In a study of 44,300 UK patients who used epilepsy drugs between 1990 and 2005, researchers found an increased risk of suicide, attempted suicide or “self-harm” only among current users of certain newer medications that have previously been linked to a risk of depression.

Those drugs include topiramate (Topamax), tiagabine (Gabitril), levetiracetam (Keppra) and vigabatrin (Sabril).

The findings, published in the journal Neurology, add to a debate about the Food and Drug Administration’s decision, in 2008, to require all epilepsy medications to carry a warning about the risk of suicidal behavior.

The move arose from the findings of an FDA “meta-analysis” of 199 clinical trials testing 11 different epilepsy medications. That analysis, which combined the results of all the trials, found that patients receiving medication had a higher rate of suicidal thoughts and behavior during the study periods than those given a placebo — 0.4 percent, versus 0.2 percent.

The analysis was not, however, able to distinguish whether the risk was associated with any particular drugs. And critics argued that requiring all epilepsy medications to carry a suicide warning was too broad a measure, as the drugs are not all alike.

These latest findings offer some support for that contention. But they do not mean that the drugs implicated in this study are the only ones connected to suicide risk, according to the researchers and others who reviewed the study.

For one, the findings are based on a review of information from a database — a study design that cannot prove cause-and-effect.

Moreover, there were only a small number of documented suicides, suicide attempts or instances of self-harm (self-inflicted injuries without a clear intent of suicide), according to Dr. Frank Andersohn and his colleagues at Charite-University Medical Center in Berlin.

The researchers found 453 cases among all 44,300 patients, based on a UK database of electronic medical records.

They then attempted to look at the risk of suicidal behavior and self-harm according to different categories of epilepsy drug. Topiramate, tiagabine, levetiracetam and vigabatrin were grouped together as newer drugs with a “high” risk of depression — based on the fact that in clinical trials, more than 1 percent of patients using the drugs developed depression.

Another group included four newer medications considered to have a low depression risk: gabapentin (Neurontin), lamotrigine (Lamictal), oxcarbazepine (Trileptal) and pregabalin (Lyrica). The other two groups were barbiturates and older epilepsy drugs like valproate (Depakine, Epilim) and carbamazepine (Carbatrol, Tegretol).

Overall, the researchers found a three-fold higher risk of suicidal behavior or self-harm among current users of the group including topiramate, tiagabine, levetiracetam and vigabatrin, as compared with patients who had not used any epilepsy medication in the past year.

However, the numbers, again, were small.

There were only two cases each among current users of topiramate, levetiracetam and vigabatrin, and none among tiagabine users.

The findings, therefore, need to be “interpreted with caution” and confirmed in future studies, Andersohn and his colleagues write.

The results also differ from those of a study published in April in the Journal of the American Medical Association. In that study, researchers found that new users of gabapentin, lamotrigine, oxcarbazepine and tiagabine had a higher suicide risk than those on topiramate — one of the drugs linked to an increased risk in this latest study.

An editorial published with the study agrees that the research is a “good initial attempt” at looking at a complicated question, but more work is needed.

Epilepsy itself is linked to a higher-than-average risk of depression and suicide, pointed out Dr. Josemir W. Sander of the University College London in the UK, one of the editorial authors. That, he told Reuters Health in an email, can make it hard to “disentangle” the potential effects of epilepsy medications themselves.

“The fact that each study into this issue seems to come up with different answers just confirms my belief that this does not have an easy answer,” Sander said.

A limitation of the current study is that it lacked detailed descriptions of patients’ epilepsy type and any co-existing psychiatric disorders, according to Sander.

There is “no doubt,” he explained, that there are many different subgroups of people with epilepsy, and certain patients are more vulnerable to any increased risk of suicidal behavior linked to medications.

For now, Sander said, it is important for people with epilepsy to have a psychiatric evaluation before starting a new drug — a step the FDA has advised doctors to take.

Indeed, the key message for people with epilepsy is that the most important factor in their risk of suicidal thoughts or behavior is whether they have a history, or a family history, of depression or anxiety, according to Dr. Andres Kanner, a professor of neurological sciences at Rush Medical College in Chicago, and chair of the American Epilepsy Society’s task force on the psychiatric aspects of epilepsy.

Certain epilepsy medications may facilitate the development of suicidal thoughts and behavior in vulnerable people, Kanner told Reuters Health, but any risk linked to a drug itself would be small.

“Make sure your doctor knows if you have a history of depression or anxiety,” Kanner advised, noting that that includes a personal or family history. The doctor can then consider that in the overall management of a patient’s epilepsy.

Going forward, Sander said there remains an “urgent” need for clinical trials looking at individual epilepsy drugs in different subgroups of patients, to get a clearer picture of each medication’s full risk “profile.”

The study was funded by drugmaker Bayer Schering Pharma, and two co-authors on the work have served as consultants for Novartis and Sanofi-Aventis — makers of two of the medications not linked to suicide risk in this study.

Sander and his co-author on the editorial have ties to several makers of epilepsy drugs — including ones that were and were not linked to suicide risk in this study. The companies include UCB (maker of Keppra), Pfizer (Neurontin) and GlaxoSmithKline (Lamictal).

Kanner has also received research support from various companies that make epilepsy drugs.

Source: Reuters

A Oxford University team will use adult stem cells, which have the ability to become any cell in the human body – to examine the neurological condition.

Skin cells will be used to grow the brain neurons that die in Parkinson’s, a conference will hear.

The research will not involve the destruction of human embryos.

Induced pluripotent stem (IPS) cells were developed in 2007.

At the time, scientists said it had the potential to offer many of the advantages of embryonic stem cells without any of the ethical downsides.

Three years on, it seems to be living up to that claim.

Compare and contrast

The team at Oxford University is among the first in the world to use IPS to carry out a large scale clinical investigation of Parkinson’s, which is currently poorly understood.

Researchers will be taking skin cells from 1,000 patients with early stage Parkinson’s and turning them into nerve cells carrying the disease to learn more about the brain disorder, the UK National Stem Cell Network annual science meeting will hear.

The technique is useful because it is difficult to obtain samples of diseased nerve tissue from patient biopsies.

IPS enables the researchers to create limitless quantities of nerve cells to use in experiments and to test new drugs.

“Parkinson’s disease is the second most common neurodegenerative disease in the UK and is set to become increasingly common as we live longer,” said Dr Richard Wade-Martins, head of the Oxford Parkinson’s Disease Centre.

“Once we have neurons from patients we can compare the functioning of cells taken from patients with the disease and those without to better understand why dopamine neurons die in patients with Parkinson’s.”

The research is being funded by Parkinson’s UK.

The charity’s director of research, Kieran Breen, described it as “vital research that will help us better understand the causes of this devastating condition and how it develops and progresses.

“We hope the work will pave the way for new and better treatments for people with Parkinson’s in the future.”

About 120,000 people in the UK are living with Parkinson’s.

Source: BBC News

Researchers have been able for the first time to map the protein structure of human synapses, the junctions between nerve cells responsible for transmitting information, offering scientists a new way of looking at diseases that affect millions of people around the world.

It also opens potential new ways of finding and developing drugs for brain diseases, and may in future allow doctors to make genetic diagnoses of the conditions, said Seth Grant, the neuroscientist at Cambridge University’s Sanger Institute who led the study.

“We now recognize that these synapse proteins are the molecular basis of many brain diseases,” he told reporters before presenting his findings at the Forum for European Neuroscience in Amsterdam on Monday. “We know of no other molecular structure which is responsible for more brain diseases — so we think it’s a major discovery.”

Grant’s team used a technique called proteomics to analyze all the proteins in human brain cells. Humans have around a million billion brains cells and these are connected by synapses, which play a pivotal role because they create circuits that allow the brain to learn and remember things.

The scientists found around 1,500 proteins in human synapses, each of which is encoded by a gene. They then managed to link genetic defects in some of these with key diseases such as autism, bipolar disorder, depression and schizophrenia.

“By understanding the composition of the synapse, we can also ask which proteins are important to diseases, and therefore get a sense of the disease burden that the synapse is involved with,” Grant said.

“Rather than thinking that a gene causes a particular disease, what we’re seeing now is that the gene mutation disrupts the (protein) complexes that cause the disease. We found that defects in the genes that encode these human synapse proteins are really a major cause of diseases.”

In a follow-up study using mice, Grant’s team found that by using various drugs to change the proteins in the synapse, the link to disease was also altered.

Grant said his team now planned to investigate whether the links between defects in synapse proteins and disease that they found in mice are also borne out in humans.

“If they are, then it has the potential to radically refocus scientists’ approach to the study of brain diseases,” he said.

Source: Reuters

Researchers from Nottingham University, who presented their study at the Forum for European Neuroscience in Amsterdam, said the patterns suggest it may be possible in future to identify those at risk of becoming ill before they develop symptoms.

“If we can identify people who are at particularly high risk of developing schizophrenia, perhaps using neurocognitive brain markers, then we might be able to reduce that risk and also help them to function better,” said Dr Maddie Groom, who worked on the study and gave a briefing to reporters in London.

“If we give them a better start, they may encounter the illness in a more positive way and not get quite so ill.”

Hundreds of millions of people worldwide are affected by mental, behavioral and neurological illnesses such as schizophrenia, attention deficit hyperactivity disorder (ADHD), depression, epilepsy and dementia.

Many people who go on to develop diverse mental health problems will have a history of behavioral problems going back to childhood, but experts say the problem with finding them at that stage is that differences then are often extremely subtle.

In one study, Groom and her colleagues investigated looked at the healthy siblings of people with schizophrenia, who also have a very slightly increased risk of developing schizophrenia compared with the general population.

Using brain imaging to read activity levels, the scientists asked the siblings to perform task which involved playing an alien-zapping computer game in which they needed to respond quickly, and crucially, halt the urge to respond if the wrong kind of alien popped up. The task was called a “go, no-go” task.

“When we measured the brain activity of the siblings of people with schizophrenia, their brain activity was reduced at the time when they needed to pay attention to the stimulus, and when they needed to inhibit their response,” Groom explained.

She said this suggested the subtle differences in brain activity may act as a risk marker for the disorder.

In a second study, scientists compared brain activity of children with ADHD — a mental disorder that affects between 8 and 12 percent of children, and 4 percent of adults worldwide.

The researchers used the same “go, no-go” task in various scenarios, including when the children were taking their medication, Ritalin, and when they were not, and then using an additional system of rewards and penalties.

Millions of people take ADHD drugs including Novartis Ritalin, which is known generically as methylphenidate, and Shire Plc’s Adderall and Vyvanse. In the United States alone, 2008 sales for these drugs was about $4.8 billion, according to data from IMS Health.

Groom’s results showed that children who were taking medication, and children given an incentive, performed better than those who had neither medicines nor incentives.

This suggests, Groom said, that doctors may be able to find new ways to treat children with ADHD using a combination of behavioral strategies and drugs.

Source: Reuters

The finding opens the way for a revival of the controversial and unpredictable procedure, which was halted in the mid-1990s after many patients suffered bouts of serious sudden and uncontrolled movements.

Researchers from Britain and Sweden have found that the sudden movements, called dyskinesias, which are a common side effect of treatment for Parkinson’s disease, are a result of excess serotonin cells in the transplanted tissue that trick the brain into releasing unregulated levels of dopamine.

Dopamine is a brain chemical that helps control movement, while serotonin is brain chemical which acts as a messenger.

Marios Politis of Imperial College London, who led the study, said its findings should allow scientists to modify the tissue used in future brain transplant trials for Parkinson’s patients using foetal cells and from other sources, such as bioengineered cells or stem cells.

Politis and colleagues, whose results were published in the journal Science Translational Medicine on Wednesday, studied two Parkinson’s patients who had received transplants of brain cells from aborted foetuses 13 and 16 years ago.

Although these patients experienced remarkable improvement in their Parkinson’s symptoms and their transplants were still functional, they were suffering from troublesome dyskinesias.

Using positron emission tomography (PET) scans and radiotracers that can visualise the function of brain chemicals in living humans, the researchers found that the transplants had replaced some of the dopamine-producing brain cells that decay during Parkinson’s disease.

But they also found abnormally high levels of serotonin-producing neurons within the transplanted tissue.

“The serotonin cells were very very highly excessive compared to what normal people have,” Politis said in a telephone interview. “This provoked a false action by taking the dopamine and releasing it in an unregulated manner, and this created these involuntary movements.”

Parkinson’s is a neurodegenerative disease that affects one to two percent of people over the age of 65. Sufferers have tremors, sluggish movement, muscle stiffness, and difficulty with balance. Although drugs can improve symptoms for a while, there are none that can slow or halt the disease.

These study results come just ahead of a scheduled new round of experimental work due to be carried out by European and American experts, who plan to begin new brain tissue transplant trials in Parkinson’s patients from 2012.

Politis said the study also suggested that drugs known as serotonin receptor agonists — such as the anxiety drug buspirone which is available as a generic and sold by Bristol-Myers Squibb under the brand Buspar — could be used to reduce dyskinesias in Parkinson’s patients who are still suffering the side-effects from previous transplants.

But he said since buspirone was a short-acting drug, it would be good to see drug firms developing longer acting and slow-release versions which may be of more benefit.

Source: Reuters

The standard treatments for Parkinson’s disease, which work by increasing dopamine signalling in the brain, can trigger highly risky behaviours, known as ‘impulsive-compulsive spectrum behaviours’ (ICBs) in approximately 5-10% of patients.

New results, published today in the journal Neuropsychopharmacology, uncover a possible explanation for this behaviour ? impaired self-control combined with surprisingly normal motivation. Researchers have shown that Parkinson’s patients with ICBs are much more willing to take immediate but smaller benefits rather than waiting for larger ones in the future.

“Some patients end up gambling away their life savings while others run up huge credit card debts. This work sheds light on the reasons behind such behaviours, and may help to treat sufferers of Parkinson’s disease in the future,” said Charlotte Housden who carried out the work at UCL’s Institute of Cognitive Neuroscience, and is now at the University of Cambridge.

Researchers studied a group of 36 Parkinson’s disease patients, half of whom had ICBs, and compared them to a group of 20 elderly volunteers without Parkinson’s disease. All the participants completed two tests: a computer game that measured motivation, on which the participants attempted to win cash by responding quickly and learning associations between pictures and money; and a questionnaire about financial decisions.

This questionnaire measured a form of impulsivity called “delay discounting”, by asking whether someone would prefer receiving a smaller payment quickly, as opposed to waiting for a larger payment. For example, would you prefer to receive ?50 today or ?80 in a month’s time?

The data revealed a clear pattern of results. Against the researchers’ expectations, the Parkinson’s patients who suffered from ICBs were not more motivated to win money on the computer game than the control volunteers. They were also no better at learning about which stimuli predicted money. On the other hand, they were considerably more likely to choose smaller immediate payments over larger but delayed ones on the questionnaire.

Dr Jonathan Roiser, from the UCL Institute for Cognitive Neuroscience, and supervisor of the study said: “The pattern of more impulsive choices together with intact motivation and learning suggests that ICBs may be mediated by impaired self-control, and not excessive motivation for rewards.”

The researchers hope that this study might help in the identification and treatment of ICBs in the future.

Charlotte Housden explained: “Often, when neurologists identify these risky behaviours, their only option is to reduce the dose of drugs which treat the primary symptoms of Parkinson’s disease, such as tremor and stiffness. However, this is far from ideal, since an inevitable consequence of this strategy is that these primary symptoms get worse. Our results suggest that treating impulsivity in Parkinson’s disease patients with ICBs, for example with drugs used to treat other types of impulsive behaviours, might reduce their risky behaviours without worsening their primary symptoms.”

Source: GEN

The database, a public/private partnership to be announced on Friday, will give academic and industry researchers worldwide access to information from more than 4,000 patients with neurodegenerative diseases.

Bringing the data together, rather than keeping pieces of it within each drug company, will give scientists a larger amount of information on how the diseases progress and how they differ in various patients.

Backers hope the approach will jump start research into treatments for some of the toughest and most common brain disorders. Despite decades of study, doctors still have few effective treatments for Alzheimer’s disease, which affects more than 26 million people globally. It is the most common form of dementia.

An estimated four million people worldwide have Parkinson’s disease, which causes trembling and other symptoms.

Information in the new database should help drugmakers design more efficient clinical trials of potential treatments, said Dr. Raymond Woosley, president and chief executive of the Critical Path Institute, a nonprofit organization working to improve drug development.

Some patients, for example, develop Alzheimer’s in their 80s while for others it starts in their 40s, Woosley said. The disease probably evolves differently in those groups, but companies only have small numbers in each age range to study in their own trials.

“If you have 4,000 patients (in the database), you begin to have enough data to see their real course” and can target a drug to specific types of patients, Woosley said in an interview.

The database is coordinated by the Coalition Against Major Diseases, an organization of patient groups and 13 drugmakers that is part of the Critical Path Institute.

Companies in the coalition include Pfizer Inc, GlaxoSmithKline PLC, Johnson & Johnson and Sanofi-Aventis.

Officials from the Food and Drug Administration, the National Institutes of Health and the European Medicines Agency serve as advisers.

Source: Reuters

The incidence of major depression among 559 people with traumatic brain injury was nearly eight times greater than would be expected in the general population, the researchers report in the May 19th issue of the JAMA/Journal of the American Medical Association.

While major depression during the first year was associated with a poorer quality of life and ability to function, “less than half of the people who were found to have major depression received any treatment during the first year,” Dr. Jesse R. Fann from the University of Washington School of Medicine in Seattle and one the study’s principal investigators told Reuters Health.

An estimated three million Americans are living with a traumatic brain injury — defined as a sudden violent blow to the head or penetrating wound that affects normal brain function. The most common cause is automobile accidents. Traumatic brain injury is also a “signature injury among wounded soldiers,” the investigators note.

Noting that treatment for traumatic brain injury normally focuses on the injury and its effect on a person’s ability to think clearly, Fann and colleagues wanted to clarify how often severe depression develops after a major traumatic brain injury and if it affects recovery.

Of the 1,080 brain injury patients admitted to one trauma center in Seattle between June 2001 and March 2005, 559 agreed to participate in the study and were followed for 12 months. Study participants were mostly men injured in automobile accidents.

The researchers report that more than half of the participants (about 53 percent) were diagnosed with major depression at some point in the first year after their brain injury – a rate that is about 8 times greater than would be expected.

Not counting those that were depressed at the time they were injured, 233 of the remaining 471 participants (49 percent) experienced “new” major depression.

For a variety of reasons, the investigators say the rates of major depression after traumatic brain injury are probably “conservative” and underestimate the problem.

Major depression was associated with increased anxiety, poorer self-reported health and lower quality of life. The investigators urge making mental health services part of the normal care of patients with a traumatic brain injury.

In the current study, only 44 percent of those with major depression received antidepressants or counseling.

Because major depression after traumatic brain injury “is an invisible disorder within an often invisible injury, aggressive efforts are needed” to educate doctors, promote detection and treat patients where warranted, they conclude.

Fann cautions against generalizing these study findings to traumatic brain injury suffered by soldiers on the battle field.

“These were civilian injuries; the findings, however, are consistent with military studies showing that head injuries, especially when there has been a loss on consciousness, do have a significantly higher rate of depression.”

SOURCE: jama.ama-assn.org

JAMA/Journal of the American Medical Association May 19, 2010

The study of more than 3,000 people with Parkinson’s disease confirms that so-called dopamine agonists, such as GlaxoSmithKline’s Requip or ropinirole or Boehringer Ingelheim’s Mirapex or pramipexole, can cause impulse control problems.

And it may mean doctors who prescribe the drugs for other conditions like restless legs syndrome should watch for these symptoms in patients, they said.

“For some time now we’ve suspected there might be an association between exposure to dopamine agonists and the development of impulse control problems in patients,” said Dr. Daniel Weintraub of the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center, whose study appears in the Archives of Neurology.

Dopamine agonists work by helping the brain make more dopamine, the message-carrying chemical made by brain cells destroyed by Parkinson’s. Patients with the incurable disease have difficulties with movement, muscle control and balance and can eventually become paralyzed and die.

Weintraub’s team studied 3,090 Parkinson’s patients. Nearly all were taking either a dopamine agonist or a levodopa dopamine replacement drug such as Bristol-Myers Squibb’s Sinemet.

They found impulse control disorders in 13.6 percent of patients taking a dopamine agonist, including compulsive gambling in 5 percent of patients, compulsive sexual behavior in 3.5 percent of patients, compulsive buying in 5.7 percent and binge-eating in 4.3 percent.

And 4 percent of patients had two or more of these disorders, the team found.

“It confirms that dopamine agonist treatment is associated with one or more impulse control disorders in patients with Parkinson’s disease,” he said.

Weintraub said there was also an association with the impulsive behaviors in patients taking levodopa, but it was much weaker.

Weintraub said more study is needed to see whether impulse control problems occur at the same rates in people who take dopamine agonists for restless legs syndrome because the drugs are often given at lower doses.

Source: Reuters

“There is no meaningful difference between these agents,” Dr. Sebastian Schneeweiss of Brigham and Women’s Hospital and Harvard Medical School in Boston, one of the study’s authors, told Reuters Health. This means that psychiatrists prescribing antidepressants can base their choice on what works best for the patient, rather than what’s safest, he explained.

But the findings don’t mean that the drugs are risk-free, Schneeweiss added. “You always have to worry about the safety of these medications, the increased (suicide risk) is still there,” he said.

The US Food and Drug Administration issued a warning in 2004 that children and adolescents taking antidepressants might have an increased risk of suicidal thoughts and behaviors. In 2006, it extended the warning to include young adults up to age 25. All antidepressant labels must now carry a “black box” warning stating that they can increase a person’s likelihood of suicidal thoughts and behaviors.

But it has been difficult to pin down whether a certain antidepressant drug or class of medications might be more dangerous — or safer — than others, Schneeweiss noted. To investigate, he and his colleagues looked at data on nearly 300,000 adults in British Columbia, Canada, who had been prescribed antidepressants between 1997 and 2005. They evaluated whether specific medications would increase the risk that a person would attempt or complete suicide during their first year of taking that drug.

Among the 287,543 men and women in the study, there were 751 suicide attempts and 104 suicides.

Schneeweiss and his team found no difference in risk between different classes of medications, such as selective serotonin reuptake inhibitors (SSRIs for short, which include Prozac, Zoloft and other widely used medications) or older antidepressants called tricyclic antidepressants. Risks also were similar for individual SSRIs.

In April, Schneeweiss and his colleagues published a similar study in the journal Pediatrics of 20,000 10- to 18-year-olds that found no difference in suicide risk among antidepressants.

It’s still unclear why antidepressants could increase suicide risk, Schneeweiss noted in an interview. “You cannot really tease that apart in non-randomized studies,” he added. But for now, he and his colleagues conclude, “clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent.”

Source: Reuters