The findings, published in Translational Psychiatry, come from a clinical trial registered as NCT00088699 and conducted under the Intramural Research Program of the National Institutes of Health. Treatment-resistant depression, typically defined as depression that fails to respond adequately to two or more adequate antidepressant trials, affects a substantial minority of the millions of people living with major depressive disorder worldwide. For these patients, insomnia and anxiety are not incidental companions but core burdens that shape daily functioning, suicide risk and quality of life. Understanding whether ketamine relieves these burdens together or separately is therefore far more than an academic exercise; it determines how clinicians should monitor, counsel and follow up with patients in the critical first day after infusion.

The study’s design was straightforward but rigorous. Each participant was assessed at baseline, immediately before receiving the infusion, and again twenty-four hours afterward. Depression severity was quantified with the Montgomery–Åsberg Depression Rating Scale, a clinician-administered instrument widely regarded as sensitive to rapid change. Anxiety was measured with the Hamilton Anxiety Rating Scale, and insomnia was captured using the insomnia items embedded in the Hamilton Depression Rating Scale. To analyze the data, the researchers employed linear mixed-effects models, a statistical framework that can account for repeated measurements within the same individual while estimating the average pre-to-post change across the group. The results were unambiguous: depression scores fell by an estimated 11.72 points on the MADRS, anxiety scores dropped by 7.87 points on the HAM-A, and insomnia scores declined by 0.89 points, with all three changes reaching statistical significance at P less than 0.001.

Those headline numbers confirm what a growing body of literature has suggested since the early 2000s, when researchers first reported that a subanesthetic dose of ketamine could lift depressive symptoms within hours in patients who had exhausted conventional options. Ketamine acts primarily as an antagonist of the N-methyl-D-aspartate receptor, a glutamate-gated ion channel, and its rapid antidepressant effects are thought to be mediated downstream through activation of AMPA receptors, stimulation of brain-derived neurotrophic factor signaling, and the restoration of synaptic connections eroded by chronic stress. The metabolite (2R,6R)-hydroxynorketamine has also been implicated in the antidepressant response, a discovery that has fueled an entire pipeline of ketamine-derived therapeutics now in clinical development.

But the real novelty of the new study lies in its dissection of how the three symptom domains interact. At baseline, before any drug was given, insomnia severity showed a moderate correlation with anxiety severity, with a Spearman rank correlation coefficient of 0.36, and anxiety correlated with depression with a Pearson correlation coefficient of 0.39. After ketamine, the association between anxiety and depression actually strengthened, rising to a Pearson correlation of 0.57, while the insomnia-anxiety link held steady at a Spearman coefficient of 0.36. Most tellingly, when the researchers computed change scores for each domain and correlated them, changes in anxiety were strongly associated with changes in depression, with a Spearman coefficient of 0.61, whereas changes in insomnia were not significantly associated with changes in either of the other two domains.

This dissociation carries real clinical weight. If insomnia improvement were simply a downstream consequence of mood lifting, one would expect patients whose depression improved most to also sleep most dramatically better. The data say otherwise. Instead, the study found that the single best predictor of how much a patient’s insomnia improved was how severe that insomnia was at baseline: greater baseline insomnia severity was associated with larger absolute reductions in insomnia scores. In other words, ketamine appears to act on sleep complaints in proportion to how disturbed sleep was to begin with, rather than as a ripple effect of the drug’s antidepressant action. This pattern hints at partially separable neurobiological mechanisms, perhaps involving ketamine’s effects on arousal circuitry, glutamatergic signaling in sleep-regulating regions, or the drug’s known sedative and psychotomimetic properties during the acute infusion period.

Supporting this interpretation, exploratory polysomnography analyses conducted in a subset of participants suggested objective sleep changes in the twenty-four hours after infusion: total sleep time increased, slow-wave sleep, the deep restorative stage most associated with synaptic homeostasis, increased, sleep efficiency improved, and sleep latency, the time it takes to fall asleep, shortened. Polysomnography, the gold standard for sleep measurement, records brain waves, eye movements, muscle tone and breathing overnight, providing an objective counterpoint to questionnaire-based insomnia ratings. The concordance between subjective insomnia improvement and objective sleep architecture changes, while exploratory in this dataset, strengthens the case that ketamine genuinely reshapes sleep physiology rather than merely altering how patients report their nights.

The research team, which included investigators from the NIMH’s Experimental Therapeutics and Pathophysiology Branch, Jena University Hospital, Philipps University of Marburg, the National Institute on Alcohol Abuse and Alcoholism, the University of Wisconsin-Madison and the University of British Columbia, went one step further by attempting to classify which patients would experience insomnia improvement. Using linear discriminant analysis and logistic regression as exploratory tools, they sought statistical signatures that might separate improvers from non-improvers. Such classification approaches, if validated in larger samples, could eventually help clinicians identify before an infusion which patients are likely to gain sleep benefits, allowing targeted adjunctive treatments, such as cognitive behavioral therapy for insomnia, for those less likely to respond on the sleep front.

The study is not without limitations, and the authors are careful to frame the insomnia findings appropriately. The insomnia measure was derived from items within the Hamilton Depression Rating Scale rather than a dedicated insomnia instrument, which may limit sensitivity to the full breadth of sleep complaints. The twenty-four-hour window captures only the earliest phase of ketamine’s action, and the drug’s antidepressant effects typically wane over days to two weeks, raising open questions about whether the dissociation between sleep and mood trajectories persists or collapses over longer follow-up. The sample of seventy-one patients, while respectable for an intramural trial of a hard-to-treat population, limits statistical power for subgroup analyses, and the polysomnography component was explicitly exploratory. The open-access paper, published on 6 October 2026 with the DOI 10.1038/s41398-026-04443-2, also notes that the version shared early is subject to further editorial edits before the final Version of Record.

Even with those caveats, the implications are immediate. Clinicians administering ketamine for treatment-resistant depression should not assume that a patient whose mood and anxiety improve will necessarily report better sleep, nor that a poor sleep response signals treatment failure on the mood front. The two domains deserve separate monitoring, and patients can be counseled that sleep improvements, when they occur, may scale with the severity of their pre-existing insomnia rather than with the depth of their mood response. For researchers, the study adds to a shifting view of ketamine not as a single blunt instrument but as a pharmacological scalpel whose blades cut along partly independent neural pathways, and it sets the stage for mechanistic work aimed at understanding why the brain’s sleep machinery responds to this anesthetic-turned-antidepressant on a schedule of its own.

Subject of Research: Short-term effects of ketamine on depression, anxiety and insomnia symptoms in treatment-resistant depression

Article Title: Insomnia and anxiety exhibit distinct short-term associations following ketamine in treatment-resistant depression

Article References: Hejazi, N. S., Kheirkhah, M., Chholak, R., Riedner, B., Jamalabadi, H., Walter, M., Hofmann, S. G., Duncan, W., Jr, Goldman, D., & Zarate, C. A., Jr (2026). Insomnia and anxiety exhibit distinct short-term associations following ketamine in treatment-resistant depression. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04443-2

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04443-2

Keywords: ketamine, treatment-resistant depression, insomnia, anxiety, depression, polysomnography, NMDA receptor, Translational Psychiatry, sleep architecture, MADRS, HAM-A, rapid-acting antidepressants

The research team, led by Seri Lim and Joshua Ryan Smith of Vanderbilt University Medical Center, along with collaborators at Massachusetts General Hospital, Harvard Medical School, and the University of Queensland, combined a case series of five patients treated at Vanderbilt with a systematic review of the international literature. By pooling participant-level data rather than relying on study-level summaries, the investigators assembled a cohort of 27 individuals with Down syndrome regression disorder and co-occurring catatonia who had received electroconvulsive therapy. According to the authors, this represents the largest analysis conducted so far on the use of the treatment in this population.

Down syndrome itself is the most common genetic cause of intellectual disability worldwide, arising in roughly one in 800 to 1,000 live births, most often through trisomy of chromosome 21. More than 214,000 people with Down syndrome live in the United States alone. Down syndrome regression disorder, previously called Down syndrome disintegrative disorder, is a potentially life-threatening complication marked by an acute or subacute loss of previously acquired skills, cognitive decline, affective instability, and language regression. Patients may develop new-onset insomnia, psychomotor slowing, mutism, and catatonia. The underlying causes remain poorly understood, though researchers have hypothesized roles for autoimmune dysregulation, psychosocial stressors, and co-morbid psychiatric illness.

Catatonia, the condition at the heart of the new analysis, is a treatable psychomotor syndrome characterized by distinct physical examination findings such as staring, grimacing, rigidity, and mutism. It can occur across the neurodivergent spectrum and throughout the lifespan, and it carries substantial morbidity and mortality, particularly among children and adolescents. Individuals with neurodevelopmental disorders face an elevated risk of delayed diagnosis, and their catatonia may present unusually, with loss of previously acquired skills and communicative abilities that mirror the broader regression seen in Down syndrome regression disorder. Some researchers have even questioned whether catatonia is a core component of the regression disorder itself, or whether the condition belongs on the catatonia spectrum.

To quantify the effect of electroconvulsive therapy, the team relied on the Bush-Francis Catatonia Rating Scale, a 23-item clinical instrument that grades the severity of each catatonic sign, with a maximum possible score of 69. Across the combined dataset, 17 pre-treatment and 15 post-treatment scores were available from 18 patients across seven sites or studies. The mean score before treatment was 17.40, falling to 4.40 afterward. A generalized estimating equations analysis, which accounts for the clustering of patients within the same study, found a statistically significant reduction of 13.00 points, with a 95 percent confidence interval spanning from 17.70 down to 8.18 and a p-value below 0.001. In plain terms, the treatment was associated with a substantial and statistically robust easing of catatonic symptoms.

The clinical picture of the patients underscores how difficult these cases are. The 27 patients, whose average age was 20.7 years, had collectively failed dozens of medication trials before turning to electroconvulsive therapy, with a mean of 2.4 failed psychiatric medications per patient. Lorazepam, a benzodiazepine and standard first-line agent for catatonia, had been tried in two-thirds of the cohort. Selective serotonin reuptake inhibitors such as sertraline and fluoxetine, antipsychotics such as quetiapine and aripiprazole, mood stabilizers, anticonvulsants, and even the NMDA receptor antagonist memantine had all been deployed with limited success. Medical and psychiatric comorbidities were common, including hypothyroidism in more than a fifth of patients, celiac disease, autoimmune encephalitis, major depressive disorder, and autism spectrum disorder.

The technical details of the treatment at Vanderbilt offer a rare window into how electroconvulsive therapy is actually delivered in this population. All five Vanderbilt patients received bitemporal electrode placement with brief-pulse stimulation, undergoing 171 treatments in total. Anesthesia was induced with methohexital at a mean dose of 68.4 milligrams, with succinylcholine providing muscle relaxation. Electroencephalographic seizure duration averaged 60.9 seconds, and propofol was used to terminate prolonged seizures, defined as those exceeding two minutes, in 19 percent of sessions. Notably, in about 16 percent of treatments, intramuscular ketamine was required to establish intravenous access because agitation or distress prevented conventional placement, a maneuver the authors report as the first described in this population. Despite the intensity of the treatment course, no severe adverse events were documented, although all five patients had difficulty verbalizing subjective side effects because of their intellectual disability.

The findings arrive with important caveats. The sample remains small, the data were collected retrospectively, and the analysis carries an inherent bias toward positive outcomes: patients unlikely to continue receiving dozens of electroconvulsive sessions unless some benefit was observed. Reporting of treatment parameters and rating scales was inconsistent across the studies included in the systematic review, and many patients received concurrent therapies, including intravenous immunoglobulin in a third of cases, making it impossible to isolate the specific contribution of the electrical stimulation. The authors also note that eight patients in the cohort were under 18, an age group whose access to electroconvulsive therapy is restricted by state-dependent legislation in the United States, and that stigma, limited education, and provider shortages limit availability worldwide.

Even so, the study marks a turning point for a condition that has lacked any evidence-based treatment algorithm. The authors recommend that future research examine electroconvulsive therapy for catatonia in Down syndrome regression disorder prospectively, with standardized reporting of electrode placement, pulse width, seizure duration, acute and maintenance treatment schedules, and cognitive outcomes. They also call for improved screening, including telemedicine-based catatonia assessments, to speed diagnosis in a population where symptoms are easily mistaken for the regression itself. Given the significant improvement in both regression and catatonic symptoms observed, the researchers suggest that clinicians should consider electroconvulsive therapy earlier in the disease course rather than as a last resort after years of failed medication trials.

For a condition that can strip away speech, movement, and independence in a matter of months, the message of this study is quietly radical: a treatment often portrayed as barbaric may, carefully administered, give young people with Down syndrome their lives back. The evidence base is still thin, built on 27 patients and seven research sites, but the signal is strong, the treatment was well tolerated, and the alternative for many families is watching a child disappear into unresponsive silence. As the authors conclude, more rigorous research is needed, but the era of assuming nothing can be done for regression in Down syndrome may finally be coming to an end.

Subject of Research: Electroconvulsive therapy for catatonia in Down syndrome regression disorder

Article Title: Use of Electroconvulsive Therapy for Catatonia in Down Syndrome Regression Disorder: A Systematic Review, Case Series, and Analysis

Article References: Lim, S., Kang, K., Oey, E., Santoro, S., Franklin, C., Luccarelli, J., Tamargo, R., Hamilton, C., Marler, S., Adegoke, T., Wilson, J. E., & Smith, J. R. (2026). Use of Electroconvulsive Therapy for Catatonia in Down Syndrome Regression Disorder: A Systematic Review, Case Series, and Analysis. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-026-07500-3

Image Credits: AI Generated

DOI: 10.1007/s10803-026-07500-3

Keywords: Down syndrome, Down syndrome regression disorder, catatonia, electroconvulsive therapy, Bush-Francis Catatonia Rating Scale, systematic review, case series, psychiatry, neurodevelopmental disorders, regression, ketamine, Vanderbilt University Medical Center

The research team, anesthesiologist Ali Ümit Eşbah and gastroenterologist Serkan Torun, analyzed records from patients aged 65 and older who underwent ERCP under deep sedation between 2015 and 2025. From that pool, 150 patients met the inclusion criteria. The study’s primary outcome, hemodynamic instability, was defined with clinical precision: either a drop of 30 percent or more in mean arterial pressure, the average pressure that drives blood through the body’s organs, or the need for vasopressor drugs to prop up failing circulation. This dual definition matters because it captures both the passive warning sign of a falling pressure curve and the active clinical response of an anesthesiologist reaching for rescue medication.

The headline finding is a frequency figure that should give clinicians pause: 46 of the 150 patients, or 30.7 percent, experienced hemodynamic instability during their procedure. Nearly one in three older adults in this cohort required either a substantial blood pressure intervention or vasopressor support. ERCP is already a demanding procedure for sedation teams because it is performed with the patient in a prone or semi-prone position, which restricts access to the airway and complicates monitoring. Combine that with the physiological vulnerabilities of advanced age, reduced cardiovascular reserve, blunted baroreceptor reflexes, and frequent comorbidities, and the sedation phase becomes one of the riskiest stretches of the entire procedure.

Using multivariable logistic regression, the researchers identified several independent predictors of instability. Advanced age itself increased risk, as did an American Society of Anesthesiologists physical status classification of III or IV, meaning severe systemic disease or life-threatening illness. Patients who arrived with a lower baseline mean arterial pressure were also more likely to cross the instability threshold, a finding that is intuitive but clinically actionable: the lower the starting point, the smaller the drop needed to reach the 30 percent reduction cutoff. Prolonged procedure duration emerged as a fourth predictor, likely reflecting both the cumulative cardiovascular stress of extended sedation and the fact that longer, more complex ERCPs tend to be performed in sicker patients.

The most provocative result concerns sedation strategy. Patients who received ketofol, a mixture of propofol and ketamine, had significantly lower odds of hemodynamic instability than those given propofol alone. The adjusted odds ratio was 0.50, with a 95 percent confidence interval of 0.25 to 0.99 and a p-value of 0.047. In plain terms, after accounting for other measured risk factors, the ketofol group’s odds of instability were about half those of the propofol-only group, and the result just crossed the conventional threshold for statistical significance.

The pharmacology behind this comparison is worth unpacking. Propofol is the workhorse of procedural sedation, prized for its rapid onset and quick offset, but it is a potent vasodilator and myocardial depressant. It lowers blood pressure partly by relaxing blood vessels and partly by blunting the sympathetic nervous system’s compensatory responses. Ketamine, by contrast, is a dissociative anesthetic that stimulates sympathetic outflow, typically raising heart rate and blood pressure. Blending the two is an attempt to have it both ways: propofol provides smooth hypnosis and amnesia while ketamine’s sympathomimetic activity counteracts propofol’s cardiovascular depression. The Düzce findings suggest that, in elderly ERCP patients, this counterbalancing may translate into a real reduction in clinically significant blood pressure crashes.

Because sedation strategy was not randomized, the researchers could not simply compare raw outcomes between groups; sicker patients may have been preferentially given one regimen over the other. To address this, they performed an inverse probability of treatment weighting analysis, or IPTW. This statistical technique reweights the two sedation groups as if treatment assignment had been random, based on each patient’s measured characteristics, thereby reducing the influence of confounding by indication. Under IPTW, the association held: the odds ratio for instability with ketofol was 0.55, with a 95 percent confidence interval of 0.31 to 0.98 and a p-value of 0.043. The consistency of the effect across two different analytical approaches strengthens the signal, even if it does not prove causation.

The authors are careful about the limits of their design, and that caution is warranted. As a retrospective, non-randomized study of 150 patients at a single center, residual confounding cannot be excluded. Unmeasured variables, such as the exact doses and titration patterns of sedatives, fluid management, the difficulty of individual cannulations, or subtle differences in patient physiology not captured in the chart, could all have influenced the results. The confidence intervals, while excluding unity, come close to it, and a finding with a p-value just under 0.05 in a modest sample should be treated as hypothesis-generating rather than practice-changing. A randomized controlled trial would be the definitive test of whether ketofol genuinely protects elderly patients or whether the association reflects selection of healthier patients for the combination regimen.

Still, the study fills a genuine gap. ERCP volumes are rising worldwide as populations age, and biliary disease remains one of the most common reasons older adults need urgent endoscopic intervention. Sedation-related hypotension in this population is not a trivial event: sustained low mean arterial pressure can compromise coronary and cerebral perfusion, precipitating myocardial injury or delirium in patients with little reserve to spare. Identifying who is at risk, the very old, the ASA III-IV patient, the one who starts with a marginal baseline pressure, and the one facing a long procedure, allows sedation teams to plan ahead with arterial line monitoring, preemptive fluid loading, or vasopressor availability.

The practical takeaway is twofold. First, hemodynamic instability during ERCP sedation in older adults is common enough, at roughly 31 percent in this cohort, that it should be anticipated rather than treated as a surprise. Second, the ketofol signal, replicated across multivariable regression and IPTW, gives anesthesiologists and gastroenterologists a concrete, testable option to weigh against propofol-only protocols in elderly patients. The study received no external funding, was approved by the Non-Interventional Clinical Research Ethics Committee of Düzce University, and is published open access. Whether ketofol’s apparent advantage survives the scrutiny of randomized trials remains to be seen, but for now it offers a data-driven starting point for a conversation that every sedation team caring for elderly ERCP patients should be having.

Subject of Research: Predictors of sedation-related hemodynamic instability during ERCP in older adults and the effect of ketofol versus propofol sedation

Article Title: Predictors of hemodynamic instability during ERCP sedation in older adults: impact of sedation strategy in a retrospective cohort

Article References: Eşbah, A. Ü., & Torun, S. (2026). Predictors of hemodynamic instability during ERCP sedation in older adults: impact of sedation strategy in a retrospective cohort. BMC Geriatrics. https://doi.org/10.1186/s12877-026-08405-7

Image Credits: AI Generated

DOI: 10.1186/s12877-026-08405-7

Keywords: ERCP, deep sedation, ketofol, propofol, ketamine, hemodynamic instability, older adults, geriatrics, anesthesiology, retrospective cohort, mean arterial pressure, vasopressors

The study was led by Professor Shammi Ramlakhan, an emergency medicine consultant working at Sheffield Children’s Hospital, the University of Sheffield and Sheffield Hallam University in the United Kingdom. He presented the results at the congress on Sunday, describing a problem that emergency clinicians across Europe will recognise immediately. According to Ramlakhan, nearly a third of children with moderate to severe pain do not receive adequate pain relief within the 15 to 20 minutes recommended in international guidance. That gap matters, because unrelieved pain in childhood is not merely a momentary distress; it can heighten fear of medical care, complicate examinations and procedures, and leave lasting psychological imprints on young patients and their families.

The trial enrolled 152 children aged between one and 17 years who presented with moderate to severe pain at one of seven hospital emergency departments in the United Kingdom and Spain between May 2024 and May 2025. The majority of participants had limb injuries, including fractures and dislocations, while others had burns or injuries to soft tissue. These are precisely the presentations that fill paediatric emergency departments every day, and they are the cases in which timely analgesia can make the difference between a manageable visit and a traumatic ordeal.

Every child in the study received the same combination of two analgesic medications: sufentanil, a potent opioid, and ketamine, a dissociative anaesthetic with strong analgesic properties. The drugs were administered together via a nasal spray, with the dose adjusted to each child’s body weight simply by varying the number of puffs. This dosing system is one of the study’s most significant technical features. Intravenous cannulation, the traditional route for strong analgesia in emergency care, is itself painful, frightening and technically difficult in small, distressed children with injured limbs. A spray that eliminates the needle removes a major barrier to early treatment and allows analgesia to begin within minutes of arrival.

The researchers assessed each child’s pain using standard validated instruments at two time points: 15 minutes and 30 minutes after administration. They also monitored for adverse effects throughout. The results were striking. After 15 minutes, more than half of the children, 54 percent, were already in less pain. By 30 minutes, the vast majority, 88 percent, reported reduced pain, and in 86.2 percent of children the pain score had fallen by around half. For a single, needle-free administration delivered in a busy emergency department, that speed and magnitude of effect is notable, particularly given that the treatment window studied matches the timelines set out in international paediatric pain guidance.

Safety findings were equally encouraging. Side effects were mild and consisted of nausea or vomiting, dizziness and nasal itching. No major adverse events were reported. Ramlakhan noted that children tolerated the spray well and emphasised the practical significance of the result: the treatment gives doctors a simple and effective option in a setting where, in his words, very few options currently exist. The absence of significant drowsiness is also clinically relevant, because heavy sedation can obscure the neurological assessment of a child and complicate decisions about imaging and further management.

The nasal spray was being tested under the European Medicines Agency’s paediatric-use marketing authorisation, or PUMA, scheme. This regulatory pathway exists specifically to encourage manufacturers to develop and adapt medicines for children, a population that has historically been underserved by the pharmaceutical industry because paediatric formulations are commercially less attractive and clinically more demanding to validate. Many drugs used in paediatric emergency care are administered off-label, with dosing extrapolated from adult evidence. A product developed and authorised specifically for children, with a dosing system designed around their weight and their tolerance, addresses a structural weakness in paediatric medicine. The researchers say the treatment should be available for use in Europe in the near future.

Independent commentary on the work underlined how significant the gap is that this spray could fill. Dr Maša Sorić, a member of the European Society for Emergency Medicine abstract selection committee and head of the emergency department at University Hospital Merkur in Zagreb, Croatia, who was not involved in the research, pointed out that millions of children are seen in European emergency departments every year, many suffering painful injuries, and that being in hospital can itself be frightening for children and their families. In her assessment, the study evaluated a nasal spray containing two existing types of pain relief with a very simple dosing system, and the results suggest it reduces pain quickly and effectively without the need for an injection, without causing excessive drowsiness and with only mild side effects.

Sorić also framed the broader clinical context: doctors want to give patients effective treatments, including treatment for pain, but the analgesic options currently available for children are limited. Her remarks reflect a long-standing tension in emergency medicine. Strong opioids and anaesthetics are the tools that work fastest, yet in children they have traditionally required intravenous access, careful titration and monitoring resources that many departments struggle to mobilise quickly. Weaker oral medications, meanwhile, often act too slowly or too weakly for severe pain. A nasal spray that combines a fast-acting opioid with ketamine, dosed by puff count and requiring no cannula, sits in the gap between those extremes and could realistically be administered by nursing staff within minutes of triage.

The study was experimental in design and involved people as its research subject, and its findings were presented at a congress rather than yet published in a peer-reviewed journal, so wider confirmation will be watched with interest. Even so, the combination of a large multi-centre cohort across two countries, validated pain assessments, a dosing method simple enough for routine practice and a clean safety profile makes a persuasive case. If the treatment reaches European emergency departments as its developers expect, the change could be felt immediately by the patients least equipped to articulate their suffering. A child with a broken arm who receives effective analgesia within fifteen minutes of arrival, without a needle, experiences a fundamentally different hospital visit from one who waits in pain. For clinicians who have spent years working around the absence of good paediatric pain options, a spray bottle may prove to be one of the most consequential tools the specialty has gained.

Subject of Research: Needle-free nasal spray analgesia for children with moderate to severe pain in emergency departments

Article Title: Nasal spray brings pain relief for children treated in the emergency department

Article References: Nasal spray brings pain relief for children treated in the emergency department. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: nasal spray, pain relief, children, emergency department, sufentanil, ketamine, paediatric medicine, analgesia, European Emergency Medicine Congress, needle-free, PUMA, clinical trial

The evidence for this drift is economic as much as scientific. Drawing on workforce research by Tadmon and Olfson published in the American Journal of Psychiatry, the authors describe a profession whose practice has narrowed under financial pressure. Psychiatrists increasingly deliver brief medication-management visits rather than the psychotherapy that once defined the field, a shift driven by reimbursement structures, administrative burdens and the economics of outpatient care. Studies from Hughes and colleagues in Psychiatric Services reinforce the picture, documenting how access to psychiatrists providing talk therapy has contracted even as demand for mental health care has surged. The result is a specialty whose self-image, rooted in the integration of biological and psychological treatment, no longer matches the reality of a fifteen-minute medication check.

At the same time, an entirely new therapeutic arsenal has matured. Repetitive transcranial magnetic stimulation, now supported by accelerated protocols that can deliver a full treatment course in days rather than weeks, has moved from experimental novelty to mainstream clinical tool. Esketamine nasal spray and off-label ketamine have introduced rapid-acting pharmacological interventions that require monitored, procedure-like administration. Electroconvulsive therapy, long the most effective treatment for severe depression, continues to evolve with modern techniques such as right unilateral ultrabrief pulse stimulation. Psychedelic-assisted therapies, including psilocybin and MDMA, are advancing through late-stage clinical trials and promise to add further procedurally intensive options. Each of these treatments shares a defining feature: the psychiatrist is no longer simply prescribing a medication, but directly performing or supervising a physical intervention on the brain.

The authors argue that this convergence of forces has created an identity crisis. Professional identity, as the medical education literature from Cruess and colleagues emphasizes, is not a cosmetic matter; it shapes how clinicians see their roles, how trainees choose specialties, how institutions allocate resources and how the public understands what a profession offers. A field that defines itself around diagnostic evaluation and pharmacological management is poorly equipped to steward technologies that require procedural skill, anatomical and neuroscientific knowledge, and rigorous safety protocols. Without a coherent identity, the authors warn, psychiatry risks ceding these interventions to other specialties or to commercial actors operating outside the traditional structures of academic medicine.

Their proposed solution is interventional psychiatry, defined not as a replacement for existing psychiatric practice but as an integrative framework that unites psychiatric judgment with procedural care. The concept is deliberately broad. It encompasses neuromodulation techniques such as TMS, vagus nerve stimulation and deep brain stimulation; pharmacological interventions requiring procedural administration, including ketamine and esketamine; convulsive therapies such as ECT; and, prospectively, psychedelic-assisted treatments. What binds them together is a shared logic: the psychiatrist’s diagnostic acumen, formulation skills and longitudinal therapeutic relationship remain central, but they are now paired with hands-on technical competence and an understanding of circuit-level neuroscience.

To help clinicians and institutions think about this expanding toolkit, the paper introduces a risk–skill matrix, a conceptual map that plots interventions according to the technical skill they demand and the risk they carry to patients. The matrix serves several purposes. It clarifies which treatments can be delivered safely in routine outpatient settings and which require specialized facilities, anesthesia support or intensive monitoring. It provides a rational basis for credentialing and privileging decisions, an increasingly urgent question as TMS clinics proliferate and ketamine administration spreads into commercial practice. And it offers trainees a structured way to understand the competencies they must acquire, from basic certification in office-based neuromodulation to advanced fellowship-level training in interventional procedures.

The historical analogy the authors reach for is cardiology. In 1977, Andreas Grüntzig performed the first coronary angioplasty, an event documented in The Lancet, and in the decades that followed cardiology transformed from a largely diagnostic and pharmacological specialty into one defined by interventional procedures. That transformation did not diminish the cardiologist’s medical judgment; it amplified it, demanding deeper integration of physiology, imaging and procedural technique. The authors contend that psychiatry now stands at a comparable inflection point. Just as interventional cardiology emerged as a recognized identity within cardiology, interventional psychiatry can serve as the organizing concept for a specialty whose therapeutic reach is expanding into direct neural intervention.

The idea itself is not entirely new. As early as 2014, Williams and colleagues argued in the Journal of Clinical Psychiatry and Academic Psychiatry for the development of interventional psychiatry fellowships and training pathways, and subsequent work by Trapp and Williams, along with a 2021 review in the American Journal of Psychiatry led by McIntyre, helped build the scientific case for circuit-based therapeutics in psychiatry. What the new Comment adds is a comprehensive professional framework: a definition, a conceptual structure for classifying interventions, and a roadmap for how training, credentialing and practice organization should evolve. The authors, who span academic centers including Yale, the University of California San Diego, Oxford and Toronto as well as clinical practice, frame the proposal as an evolutionary step rather than a rupture with psychiatric tradition.

The implications for training are among the most concrete. Current residency requirements, governed by the Accreditation Council for Graduate Medical Education, provide limited structured exposure to procedural techniques, and the authors suggest that the field must decide whether interventional competencies should be embedded in core residency training or developed through dedicated fellowships. Either path carries consequences for workforce planning. If interventional psychiatry becomes a recognized subspecialty, it could attract trainees drawn to the technical and neuroscientific dimensions of mental health care, potentially strengthening recruitment into a specialty that has struggled to meet demand. It could also reshape the economics of practice, since procedural services are typically reimbursed differently from brief medication visits, potentially relieving some of the financial pressures that pushed psychotherapy out of psychiatric practice in the first place.

The authors are candid that the framework raises difficult questions. Boundaries must be drawn carefully to avoid implying that interventional techniques should replace psychotherapy or psychosocial care, which remain essential components of treatment for many conditions. Equity of access is a serious concern, since advanced interventions are concentrated in urban and well-resourced settings, and the authors’ own disclosed ties to industry and clinical enterprises underline the commercial stakes involved in how the field develops. Yet their central claim stands on solid ground: the tools of psychiatry have changed faster than its identity, and a profession that treats the brain with electricity, magnetic fields and rapidly acting molecules needs a name and a structure that reflect that reality. Interventional psychiatry, they argue, is that name, and the coming years will determine whether the profession embraces the framework deliberately or continues to evolve by accident.

Subject of Research: A proposed professional framework defining interventional psychiatry amid the growth of procedural mental health treatments

Article Title: Defining interventional psychiatry: a framework for professional identity and practice evolution

Article References: Sauvé, W. M., Insel, T. R., Albright, B. B., Koo, M., Berman, R. M., Stahl, S., Manji, H. K., McIntyre, R. S., & Qian, J. J. (2026). Defining interventional psychiatry: a framework for professional identity and practice evolution. Nature Mental Health. https://doi.org/10.1038/s44220-026-00708-3

Image Credits: AI Generated

DOI: 10.1038/s44220-026-00708-3

Keywords: interventional psychiatry, psychiatry, neuromodulation, transcranial magnetic stimulation, electroconvulsive therapy, ketamine, esketamine, psychedelic therapy, professional identity, medical training, Nature Mental Health, mental health care

The research team, led by investigators at Iuliu Hațieganu University of Medicine and Pharmacy, tested eight widely used anaesthetic compounds—noradrenaline, lidocaine, rocuronium bromide, suxamethonium chloride, ropivacaine, fentanyl, ketamine and propofol—against a panel of five human cancer cell lines and one normal cell line. The tumour models included lung adenocarcinoma (A549), colorectal carcinoma (HCT116), hepatocellular carcinoma (HUH7), triple-negative breast cancer (MDA-MB-231) and cutaneous melanoma (SK-MEL-28), each genetically characterised for key mutations in p53, KRAS and BRAF. Normal human fibroblasts served as a healthy comparator.

The first and most striking result was the sheer heterogeneity of response. Using the MTT metabolic assay after 48 hours of exposure, the researchers calculated IC50 values—the concentrations needed to halve cell viability—that varied enormously between drugs and between cell lines. Lidocaine was highly potent against the colon and liver cancer cells, yet barely affected the triple-negative breast cancer line. Rocuronium bromide showed no inhibitory effect on liver and breast cancer cells but was strikingly active against melanoma. Fentanyl, at the doses and exposure times tested, failed to reduce metabolic activity in any of the cell lines. Ketamine and propofol, both intravenous agents, inhibited growth across most tumour models, with colon cancer cells proving the most sensitive to ketamine at 337 micromolar.

Importantly, the normal fibroblasts were generally more resistant than the tumour cells. Only four of the eight compounds—noradrenaline, ropivacaine, ketamine and propofol—reached an inhibitory threshold in the healthy cells, and for ropivacaine, ketamine and propofol the required doses were higher than those needed to suppress the cancer lines. That therapeutic window, the authors note, is a prerequisite for any future clinical relevance, since an ideal perioperative agent should harm tumour cells without damaging surrounding healthy tissue.

Beyond simple viability, the team probed whether the drugs could blunt two hallmarks of aggressive cancer: migration and the capacity to seed new colonies. In wound-healing assays, none of the compounds stimulated migration, and several strongly inhibited it, though in a strikingly cell-line-dependent fashion. Suxamethonium chloride nearly halted the movement of lung cancer cells, allowing only 23 percent wound closure, while lidocaine and ketamine were the most effective suppressors of breast cancer cell migration. Melanoma cells proved remarkably stubborn, with rocuronium bromide the only agent to completely block their movement. Colony formation assays told a similar story of selective vulnerability: propofol and ketamine inhibited colony formation in every tumour line tested, whereas noradrenaline was the sole compound able to suppress melanoma colonies.

Confocal fluorescence microscopy revealed the structural chaos the drugs inflict inside cells. Treated tumour cells displayed mitochondrial fragmentation and depolarisation, nuclear condensation, collapse of the F-actin cytoskeleton, cell swelling and the formation of tunnelling nanotubes—thin membrane bridges that emerge under cellular stress. The pattern of damage differed by drug and by tumour type. Lidocaine and noradrenaline wrecked the mitochondrial networks and actin filaments of lung cancer cells, while propofol triggered extensive mitochondrial fragmentation in liver cancer cells. Because cytoskeletal integrity and mitochondrial function underpin both motility and survival, these structural disruptions likely explain the functional losses measured in the migration and colony assays.

Flow cytometry added a dynamic dimension. Several compounds, most notably ketamine and propofol, pushed cells into a quiescent G0/G1 arrest, effectively freezing them before DNA replication. In lung cancer cells, ketamine trapped nearly 85 percent of the population in G0/G1, compared with 70 percent in untreated controls. In breast cancer cells, propofol froze 70 percent of cells in the same phase. Apoptosis measurements using PoPRO1 and 7-AAD staining showed that rocuronium bromide drove almost half of the triple-negative breast cancer population into late apoptosis within 24 hours, while colon cancer cells resisted all compounds, with no agent inducing more than 20 percent cell death. Melanoma cells were highly sensitive to noradrenaline and rocuronium, each triggering roughly 35 percent apoptosis.

At the molecular level, the picture grew more nuanced. Gene expression analysis of caspases 3, 8 and 9—the proteases that execute apoptosis—alongside the stress regulator NRF2, the inflammatory transcription factor NF-κB and the cyclin-dependent genes controlling cell cycle progression, revealed cell-specific signatures. In colon cancer cells, ropivacaine, fentanyl and ketamine significantly upregulated caspase 8, while rocuronium, suxamethonium and ropivacaine suppressed NRF2, hinting at a collapse of redox homeostasis. Liver cancer cells responded with a significant upregulation of CDK1-cyclin B and downregulation of CDK4-cyclin D, a pattern consistent with a compensatory attempt to escape a G1 blockade. Western blotting for cleaved PARP and cleaved caspase 3 confirmed that some drug–cell combinations, particularly lidocaine and ketamine in liver cancer cells, activate the classical caspase-dependent apoptosis pathway, whereas melanoma cells showed no detectable PARP or caspase 3 cleavage at all, suggesting they rely on entirely different death mechanisms.

The authors are careful to place these results in context. The experimental concentrations deliberately extended far beyond those achievable in patients, in order to characterise pharmacological activity and determine IC50 values. For propofol, lidocaine, ketamine, ropivacaine and fentanyl, clinically achievable perioperative plasma concentrations do fall within the tested ranges, but most experimental doses exceeded routine clinical exposure, and effects seen only at supraphysiological concentrations may not translate to the operating room. Succinylcholine, with a plasma half-life under one minute, poses particular interpretive challenges when compared against 48-hour in vitro exposures. The two-dimensional monolayer cultures also lack the stromal architecture, immune cells and extracellular matrix of real tumours, and perioperative neuroendocrine stress and transient immunosuppression cannot be recapitulated in a dish.

Nevertheless, the study’s central message is cautiously encouraging: across every assay, no anaesthetic compound stimulated tumour cell proliferation, and most acted as growth inhibitors. The pronounced heterogeneity—colon cancer cells resisting cell death while breast cancer cells succumbed to rocuronium, for instance—supports the authors’ vision of a personalised anaesthetic strategy, in which the drugs chosen for cancer surgery might one day be matched to the molecular profile of the tumour being removed. With randomised clinical trials to date showing largely neutral effects of anaesthetic technique on long-term oncological outcomes, the researchers argue that rigorous translational work, integrating pharmacokinetic data with clinically relevant exposure models and progressing through in vivo studies, is essential before laboratory observations can be turned into perioperative practice. For now, the operating room remains a place where the drugs that quiet the nervous system may also, quietly, influence the fate of lingering cancer cells.

Subject of Research: In vitro effects of commonly used anaesthetic compounds on the proliferation, migration, cell cycle and gene expression of solid tumour cell lines

Article Title: In Vitro Effects of Anaesthetic Compounds on a Panel of Solid Tumour Cell Lines—An Exploratory Study

Article References: Grajdieru, O., Sabo, A. C., Tigu, A. B., Ivancuta, A., Moldovan, C. S., Uhl, A., Ungurenasu, M. C., Balmez, A.-I., Moisescu, A., Pîrv, S., Nistor, M., Muresan, X.-M., Cenariu, D., Tomuleasa, C., & Constantinescu, C. (2026). In Vitro Effects of Anaesthetic Compounds on a Panel of Solid Tumour Cell Lines—An Exploratory Study. Journal of Cellular and Molecular Medicine, 30(18), Article e71307. https://doi.org/10.1111/jcmm.71307

Image Credits: AI Generated

DOI: 10.1111/jcmm.71307

Keywords: anaesthetic drugs, cancer cell lines, propofol, ketamine, lidocaine, tumour recurrence, perioperative medicine, apoptosis, cell cycle arrest, triple-negative breast cancer, in vitro study, cancer biology