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.
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.
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.
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.