Treatment-resistant depression (TRD) remains a major clinical challenge. Intranasal esketamine, used adjunctively with an oral antidepressant, has been evaluated in randomized trials, but uncertainty persists regarding the magnitude and consistency of benefit, durability, and key harms. This systematic review and meta-analysis included randomized controlled trials comparing intranasal esketamine plus an oral antidepressant versus placebo nasal spray plus the same oral antidepressant in TRD. Acute induction (≈4 weeks) and maintenance randomized-withdrawal phases were analyzed separately. Depression outcomes were assessed primarily using the Montgomery–Åsberg Depression Rating Scale (MADRS), and functional outcomes using the Sheehan Disability Scale (SDS). Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0. Random-effects models pooled mean differences (MD) for continuous outcomes, risk ratios (RR) for binary outcomes, and hazard ratios (HR) for relapse prevention. Certainty of evidence was rated using GRADE. From 1,518 records, nine reports representing six unique RCTs (1,836 participants) were included. Four acute induction RCTs (n=937) showed greater symptom reduction at day 28 with esketamine (MADRS MD −2.99, 95% CI −5.10 to −0.89; I²=48.5%). Rapid improvement was evident by day 2 (MD −3.25, 95% CI −4.65 to −1.85). Esketamine increased day-28 response (RR 1.44, 95% CI 1.20–1.74) and remission (RR 1.52, 95% CI 1.20–1.92), corresponding to approximately +154 responders and +106 remitters per 1,000 patients, respectively, based on pooled control risks. Functioning improved (SDS MD −1.70, 95% CI −2.61 to −0.79). Two maintenance randomized-withdrawal RCTs (n=899) demonstrated reduced relapse risk with continued esketamine (HR 0.51, 95% CI 0.42–0.62; I²=0%). In acute induction, esketamine increased any treatment-emergent adverse event (TEAE) (RR 1.37, 95% CI 1.25–1.50) and discontinuation due to adverse events (RR 2.68, 95% CI 1.35–5.29), with notable increases in dissociation (RR 7.33, 95% CI 4.49–11.98) and blood pressure increased events (RR 3.96, 95% CI 2.24–7.01). Maintenance TEAE rates were similar between groups (RR 1.07, 95% CI 0.99–1.17). Intranasal esketamine plus an oral antidepressant provides rapid, modest acute improvement and reduces relapse risk during maintenance among stabilized responders/remitters, but increases acute adverse events, supporting use within supervised care and individualized benefit–risk assessment.
Opinion: On the reasons for underutilization of ECT in individuals with intellectual and developmental disability
Exercise interventions are most consistently supported for depressive disorders: an umbrella review of diagnosed depressive and anxiety disorders
BackgroundExercise is increasingly discussed as part of lifestyle-based and multimodal care for mood and anxiety disorders, but review-level evidence often mixes formally diagnosed clinical populations with symptom-defined or medically mixed samples.MethodsWe conducted an umbrella review of systematic reviews, meta-analyses, and network meta-analyses of structured exercise interventions for adults with depressive or anxiety disorders. Six databases were searched from inception to 1 March 2026. Primary outcomes were depressive and anxiety symptom severity, remission, and response; secondary outcomes were acceptability and tolerability. Review quality was appraised with AMSTAR 2, and primary-study overlap was quantified with corrected covered area (CCA), including overall and symptom-cluster analyses. The synthesis was designed to summarize review-level credibility and clinical interpretability rather than to generate a second-order pooled efficacy estimate.ResultsNine reviews met eligibility criteria; four supplied directly extractable primary overall review-level estimates for core psychiatric symptom outcomes. AMSTAR 2 appraisal rated one review as high, three as low, and five as critically low. Recalculated overall overlap was slight (112 primary-study occurrences, 89 unique primary studies; CCA = 3.23%), although cluster-level analyses identified localized redundancy, particularly within anxiety-disorder-specific reviews. In major depressive disorder, one clinically focused review reported a large reduction in depressive symptoms for aerobic exercise versus non-exercise comparators (Hedges’ g = -0.79, 95% CI -1.00 to -0.57; I² = 21%). Across diagnosed depressive and/or anxiety disorders, broader review-level estimates also favored exercise for depressive symptoms (SMD = -0.97, 95% CI -1.28 to -0.66) and anxiety symptoms (SMD = -0.66, 95% CI -1.09 to -0.23), but heterogeneity was high. Anxiety-disorder-specific evidence was less secure: the primary DSM-IV anxiety-disorder pooled estimate showed no clear benefit over selected controls (SMD = 0.02, 95% CI -0.20 to 0.24). Acceptability estimates were close to null, and adverse-event reporting was too sparse to support confident safety conclusions.ConclusionExercise is best supported as an adjunctive, patient-centered component of care for depressive disorders. Anxiety-disorder-specific efficacy remains uncertain when comparator rigor, diagnostic heterogeneity, and localized overlap are considered, and safety reporting needs substantial improvement.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261364264.
Health outcomes across socioeconomic strata B, C, and DE among Brazilian adults living in moderate social vulnerability
ObjectivesThis study examined whether socioeconomic status was associated with anxiety symptoms, depressive symptoms, BMI, waist-to-hip ratio, and quality of life among Brazilian adults living in areas of moderate social vulnerability. In addition, we described anxiety and depressive symptoms, BMI and waist-to-hip ratio, and quality of life in individuals living in moderate social vulnerability.MethodsThis is a cross-sectional study. In a socially vulnerable cohort, interviews captured demographics, comorbidities, medications, anxiety and depressive symptoms, and quality of life, followed by measurement of anthropometric characteristics.ResultsAmong 299 socially vulnerable adults, 8% had moderate–severe depressive symptoms and 7% had moderate–severe anxiety symptoms; ~50% showed increased risk of cardiometabolic diseases (i.e., waist-to-hip ratio greater or equal to 0.90 for men and 0.85 for women, respectively). Poor quality of life affected 4–12% across domains. Mental health, anthropometrics (waist-to-hip ratio, BMI), increased risk of cardiometabolic diseases and quality of life in physical, social and environmental domains did not differ by socioeconomic status (B, C, DE; all P>0.05). Poor psychological quality of life was more frequent among participants in higher socioeconomic status (B: 8%; C: 6%; DE: 4%, P = 0.0157). Linear regression analyses showed no statistically significant differences across socioeconomic status in depressive symptoms, anxiety symptoms, BMI, waist-to-hip ratio, or quality of life scores in any domain (all P>0.05).ConclusionsOur findings suggest that, among Brazilian adults living in moderate social vulnerability and classified within socioeconomic status B, C, and DE, mental health, BMI, waist-to-hip ratio, and quality-of-life indicators were similar across socioeconomic strata. However, these results should be interpreted as reflecting intra-group socioeconomic differences within a moderately vulnerable population and should not be generalized to individuals from the highest socioeconomic status.
Author Correction: Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates
Nature Biotechnology, Published online: 03 July 2026; doi:10.1038/s41587-026-03246-6
Author Correction: Improved RNA base editing with guide RNAs mimicking highly edited endogenous ADAR substrates
Lassa fever countermeasures gather pace
Nature Medicine, Published online: 03 July 2026; doi:10.1038/s41591-026-04478-4
Two early phase clinical trials represent progress in Lassa fever vaccine and therapeutic development, including the first interventional treatment trial in decades.
Generalizable AI predicts immunotherapy outcomes across cancers and treatments
Nature Medicine, Published online: 03 July 2026; doi:10.1038/s41591-026-04502-7
COMPASS is a pan-cancer foundation model that predicts immunotherapy response, across cancer types and treatments, from bulk tumor transcriptomes.
Immune aging biomarkers for clinical trials
Nature Medicine, Published online: 03 July 2026; doi:10.1038/s41591-026-04493-5
The authors present a framework for the selection of immune aging biomarkers suitable for clinical trials in geroscience, alongside a translational roadmap for biomarker development to support the next generation of clinical studies on immune aging.
The Download: a smoking “endgame” and a new Elizabeth Bear story
This is today’s edition of The Download, our weekday newsletter that provides a daily dose of what’s going on in the world of technology.
The UK’s generational tobacco ban might not work. I’m supporting it anyway.
—Jessica Hamzelou
As the parent of two little girls, I often think about how their childhood is different from mine. The seven-year-old is learning about AI at school. The five-year-old is given internet-based homework every week. And they are both absolutely repulsed by the idea of smoking.
That was not the prevailing sentiment when I was young. Smoking was a central part of our culture. Which is why the UK’s recent passing of a generational sales ban on tobacco products feels like such a big deal.
This is what’s described as an “endgame” approach. While many tobacco control strategies—such as taxation or gory imagery—aim to reduce consumption, policies like the UK’s are designed to eliminate it entirely. It’s a new approach, and no one knows whether it will work. But it’s an enticing prospect—and it’s starting to look a lot less radical.
Find out why generational tobacco bans are gaining support.
This story is from The Checkup, our weekly biotech newsletter. Sign up to receive it in your inbox every Thursday.
You do your own time
—You do your own time is a short story by Elizabeth Bear, an award-winning speculative fiction author.
There we were, a regular murderers’ row of librarians. Turning around in the nave of our library to greet the sound of footsteps, pistols leveled in case whoever was coming in didn’t respect sanctuary.
I pulled down a solid-state drive full of biographies and case studies of people who had spent time—and sometimes their whole lives—in labor camps or chattelhood. It was illegal to possess, and the feds used smart agents to track down and obliterate any copies. Which was why we were sending one to the stars.
What’s left behind when a name is erased from the system? No legacy, no memory—that is the point of media and narrative control. So that was our plan: to preserve it, for later generations, or just as a silent record of our existence.
Read the rest of this short story in full.
—Elizabeth Bear
This story is from the latest edition of our magazine, which is all about engineering. Subscribe now to get a copy, plus all our other issues and a range of subscriber-only content.
The must-reads
I’ve combed the internet to find you today’s most fun/important/scary/fascinating stories about technology.
1 An EU lawmaker investigating spyware was hacked by that spyware
Citizen Lab found Pegasus spyware on Stelios Kouloglou’s phone. (Wired $)
+ It said the EU “looks the other way” on spyware abuses. (Guardian)
+ Meet the director of Citizen Lab. (MIT Technology Review)
2 Anthropic is closing loopholes that allow Chinese access to Claude
It’s targeting VPNs, relay services, and overseas accounts. (FT $)
+ Users in China keep finding new workarounds. (Wired $)
3 A Tesla driver has been charged with manslaughter after a fatal crash
Court records show he was using automated driver-assistance. (WSJ $)
+ Tesla sales have surged 25% after a rebound in Europe. (NYT $)
4 Trump bought lots of tech stock the day he unveiled his AI Action Plan
He acquired up to $5 million in stock from Amazon and others. (Engadget)
+ His AI Action Plan was a distraction. (MIT Technology Review)
5 Companies are throttling employees’ AI use because it’s too expensive
They’re pleading with workers to use less powerful models. (404 Media)
+ Tesla has capped their AI spending at $200 per week. (The Information $)
6 The Energy Dept wants data centers on backup power in heat waves
It wants them to free up power for AC. (NYT $)
+ People near data centers are dreading heat wave pollution. (Politico $)
+ No one wants a data center in their backyard. (MIT Technology Review)
7 A Meta glasses feature just went from free to a subscription service
“Conversation Focus” will now cost $19.99 per month. (BBC)
+ The move heralds a new era of consumer tech subscriptions. (Wired $)
8 Random wobbles in time could solve gravity’s greatest mystery
A new idea could reconcile gravity and quantum mechanics. (New Scientist $)
9 Peter Thiel claims the pope is “working for the Chinese Communists”
By pushing for stricter AI rules that may benefit Chinese interests. (CNN)
+ Pope Leo XIV said AI must be “disarmed” in his first major teaching. (BBC)
+ His encyclical offered a template for steering AI. (MIT Technology Review)
10 Supersonic flight over land could finally be legal again
Regulators want to lift a ban—so long as the planes are quiet. (Ars Technica)
Quote of the day
“We don’t have robots that are nearly as good at understanding the physical world as a rat.”
—Yann LeCun, the founder of AMI Labs and Meta’s former chief AI scientist, tells the BBC that AI isn’t as smart as many think.
One More Thing
MARCO GIANNAVOLA
How two brothers became go-to experts on America’s “mystery drone” invasion
On a Friday evening in December, every tier of US law enforcement was dispatched to a military research installation outside Boston after a squadron of 15 to 20 drones was spotted violating restricted airspace. The culprits could not be found.
It was the latest in a series of purported drone sightings along the US East Coast. Lacking coordination or clarity from the White House, the Pentagon, and the intelligence community, law enforcement officers turned to an unlikely source: twin brothers from Long Island who hunt UFOs.
The Tedescos have built a mobile field lab to investigate unexplained aerial phenomena. Now members of the FBI want their support.
Discover how the brothers are helping law enforcement investigate UFOs.
—Matthew Phelan
We can still have nice things
A place for comfort, fun, and distraction to brighten up your day. (Got any ideas? Drop me a line.)
+ This record-breaking drone show is a mind-bending display of aerial light.
+ A Paris bakery is taking a bite out of food waste by repurposing croissants.
+ Relive your childhood with a classic episode from the Mister Rogers archive.
+ See graffiti through new eyes with this project that prettifies tags and makes them legible.
The UK’s generational tobacco ban might not work. I’m supporting it anyway.
As the parent of two little girls, I often think about how their childhood is different from mine. The seven-year-old is learning about AI at school. The five-year-old is given internet-based homework every week. And they are both absolutely repulsed by the idea of smoking.
That was not the prevailing sentiment when I was young. My parents smoked. The customers at our family’s restaurant smoked. Cartoon characters smoked. My friends and I would buy little cigarette-box-shaped packets of sugary white sticks and pretend to smoke in the playground. Smoking was a central part of our culture.
Which is why the UK’s recent passing of a generational sales ban on tobacco products feels like such a big deal. As part of the Tobacco and Vapes Act 2026, retailers are prohibited from selling tobacco products to anyone born after January 1, 2009, in perpetuity. It doesn’t matter when those people turn 18—or 38 or 68, for that matter. It will always be illegal to sell to anyone born after that date.
This is what’s described as an “endgame” approach. While many tobacco control strategies—such as taxation or gory imagery—aim to reduce consumption, policies like the UK’s are designed to eliminate it entirely. It’s a new approach, and no one knows whether it will work.
The Maldives was the first country to implement a generational smoking ban, in November last year. It’s too soon to say how that has panned out.
Nor do we know if these laws will even last. In 2022, New Zealand passed a similar generational sales ban as part of a broader anti-smoking law. But it was never enacted—the law was repealed by a new government in February 2024.
In the UK, both major parties support the ban. But Nigel Farage, whose right-wing party has seen a recent surge in support, has promised that “the generational smoking ban will not last long if Reform gets the chance to start rebuilding our mismanaged country.”
Chris Bostic, an attorney and former policy director for the advocacy group Action on Smoking and Health, says he and his colleagues began promoting the idea of a generational ban in the United States 11 years ago. Back then, they struggled to win support, even from major health charities. “People said we were crazy … [and] that this was impossible,” he says. Opponents argued that bans would infringe on personal freedoms.
“The public health argument is: Well, what about freedom from addiction?” says Britta Matthes, a tobacco control researcher at the University of Bath in the UK. Most people who smoke began when they were teenagers, want to quit, and wish they’d never started. Tobacco is arguably the most harmful consumer product of all time. It will kill half its users who don’t quit, according to the World Health Organization.
It also kills people who don’t smoke. Of the 7 million who die from tobacco every year, 1.6 million are nonsmokers who were exposed to secondhand smoke, according to the WHO.
Generational sales bans are a long-term strategy that will only protect future smokers. Most experts agree that people who already smoke should be a main consideration for any policy, and that a multipronged approach is probably the best way to go. Janet Hoek at the University of Otago, who has explored tobacco control policies in New Zealand, believes that enforcing very low limits on nicotine levels and banning filters—an environmental scourge that does not make smoking safer, as many people believe—might be a “powerful combination,” for example.
But preventing teenagers from starting to smoke in the first place is an enticing prospect, even among the majority of people who smoke. And it’s starting to look a lot less radical.
The US has quietly been making progress on a smaller scale. Since 2021, Brookline, a town in the Boston area, has banned the sale of tobacco products to anyone born after January 1, 2000. The idea has spread. Today there are 23 towns in Massachusetts with similar bans, says Bostic. Nine towns across Minnesota, New York, and California have implemented other endgame policies.
The UK law has normalized the idea more than ever, he adds. His colleagues are already fielding calls from health agencies around the world. “People [are] saying, Wow I can’t believe the UK just did this—can we do this here?” he says.
Norms change. Like many other millennials, I vividly remember my first night out after a ban on indoor smoking took effect. My clothes didn’t stink! My hair still felt clean! And my throat wasn’t scratchy the next morning! Now that’s just normal. I hope a tobacco-free world can be the new normal for my kids.