Deconstructing the placebo response: Why does it work in treating depression?

In the past three decades, the power of placebos has gone through the roof in treating major depressive disorder. In clinical trials for treating depression over that period of time, researchers have reported significant increases in patient’s response rates to placebos — the simple sugar pills given to patients who think that it may be actual medication.

New research conducted by UCLA psychiatrists helps explain how placebos can have such a powerful effect on depression.

“In short,” said Andrew Leuchter, the study’s first author and a professor of psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior, “if you think a pill is going to work, it probably will.”

The UCLA researchers examined three forms of treatment. One was supportive care in which a therapist assessed the patient’s risk and symptoms, and provided emotional support and encouragement but refrained from providing solutions to the patient’s issues that might result in specific therapeutic effects. The other two treatments provided the same type of therapy, but patients also received either medication or placebos.

The researchers found that treatment that incorporating either type of pill — real medication or placebo — yielded better outcomes than supportive care alone. Further, the success of the placebo treatment was closely correlated to people’s expectations before they began treatment. Those who believed that medication was likely to help them were much more likely to respond to placebos. Their belief in the effectiveness of medication was not related to the likelihood of benefitting from medication, however.

“Our study indicates that belief in ‘the power of the pill’ uniquely drives the placebo response, while medications are likely to work regardless of patients’ belief in their effectiveness,” Leuchter said.

The study appears in the current online edition of the British Journal of Psychiatry.

At the beginning and end of the study, patients were asked to complete the Hamilton Rating Scale for Depression, giving researchers a quantitative assessment of how their depression levels changed during treatment. Those who received antidepressant medication and supportive care improved an average of 46 percent, patients who received placebos and supportive care improved an average of 36 percent, and those who received supportive care alone improved an average of just 5 percent.

“Interestingly, while we found that medication was more effective than placebo, the difference was modest,” Leuchter said.

The researchers also found that people who received supportive care alone were more likely to discontinue treatment early than those who received pills.

People with major depressive disorder have a persistent low mood, low self-esteem and a loss of pleasure in things they once enjoyed. The disorder can be disabling, and it can affect a person’s family, work or school life, sleeping and eating habits, and overall health.

In the double-blind study, 88 people ages 18 to 65 who had been diagnosed with depression were given eight weeks of treatment. Twenty received supportive care alone, 29 received a placebo with supportive care and 39 received actual medication with supportive care.

The researchers measured the patients’ expectations for how effective they thought medication and general treatment would be, as well as their impressions of the strength of their relationship with the supportive care provider.

“These results suggest a unique role for people’s expectations about their medication in engendering a placebo response,” Leuchter said. “Higher expectations of medication effectiveness predicted an improvement in placebo-treated subjects, and it’s important to note that people’s expectations about how effective a medication may be were already formed before they entered the trial.”

Leuchter said the research indicates that factors such as direct-to-consumer advertising may be shaping peoples’ attitudes about medication. “It may not be an accident that placebo response rates have soared at the same time the pharmaceutical companies are spending $10 billion a year on consumer advertising.”

(Image credit: © Chris Lamphear)

(Image caption: An undated handout picture released by Japan’s Riken research institute and Foundation for Biomedical Research and Innovation, shows a retina sheet prepared from iPS cells of a woman for transplant surgery. Japanese researchers on Friday conducted the world’s first surgery to implant “iPS” stem cells in a human body in a major boost to regenerative medicine, two institutions involved said. — PHOTO: AFP/RIKEN AND FOUNDATION FOR BIOMEDICAL RESEARCH AND INNOVATION. Adapted from: The Straits Times)

Japanese doctors test method for restoring impaired vision

Japanese doctors have successfully carried out the first ever implantation of a retina grown from induced pluripotent stem cells (iPS).

The recipient was a 70-year-old woman suffering from macular degeneration.

The procedure took place Friday at the Institute of Biomedical Research and Innovation in the southern city of Kobe, under the direction of a group of scientists from the Riken Institute.

Researchers extracted skin samples from women to grow iPS cells capable of serving as retinal tissue, which then were used to surgically replace part of the macula, the main photo-receptor layer of the retina.

The scientists said that their priority was not to attempt to restore the patient’s sight, but to determine if there are any unforeseen side effects, such as tumours, arising from the procedure.

According to the researchers, who will study the patient’s evolution over the next four years, since the patient will have already lost most of the cells responsible for vision, a transplant may bring only slight improvement or merely slow down the rate of degeneration.

Macular degeneration is an age-related disease that currently affects about 700,000 people in Japan and is the principal cause of blindness in the world.

(Image caption: MRI scans showing brain damage in the stroke patients before treatment. Source: Stem Cells Translational Medicine.)

Stem cells show promise for stroke in pilot study

A stroke therapy using stem cells extracted from patients’ bone marrow has shown promising results in the first trial of its kind in humans.

Five patients received the treatment in a pilot study conducted by doctors at Imperial College Healthcare NHS Trust and scientists at Imperial College London.

The therapy was found to be safe, and all the patients showed improvements in clinical measures of disability.

The findings are published in the journal Stem Cells Translational Medicine. It is the first UK human trial of a stem cell treatment for acute stroke to be published.

The therapy uses a type of cell called CD34+ cells, a set of stem cells in the bone marrow that give rise to blood cells and blood vessel lining cells. Previous research has shown that treatment using these cells can significantly improve recovery from stroke in animals. Rather than developing into brain cells themselves, the cells are thought to release chemicals that trigger the growth of new brain tissue and new blood vessels in the area damaged by stroke.

The patients were treated within seven days of a severe stroke, in contrast to several other stem cell trials, most of which have treated patients after six months or later. The Imperial researchers believe early treatment may improve the chances of a better recovery.

A bone marrow sample was taken from each patient. The CD34+ cells were isolated from the sample and then infused into an artery that supplies the brain. No previous trial has selectively used CD34+ cells, so early after the stroke, until now.

Although the trial was mainly designed to assess the safety and tolerability of the treatment, the patients all showed improvements in their condition in clinical tests over a six-month follow-up period.

Four out of five patients had the most severe type of stroke: only four per cent of people who experience this kind of stroke are expected to be alive and independent six months later. In the trial, all four of these patients were alive and three were independent after six months.

Dr Soma Banerjee, a lead author and Consultant in Stroke Medicine at Imperial College Healthcare NHS Trust, said: “This study showed that the treatment appears to be safe and that it’s feasible to treat patients early when they might be more likely to benefit. The improvements we saw in these patients are very encouraging, but it’s too early to draw definitive conclusions about the effectiveness of the therapy. We need to do more tests to work out the best dose and timescale for treatment before starting larger trials.”

Over 150,000 people have a stroke in England every year. Survivors can be affected by a wide range of mental and physical symptoms, and many never recover their independence.

Stem cell therapy is seen as an exciting new potential avenue of treatment for stroke, but its exact role is yet to be clearly defined.

Dr Paul Bentley, also a lead author of the study, from the Department of Medicine at Imperial College London, said: “This is the first trial to isolate stem cells from human bone marrow and inject them directly into the damaged brain area using keyhole techniques. Our group are currently looking at new brain scanning techniques to monitor the effects of cells once they have been injected.”

Professor Nagy Habib, Principal Investigator of the study, from the Department of Surgery and Cancer at Imperial College London, said: “These are early but exciting data worth pursuing. Scientific evidence from our lab further supports the clinical findings and our aim is to develop a drug, based on the factors secreted by stem cells, that could be stored in the hospital pharmacy so that it is administered to the patient immediately following the diagnosis of stroke in the emergency room. This may diminish the minimum time to therapy and therefore optimise outcome. Now the hard work starts to raise funds for this exciting research.”

Clues to curbing obesity found in neuronal ‘sweet spot’

Preventing weight gain, obesity, and ultimately diabetes could be as simple as keeping a nuclear receptor from being activated in a small part of the brain, according to a new study by Yale School of Medicine researchers.

Published in the Aug. 1 issue of The Journal of Clinical Investigation (JCI), the study showed that when the researchers blocked the effects of the nuclear receptor PPARgamma in a small number of brain cells in mice, the animals ate less and became resistant to a high-fat diet.

“These animals ate fat and sugar, and did not gain weight, while their control littermates did,” said lead author Sabrina Diano, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine. “We showed that the PPARgamma receptor in neurons that produce POMC could control responses to a high-fat diet without resulting in obesity.”

POMC neurons are found in the hypothalamus and regulate food intake. They are the neurons that when activated make you feel full and curb appetite. PPARgamma regulates the activation of these neurons.

Diano and her team studied transgenic mice that were genetically engineered to delete the PPARgamma receptor from POMC neurons. They wanted to see if they could prevent the obesity associated with a high-fat, high-sugar diet.

“When we blocked PPARgamma in these hypothalamic cells, we found an increased level of free radical formation in POMC neurons, and they were more active,” said Diano, who is also professor of comparative medicine and neurobiology at Yale and director of the Reproductive Neurosciences Group.

The findings also have key implications in diabetes. PPARgamma is a target of thiazolidinedione (TZD), a class of drugs used to treat type 2 diabetes. They lower blood-glucose levels, however, patients gain weight on these medications.

“Our study suggests that the increased weight gain in diabetic patients treated with TZD could be due to the effect of this drug in the brain, therefore, targeting peripheral PPARgamma to treat type 2 diabetes should be done by developing TZD compounds that can’t penetrate the brain,” said Diano. “We could keep the benefits of TZD without the side-effects of weight gain. Our next steps in this research are to test this theory in diabetes mouse models.”

Glucose ‘control switch’ in the brain key to both types of diabetes

Researchers at Yale School of Medicine have pinpointed a mechanism in part of the brain that is key to sensing glucose levels in the blood, linking it to both type 1 and type 2 diabetes. The findings are published in the July 28 issue of Proceedings of the National Academies of Sciences.

“We’ve discovered that the prolyl endopeptidase enzyme — located in a part of the hypothalamus known as the ventromedial nucleus — sets a series of steps in motion that control glucose levels in the blood,” said lead author Sabrina Diano, professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences, Comparative Medicine, and Neurobiology at Yale School of Medicine. “Our findings could eventually lead to new treatments for diabetes.”

The ventromedial nucleus contains cells that are glucose sensors. To understand the role of prolyl endopeptidase in this part of the brain, the team used mice that were genetically engineered with low levels of this enzyme. They found that in absence of this enzyme, mice had high levels of glucose in the blood and became diabetic.

Diano and her team discovered that this enzyme is important because it makes the neurons in this part of the brain sensitive to glucose. The neurons sense the increase in glucose levels and then tell the pancreas to release insulin, which is the hormone that maintains a steady level of glucose in the blood, preventing diabetes.

“Because of the low levels of endopeptidase, the neurons were no longer sensitive to increased glucose levels and could not control the release of insulin from the pancreas, and the mice developed diabetes.” said Diano, who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

Diano said the next step in this research is to identify the targets of this enzyme by understanding how the enzyme makes the neurons sense changes in glucose levels. “If we succeed in doing this, we could be able to regulate the secretion of insulin, and be able to prevent and treat type 2 diabetes,” she said.