Annals of General Psychiatry
November 26, 2023
Giuseppe Maina, Marina Adami, Giuseppe Ascione et al.
56 citations
A Delphi panel of 60 Italian psychiatrists found wide variation in how treatment-resistant depression (TRD) is managed in Italy, highlighting a need for standardized strategies and treatments specifically approved for TRD. High consensus emerged on adding lithium or antipsychotics as augmentation therapies and on the need for long-term maintenance therapy. Esketamine nasal spray was identified as the best option for TRD patients, with agreement that it can be administered in a community outpatient setting given appropriate educational support for patients.
International journal of molecular sciences
December 5, 2024
Simone Pardossi, Andrea Fagiolini, Alessandro Cuomo
43 citations
Brain-derived neurotrophic factor (BDNF) supports neuroplasticity and neuronal survival, and its expression is reduced in depression-related brain regions. This narrative review summarizes human studies of BDNF changes in patients treated with ketamine or esketamine. Traditional antidepressants can increase BDNF levels, and ketamine and esketamine produce rapid antidepressant effects partly through glutamate pathways and neurotrophic mechanisms involving BDNF. Clinical findings are mixed; most studies report increased plasma BDNF after intravenous ketamine, but some contradict this. Few studies examine BDNF and esketamine. More research with larger samples and intranasal esketamine, approved for treatment-resistant depression, is needed.
Neuroscience & Biobehavioral Reviews
April 4, 2025
Claudio Agnorelli, Kate Godfrey, Gabriela Sawicka et al.
32 citations
Classic psychedelics (LSD, psilocybin, N,N-DMT) and non-classic psychedelics (ketamine, MDMA) enhance neuroplasticity—the nervous system's ability to adapt—through molecular, structural, and functional changes. Animal studies indicate these drugs induce meta-plasticity (heightened sensitivity to environmental stimuli) and hyper-plasticity (re-opening developmental windows for long-term structural changes), with implications for mood and behavior. Translating these findings to humans faces challenges due to limitations in current imaging techniques, but promising new directions include novel PET radioligands, non-invasive brain stimulation, and multimodal approaches. This review informs the development of targeted interventions for neuropsychiatric disorders.
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.
Children (Basel, Switzerland)
June 29, 2024
Simone Pardossi, Andrea Fagiolini, Simona Scheggi et al.
12 citations
Depression in adolescents is difficult to treat, especially when accompanied by suicidal thoughts or when it does not respond to standard treatments. Treatment-resistant depression affects up to 40% of adolescents with major depressive disorder and can severely impair development and quality of life. A review of existing research suggests that ketamine reduces depressive symptoms in adolescents with treatment-resistant depression, while esketamine reduces both depressive symptoms and suicidal ideation. Both drugs show favorable safety and tolerability. Prompt treatment with these medications may lower suicide risk and create an opportunity for longer-term therapies, though more research is needed to optimize protocols and assess long-term effects.
Molecular psychiatry
January 14, 2025
Claudio Agnorelli, Alessandra Cinti, Giovanni Barillà et al.
8 citations
In patients with bipolar disorder and treatment-resistant depression, a subanesthetic dose of ketamine alters brain activity patterns measured by EEG. Ketamine reduced low-frequency power and increased gamma oscillatory power, flattened the slope of power spectra, and increased brain signal entropy, especially in high-frequency bands. Patients who responded later to treatment showed greater EEG changes than early responders, suggesting underlying differences in treatment sensitivity. These neurophysiological effects may help explain ketamine's therapeutic mechanisms and could guide personalized treatment for mood disorders.
Journal of affective disorders
May 1, 2025
Alessandro Cuomo, Simone Pardossi, Giovanni Barillà et al.
7 citations
In patients with treatment-resistant bipolar disorder, intravenous ketamine (average dose 0.8 mg/kg) significantly reduced depressive symptoms, including inner tension, sleep reduction, and suicidal ideation, over four weeks without triggering manic switches. Fifty-nine patients were treated consecutively, and improvements in Montgomery-Åsberg Depression Rating Scale scores were observed from the second week onward. Adverse events were generally mild to moderate. The findings suggest ketamine can be a well-tolerated option for bipolar depression when carefully monitored, though caution is warranted due to the inherent risk of mood switching in bipolar disorder.
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.
arXiv (Cornell University)
November 29, 2024
Claudio Agnorelli, Meg J. Spriggs, Kate Godfrey et al.
2 citations
Classic psychedelics (LSD, psilocybin, N,N-DMT) and non-classic psychedelics (ketamine, MDMA) enhance neuroplasticity, the nervous system's ability to adapt. Animal studies indicate these drugs induce meta-plasticity, heightening sensitivity to environmental stimuli, and hyper-plasticity, reopening developmental windows for long-term structural changes that affect mood and behavior. Translating these findings to humans is challenged by limitations in current imaging techniques, but emerging approaches like novel PET radioligands, non-invasive brain stimulation, and multimodal methods offer promising directions. This review informs development of targeted interventions for neuropsychiatric disorders and advances understanding of psychedelics' therapeutic potential.
Therapeutic advances in psychopharmacology
January 1, 2026
Alessandro Cuomo, Roger Mcintyre, Despoina Koukouna et al.
1 citation
Among 45 patients with treatment-resistant depression treated with intranasal esketamine alongside oral antidepressants in a routine clinic, depression severity scores dropped from an average of 40.0 to 22.9 at four weeks and to 9.70 at 52 weeks, with scores remaining near 9-10 at later follow-ups. Eight patients stopped treatment, mostly due to lack of efficacy or side effects. No manic symptoms emerged, and side-effect ratings were low. The findings suggest sustained symptom improvement and a favorable long-term safety profile for those who continued treatment, though the observational design, concurrent treatments, and survivor bias limit the conclusions.
ChemRxiv
February 7, 2023
Vito F. Palmisano, Claudio Agnorelli, David Erritzøe et al.
1 citation
Classic psychedelics target the 5-HT2A serotonin receptor, but their precise mode of action remains unclear. Computational modeling of the receptor's orthosteric binding pocket for several psychedelics—including serotonin, LSD, DMT, and a photoswitchable analog (AzoDMT)—revealed two nearly equivalent binding poses. LSD and serotonin preferred the canonical crystallized pose, whereas DMT and 4-OH-DMT slightly favored a newly identified pose. The cis form of AzoDMT was the most stable, and its azobenzene domain interacted with the same residue (L229) responsible for LSD's extracellular loop closure. These simulations clarify drug–protein interactions and may aid development of new psychedelic compounds.
Psychiatry research
August 1, 2026
Pietro Carmellini, Andrea Fagiolini, Mario Pinzi et al.
In a real-world clinic, intravenous ketamine reduced depressive symptoms in patients with treatment-resistant unipolar and bipolar depression. Both groups improved significantly, but those with bipolar depression showed faster and greater improvement starting at two weeks and lasting through three months. Dissociative side effects were mild and did not increase over time; women with unipolar depression reported higher dissociative symptoms at three months. No sex differences in antidepressant efficacy were found. The findings suggest ketamine is effective for treatment-resistant depression, with stronger benefits for bipolar depression.
Pharmaceuticals (Basel, Switzerland)
April 24, 2026
Pietro Carmellini, Alessandro Cuomo, Maria Beatrice Rescalli et al.
Depression likely arises from a mix of two interacting biological problems: imbalances in monoamine neurotransmitters (like serotonin) and disruptions in glutamate signaling that impair the brain's ability to adapt and form new connections. These two systems can combine in different ways across individuals, helping explain why some people respond to standard antidepressants while others do not. Rapid-acting treatments such as ketamine work by directly targeting the glutamate system to boost synaptic plasticity, offering faster relief, especially for treatment-resistant depression. A framework called the 'monoamine-glutamate continuum' may guide future precision psychiatry by matching treatments to each person's specific neurobiological profile.
Expert opinion on pharmacotherapy
February 1, 2026
Alessandro Cuomo, Mario Pinzi, Andrea Fagiolini
Major depressive disorder remains a leading cause of disability globally. Many patients do not respond adequately to traditional antidepressants. This review examines phase 3 clinical trial evidence for newer agents, including brexanolone, intranasal esketamine, dextromethorphan-bupropion, vortioxetine, and glucagon-like peptide-1 receptor agonists. These treatments offer rapid symptom relief and potential cognitive or metabolic benefits for conditions like postpartum depression, acute suicidal ideation, and treatment-resistant depression. However, limited integration into clinical guidelines, insufficient long-term data, and implementation barriers restrict their use. The authors call for clearer treatment sequencing strategies and harmonized recommendations to support more individualized depression management.
bioRxiv Preprint Server
May 1, 2025
Claudio Agnorelli, Joseph Peill, Gabriela Sawicka et al.
preprint
A single psychedelic dose of ketamine (1 mg/kg, intravenous) alters brain chemistry and connectivity in healthy people for at least one to eight days. After the dose, glutamate levels in the anterior cingulate cortex rose significantly. Functional connectivity decreased within high-order networks such as the default mode network, while integration between low- and high-order networks increased. Increases in a PET marker of synaptic plasticity correlated with reduced intrinsic activity in default mode network regions and a diminished influence of the posterior cingulate cortex on global network dynamics. The posterior cingulate cortex appears to be a central hub through which ketamine may reshape brain hierarchies over the long term.
ChemRxiv
Vito Federico Palmisano, Claudio Agnorelli, Andrea Fagiolini et al.
The ability of classic psychedelics to permeate neuronal membranes and reach intracellular 5-HT2A receptors is critical for their therapeutic effects. Using molecular dynamics simulations, this computational study examined how structural modifications to tryptamines affect membrane permeability. Dimethylation of the primary amine group and adding a methoxy group at position 5 increased permeability. In contrast, substitutions at other positions on the indole ring and protonation of the molecules raised the energy barrier at the bilayer center, making the compounds highly impermeable. These findings can guide future drug design to develop psychedelics with enhanced activity.
arXiv Preprint Archive
November 29, 2024
Claudio Agnorelli, Meg Spriggs, Kate Godfrey et al.
Psychedelics like LSD and psilocybin can rewire brain connections after just one dose, unlike traditional psychiatric medications. These compounds boost the brain's natural plasticity, helping neurons form new pathways and adapt to change. Studies show they create a window of enhanced learning and adaptation, leading to lasting improvements in mood and behavior.