Specifically designed cocktails of broadly neutralising antibodies (bNAbs) could help treat HIV while minimising the risk of the virus escaping treatment, researchers reported in eLife.
The study shows that computational approaches to selecting combinations of bNAbs based on viral genetics could help prevent viral escape, making HIV treatment more effective. It may also offer a strategy for designing effective combinations of bNAbs for treating other rapidly evolving pathogens.
bNAbs offer a promising new tool to treat or potentially cure infections with rapidly evolving viruses such as HIV. Clinical trials using a single bNAb to treat HIV have shown that some viral strains may survive the treatment and lead to a rebound of viruses in the blood. Combinations of bNAbs may therefore be a more effective approach, but finding the best combinations is a challenge.
“For our study, we proposed using a computational approach to predict the effectiveness of bNAb combinations based on the HIV genetics,” said researcher Colin LaMont.
LaMont and colleagues analysed the genetics of HIV viruses collected over 10 years from 11 untreated patients with HIV, and used this data to predict which viral strains might be able to escape treatment with different bNAbs and whether dodging bNAbs had a survival cost. Next, using computational methods, they applied the knowledge gained to predict viral rebounds in three real-life trials of bNAbs.
Finally, the team used their computational approach to find a combination of bNAbs that is least likely to allow any virus to escape. They also found that some bNAbs, such as 10-1074, are better against diverse populations of viruses because mutations that allow viruses to escape also make the virus less likely to survive. Others, including PGT121, are more effective against less diverse viral populations because mutations that enable escape are rare. Overall, the results suggested that the optimal combination includes three bNAbs: PG9, PGT151 and VRC01.
“We’ve shown the combination of PG9, PGT151 and VRC01 reduces the chance of viral rebound to less than 1%,” LaMont said. “It does this by targeting three different regions of the virus’ protective outer wrapping, or envelope.”
“Combining bNAbs, administered via intravenous infusion every few months, with current antiretroviral therapies (ART) that require daily doses could further improve long-term HIV treatment success,” suggested senior author Armita Nourmohammad, Assistant Professor at the University of Washington.
ART hinders HIV multiplication and ability to create new variants, limiting the genetic diversity of the viral population and reducing the odds of bNAb escape variants emerging. The authors say that more studies are needed to confirm the potential benefits of combining ART and bNAbs.
“Our study shows that leveraging genetic data can help us design more effective HIV therapies,” Asst Prof Nourmohammad concluded. “Our approach may also be useful for designing therapies against other rapidly evolving agents that cause disease, such as the Hepatitis C virus, drug-resistant bacteria, or cancer tumour cells.”
Research published in the Journal of the National Cancer Institute found that menopausal hormone therapy for breast cancer survivors is not associated with breast cancer reoccurrence, despite worries among some researchers and physicians.
Hot flashes and night sweats, as well as vaginal dryness and urinary tract infections, are common in breast cancer survivors, worsening quality of life and can lead patients to discontinue therapy. These symptoms may be alleviated by vaginal oestrogen therapy or menopausal hormone therapy (MHT). However, the safety of systemic and vaginal oestrogen use among breast cancer survivors, particularly those with oestrogen receptor-positive disease, has been unclear.
Many doctors caution breast cancer survivors against using MHT following the demonstration of an increased risk of breast cancer recurrence in two trials in the 1990s. Though later studies have not shown increased recurrence, they were seriously limited, with small sample sizes and short follow-up periods.
This study compared hormonal treatment with the risk of breast cancer recurrence and mortality in a large cohort of Danish postmenopausal women treated for early-stage oestrogen receptor-positive breast cancer.
Participants were diagnosed between 1997 and 2004 with early-stage breast cancer who received no treatment or five years of hormone therapy.
Among 8461 women, 1957 and 133 used vaginal oestrogen therapy or MHT, respectively, after diagnosis. No increase was seen in the risk of recurrence or mortality for those who received either vaginal oestrogen therapy or MHT.
“This large cohort study helps to inform the nuanced discussions between clinicians and breast cancer survivors about the safety of vaginal oestrogen therapy,” said Elizabeth Cathcart-Rake, writing in an accompanying editorial. “These results suggest that breast cancer survivors on tamoxifen with severe genitourinary symptoms can take vaginal estrogen therapy without experiencing an increase in their risk for breast cancer recurrence. However, caution is still advised when considering vaginal oestrogen for breast cancer survivors on aromatase inhibitors, or when considering menopausal hormonal therapy.”
Decades of research has provided no clear evidence that serotonin levels or serotonin activity are responsible for depression, according to a major review of existing literature.
Published in Molecular Psychiatry, this new umbrella review is an overview of existing meta-analyses and systematic reviews. It suggests that depression is not likely to be caused by a chemical imbalance. It also calls into question what antidepressants do: most antidepressants are selective serotonin reuptake inhibitors (SSRIs), whose mechanism of action was supposedly to correct abnormally low serotonin levels. But there is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression.
Lead author Professor Joanna Moncrieff, at University College London said: “It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin.
“The popularity of the ‘chemical imbalance’ theory of depression has coincided with a huge increase in the use of antidepressants. Prescriptions for antidepressants have risen dramatically since the 1990s, with one in six adults in England and 2% of teenagers now being prescribed an antidepressant in a given year.
“Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence.”
The umbrella review aimed to capture all relevant studies, encompassing tens of thousands of participants, that have been published in the most important fields of research on serotonin and depression.
Research that compared levels of serotonin and its breakdown products in the blood or brain fluids found no difference between participants diagnosed with depression and healthy controls.
Research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression. However, the researchers say the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out.
Some studies artificially lowered serotonin levels were by depriving participant’s diets of the necessary amino acid. These studies have been cited as demonstrating that a serotonin deficiency is linked to depression. A meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers, however. There was very weak evidence in a small subgroup of people with a family history of depression, but this only involved 75 participants, and more recent evidence was inconclusive.
Very large studies involving tens of thousands of patients looked at gene variation, including the gene for the serotonin transporter, and found no difference between people with depression and healthy controls. These studies also examined stressful life events, and found these to strongly increase people’s risk of becoming depressed. A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression. But larger, more comprehensive studies suggest this was a false finding.
These findings together led the authors to conclude that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”
The researchers say their findings are important as studies show that as many as 85–90% of the public believes that depression is caused by low serotonin or a chemical imbalance. A growing number of scientists and professional bodies are recognising the chemical imbalance framing as an over-simplification. Evidence also suggests that believing that low mood is caused by a chemical imbalance leads to pessimism about recovery, and the possibility of managing moods without medical help. This is important because most people will at some point in their lives meet criteria for anxiety or depression.
A large meta-analysis provided evidence that people who used antidepressants actually had lower levels of serotonin in their blood. The researchers concluded that some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations. The researchers say this may imply that the increase in serotonin that some antidepressants produce in the short term could lead to compensatory changes in the brain that produce the opposite effect in the long term.
Though antidepressants’ efficacies was not examined, the authors encourage looking into treatments such psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress and loneliness.
Professor Moncrieff said: “Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities. We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.”
Co-author Dr Mark Horowitz said: “I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures. Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down.
“One interesting aspect in the studies we examined was how strong an effect adverse life events played in depression, suggesting low mood is a response to people’s lives and cannot be boiled down to a simple chemical equation.”
Professor Moncrieff added: “Thousands of people suffer from side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise. We believe this situation has been driven partly by the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this belief is not grounded in science.”
Antisense oligonucleotides (ASOs), are molecules that can be used to control protein levels in cells. Researchers detail in Nature how they leveraged ASO technology to develop the first FDA-approved treatment for spinal muscular atrophy called Spinraza®. The drug has helped over 11 000 patients make more of a protein that certain neurons in the spine need.
Cold Spring Harbor Laboratory Professor Adrian Krainer, who developed the drug, has been searching for more ways ASOs can help treat other disorders. He has identified cystic fibrosis (CF), where patients produce insufficient amount of the protein CFTR. His team discovered how to use ASOs to make more of an imperfect but still functional version of CFTR. This could lead to a new treatment approach that may help alleviate CF symptoms.
The imperfect CFTR protein results from a gene mutation. The faulty instructions to produce the protein are eliminated and the protein isn’t made, since in general, imperfect proteins may be disruptive. Prof Krainer’s ASOs trick cells into following the faulty instructions and making the imperfect CFTR protein. His team found that, in this case of CF, having an imperfect version of the protein is better than having none at all. Their method improved the function of lung cells, suggesting the ASO strategy could improve symptoms in CF patients with this mutation.
The team’s discovery spotlights a new way ASOs can be used to treat disease. The study was led by Young Jin Kim, a former MD-PhD student in the Krainer laboratory. Prof Krainer hopes to continue expanding the potential of ASO technology in therapeutics. He thinks in the future ASOs may increasingly become a way to tailor therapies specific to an individual’s unique genetic mutations. “If more of this type of drug, ASOs, are approved,” Prof Krainer said, “I wouldn’t be surprised if in the not-so-distant future ASOs become a routine way to make personalised medicines.”
University of Reading scientists have shown that taking high doses of Vitamin B6 reduces feelings of anxiety and depression to a small degree. Study participants reported feeling less anxious and depressed after taking the supplements every day for a month.
The study, published in Human Psychopharmacology: Clinical and Experimental, demonstrates that certain supplements thought to modify levels of activity in the brain could be useful for preventing or treating mood disorders.
The study’s lead author, Dr David Field, explained: “The functioning of the brain relies on a delicate balance between the excitatory neurons that carry information around and inhibitory ones, which prevent runaway activity. Recent theories have connected mood disorders and some other neuropsychiatric conditions with a disturbance of this balance, often in the direction of raised levels of brain activity. Vitamin B6 helps the body produce a specific chemical messenger that inhibits impulses in the brain, and our study links this calming effect with reduced anxiety among the participants.”
While previous studies have produced evidence that multivitamins or Marmite can reduce stress levels, few studies have been carried out into which particular vitamins contained within them drive this effect. The new study focused on the potential role of Vitamins B6, which is known to increase the body’s production of GABA (Gamma-Aminobutyric Acid), the primary inhibitory neurotransmitter.
In the current trial, more than 300 participants were randomised to either Vitamin B6 or B12 supplements far above the recommended daily intake (about 50 times higher) or placebo, and took one a day with food for a month. Vitamin B12 had little effect compared to placebo, but Vitamin B6 was found to have a significant effect. Raised levels of GABA among participants who had taken Vitamin B6 supplements were confirmed by visual tests carried out at the end of the trial, supporting the hypothesis that B6 was responsible for the reduction in anxiety. Subtle but harmless changes in visual performance were detected, consistent with controlled levels of brain activity.
Dr Field notes that, while many foods contain Vitamin B6, “the high doses used in this trial suggest that supplements would be necessary to have a positive effect on mood. It is important to acknowledge that this research is at an early stage and the effect of Vitamin B6 on anxiety in our study was quite small compared to what you would expect from medication. However, nutrition-based interventions produce far fewer unpleasant side effects than drugs, and so in the future people might prefer them as an intervention.
“To make this a realistic choice, further research is needed to identify other nutrition-based interventions that benefit mental wellbeing, allowing different dietary interventions to be combined in future to provide greater results. One potential option would be to combine Vitamin B6 supplements with talking therapies such as Cognitive Behavioural Therapy to boost their effect.”
