a consensus on practical management. They recommend a treatment algorithm for TRD with intranasal esketamine, including guidance for patients with psychiatric comorbidities and for those who show less than a 50% symptom reduction after the first induction phase. Treatment should occur at the patient's usual mental health center, with dose optimization and flexible management based on clinical progress. This is the first such consensus in Spain.
Scientific reports
July 1, 2025
Yvan Gomez, Ayako Nakaki, Allegra Conti et al.
3 citations
An 8-week Mindfulness-Based Stress Reduction program during pregnancy is associated with changes in maternal brain structure and chemistry. Pregnant women who completed the program showed larger surface area in the right superior frontal region and higher concentrations of the metabolite myo-inositol compared to those receiving usual care. Higher scores on mindfulness facets of non-judgmental and non-reactivity were also linked to larger frontal area. These findings suggest the intervention may influence the maternal brain in the third trimester.
Molecular psychiatry
May 29, 2026
Mickael Eskinazi, Rayan Nasserdine, Romane M Cusin et al.
A systematic review of 23 studies examined whether serotonergic psychedelics (psilocybin, LSD, mescaline, DMT/ayahuasca) or MDMA can trigger manic or hypomanic symptoms. Rates of such symptoms ranged from 5.8% in controlled trials of psilocybin-assisted therapy for depression to 30% in naturalistic studies of people with bipolar disorder. When manic symptoms occurred, they were typically acute and self-limited. Higher risks were seen in individuals with bipolar I disorder, family vulnerability, polysubstance use, or unsupervised use. Registry data showed a 4% prevalence of later transition to bipolar disorder, with little evidence for a hallucinogen-specific signal. The authors conclude that these substances pose a low but clinically meaningful relative risk of transient mood symptoms in susceptible individuals while remaining relatively safe in controlled settings.
European Neuropsychopharmacology
March 12, 2026
Natalia E. Fares-Otero, Yuki Furukawa, Marit Sijbrandij et al.
A systematic review and meta-analysis of randomized controlled trials found that MDMA-assisted therapy (MDMA-AT) was associated with reductions in PTSD symptom severity and dissociative symptoms, and may improve functioning, compared with control conditions. No clear benefit was observed for depressive symptoms. The analysis included 8 trials with 298 participants for the primary outcome. However, the overall certainty of the evidence was very low due to high risk of bias in outcome measurement, deviations from intended interventions, small sample sizes, and lack of active controls in most studies. Larger, higher-quality trials with active controls and long-term follow-up are needed to determine efficacy.
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.