The protocol emphasized the immediate start of dialysis as soon as MALA was identified, using one of three methods: intermittent hemodialysis, continuous kidney replacement therapy, or peritoneal dialysis. The program was introduced at Maharat Nakhonratchasima Hospital (MNRH) in Thailand, while Burirum Hospital (BH) served as a comparison site and continued standard care without the new approach.

Over a five-year study period, the researchers analyzed 347 total cases (70 at MNRH before the protocol, 129 after the protocol, and 148 at BH).

Major Reductions in Deaths and Faster Treatment

Results showed striking improvements at Maharat Nakhonratchasima Hospital. The 30-day death rate fell from 25.7% before the new system to 13.9% afterward. At Burirum Hospital, which did not adopt the protocol, mortality rates remained unchanged (27.2% and 30%).

The ongoing data at MNRH showed a steady decline in deaths, dropping by 2.08% per quarter throughout the intervention period. Average "door-to-dialysis" time -- the time between a patient's hospital admission and the start of dialysis -- was shortened from 870 minutes to 690 minutes. Awareness of MALA among medical staff also rose dramatically, from 38.5% to 89.9% after implementation.

Faster Response, Greater Awareness, and Better Outcomes

"A standardized MALA protocol covering diagnosis, access, and treatment shortened door-to-dialysis time, increased awareness, and reduced care variation," said corresponding author Watanyu Parapiboon, MD, of Maharat Nakhon Ratchasima Hospital in Thailand. "Fast-track dialysis pathways should be adopted for time-sensitive conditions like MALA. Availability of all dialysis modalities ensures flexibility and enables timely treatment initiation."

Study: "Reducing Mortality in Metformin-Associated Lactic Acidosis (MALA) Through a Fast-Track Clinical Pathway: A Controlled Interrupted Time Series Quality Improvement Study."

Metformin Overview

Metformin is one of the most commonly prescribed medications for managing type 2 diabetes. It works by improving the body's sensitivity to insulin, reducing the amount of glucose produced by the liver, and enhancing glucose uptake by muscle cells. The drug is well established for its effectiveness, affordability, and relatively low risk of causing low blood sugar. Beyond diabetes control, research has explored metformin's potential benefits in weight management, heart health, and even aging, although its primary role remains in helping people with type 2 diabetes maintain stable blood sugar levels.

Metformin-Associated Lactic Acidosis Overview

Metformin-associated lactic acidosis (MALA) is a rare but serious medical emergency in which lactic acid accumulates in the bloodstream due to the body's impaired ability to clear it while taking metformin. This condition can lead to dangerously low blood pH, muscle weakness, rapid breathing, confusion, and in severe cases, organ failure or death. MALA typically occurs in patients with underlying kidney problems, liver disease, or conditions that limit oxygen delivery to tissues. While extremely uncommon, it requires urgent diagnosis and immediate treatment -- often including dialysis -- to remove excess acid and prevent life-threatening complications.

The study, published in Nature Mental Health, re-examined results from the landmark PANDA trial, originally released in 2019. That earlier research found that sertraline eased anxiety before it had a measurable impact on depression. In this new work, scientists applied a more detailed method known as network analysis, which allowed them to track how specific symptoms -- rather than overall depression scores -- responded to the medication.

Breaking Down Symptom Changes

By examining symptom-level data, the team found that patients taking sertraline experienced measurable improvements in low mood and suicidal thoughts within two weeks. At the same time, some physical side effects such as tiredness, reduced appetite, and lower libido were noted. Because these effects overlap with common symptoms of depression, interpreting their cause requires caution.

The researchers suggest that earlier analyses, which combined all depressive symptoms into a single measure, may have masked improvements in the most central emotional symptoms of depression.

In this refined analysis, early benefits were seen in feelings of sadness, self-criticism, restlessness, and suicidal ideation.

Revisiting the PANDA Trial

The PANDA trial, a randomized controlled study, investigated how sertraline affected people in England experiencing mild to moderate depressive symptoms. In 2019, results published in The Lancet Psychiatry showed that anxiety and overall mental health improved within six weeks of treatment, while major depressive symptoms did not meaningfully improve until 12 weeks.

This new analysis focused on data from 571 participants who provided complete symptom records. The findings suggest that emotional recovery may begin earlier than previously believed, with certain core depressive features responding more quickly to sertraline than the overall depression scores indicated.

Side Effects and Emotional Balance

Some physical or "somatic" symptoms, including poor sleep and low libido, tended to worsen initially. While these may be side effects of selective serotonin reuptake inhibitors (SSRIs) like sertraline, they are also frequent signs of depression itself, making the results more complex to interpret.

Lead author Dr. Giulia Piazza (UCL Psychiatry and UCL Psychology & Language Sciences) explained, "We have now painted a more complex picture of sertraline's effects on the different symptoms of depression. Instead of thinking of depression and anxiety as each being a single, uniform condition, network analysis considers that they're each a constellation of symptoms, that can appear in different combinations for different people."

She added that understanding these relationships could reveal how certain symptoms, such as poor sleep, may trigger others like reduced concentration and self-esteem.

Timeline of Effects

The analysis showed that improvements in emotional and anxiety symptoms began within two weeks and continued to increase over time. Meanwhile, physical symptoms worsened slightly in the early stages but stabilized after about six weeks.

Dr. Piazza noted, "It appears that the adverse effects on somatic symptoms like poor sleep and libido may stabilize after six weeks, which is then counteracted by continued improvements in emotional symptoms, the core symptoms of depression."

Broader Impact and Clinical Implications

Sertraline, a member of the SSRI class, remains one of the most frequently prescribed treatments for both depression and generalized anxiety disorder.

Professor Glyn Lewis (UCL Psychiatry), who led the original PANDA trial, said, "Our findings provide robust evidence that continues to support the prescription of sertraline for people experiencing depressive and anxiety symptoms. These findings will help patients and clinicians to make more informed decisions about treatment."

Co-senior author Professor Jean-Baptiste Pingault (UCL Psychology & Language Sciences) added, "We found that the beneficial effects of sertraline can be detected very early on, as soon as two weeks after people start taking the antidepressant. Beyond this study, our results highlight the importance of considering symptom-level effects when developing novel drugs and evaluating existing drugs in psychiatry, and how this can help us to understand how these drugs work and how they can help patients."

The research was supported by Wellcome, while the original PANDA trial received funding from the National Institute for Health Research (NIHR) and the NIHR University College London Hospitals Biomedical Research Centre.

* Original results of the PANDA trial published on UCL News in 2019: Antidepressants may reduce anxiety more than depressive symptoms.

Progerin has a harmful "dominant-negative" effect on cells, meaning it interferes with normal cell function. This abnormal protein triggers multiple cellular problems, such as deformation of the nuclear envelope (NE), increased DNA damage, shortened telomeres, cell cycle arrest, and reduced ability to divide. Interestingly, growing evidence suggests that small amounts of progerin are also present during natural aging and in chronic kidney disease (CKD). Because of this, therapies that enhance the removal of progerin could hold promise for treating HGPS, CKD, and other conditions linked to aging.

Investigating How Cells Manage Progerin

A research team led by Professor Chuanmao Zhang from Peking University and Kunming University of Science and Technology has long been focused on uncovering the biological mechanisms behind aging and progeria. In a recent study published in Science China Life Sciences, the group identified a key process in which lysosomes -- tiny cellular compartments responsible for breaking down waste -- play a central role in clearing progerin.

Their study revealed that defects in lysosomes contribute to the accumulation of progerin in HGPS cells. More importantly, they demonstrated that stimulating lysosome activity can restore this cellular "cleanup" function, helping remove progerin and reducing signs of cell aging. These discoveries highlight lysosomes as an important new target for potential therapies in HGPS, CKD, and other age-related diseases.

How Progerin Builds Up Inside Cells

Using a combination of immunofluorescence imaging, live-cell observation, and biochemical analysis, the researchers tracked how progerin behaves inside cells. They observed that progerin, which first appears near the nuclear envelope, can move into the cell's cytoplasm through a process called nuclear envelope budding. Once in the cytoplasm, progerin should normally be degraded through the cell's autophagy-lysosome pathway -- a key recycling system.

However, in HGPS cells, this system fails to work efficiently, allowing progerin to accumulate. To investigate why, the team performed RNA sequencing on primary cells from two patients with HGPS. The results showed a significant reduction in the activity of genes linked to lysosome function. Further tests, including RT-qPCR, immunofluorescence, and biochemical assays, confirmed that lysosomes in these cells were indeed defective.

Restoring Lysosome Function to Fight Cellular Aging

Next, the researchers tested whether repairing the lysosomal defects could enhance progerin clearance and slow down cellular aging. They activated lysosome biogenesis -- the process by which new lysosomes are formed -- through two methods: by stimulating protein kinase C (PKC) or by inhibiting mammalian target of rapamycin complex 1 (mTORC1).

Both approaches successfully improved lysosome function, boosted the removal of progerin, and reduced signs of cellular aging, such as DNA damage, growth arrest, and loss of cell vitality. These findings suggest that reawakening the cell's own cleanup machinery could help reverse some of the harmful effects of progerin buildup.

Toward Anti-Aging Therapies Targeting Lysosomes

This research clearly establishes lysosomes as key players in removing progerin and maintaining cellular health. It also points to lysosome activation as a potential strategy for combating premature and natural aging. By targeting the body's built-in recycling systems, scientists may eventually find new ways to treat HGPS and a wide range of age-related diseases.