According to recent research on rats, a new class of faster acting, more selective antidepressants may provide relief in days rather than weeks. “We hope that this study may contribute to the development of new compounds, so that clinical trials can be conducted in the near future,” commented Guillame Lucas of McGill University (QC, Canada), whose work was published in the September 6 issue of Neuron.
Existing antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), work by increasing the concentration of serotonin between nerves, and usually require 6 weeks to take effect. By contrast, these novel receptor agonists specifically target serotonin type-4 receptors and “may act 4–7-times more rapidly,” according to the researchers.
To test the antidepressant action of two such agonists, Lucas and his colleagues compared the drugs RS 67333 and prucalopride with a SSRI (Celexa) in rats. In the experiment, rodents were made to swim, and the time it took them to give up was used as a measure of depression; the quicker they stop and become immobile, the sadder they are. Both drugs significantly reduced the time of this immobility.
The researchers also found that the serotonin agonists worked much quicker and more effectively than conventional drugs. In a rat model of chronic depression, where mild stress is linked to reduced intake of sugar water, improvements with one of the new compounds were seen after only 3 days and completely erased the depressive symptoms after 1 week; contrast this with SSRIs, which takes weeks to alleviate the behavior.
However, as pointed out by Gerald Frye from Texas A&M Health Science Center College of Medicine (TX, USA), the McGill study “looks promising from an animal standpoint, and the animal systems they’re using are pretty good, but this can only predict. The only way we’ll know is when a clinical trial is done.”
Nevertheless, the prospect of a new class of drugs with rapid onset of action is good news for depression sufferers; delays associated with SSRIs can be critical and “are not only a matter of patient comfort, it’s really important, especially when you are treating major depressions that could lead to suicide,” as Lucas stated.
Source: Lucas G, Rymar VV, Du J et al. Serotonin(4) (5-HT4) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55, 712–725 (2007).
Mind the gap: world’s mental healthcare
Data from a worldwide investigation into the use of mental health facilities reveals startling undertreatment of people with mental illness. The survey, conducted by Philip Wang and colleagues as part of the WHO World Mental Health Survey Initiative, has prompted a ‘call for action’ to increase human and financial resources to mental health services.
It has been estimated that approximately 37% of the world’s population is currently suffering from mental disorders, admitting them to the top ten league of illnesses causing disability. Shockingly, this survey reveals that two-thirds of the world’s mentally ill are left without treatment, and more than half of the most severely affected receive no care at all.
Published in the September issue of The Lancet, the study describes personal interviews with 84,848 individuals in 17 developed and undeveloped countries. Respondents were asked about mental disorders such as anxiety, mood and substance abuse, whether they received any services, and if so, what kind of care (e.g., general medical professional, mental health professional or religious counselor).
The survey found that fewer people in developing countries sought mental services compared with those in the developed world (e.g., 11% in France compared with 1.6% in Nigeria). In all countries surveyed, educated individuals are more likely to seek out services, as are women and middle-aged people, and help is mainly received from the general medical sector. “Good treatments are available for many mental disorders. Yet, the world continues to struggle with the very real challenge of providing these services to the people who most need them,” commented Thomas Insel, Director of the National Institute of Mental Health (MD, USA).
Also, for both low- and high-income countries, of those treated few receive minimally adequate services. In the USA, for example, the proportion of sufferers receiving adequate service is a mere 18%. “We need to help developing countries implement more effective mental healthcare services, but we also need to do a better job at home,” added Wang.
The WHO considers this treatment gap a serious issue that needs to be addressed by public health planners. “We can only improve the services available to people with mental disorders if there is a major and rapid increase in investment in this area,” Benedetto Saraceno, WHO Director of Mental Health and Substance Abuse, urged.
Source: Wang PS, Aguilar-Gaxiola S, Alonso J et al. Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys. Lancet 370(9590), 841–850 (2007).
Cracking the ‘neural code’
In a landmark study, a group of researchers from the Weill Medical College (NY, USA) have shed some light on how the brain’s neural code may be decoded. Currently, scientists are unable to interpret the complex combinations of signals produced during neural activity.
“It’s like we’re hearing Morse code, but have no training in understanding what the separate beeps and dashes mean,” commented lead author Daniel Butts. “And the brain’s neural code is infinitely more complex than Morse code.”
Published in the September 6 issue of Nature, the group investigated the electrical activity created in the lateral geniculate nucleus of the visual system when animals were shown a ‘natural movie stimulus’, which was designed to represent real-world conditions.
“If you were trying to decipher Morse code, you’d first want to know which units were important to focus on – is it the individual beeps? The series of beeps? – and which gaps between beeps signaled that a new unit of the language was present,” Butts explained. “That’s what this paper was all about.”
“We discovered that the specific timing of these electrical pulses is crucial to interpreting how the neural code works as the brain represents what it sees in the natural environment. Understanding the ‘time scales’ that matter to the brain gives us insight into which units of the neural code we need to focus on if we ever hope to decode it,” Butts commented.
The authors stress that a great deal more work needs to be carried out in this field of research, but that the potential benefits of understanding neural codes are astounding.
“The neural code is the key to understanding the patterns of electrical impulses that neurons use to communicate. These electrical patterns allow the brain to make sense of incoming stimuli, make decisions based on that information, and coordinate its activities to carry out tasks,” Butts explained.
“Imagine, if we knew what specific signals meant, we might very easily diagnose brain illnesses based on those electrical signatures. We could also track a patient’s recovery, much like cardiologists track the health of heart patients using EKGs. Understanding the neural code would also greatly aid in psychiatric drug research; we could understand a medicine’s effect in the brain based on its known effects on its electrical activity, for example. And then there’s the field of ‘neural prosthetics’, building direct links between the brain and machines that might allow the paralyzed to regain movement or the blind to see.”
Source: Butts DA, Weng C, Jin J et al. Temporal precision in the neural code and the timescales of natural vision. Nature 449(7158), 92–95 (2007).
A new weapon in the treatment of brain tumors
An adenovirus, termed Delta-24-RGD, has shown promising results in the treatment of aggressive brain tumors both in vitro and in vivo. The study, published in the September 18 issue of the Journal of the National Cancer Institute, showed that Delta-24-RGD is able to target and kill cancer stem cells.
Explaining the reasoning behind targeting the cancer stem cells, lead author Juan Fueyo commented, “Research has shown that these cancer stem cells are the origin of the tumor, that they resist the chemotherapy and radiation that we give to our patients, and that they drive the renewed growth of the tumor after surgery. So we decided to test Delta-24-RGD against glioma stem cells and tumors grown from them.”
The researchers, from both Japan and the USA, firstly investigated the effectiveness of Delta-24-RGD on glioblastoma multiforme (GBM) stem cells in vitro. They took four GBM specimens and derived brain tumor stem cell lines from each specimen. All of these stem cell lines exhibited characteristics as well as containing protein signatures of GBM. When Delta-24-RGD was added, all four stem cell lines were destroyed.
Following on from this, the researchers produced tumors in mice by grafting the stem cell lines into their brains. Some of these mice then received injections of Delta-24-RGD. Those that were treated survived for an average of 66 days compared with only 38.5 days survival of the untreated mice.
“We have shown first in laboratory experiments and then in stem cell-derived human brain cancer in mice, that we have a tool that can target and eliminate the cells that drive brain tumors,” said Fueyo.
Interestingly, two of the eight mice that received treatment survived for the study duration of 92 days. “It’s important in animal models to see improvement in survival in the majority of animals, but to have some be cured and survive a long time without neurological symptoms is very rare,” Fueyo commented.
The group now plans to investigate precisely why the cancer stem cells go through induced autophagic cell death. “Our next experiments will address whether the cell kills itself or dies defending itself against the virus. Sure, the cell dies either way, but the distinction is important because the virus could be redesigned to either fuel or block autophagy to make it more effective. The autophagic protein Atg5 is heavily expressed in the dead tumor cells, making it a potential biomarker of the virus’ effectiveness,” explained Fueyo.
According to the Brain Tumor Society, every year approximately 200,000 people in the USA are diagnosed with primary or metastatic brain tumors. Gliomas make up approximately 40% of all brain tumors; the most common of these in adults being the GBM. This aggressive brain tumor has very poor survival rates, with 30% survival 1 year after diagnosis, and only 2% 10 years after diagnosis.
With such a poor survival rate for brain tumors in general, and for GBM in particular, it is clear that improved therapies, such as Delta-24-RGD, for these aggressive cancers are urgently needed.
Source: Jiang H, Gomez-Manzano C, Aoki H et al. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J. Natl Cancer Inst. (2007) (Epub ahead of print).
Alzheimer’s patients live longer on a Mediterranean diet
It has already been shown that eating a Mediterranean diet is associated with a reduced risk of developing Alzheimer’s disease (AD). However, in a recent study, researchers at Columbia University (NY, USA) have demonstrated that the Mediterranean diet also increases lifespan in AD sufferers.
Published in the September 11 issue of Neurology, the researchers report that AD sufferers who adhered to a Mediterranean diet were 73% less likely to die during the study follow-up period of 4.4 years than those who stuck to a Western style diet.
A total of 192 participants who had been diagnosed with AD were investigated. These patients were spilt into three groups depending on how much they adhered to the Mediterranean diet. Participants were followed up every 18 months and during the study duration 85 (44%) of the participants died.
The researchers found that the longevity of the participants was correlated with the adherence to the Mediterranean diet in what appeared to be a dose-dependent manner.
“AD patients who adhered to the diet to a moderate degree lived an average 1.3 years longer than those people who least adhered to the diet. And those AD patients who followed the diet very religiously lived an average of 4 years longer,” commented lead author Nikolaos Scarmeas.
The group is now keen to investigate how the diet affects AD sufferers’ cognition and quality of live. “New benefits of this diet keep coming out,” Scarmeas noted. “We need to do more research to determine whether eating a Mediterranean diet also helps AD patients have slower rates of cognitive decline, maintain their daily living skills, and have a better quality of life.”
Source: Scarmeas N, Luchsinger JA, Mayeux R, Stern Y. Mediterranean diet and Alzheimer’s disease mortality. Neurology 69(11), 1084–1093 (2007).
Intelligent networks
Based on a comprehensive review of brain imaging studies, a ‘Parieto–Frontal Integration Theory’ (P-FIT) for the neural basis of human intelligence has been proposed by Richard Haier of the University of California (CA, USA), and Rex Jung of the University of New Mexico (NM, USA). Despite different approaches, a surprising consistency in the results points to the frontal and the parietal lobes as the brains’ intelligence hotspots.
Previous studies by the same researchers have shown that regions linked to intelligence are likely to be scattered throughout the brain, thus ruling out a single ‘intelligence center’. Writing in the Journal of Behavioral and Brain Sciences, Haier and Jung now report that intelligence areas may overlap, and interact with those associated with higher cognitive functions, such as attention, memory and language.
“Recent neuroscience studies suggest that intelligence is related to how well information travels throughout the brain. Our review of imaging studies identifies the stations along the routes intelligent information processing takes. Once we know where the stations are, we can study how they relate to intelligence,” stated Haier.
According to their P-FIT, intelligence levels may be founded on how efficiently the frontal–parietal networks process information. “Individual differences in intelligence depend, in part, upon individual differences in specific areas of the brain and in the connections between them,” explained Earl Hunt, a psychologist at the University of Washington (WA, USA).
Elucidating the nature of intelligence is a longstanding mystery to researchers in the field, but this review is nevertheless one step in the right direction. “We have a long way to go before we understand the details, but our P-FIT model provides a framework for testing new hypotheses in future experiments,” Haier concluded.
Source: Jung RE, Haier RJ. The Parieto–Frontal Integration Theory (P-FIT) of intelligence: converging neuroimaging evidence. Behav. Brain Sci. 30(2), 135–154 (2007).