Mild to severe depression might be better treated with alternatives to antidepressant drugs, which do not help patients much more than an inactive placebo, researchers said Tuesday.

Combining data from six studies that examined the effectiveness of two commonly prescribed antidepressants — paroxetine and imipramine — found the drugs produced benefits only slightly greater than a placebo in patients with mild to severe depression.

“They would have done just as well or just about as well with a placebo,” said Robert DeRubeis, a psychologist at the University of Pennsylvania, Philadelphia, who with colleagues performed the meta-analysis.

Paroxetine is one of a popular class of drugs, selective serotonin reuptake inhibitors, and is sold under the brand name Paxil by GlaxoSmithKline. Imipramine is an older tricyclic antidepressant drug developed in the 1950s.

The so-called placebo effect is powerful in treating depression, where people believe they are helped even though they are taking an inactive sugar pill, DeRubeis said.

CONSIDER ALTERNATIVES?

In the report published in the Journal of the American Medical Association involving nearly 800 patients, the drugs’ impact was noticeably stronger than a placebo in people diagnosed with very severe cases of depression.

Using a scoring system for depression where a diagnosis of 24 or above indicates a very severe case, the researchers said patients treated with drugs saw their scores drop by 13 points, compared to a drop of 9 points for those given a placebo.

But for those with initial depression scores of 23 or below the drop averaged 8 points for those given antidepressants and 7 points for those given a placebo. Roughly half of those prescribed antidepressants fit into the mild to severe categories.

“Our data should give some pause” to doctors and patients weighing antidepressants, DeRubeis said in a telephone interview. “They should give some consideration to other alternatives.”

Exercise has been shown to be helpful to stem depression, as does psychotherapy, and even “self-treatment” with the aid of the plethora of self-help literature, he said.

A spokeswoman for GlaxoSmithKline said the report “contributes to the extensive research” into antidepressants, noting that Paxil received U.S. government approval in 1992 and has helped “millions of people battling mental illness.

“The studies used for the analysis in the JAMA paper differ methodologically from studies used to support the approval of paroxetine for major depressive disorder, so it is difficult to make direct comparisons between the results,” spokeswoman Sarah Alspach said.

At least 27 million Americans take antidepressants, nearly double the number that did in the mid-1990s, according to a study by Columbia University and University of Pennsylvania researchers reported in the Archives of General Psychiatry.

More than 164 million prescriptions for antidepressants were written in 2008, totaling nearly $10 billion in U.S. sales, according to IMS Health. Global sales were twice that.

The World Health Organization is changing its advice on HIV drugs, asking that they be given sooner and to breastfeeding mothers with the virus.

Experts say the advice is based on the most up-to-date information available and will cut infection rates and save lives.

But it will mean many more people needing treatment, which will cost more money and time.

An estimated 33.4 million people are living with HIV/Aids.

Demand

The World Health Organization (WHO) wants adults and adolescents to receive anti-retroviral therapy (ART) before their immune system strength falls below 350 cells per cubic millimetre of blood, regardless of whether they show symptoms.

It also wants the drug Stavudine, widely used in developing countries because of its low cost and widespread availability, to be phased out in favour of Zidovudine or Tenofovir, which do not have the same long-term and irreversible side effects.

And for the first time, the WHO is calling for breastfeeding mothers, or their babies, to be given the drugs to prevent transmission of the disease.

The International Development Minister, Mike Foster, said the guidelines would be supported though they would “significantly increase the demand for treatment”.

“The Department for International Development is committed to increasing access to effective and affordable HIV treatments,” he said.

“That is why UK aid supports the cheaper manufacturing of current treatments, and the Unitaid [the UN body on drugs for killer diseases] patent pool to help develop new, effective and affordable HIV treatments, particularly for children and for people living in developing countries.”

Falling prices and increased testing have led to a marked rise in the number of people in the poorest parts of the world receiving treatment for HIV.

The number of people on anti-retrovirals had risen by a million by the end of 2008, a 36% increase from the previous year, the WHO said.

But despite the progress, less than half of those needing treatment, currently receive it.

The WHO estimates that since the availability of effective HIV drugs in 1996, some 2.9 million lives have been saved.

“Translating metabolic exchange with imaging mass spectrometry,” was published Nov. 8 in Nature Chemical Biology, a prominent scientific journal. The article describes a technique developed by a collaborative team that includes Dr. Paul Straight, AgriLife Research scientist in the department of biochemistry and biophysics at Texas A&M University in College Station, Dr. Pieter Dorrestein, Yu-Liang Yang and Yuquan Xu, all at the University of California, San Diego.

“Microorganisms encode in their genomes the capacity to produce many small molecules that are potential new antibiotics,” Straight said. “Because we do not understand the circumstances under which those molecules are produced in the environment, we see only a small fraction of them in the laboratory.”

An example is the antibiotic erythromycin, which is often prescribed for people who are allergic to penicillin, Straight said.

“We know that Saccharopolyspora erythraea, the bacteria from which erythromycin is derived, encodes the capacity to produce numerous other small molecules that might be potentially valuable drugs,” he said. “Conventional microbial culture and drug discovery techniques uncovered erythromycin. Other potentially useful metabolites may require some unconventional methods for identification.”

Historically, medicinal drugs have been discovered serendipitously or by finding the active ingredient in homeopathic remedies, Straight said. For example, the use of blue mold for treating wounds was a folk remedy dates back to the Middle Ages. But scientists didn’t isolate and purify the active ingredient, penicillin, until the early 20th century, which marks the beginning of the era of ‘natural product’ medicines originating from microorganisms.

Modern methods of drug discovery rely on screening technologies, knowledge of how infection is controlled and why diseases originate at the molecular level. Some new drugs can be designed accordingly from the ground up, often at significant cost, but serendipitous discovery of what nature has to offer is still a valid approach, he said.

Microorganisms, such as the bacteria that produces erythromycin, have been communicating and battling with each other for millennia using similar small molecules.

“What we learn about how microbes interact and exchange chemicals, and how the presence of one signaling molecule or antibiotic changes the output of potential antibiotics from a neighboring microbe, will guide us to new strategies for boosting the number of potential therapeutic drugs from any given bacteria,” Straight said.

The National Institutes of Health recognizes the need to boost development of new drug compounds, he said.

“Globally, there is a shortage of new antibiotics that are being discovered by pharmaceutical companies in the traditional way and an ever-increasing number of multiple drug-resistant pathogens and newly emerging pathogens,” Straight said.

The method of Straight, Dorrestein and colleagues employed an instrument called a “matrix-assisted laser desorption/ionization mass spectrometer.” The device ionizes part of the sample with a laser beam while a crystalline matrix prevents the bio-molecules from being destroyed.

The plate upon which the bio sample sits is moved during the scan, from which hundreds to thousands of spectra are collected. The data is then processed as a grid and rendered as false-color by computer, then overlaid on a visual image of the sample.

Straight, Dorrestein and colleagues used two common bacteria that are cultured in the laboratory for their tests, Bacillus subtilis and Steptomyces coelicolor, both commonly found in soils. The bacteria were cultured together and their complex chemical interaction recorded using the mass spectrometer.

In competition for resources, the bacteria produced small molecules that alter antibiotic production from patterns present when cultured separately, Straight said. For example, they found that production of an antibiotic that targets Gram-positive organisms (Streptococcus and Staphylococcus are examples of Gram-positive organsims) was inhibited in one bacteria by the other.

The data reveal the chemical complexity of interspecies encounters. Using genetic sequencing, the researchers found that bacteria may dedicate up to 20 percent of their DNA to the bio-synthesis of small molecules in their communications and chemical battles with other microorganisms.

Bacterial infections themselves can cause many problems for both mother and fetus if they are left unchecked, so expectant mothers shouldn’t avoid antibiotics entirely. Instead, women should discuss their choices of antibiotics with their doctors.

A new study provided the first large analysis of the use of antibiotics during pregnancy. The study found that mother of babies that had birth defects were more likely than mothers who had healthy babies to report taking two types of antibiotics during their pregnancy: urinary germicides which are called nitrofurantoins (brand names Macrobid and Furadantin) and sulfa drugs (brand names Bactrim and Thiosulfil Forte).

However, this was the first time an association had been found between urinary tract treatments and birth defects, said lead author Krista Crider, who is a geneticist with the Centers for Disease Control and Prevention, which funded the research for the study. “Additional studies are going to need to be done to confirm these findings.”

Used for many decades already, the antibiotics in question predate the Food and Drug Administration and its requirements for very rigorous testing for safety. The FDA now grades all medications for safety to the fetus based on research, however, rigorous studies are lacking in so many cases that no antibiotics get the highest grade of an “A.” Sulfa drugs are the oldest antibiotics to be used and some animal studies have been conducted which found no harm during pregnancy. Nitrofurantoins have also been previously viewed to be safe by doctors to treat urinary tract infections during pregnancy. The most-prescribed antibiotics during early pregnancy, penicillins, appear to be the safest of the bunch.

Dr. Susan Mehnert-Kay, who is a family practice doctor in Tulsa, Oklahoma, who has also written about diagnosing and managing urinary tract infections, said that the new research is “very interesting” and would cause her to reconsider her antibiotic choices during early pregnancy. Dr. Michael Katz, from the March of Dimes, said that the study is very important because it looked at the drugs that have been used for decades without large studies of their safety in women who are pregnant. “Some physicians are not as attuned to this as they ought to be, so patients have the right to ask questions,” Katz stated.

The researchers analyzed the data from more than 13,000 mothers whose infants had birth defects and approximately 5,000 women who lived in the same regions that had babies who were healthy. The women were interviewed over the phone from six weeks to two years after their pregnancies. The mothers who remembered taking antibiotics during the month before they conceived through the first three months of their pregnancy were identified as exposed to the antibiotics.

The authors did acknowledge that the women’s memories could have been faulty, which is considered a substantial weakness in the study. Approximately one-third of the women who did take the antibiotics could not remember the specific type of medication they took. It is also unclear whether the birth defects were actually caused by the medications or by the underlying infections that were being treated, Crider said.

Birth defects that have been linked to sulfa drugs included rare heart and brain problems and shortened limbs. Those that were linked to nitrofurantoins included cleft palate and heart problems. The medications seemed to double or even triple the risk, depending on the type of defect. Crider said, “These defects are rare. Even with a threefold increase in risk, the risk for the individual is still quite low.” Anencephaly, which is a fatal brain problem linked to sulfa drugs, affects about 1 in 10,000 births in the United States. Cleft palate occurs in approximately 20 per 10,000 births.

Sandy Walsh, who is a spokeswoman for the FDA, said that the FDA recommends that women who are pregnant discuss medications with their doctors. The agency has also proposed changes to prescription drug labels that would require more complete information for women that are of childbearing age, women who are pregnant, and mothers who are breastfeeding, Walsh stated.

An audit covering 1,600 women presenting to a specialist clinic with a fracture showed that 31% had suffered a previous break.

Yet only 28% had been put on recommended bone-protective drugs.

A GPs’ leader said more could be done to find women at risk, but side-effects stopped some patients taking the drugs.

Normal ageing can lead to osteoporosis, a condition in which bones become fragile and break easily. The fractures are most common in bones of the spine, wrists and hips.

Women are more at risk after the menopause because they lose oestrogen which protects bones from damage.

Current guidelines from the National Institute of Health and Clinical Excellence say that women over the age of 75 who have had a fracture should automatically be offered preventive treatment with drugs such as bisphosphonates.

Because of the high risk of future fracture after a break, postmenopausal women under the age of 75 are supposed to have a bone density scan before being offered treatment if necessary.

Some experts argue that the guidelines do not go far enough, and more women with signs of bone-weakening should be offered protective therapy.

Poor uptake

In the latest analysis, 526 of 1641 postmenopausal women attending a fracture clinic had previously had a bone break, the QJM journal reported.

Overall, 27% of those were taking a bisphosphonate or other treatment such as calcium or vitamin D supplements.

Among the over-75s, only 45% were receiving bone protective therapy.

The study leader, Professor Julia Compston, said some areas of England may be better than others but the low levels of treatment found in the study were “broadly applicable” to the rest of the country.

She said reasons for lack of treatment included poor recording of fractures in patient notes; absence of incentives for GPs to treat osteoporosis, unlike many other chronic conditions; and the fact that patients “get lost” between hospitals and GPs because of poor communication.

“Someone needs to take responsibility for deciding whether a patient should be treated and there are a lot of processes that can fall down.

“Patients also need to be better informed that they might need treatment.”

In some areas of the country access to scans to measure bone density is problematic, she added.

Professor Steve Field, chairman of the Royal College of GPs, said the study highlighted the fact that more could be done to make sure treatment was available.

“But these drugs can have very unpleasant side-effects – so some patients are offered them but stop taking them,” he said.

“Exercise and diet are also important.”

One of the earliest chemotherapy drugs appears to work against a genetic fault that can trigger bowel and other cancers, UK researchers say.

In laboratory tests methotrexate, first administered in the 1940s, was found to destroy cells containing the damaged MSH2 gene.

This raises the hope of targeted treatments for those whose cancer is driven by the faulty gene.

Patient trials have already begun, EMBO Molecular Medicine reports.

The genetic condition HNPCC leaves people with a propensity to develop certain forms of cancer: some 90% of men and 70% of women will have developed bowel cancer by the time they reach 70.

METHOTREXATE Methotrexate heralded in the modern era of chemotherapy drugs In the 1940s, doctors reported remarkable results when treating children who were very ill with leukaemia It works by stopping cancer cells making and repairing DNA and therefore growing and multiplying Subsequently used as part of chemotherapy regime for many cancers, including breast, bladder and bone Over the years as medicine has developed other drugs have been preferred Still used for leukaemia and also now found to be effective for other conditions, such as Crohn’s disease and psoriasis

This accounts for about 5% of all bowel cancer cases, and the condition also contributes to tumours of the stomach, womb, ovaries and kidneys.

About 40% of people with HNPCC carry a faulty MSH2 gene. The gene usually plays a vital role in repairing DNA damage, but if it is damaged, mistakes accumulate in the cells and increase the risk of a cancer developing.

People who develop bowel cancer as a result may have more than one tumour, making the condition harder to treat.

Years after it was first used in the US, methotrexate is still commonly used in the treatment of leukaemia. It works by stopping cancer cells growing and multiplying, but is not normally deployed against solid tumours as newer, better drugs have been developed.

“What’s exciting about methotrexate is that it selectively destroys the cells lacking the MSH2 function. This indicates that it may make an excellent treatment for patients with the genetic alteration,” said Professor Alan Ashworth, who led the study at the Institute of Cancer Research.

Tailored treatment

Dr Lesley Walker of Cancer Research UK, which funded the research, said: “In the past, many treatments were developed which indiscriminately kill dividing cells. With improved scientific understanding, we are starting to be able to offer targeted therapies that are selective for the genetic faults in cancer.

“It’s really fascinating that our scientists have discovered that an old- fashioned drug of this type shows new promise for this very specific group of patients.”

Independent experts welcomed the findings.

“This is good news from one of our oldest chemotherapy drugs. It won’t be for everyone, but it does hold out hope of a tailored treatment for those affected – a form of personalised chemotherapy,” said Professor Will Steward, of the charity Beating Bowel Cancer.

Rob Glynne-Jones, chief medical advisor at Bowel Cancer UK, said: “The discovery that the faulty MSH2 gene has been found to be a specific target for Methotrexate is a really exciting development.

“It will probably only be relevant to a small proportion of patients who have bowel cancer, as HNPCC is only responsible for about 5% of bowel cancer cases. However, this is another positive step in using molecular biology and genetics to individualise a patient’s treatment.”

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