Bipolar Disorders
January 13, 2023
Giovanni Martinotti, Bernardo Dell’osso, Giorgio Di Lorenzo et al.
72 citations
Esketamine nasal spray reduced depressive symptoms in people with treatment-resistant bipolar depression as effectively as in those with unipolar treatment-resistant depression, with no significant differences in response or remission rates after one and three months. The treatment also showed greater anxiety-reducing effects in the bipolar group. No treatment-emergent affective switch occurred, supporting the safety and tolerability of esketamine for bipolar treatment-resistant depression.
Psychiatry Research
July 29, 2023
Mauro Pettorruso, Roberto Guidotti, Giacomo D’andrea et al.
56 citations
Machine learning models predicted which patients with treatment-resistant depression would respond to esketamine nasal spray. In a retrospective study of 149 patients, three random forest classifiers achieved 68.53% accuracy for response at one month and 66.26% at three months, and 68.60% accuracy for remission at three months. Features such as severe anhedonia, anxious distress, mixed symptoms, and bipolarity positively predicted response and remission, while benzodiazepine use and depression severity were linked to delayed responses. The findings suggest machine learning may aid personalized treatment decisions for treatment-resistant depression.
Cephalalgia
April 22, 2015
Cherubino Di Lorenzo, Gianluca Coppola, Giorgio Di Lorenzo et al.
40 citations
Many cluster headache patients are dissatisfied with conventional treatments and turn to illicit drugs. Among 54 respondents from an online self-help group, all were dissatisfied with standard care, and 34 had used cannabinoids, 18 psilocybin, 13 cocaine, 12 lysergic acid amide, 8 heroin, and 4 LSD. Most found suggestions for these substances on the Internet and often underestimated legal risks while overestimating safety. Patients frequently did not inform their physicians about this use, raising concerns about the physician-patient relationship in this population.
American Journal of Geriatric Psychiatry
July 8, 2023
Giacomo D’andrea, Stefania Chiappini, Roger S. McIntyre et al.
36 citations
Esketamine nasal spray (ESK-NS) shows preliminary effectiveness for treatment-resistant depression in adults aged 65 and older, with 53.3% of participants responding (MADRS score reduced by at least 50%) and 33.33% achieving remission (MADRS below 10) after three months. Common adverse effects included dizziness (50%), dissociation (33.3%), sedation (30%), and hypertension (13.33%). Twenty percent of participants discontinued treatment. These findings, from a post-hoc analysis of 30 older adults, suggest ESK-NS can be effective but is associated with high rates of treatment-emergent adverse events, most of which did not require stopping treatment.
Journal of Personalized Medicine
April 1, 2025
Marco Di, M. Pepe, G. D’andrea et al.
18 citations
Most patients with treatment-resistant depression reported positive experiences with esketamine nasal spray. In a survey of 236 outpatients, 88.4% reported enhanced quality of life. Satisfaction levels varied: 10.2% were unsatisfied, 19.1% partially satisfied, 44.4% satisfied, and 26.3% very satisfied. The most satisfied patients noted early improvements in depressed mood, suicidal thoughts, and restlessness, and reported functional gains across all domains. Artificial intelligence analysis of open-ended responses identified themes of personal growth and a desire for tailored treatment settings. Integrating patient-reported experiences may help personalize care and improve adherence.
Psychiatry Research
July 26, 2025
G. D’andrea, C. Cavallotto, M. Pettorruso et al.
16 citations
Anhedonia, the reduced ability to experience pleasure, is a core symptom of both unipolar and bipolar depression that often responds poorly to standard antidepressants. In a real-world observational study of 253 treatment-resistant patients (199 with unipolar depression, 54 with bipolar depression), repeated doses of esketamine nasal spray added to ongoing medication significantly reduced anhedonia over three months. The effect was distinct from overall mood improvement. At three months, 51.92% of bipolar and 38% of unipolar patients showed at least a 50% reduction in anhedonia scores. Dropout rates were low (around 13–14%), and manic switches were rare. The findings suggest esketamine has a targeted, transdiagnostic anti-anhedonic effect.
Psychiatry Research
August 18, 2025
Ilenia Rosa, L. Padula, Francesco Semeraro et al.
2 citations
Treatment-resistant depression (TRD) challenges standard approaches, prompting a shift toward non-monoaminergic interventions like neuromodulation and glutamatergic agents. This narrative review examines the endocannabinoid system (ECS) as a potential common pathway for these treatments. Evidence indicates that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) increase endocannabinoids anandamide and 2-arachidonoylglycerol, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors, while psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions. These findings suggest ECS modulation may unify diverse antidepressant mechanisms in TRD, offering a promising target for novel therapies.
Current neuropharmacology
April 7, 2025
Marika Alborghetti, Luana Lionetto, Ginevra Lombardozzi et al.
1 citation
In patients with treatment-resistant depression receiving intranasal esketamine (56 mg) alongside another antidepressant, those taking antidepressants that inhibit cytochrome-P450 isoforms (paroxetine, fluoxetine, duloxetine, venlafaxine) had significantly higher serum esketamine levels 20 minutes after dosing and over 72 hours compared to patients on sertraline, citalopram, escitalopram, or vortioxetine. Salivary esketamine levels were several-fold higher than serum levels at all time points and showed high variability. These pharmacokinetic differences did not affect clinical outcomes, but changes in systolic blood pressure positively correlated with serum esketamine levels, suggesting dose reduction may be warranted for patients with cardiovascular comorbidity on those CYP450-inhibiting antidepressants. Small subgroup sizes limit strong conclusions.
Translational Psychiatry
June 24, 2026
Mauro Pettorruso, Giacomo D’andrea, Antonio Inserra et al.
Emerging clinical and preclinical evidence suggests that the therapeutic benefits of psychedelics for depression and anxiety may be separable from their consciousness-altering effects. Psychedelics produce profound brain changes, including suppression of the default mode network, leading to intense subjective experiences such as ego dissolution. These effects require extensive preparation and integration, exclude individuals with certain psychiatric vulnerabilities, and raise scalability concerns. Pharmacological strategies like serotonin 2A receptor antagonism and development of biased psychedelic analogues might retain therapeutic efficacy without psychedelic experiences. Preclinical data indicate that downstream molecular and network-level mechanisms could mediate therapeutic effects independently of subjective states. Confirming this dissociation could enable more scalable, accessible treatments for broader psychiatric populations.