Brain Sciences
June 27, 2021
Giovanni Martinotti, Stefania Chiappini, Mauro Pettorruso et al.
114 citations
Ketamine and esketamine, N-methyl-D-aspartate receptor antagonists, show promise for treating obsessive-compulsive disorder (OCD), eating disorders, and substance use disorders, which share features like obsessive thoughts and compulsive behaviors. A review of literature up to April 2021, following PRISMA guidelines, found that while small studies indicate remarkable results for treatment-resistant depression, PTSD, and OCD, solid evidence for benefits in OCD spectrum and addiction is still lacking. The use is supported by glutamatergic neurotransmission dysregulation. Preliminary data are optimistic, but further studies are needed to clarify unknowns and long-term effectiveness.
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.
Science Advances
June 14, 2023
Leor Roseman, Christopher Timmermann, Daniel Golkowski et al.
65 citations
The effects of mind-altering drugs on brain function arise from complex interactions with multiple neurotransmitter systems, not just one. By linking the distribution of 19 neurotransmitter receptors and transporters (measured with PET) to changes in functional connectivity (measured with fMRI) caused by 10 drugs—anesthetics (propofol, sevoflurane, ketamine), psychedelics (LSD, psilocybin, DMT, ayahuasca), and others (MDMA, modafinil, methylphenidate)—the work shows a many-to-many mapping between drug effects and neurotransmitter systems. The drugs' impacts follow hierarchical gradients of brain structure and function, and regional susceptibility to drug-induced changes mirrors susceptibility to structural alterations from brain disorders.
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.
European Neuropsychopharmacology
May 4, 2023
Stefania Chiappini, Giacomo D’andrea, Sergio De Filippis et al.
48 citations
Esketamine nasal spray reduces depression symptoms in patients with treatment-resistant depression who also have a substance use disorder. In 26 patients followed for three months, Montgomery-Asberg depression rating scale scores decreased significantly from baseline to one month and from one to three months. Side effects occurred in 73% of patients, most commonly dissociative symptoms and sedation, but none led to lasting harm and no abuse or misuse of the medication was reported. The findings suggest esketamine is effective and safe in this population, though the study is limited by its small sample and short follow-up.
Transl Psychiatry
December 13, 2023
Marco Onofrj, Mirella Russo, Stefano Delli Pizzi et al.
42 citations
Psychosis in Parkinson's disease and Dementia with Lewy Bodies shares underlying mechanisms with altered states of consciousness seen in REM sleep, psychiatric disorders, and psychedelic drug use. Dysregulated activity in high-order thalamic nuclei, driven by ThalamoCortical Dysrhythmia (TCD), is proposed as a crucial trigger. TCD disrupts finely tuned cortico-cortical modulations normally supported by the thalamus, leading to aberrant Default Mode Network (DMN) activity. This process alters thalamic filtering of internal and external information, causing cortical input overload and DMN decoupling from task-positive networks. These changes destabilize brain metastability, producing dreamlike, dissociative, or altered states. Psychedelic drugs similarly modulate thalamic-cortical pathways. Understanding this pathophysiology bridges neurology and psychiatry, offering promising avenues for investigation and therapy.
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.
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.
Archiv der Pharmazie
March 1, 2025
Giuseppe Floresta, Alberto Granzotto, Vincenzo Patamia et al.
12 citations
Xylazine, a veterinary sedative now used recreationally with fentanyl, interacts with human serotonin 7 (5-HT7R) and kappa-opioid (KOR) receptors. Computational docking and molecular dynamics simulations identified binding motifs and showed that small structural changes can improve xylazine's affinity for these receptors. These findings may help explain xylazine's psychoactive effects and guide treatments for overdoses.
bioRxiv (Cold Spring Harbor Laboratory)
July 13, 2022
Andrea I. Luppi, Justine Y. Hansen, R. Adapa et al.
5 citations
preprint
Psychoactive drugs reshape brain function by engaging multiple neurotransmitter systems simultaneously. By mapping the distribution of 19 neurotransmitter receptors and transporters (via PET) and the connectivity changes caused by 10 drugs (anesthetics, psychedelics, and stimulants), the study shows that drug effects are organized along hierarchical gradients of brain structure and function. Additionally, brain regions susceptible to drug-induced changes are also vulnerable to structural alterations from brain disorders. These findings reveal systematic links between molecular neurochemistry and large-scale functional reorganization.
Transl Psychiatry
October 31, 2025
Giacomo D’andrea, Stefania Chiappini, Laura Ciavoni et al.
3 citations
Psychedelics and ketamine/esketamine show promise for treating depressive disorders by inducing rapid and sustained antidepressant effects. The review examines their biological mechanisms, including modulation of glutamate and serotonin systems, promotion of neuroplasticity, and changes in brain connectivity and network function. Neuroimaging studies reveal alterations in default mode network, fronto-limbic connectivity, and thalamic activity. Clinical changes are associated with these brain alterations, though the precise relationships remain under investigation. The work synthesizes current evidence on how these compounds produce observable brain changes and symptom improvement, highlighting the need for further research to clarify mechanisms and optimize therapeutic applications.
Psychiatry Research Case Reports
October 18, 2023
Giacomo D’andrea, Ornella di Marco, Francesco Maria Semeraro et al.
1 citation
A 56-year-old man with rapid cycling bipolar disorder, experiencing four or more mood episodes per year, received esketamine nasal spray during a depressive episode and was followed for 18 months. He showed substantial mood stabilization, with only a brief depressive episode when treatment was stopped for three months, which resolved after restarting esketamine. Mild dissociative symptoms occurred with initial doses, but no other serious side effects were reported. This case suggests esketamine nasal spray may have mood-stabilizing effects for rapid cycling bipolar disorder, a condition that often responds poorly to lithium and standard treatments.
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.
bioRxiv Preprint Server
June 12, 2026
Dante Sebastián Galván Rial, Gabriel A. Della Bella, Lorina Naci et al.
preprint
States of consciousness can be ordered along a single dimension defined by the entropy of spontaneous neural activity, as proposed by the Entropic Brain Theory. Applying the same analytical pipeline to pharmacological (psychedelics, modafinil, propofol anaesthesia) and clinical (schizophrenia) fMRI datasets, the temporal irregularity of brain network topology was quantified. Propofol anaesthesia occupied the low-entropy end; psychedelic states and schizophrenia occupied the high end. This ordering tracks combined modulations of the level and content of consciousness, from reduced awareness under anaesthesia to heightened arousal and expanded experience under psychedelics and disorganised processing in schizophrenia. The result was not reducible to fluctuations in mean functional connectivity and was supported by convergent reorganisation of higher-order association cortex.