Success Of Pfizer Pancreatic Cancer Drug Stops Trial
Global drug company Pfizer Inc announced yesterday, 12 March, that a phase 3 clinical trial of its pancreatic cancer drug Sutent (sunitinib malate) stopped early because the drug showed significant benefits in patients.
Sutent is designed to treat patients with advanced pancreatic islet cell tumors, also known as pancreatic neuroendocrine tumors.
It is an oral multi-kinase inhibitor (blocks the action of molecules that help the cancer to spread) and is already approved for the treatment of both advanced renal cell carcinoma (RCC) and second-line gastrointestinal stromal tumor (GIST). More than 38,000 patients with these diseases have been treated with the drug, both in clinical settings and in trials.
The independent Data Monitoring Committee (DMC) that was overseeing this trial recommended it stop after finding that the drug had shown greater progression-free survival compared to placebo (patients lived longer without the cancer spreading), and best supportive care in patients with pancreatic islet cell tumors, said Pfizer in a press statement. Once the trial data is fully analyzed, it will be presented at a scientific meeting, they added.
Pancreatic islet cell tumors are rare, with an incidence of 5 to 10 per million worldwide annually. Such tumors include insulinomas, glucagonomas and gastrinomas, and current treatment options are limited.
The participating centers have now been informed of the decision, so all the patients taking part in the trial can choose to continue on Sutent or switch from placebo to the drug.
Dr Mace Rothenberg, senior vice president of medical development and clinical affairs for Pfizer's Oncology Business Unit told the press:
"We are delighted by these findings which demonstrate that Sutent provides a benefit for patients with advanced, well-differentiated pancreatic islet cell tumors -- a rare cancer with limited treatment options."
"These and previously reported phase 2 data contribute to the growing body of evidence indicating activity with sunitinib in patients with pancreatic islet cell tumors," he added.
The phase 3 trial followed the successful completion of the phase 2 trial which was reported in the July 2008 issue of the Journal of Clinical Oncology.
Pfizer reported that this is the second phase 3 trial of Sutent that has stopped early on the recommendation of the trial's DMC because it has shown benefits to patients. In January 2005, when Sutent was being trialled for use with GIST patients, the trial was unblinded early when results showed the drug delayed tumor progression compared to placebo.
The company is also looking to test the drug in phase 3 trials for the treatment of other solid tumors, including advanced breast cancer, advanced non-small cell lung cancer, advanced colorectal cancer, advanced hepatocellular carcinoma and advanced hormone-refractory prostate cancer.
According to the Associated Press, the news sent Pfizer shares up by nearly 10 per cent on Thursday. Sutent is already the New-York based company's best-selling cancer drug, earning 847 million dollars in sales in 2008, of which 254 million was in the US, said the AP announcement.
Sources: Pfizer, Associated Press.
Sutent is designed to treat patients with advanced pancreatic islet cell tumors, also known as pancreatic neuroendocrine tumors.
It is an oral multi-kinase inhibitor (blocks the action of molecules that help the cancer to spread) and is already approved for the treatment of both advanced renal cell carcinoma (RCC) and second-line gastrointestinal stromal tumor (GIST). More than 38,000 patients with these diseases have been treated with the drug, both in clinical settings and in trials.
The independent Data Monitoring Committee (DMC) that was overseeing this trial recommended it stop after finding that the drug had shown greater progression-free survival compared to placebo (patients lived longer without the cancer spreading), and best supportive care in patients with pancreatic islet cell tumors, said Pfizer in a press statement. Once the trial data is fully analyzed, it will be presented at a scientific meeting, they added.
Pancreatic islet cell tumors are rare, with an incidence of 5 to 10 per million worldwide annually. Such tumors include insulinomas, glucagonomas and gastrinomas, and current treatment options are limited.
The participating centers have now been informed of the decision, so all the patients taking part in the trial can choose to continue on Sutent or switch from placebo to the drug.
Dr Mace Rothenberg, senior vice president of medical development and clinical affairs for Pfizer's Oncology Business Unit told the press:
"We are delighted by these findings which demonstrate that Sutent provides a benefit for patients with advanced, well-differentiated pancreatic islet cell tumors -- a rare cancer with limited treatment options."
"These and previously reported phase 2 data contribute to the growing body of evidence indicating activity with sunitinib in patients with pancreatic islet cell tumors," he added.
The phase 3 trial followed the successful completion of the phase 2 trial which was reported in the July 2008 issue of the Journal of Clinical Oncology.
Pfizer reported that this is the second phase 3 trial of Sutent that has stopped early on the recommendation of the trial's DMC because it has shown benefits to patients. In January 2005, when Sutent was being trialled for use with GIST patients, the trial was unblinded early when results showed the drug delayed tumor progression compared to placebo.
The company is also looking to test the drug in phase 3 trials for the treatment of other solid tumors, including advanced breast cancer, advanced non-small cell lung cancer, advanced colorectal cancer, advanced hepatocellular carcinoma and advanced hormone-refractory prostate cancer.
According to the Associated Press, the news sent Pfizer shares up by nearly 10 per cent on Thursday. Sutent is already the New-York based company's best-selling cancer drug, earning 847 million dollars in sales in 2008, of which 254 million was in the US, said the AP announcement.
Sources: Pfizer, Associated Press.
Drugs In US Drinking Water
A five month investigation by the Associated Press has discovered that small quantities of drugs, including antibiotics, sex hormones, and anti-seizure compounds, have been found in public drinking water supplied to over 40 million Americans across the US.
While the concentrations are so small they have to be measured in parts per billion or even parts per trillion, and water companies insist these levels are within safety limits, the AP said the long term effects on people's health of so many prescription drugs and over the counter medicines such as acetaminophen (paracetamol) and ibuprofen, even in tiny amounts, are starting to worry scientists.
Drugs and their derivatives get into the drinking water supply because when people on medication go to the toilet they excrete whatever the body does not absorb and any matabolized byproducts. Water companies treat the waste before discharging it into rivers, lakes and reservoirs, and then treat it again before it enters the drinking water system. However, the various treatments don't remove all traces of drugs.
For five months, the AP National Investigative Team visited treatment plants, interviewed over 200 scientists, officials and academics, analyzed federal databases and reviewed hundreds of scientific reports.
Among their enquiries the AP investigators came across research studies that have "gone virtually unnoticed by the general public" where scientists were alarmed at the effect of the drinking water contaminants on human cells and wildlife.
The investigators also found that water companies don't like to publish the results of drug screening tests because they think the public would not know how to interpret them and would become unduly alarmed. However, the US Environmental Protection Agency (EPA) assistant administrator for water, Benjamin H Grumbles told AP that:
"We recognize it is a growing concern and we're taking it very seriously."
The AP investigators discovered that drugs have been found in the drinking water of 24 major metropolitan areas across the country. Here are some of the key findings:
* Southern California: a portion of drinking water that supplies 18.5 million people contained traces of anti-epileptic and anti-anxiety drugs.
* Philadelphia: treated drinking water contained 56 drugs or byproducts, including pharmaceuticals for pain, infection, cholesterol control, heart conditions, asthma.
* San Francisco: a sex hormone was detected in the drinking water.
* Washington DC: six drugs were found in the drinking water supply of the capital and surrounding area.
* Tucson, Arizona: an antibiotic and two other medications were found in the drinking water.
* Northern New Jersey: drinking water for 850,000 residents was found to contain carbamazepine, a mood stabilizer, and a metabolized byproduct of angina medication. This was found by US Geological Survey researchers who analyzed a treatment plant.
The AP report paints a rather chaotic and inconsistent picture of what is happening nationwide, with some water companies testing for a vast range of pharmaceutical compounds and others only testing for two. This is not surprising, since the AP team found that the "federal government doesn't require any testing and hasn't set safety limits for drugs in water".
It is not just waste water that is contaminated. The AP report says that watersheds, the natural source of most of the country's drinking water, are also affected. The AP investigators said tests were carried out in the watersheds of 35 of the 62 major water utilities they surveyed and drugs were found in 28 of them. Six of the 28, when contacted by the AP, said they did not test their drinking water, despite the watersheds being contaminated.
It would seem that no source of drinking water is entirely free of drugs. People who drink water from their own wells may not realize where the water comes from. It could come from a contaminated watershed, like one part of New York City's upstate watershed that tested positive for caffeine, often a marker of other drugs being present. One possible source of contamination for watersheds could be leaky septic tanks, according to one researcher interviewed by the AP team.
Bottled water and home filtration systems are also affected. According to the industry's main trade group, bottlers do not test or treat for pharmaceuticals (and some of these just repackage tap water said the AP).
Even aquifers, deep underground water systems that supply 40 per cent of the US water demand, are affected. The AP report mentions scientists examined aquifers located near landfill and other potential sources of contamination in in 24 states and found traces of hormones, antibiotics and other drugs.
As more and more people in the world take more and more drugs, and flush them, either unused or after metabolizing them, the concentrations entering the water system goes up. This problem is not confined to the US and the AP report cites evidence from other countries, including lakes in Switzerland and Canada. And it is not just human waste that puts drugs into the water system, but animal waste too, ranging from drugs used to treat domestic pets, to steroids used to treat cattle.
There is already evidence that drugs in the waterways is damaging wildlife, a prime example being male fish that are starting to create egg yolk proteins, a characteristic of female fish.
A large problem appears to be lack of funding to investigate the long term effects of trace amounts of pharmaceuticals, or the disproportionate way that limited funds are being used. The AP team interviewed Shane Snyder, research and development project manager at the Southern Nevada Water Authority, who said:
"I think it's a shame that so much money is going into monitoring to figure out if these things are out there, and so little is being spent on human health."
" It's time for the EPA to step up to the plate and make a statement about the need to study effects, both human and environmental," added Snyder.
Perhaps it is time, suggests the AP, for the focus that is currently maitained on regulated contaminants like pesticides, lead and PCBs, which are present in larger quantities and therefore pose a greater health risk, be extended to include medicines.
Drugs are a unique case because unlike other pollutants, they were designed to act on the human body. The AP team talked to a specialist who has studied trace hormones, heart medicine and other drugs, zoologist John Sumpter of Brunel University, London, who pointed out:
"These are chemicals that are designed to have very specific effects at very low concentrations. That's what pharmaceuticals do. So when they get out to the environment, it should not be a shock to people that they have effects."
It is true to say there is no clear evidence that trace amounts of drugs in the drinking supply are causing us harm, but this is because there have been no long term studies on the combined effects of so many drugs, albeit in trace amounts. Clinical trials of drugs concern themselves with a limited time period and use dosage amounts to test safety and side effects. They don't look at the lifetime effects of trace amounts of the drug, and certainly not in combination with a large number of others.
While the concentrations are so small they have to be measured in parts per billion or even parts per trillion, and water companies insist these levels are within safety limits, the AP said the long term effects on people's health of so many prescription drugs and over the counter medicines such as acetaminophen (paracetamol) and ibuprofen, even in tiny amounts, are starting to worry scientists.
Drugs and their derivatives get into the drinking water supply because when people on medication go to the toilet they excrete whatever the body does not absorb and any matabolized byproducts. Water companies treat the waste before discharging it into rivers, lakes and reservoirs, and then treat it again before it enters the drinking water system. However, the various treatments don't remove all traces of drugs.
For five months, the AP National Investigative Team visited treatment plants, interviewed over 200 scientists, officials and academics, analyzed federal databases and reviewed hundreds of scientific reports.
Among their enquiries the AP investigators came across research studies that have "gone virtually unnoticed by the general public" where scientists were alarmed at the effect of the drinking water contaminants on human cells and wildlife.
The investigators also found that water companies don't like to publish the results of drug screening tests because they think the public would not know how to interpret them and would become unduly alarmed. However, the US Environmental Protection Agency (EPA) assistant administrator for water, Benjamin H Grumbles told AP that:
"We recognize it is a growing concern and we're taking it very seriously."
The AP investigators discovered that drugs have been found in the drinking water of 24 major metropolitan areas across the country. Here are some of the key findings:
* Southern California: a portion of drinking water that supplies 18.5 million people contained traces of anti-epileptic and anti-anxiety drugs.
* Philadelphia: treated drinking water contained 56 drugs or byproducts, including pharmaceuticals for pain, infection, cholesterol control, heart conditions, asthma.
* San Francisco: a sex hormone was detected in the drinking water.
* Washington DC: six drugs were found in the drinking water supply of the capital and surrounding area.
* Tucson, Arizona: an antibiotic and two other medications were found in the drinking water.
* Northern New Jersey: drinking water for 850,000 residents was found to contain carbamazepine, a mood stabilizer, and a metabolized byproduct of angina medication. This was found by US Geological Survey researchers who analyzed a treatment plant.
The AP report paints a rather chaotic and inconsistent picture of what is happening nationwide, with some water companies testing for a vast range of pharmaceutical compounds and others only testing for two. This is not surprising, since the AP team found that the "federal government doesn't require any testing and hasn't set safety limits for drugs in water".
It is not just waste water that is contaminated. The AP report says that watersheds, the natural source of most of the country's drinking water, are also affected. The AP investigators said tests were carried out in the watersheds of 35 of the 62 major water utilities they surveyed and drugs were found in 28 of them. Six of the 28, when contacted by the AP, said they did not test their drinking water, despite the watersheds being contaminated.
It would seem that no source of drinking water is entirely free of drugs. People who drink water from their own wells may not realize where the water comes from. It could come from a contaminated watershed, like one part of New York City's upstate watershed that tested positive for caffeine, often a marker of other drugs being present. One possible source of contamination for watersheds could be leaky septic tanks, according to one researcher interviewed by the AP team.
Bottled water and home filtration systems are also affected. According to the industry's main trade group, bottlers do not test or treat for pharmaceuticals (and some of these just repackage tap water said the AP).
Even aquifers, deep underground water systems that supply 40 per cent of the US water demand, are affected. The AP report mentions scientists examined aquifers located near landfill and other potential sources of contamination in in 24 states and found traces of hormones, antibiotics and other drugs.
As more and more people in the world take more and more drugs, and flush them, either unused or after metabolizing them, the concentrations entering the water system goes up. This problem is not confined to the US and the AP report cites evidence from other countries, including lakes in Switzerland and Canada. And it is not just human waste that puts drugs into the water system, but animal waste too, ranging from drugs used to treat domestic pets, to steroids used to treat cattle.
There is already evidence that drugs in the waterways is damaging wildlife, a prime example being male fish that are starting to create egg yolk proteins, a characteristic of female fish.
A large problem appears to be lack of funding to investigate the long term effects of trace amounts of pharmaceuticals, or the disproportionate way that limited funds are being used. The AP team interviewed Shane Snyder, research and development project manager at the Southern Nevada Water Authority, who said:
"I think it's a shame that so much money is going into monitoring to figure out if these things are out there, and so little is being spent on human health."
" It's time for the EPA to step up to the plate and make a statement about the need to study effects, both human and environmental," added Snyder.
Perhaps it is time, suggests the AP, for the focus that is currently maitained on regulated contaminants like pesticides, lead and PCBs, which are present in larger quantities and therefore pose a greater health risk, be extended to include medicines.
Drugs are a unique case because unlike other pollutants, they were designed to act on the human body. The AP team talked to a specialist who has studied trace hormones, heart medicine and other drugs, zoologist John Sumpter of Brunel University, London, who pointed out:
"These are chemicals that are designed to have very specific effects at very low concentrations. That's what pharmaceuticals do. So when they get out to the environment, it should not be a shock to people that they have effects."
It is true to say there is no clear evidence that trace amounts of drugs in the drinking supply are causing us harm, but this is because there have been no long term studies on the combined effects of so many drugs, albeit in trace amounts. Clinical trials of drugs concern themselves with a limited time period and use dosage amounts to test safety and side effects. They don't look at the lifetime effects of trace amounts of the drug, and certainly not in combination with a large number of others.
FDA Approves First Gout Drug In 40 Years
The US Food and Drug Administration has given marketing approval to a new drug that lowers levels of uric acid in the blood of patients with gout: the current treatment for the condition was developed over 40 years ago. The new drug is called ULORIC (generic name febuxostat) and Takeda Pharmaceuticals North America is the sole developer and marketer of the product in the US.
According to a statement from Takeda, febuxostat is a new highly potent non-purine selective inhibitor of xanthine oxidase, and has a completely different structure from the currently used xanthine oxidase inhibitor, which was developed over 40 years ago. Xanthine oxidase is an enzyme involved in the production of uric acid.
Febuxostat lowers the concentration of uric acid in the blood of hyperuricemic patients with gout. The drug has been proved to be safe and effective in clinical trials, and the dose does not need to be adjusted for patients with mild-to-moderate renal or hepatic impairment (kidney or liver problems).
ULORIC will be available as 40 mg or 80 mg tablets to be taken once a day. It is not recommended for asymptomatic hyperuricemia, said the company's press release.
Febuxostat was discovered by another Japanese company, Teijin Pharma. Their president Osamu Nishikawa said in a press statement released jointly with Takeda that:
"This FDA approval granted to Takeda Pharmaceuticals North America, along with the EMEA (European Medicines Agency) approval given last year to Ipsen, our licensee for febuxostat in Europe, marks a significant milestone for our global business."
He said Teijin would be developing febuxostat themselves for the Asian market, as well as collaborating with other pharma companies. The company wishes to strengthen its global operations by "expanding areas where febuxostat is available and increase the presence of the product to be widely used by patients worldwide," he added.
President of the Takeda parent company in Japan, Yasuchika Hasegawa, said:
"The approval of ULORIC offers patients and healthcare providers in the US for the first time in 40 years, a novel treatment option for patients who have hyperuricemia with gout, where there are still unmet clinical needs."
Gout is a common, painful form of arthritis that causes swollen, red, hot and stiff joints. It occurs when uric acid builds up in the blood, because the body produces too much or can't get rid of it (some medications can slow down elimination), or from eating too many foods rich in purines, such as liver and dried beans.
Pseudogout is sometimes confused with gout because the symptoms are similar; however, it is caused by calcium phosphate, not uric acid.
According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), there could be as many as 6 million Americans aged 20 and older who have had gout at some time in their lives. It is more common in men aged 40 to 50, and women rarely develop it before the menopause. Also people who have had an organ transplant are more susceptible.
NIAMS suggest people may be at risk of developing hyperuricemia and gout if they are on certain medications, these include:
* Diuretics, such as furosemide (Lasix1), hydrochlorothiazide (Esidrix, Hydro-chlor), and metolazone (Diulo, Zaroxolyn).
* Drugs containing salicylate, such as aspirin.
* Niacin, a vitamin also known as nicotinic acid.
* Cyclosporine (Sandimmune, Neoral), a medication used to suppress the immune system.
* Levodopa (Larodopa), a drug used in the treatment of Parkinson's disease..
Other related articles
* What is Gout?
Takeda Pharmaceuticals North America, Inc, whose head office is in Deerfield, Illinois, is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited whose head office is in Chuo-ku, Osaka, Japan.
According to a statement from Takeda, febuxostat is a new highly potent non-purine selective inhibitor of xanthine oxidase, and has a completely different structure from the currently used xanthine oxidase inhibitor, which was developed over 40 years ago. Xanthine oxidase is an enzyme involved in the production of uric acid.
Febuxostat lowers the concentration of uric acid in the blood of hyperuricemic patients with gout. The drug has been proved to be safe and effective in clinical trials, and the dose does not need to be adjusted for patients with mild-to-moderate renal or hepatic impairment (kidney or liver problems).
ULORIC will be available as 40 mg or 80 mg tablets to be taken once a day. It is not recommended for asymptomatic hyperuricemia, said the company's press release.
Febuxostat was discovered by another Japanese company, Teijin Pharma. Their president Osamu Nishikawa said in a press statement released jointly with Takeda that:
"This FDA approval granted to Takeda Pharmaceuticals North America, along with the EMEA (European Medicines Agency) approval given last year to Ipsen, our licensee for febuxostat in Europe, marks a significant milestone for our global business."
He said Teijin would be developing febuxostat themselves for the Asian market, as well as collaborating with other pharma companies. The company wishes to strengthen its global operations by "expanding areas where febuxostat is available and increase the presence of the product to be widely used by patients worldwide," he added.
President of the Takeda parent company in Japan, Yasuchika Hasegawa, said:
"The approval of ULORIC offers patients and healthcare providers in the US for the first time in 40 years, a novel treatment option for patients who have hyperuricemia with gout, where there are still unmet clinical needs."
Gout is a common, painful form of arthritis that causes swollen, red, hot and stiff joints. It occurs when uric acid builds up in the blood, because the body produces too much or can't get rid of it (some medications can slow down elimination), or from eating too many foods rich in purines, such as liver and dried beans.
Pseudogout is sometimes confused with gout because the symptoms are similar; however, it is caused by calcium phosphate, not uric acid.
According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), there could be as many as 6 million Americans aged 20 and older who have had gout at some time in their lives. It is more common in men aged 40 to 50, and women rarely develop it before the menopause. Also people who have had an organ transplant are more susceptible.
NIAMS suggest people may be at risk of developing hyperuricemia and gout if they are on certain medications, these include:
* Diuretics, such as furosemide (Lasix1), hydrochlorothiazide (Esidrix, Hydro-chlor), and metolazone (Diulo, Zaroxolyn).
* Drugs containing salicylate, such as aspirin.
* Niacin, a vitamin also known as nicotinic acid.
* Cyclosporine (Sandimmune, Neoral), a medication used to suppress the immune system.
* Levodopa (Larodopa), a drug used in the treatment of Parkinson's disease..
Other related articles
* What is Gout?
Takeda Pharmaceuticals North America, Inc, whose head office is in Deerfield, Illinois, is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited whose head office is in Chuo-ku, Osaka, Japan.
Understanding Of Antidepressant Drugs Enhanced By New Mouse Model Of Depression/Anxiety
A recent study finds that the antidepressant effects of drugs like Prozac involve both neurogenesis-dependent and -independent mechanisms, a finding that may lead to development of better treatments for depression and anxiety. The research, published by Cell Press in the May 28th issue of the journal Neuron, utilizes a new experimental mouse model of depression/anxiety that is the first to permit simultaneous examination of multiple effects of antidepressant treatment in the same animal.
The specific molecular influences of selective serotonin reuptake inhibitors (SSRIs) and other types of antidepressants commonly prescribed for treatment of depression and anxiety disorders are not well understood. "Recently, compelling work in rodents has suggested that SSRIs may stimulate changes in a brain region called the hippocampus as well as other brain structures," says study author Dr. Denis J. David from the University of Paris-Sud. "For example, anxiety/depression-like changes in behavior have been linked with a decrease in cell proliferation in the hippocampus, a change that is reversed by antidepressants."
Dr. David, Dr. Rene Hen from Columbia University, and their colleagues created a mouse model of depressive and anxiety disorders to investigate mechanisms of antidepressant action. Previous research confirmed that long-term exposure to glucocorticoids induces anxiety and a depressive-like state in rodents and elevated glucocorticoid levels have been linked with depression and anxiety in humans. "We developed an anxiety/depression-like model based on elevation of glucocorticoid levels that offered an easy and reliable alternative to existing models," explains Dr. David.
Chronic antidepressant treatment reversed the behavioral dysfunctions and inhibition of hippocampal neurogenesis observed in the experimental mice. When hippocampal neurogenesis was prevented, the efficacy of Prozac was blocked in some but not all of the behavioral paradigms. The researchers went on to identify candidate genes whose expression was decreased in a brain region called the hypothalamus and normalized by Prozac. Mice deficient in one of these genes, -arrestin 2, displayed a reduced response to Prozac in multiple behavioral tasks, indicating that -arrestin signaling is necessary for the antidepressant effects of Prozac.
This finding suggests that both neurogenesis-dependent and -independent mechanisms underlie antidepressant actions. "The big unanswered question is whether future drugs that directly stimulate neurogenesis will be as effective as popular antidepressants or will only ameliorate cognitive deficits," says Dr. Hen. "To begin to answer this question we are using our paradigm to test a series of compounds that may stimulate neurogenesis more directly or compounds that directly target the hypothalamus. Ultimately, it is the success of these new compounds in the clinic that will establish the predictive value of the biomarkers we have identified in this report."
The researchers include Denis J. David, Univ Paris, Chatenay-Malabry, France; Benjamin Adam Samuels, Columbia University, New York, NY; Quentin Rainer, Univ Paris, Chatenay-Malabry, France; Jing-Wen Wang, Columbia University, New York, NY; Douglas Marsteller, Lundbeck Research USA, Paramus, NJ; Indira Mendez, Columbia University, New York, NY; Michael Drew, Columbia University, New York, NY; Douglas A. Craig, Lundbeck Research USA, Paramus, NJ; Bruno P. Guiard, Univ Paris, Chatenay-Malabry, France; Jean-Philippe Guilloux, Univ Paris, Chatenay-Malabry, France; Roman P. Artymyshyn, Lundbeck Research USA, Paramus, NJ; Alain M. Gardier, Univ Paris, Chatenay-Malabry, France; Christophe Gerald, Lundbeck Research USA, Paramus, NJ; Irina A. Antonijevic, Lundbeck Research USA, Paramus, NJ; E. David Leonardo, Columbia University, New York, NY; and Rene´ Hen, Columbia University, New York, NY.
The specific molecular influences of selective serotonin reuptake inhibitors (SSRIs) and other types of antidepressants commonly prescribed for treatment of depression and anxiety disorders are not well understood. "Recently, compelling work in rodents has suggested that SSRIs may stimulate changes in a brain region called the hippocampus as well as other brain structures," says study author Dr. Denis J. David from the University of Paris-Sud. "For example, anxiety/depression-like changes in behavior have been linked with a decrease in cell proliferation in the hippocampus, a change that is reversed by antidepressants."
Dr. David, Dr. Rene Hen from Columbia University, and their colleagues created a mouse model of depressive and anxiety disorders to investigate mechanisms of antidepressant action. Previous research confirmed that long-term exposure to glucocorticoids induces anxiety and a depressive-like state in rodents and elevated glucocorticoid levels have been linked with depression and anxiety in humans. "We developed an anxiety/depression-like model based on elevation of glucocorticoid levels that offered an easy and reliable alternative to existing models," explains Dr. David.
Chronic antidepressant treatment reversed the behavioral dysfunctions and inhibition of hippocampal neurogenesis observed in the experimental mice. When hippocampal neurogenesis was prevented, the efficacy of Prozac was blocked in some but not all of the behavioral paradigms. The researchers went on to identify candidate genes whose expression was decreased in a brain region called the hypothalamus and normalized by Prozac. Mice deficient in one of these genes, -arrestin 2, displayed a reduced response to Prozac in multiple behavioral tasks, indicating that -arrestin signaling is necessary for the antidepressant effects of Prozac.
This finding suggests that both neurogenesis-dependent and -independent mechanisms underlie antidepressant actions. "The big unanswered question is whether future drugs that directly stimulate neurogenesis will be as effective as popular antidepressants or will only ameliorate cognitive deficits," says Dr. Hen. "To begin to answer this question we are using our paradigm to test a series of compounds that may stimulate neurogenesis more directly or compounds that directly target the hypothalamus. Ultimately, it is the success of these new compounds in the clinic that will establish the predictive value of the biomarkers we have identified in this report."
The researchers include Denis J. David, Univ Paris, Chatenay-Malabry, France; Benjamin Adam Samuels, Columbia University, New York, NY; Quentin Rainer, Univ Paris, Chatenay-Malabry, France; Jing-Wen Wang, Columbia University, New York, NY; Douglas Marsteller, Lundbeck Research USA, Paramus, NJ; Indira Mendez, Columbia University, New York, NY; Michael Drew, Columbia University, New York, NY; Douglas A. Craig, Lundbeck Research USA, Paramus, NJ; Bruno P. Guiard, Univ Paris, Chatenay-Malabry, France; Jean-Philippe Guilloux, Univ Paris, Chatenay-Malabry, France; Roman P. Artymyshyn, Lundbeck Research USA, Paramus, NJ; Alain M. Gardier, Univ Paris, Chatenay-Malabry, France; Christophe Gerald, Lundbeck Research USA, Paramus, NJ; Irina A. Antonijevic, Lundbeck Research USA, Paramus, NJ; E. David Leonardo, Columbia University, New York, NY; and Rene´ Hen, Columbia University, New York, NY.