The American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) recently announced new guidelines for the treatment of dementia. Surprisingly, they found that of the five US FDA-approved pharmacological treatments for dementia, no single treatment was significantly more effective than another.
Published in the March 4 issue of Annals of Internal Medicine, the researchers carried out a literature search of studies of the five FDA-approved drugs, donepezil, galantamine, rivastigmine, tacrine and memantine, and looked for evidence of beneficial effects of the drugs on cognition, global function, behavior/mood and quality of life/activities of daily living.
The results were quite shocking. “No convincing evidence demonstrates that one therapeutic treatment is more effective than another,” wrote the authors.
About 4.5 million Americans are affected by Alzheimer's disease (AD), and this number will only increase as the average age of the population increases. The number of people with the disease is expected to triple by 2050.
“Doctors, patients and family caregivers desperately want information on how to treat this disease,” Qaseem explained. “It is disheartening to find out that all we have to work with is these five drugs, and the evidence on these is scant. Consider that in 50 years; one in 45 Americans will suffer from AD. This is a huge problem.”
The researchers made three recommendations. First, they stated that clinicians should base their decision to initiate a trial of one of the pharmacological treatments on individualized assessment. Second, the choice of the agent to be used should be based on the tolerability, side-effect profile, ease of use and cost of the medication. Finally, the authors stressed that further research into the clinical effectiveness of the agents is urgently required. The authors recommended that head-to-head studies, as well as tests of combinations of the drugs should be carried out in order to learn more about the effectiveness of pharmacological treatment for dementia.
Source: Qaseem A, Snow V, Cross JT Jr et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann. Intern. Med. 148(5), 370–378 (2008).
New antipsychotic-responsive receptor complex identified
Researchers at Mount Sinai School of Medicine (NY, USA) have identified a novel receptor complex that responds to several types of antipsychotics as well as some hallucinogenic drugs.
The scientists were investigating the effects of hallucinogenic drugs on brain chemistry in mice when they noticed that glutamate receptors (mGluR2) and serotonin2A receptors (2AR) interact and work as a hybrid complex.
In the brains of untreated schizophrenic patients, it has been found that mGluR2 are underactive, whereas 2AR are overactive; a pattern which has been suggested to predispose some people to schizophrenia.
mGluR2 interacts with 2AR to form functional complexes. These complexes trigger unique cellular responses when targeted by hallucinogenic drugs, such as lysergic acid diethylamide (LSD).
“While the LSD is binding to the serotonin part of this complex, it takes glutamate and serotonin together to create the unique changes in the cell that occur with LSD,” Stuart Sealfon, lead author of the study explained.
The researchers suggested that the mGluR2–2AR complex may be involved in the altered cortical processes in schizophrenic brains, and could be a promising novel target for treatment of psychosis.
“The findings further our understanding of how hallucinations occur. They suggest a brain abnormality that may contribute to the abnormal brain function in schizophrenia,” commented Sealfon. “We can now use this information to do further study and hopefully develop more specific drug therapies for treating patients who suffer from hallucinations and psychosis.”
Source: González-Maeso J, Ang RL, Yuen T et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97 (2008).
Study suggests low testosterone levels associated with depression
In a cross-sectional study, researchers at the University of Western Australia (Perth, Australia) have found that elderly men with depression have lower levels of testosterone compared with nondepressed elderly men.
Published in the March issue of Archives of General Psychiatry, the study found that of 3987 men aged 71–89 years, a total of 203 (5.1%) met the criteria for depression; these men also had significantly lower levels of total and free testosterone. After controlling for other factors, such as body mass index and cognitive scores, it was found that men in the lowest quintile of free testosterone levels were three-times more likely to suffer from depression.
“Importantly, these results could not be explained by increasing age, education level, smoking, obesity, or poor physical health – all factors that are known to dampen testosterone and that are associated with depression,” commented lead author Osvaldo P Almeida.
The authors believe that, although more research is required to explore these results further, their findings suggest that it may be possible to use supplementation of testosterone as a treatment for elderly depressed men.
“A randomized controlled trial is required to determine whether reducing prolonged exposure to low free testosterone is associated with a reduction in the prevalence of depression in elderly men,” the authors conclude. “If so, older men with depression may benefit from systematic screening of free testosterone concentration, and testosterone supplementation may contribute to the successful treatment of hypogonadal older men with depression.”
Source: Almeida OP, Yeap BB, Hankey GJ, Jamrozik K, Flicker L. Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men. Arch. Gen. Psychiatry 65(3), 283–289 (2008).
Physical link between raised blood serotonin and autism
In a recent study, published online in the Journal of Clinical Investigation, researchers from Vanderbilt University (TN, USA) have identified a physical basis to explain the link between autism and increased levels of blood serotonin.
It has been demonstrated that many children with autism also have elevated levels of serotonin in their blood. Since the serotonin transporter (SERT) controls serotonin availability, the researchers investigated SERT regulation in platelets.
“Levels of SERT in the brain are actually quite low, so we decided to see what progress we could make with peripheral cells that have much higher quantities. This took us to platelets,” explained Randy Blakely, lead author of the study.
The researchers found that integrin β3 associates with and regulates SERT. “Prior research had fingered the integrin β3 gene as a determinant of blood serotonin levels and, independently, as a risk factor for autism,” commented Blakely. “We found that integrin β3 can put the serotonin transporter into high gear.”
Platelet SERT activity was also diminished in integrin β3 knockout mice, and SERT expression was elevated in engineered cells that expressed human SERT and an activated form of integrin β3.
“We don't think the platelet itself contributes to autism. But rather we believe that the brain's serotonin transporter may be controlled by integrin proteins in a very similar manner,” said Blakely.
The authors suggested that this finding may not only have implications for autism, but also for other disorders associated with defects in SERT, such as anxiety, depression and cardiovascular disorders.
Source: Carneiro AM, Cook EH, Murphy DL, Blakely RD. Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J. Clin. Invest. (2008) (Epub ahead of print).
New Alzheimer's disease protein target
Alzheimer's disease (AD) is a degenerative brain condition, characterized by a progressive decline in memory, thinking, comprehension, calculation, language, learning capacity and judgment. Although AD can occur at any age (even as young as 40 years), its occurrence is much more common in the aging population. There is an exponential increase in the rate of incidence with age, resulting in very few affected individuals between the ages of 40 and 50 years, an increased incidence in individuals aged between 60 and 65 years, and a high incidence among individuals over 80 years.
A large number of neurodegenerative disorders are associated with the misfolding of proteins, suggesting that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded proteins. Various mutations in the gene that encodes transthyretin (TTR) lead to the production of misfolded proteins forming insoluble aggregates that deposit in the heart, causing amyloidosis and subsequent heart failure. This same process occurs in the brain of AD individuals, and the proteins that stick together are amyloid-β (Aβ). The TTR protein is produced in the liver and functions in transporting vitamin A and the thyroid hormone through the bloodstream. It is rarely associated with brain tissue, although studies have found that it can bind with Aβ.
Recent research carried out by scientists at the Scripps Research Institute has unveiled a new protein candidate that may serve a preventative role in the development of AD. This opens up the possibility that TTR-based therapy may be used to treat or prevent the disease.
The study, led by Joel Buxbaum, investigates the effects of varied levels of the TTR protein on an AD mouse model. Transgenic APP23 mice carry a gene encoding a dominant AD mutation. These mice develop brain plaque and suffer from cognitive deficits. When bred with mice that over-expressed the human TTR protein (hTTR), a substantial improvement in their cognitive function was observed. Buxbaum states that “carrying the hTTR gene was associated with a less severe AD-like brain pathology and smaller amounts of Aβ compared to what was found in the brains of control APP23 mice.” This can be explained by the assumption that the “hTTR protein bound to Aβ either before or when it was most toxic.”
The APP23 mice were also bred with mice missing both copies of their TTR genes (mTTR) and hence lacking any endogenous TTR protein. Increased Aβ deposition was observed in these mice. Furthermore, in contrast to the usual age of development of AD in mice, which is 9–10 months, mice in this experiment developed the disease at approximately 5 months. A lack of the natural TTR protein in these mice resulted in an earlier onset of AD with increased severity.
Buxbaum and scientists have concluded that the TTR protein binds Aβ “in a manner that prevents both toxicity and plaque formation…by interfering with aggregation of the [form] of Aβ that is most likely to stick together and causing neurological and behavioral deficits…”. It is possible that a similar phenomenon may occur in the human brain. In later life, it may be the case that the levels of the TTR protein are insufficient to inhibit aggregate formation, and this opens up the gateway to new potential therapeutic targets. Increasing TTR production in the human brain or supplementing the fall in TTR levels may be the key to developing novel treatments in the prevention or deceleration of AD.
Source: Buxbaum JN, Ye Z, Reixach N et al. Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity. Proc. Natl Acad. Sci. USA 105(7), 2681–2686 (2008).