VAI Finding Leads To New Drugs For Anxiety, Depression

Researchers in the Laboratory of Structural Sciences at Van Andel Institute (VAI) have determined how the hormone corticotrophin releasing factor (CRF) precisely binds to its receptor. This detailed structural information can help drug developers design new drugs for anxiety, depression, and related disorders.
"There are a few drugs in development to treat anxiety, depression, and other conditions by targeting the cellular receptor that CRF binds to, but there are no drugs currently on the market," said VAI Distinguished Scientific Investigator Eric Xu, Ph.D., who published his laboratory's findings in The Journal of Biological Chemistry. "There is a lot of interest in this receptor as a drug target, and we are the first to determine the structural details necessary to develop an ideal drug."
CRF is a hormone and neurotransmitter secreted by the hypothalamus area of the brain and is involved in stress response. CRF has been associated with anxiety, depression, and related disorders. The hormone's receptor is a protein on the surface of a cell or in its interior that binds to the hormone, which allows the hormone to activate changes in the cell.
Using a technique known as X-ray crystallography, VAI researchers determined the molecular structure of the part of the CRF receptor that sticks outside of the cell and binds to CRF and other proteins in the same family. This detailed structural information can help drug developers engineer a drug that more perfectly fits to the receptor, making the drug more potent. Researchers determined the structure of the receptor in three different scenarios -- one with nothing bound to the receptor, one with CRF bound to the receptor, and one that shows how the receptor binds to other proteins in the same family.
To determine the structure, researchers had to crystallize the hormone and receptor in these different scenarios, a process similar to letting salty water evaporate to form salt crystals but much more difficult. The lab used a unique method to do this that they recently developed to determine the structure of the parathyroid hormone (PTH) receptor, used to treat osteoporosis. PTH and CRF receptors are in the same family of proteins.
"There are many therapeutically important receptors in the same family as CRF and PTH," said Xu, "and there is a good chance we may be able to apply our crystallizing method to even more members of this family going forward."
Established by Jay and Betty Van Andel in 1996, Van Andel Institute is an independent research organization dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process.

New Therapies Show Promise For Vascular Depression

Researchers see new treatments on the horizon for a type of depression related to blood vessels that affects the elderly, and have discovered why some elderly people fail to respond to current medications. In other studies, scientists urge caution regarding use of antipsychotics (usually for schizophrenia or other psychosis) in this and other populations to minimize metabolic, heart, and stroke risks.
The scientists spoke today at a press conference involving speakers from two symposia sponsored by National Institute of Mental Health (NIMH), a part of the National Institutes of Health, during the American Psychiatric Association Annual Meeting here.
"Mental health practitioners and patients should be aware of the relationship between vascular problems and depression, and should understand the value of preventing vascular changes that might lead to difficult-to-treat depressions, for example through early recognition and treatment of high blood pressure" says John Newcomer, MD, of Washington University in St. Louis.
Drugs Show Promise for Vascular Depression
New treatment possibilities are being explored for vascular depression, a recently recognized type of depression that usually develops in patients older than age 60 and is associated with loss of blood supply to the brain. This condition is a serious problem for elderly patients and highly effective treatments have yet to be developed, but several research teams now report progress in understanding and treating this condition.
George Alexopoulos, MD* of the Weill Cornell Medical College in White Plains, NY, and his colleagues, are investigating the specific brain abnormalities linked to blood vessel problems. Using a new magnetic resonance imaging technique called diffusion tensor imaging, Alexopoulos and his team have found that, in late life depression, higher blood pressure readings are linked to tiny white matter abnormalities, mainly in the brain’s frontal lobes and in subcortical areas. Some of these structural abnormalities were linked to impairment in specific frontal lobe functions.
The researchers are also studying the brain abnormalities preventing depressed older patients from responding to antidepressant medication. In a study of 112 elderly patients with major depression treated with the antidepressant citalopram, they found that patients were less likely to recover from their depression if they had cardiovascular disease or performed poorly on a ‘response inhibition’ task testing an aspect of cognition requiring frontal lobe function. This timed task asks a person to suppress the reading of a word (e.g., the word red) and identify the color of ink by which the word is written (e.g., blue). In a subsequent study of 48 depressed older patients treated with the antidepressant escitalopram, which is more potent than citalopram, Alexopoulos and his colleagues showed, for the first time, that patients who failed to achieve remission had more of the tiny structural abnormalities in several areas of frontal lobe and in subcortical structures compared with those who got well.
"With further refinement, the findings may improve physicians’ ability to predict who will fail to respond to antidepressants," Alexopoulos says. "Such patients may need close follow-up and different treatments such as psychotherapy or novel medications. Second, our findings can be used in the development of new treatments for those who do not respond to classical antidepressants."
Alexopoulos is now working to pinpoint activation and processing abnormalities in frontal and subcortical brain structures that predict failure to respond to antidepressants. He is studying how parts of the frontal lobe are activated when depressed patients perform cognitive tasks known to engage this area. "Preliminary findings show that depressed older patients cannot activate these frontal lobe parts as efficiently as non-depressed older adults," Alexopoulos, says.
Stimulation Therapy Tested for Vascular Depression
In other treatment strategies, Robert Robinson, MD, a professor of psychiatry at the University of Iowa, and his colleagues have found for the first time that vascular depression can be effectively treated with repetitive transcranial magnetic stimulation (rTMS), an experimental technique that also has been tested in other psychiatric disorders.
Among 92 depressed people with an average of three prior treatment failures, the researchers found that rTMS produced better remission rates than those associated with standard medication treatment. They also found that increasing the number of magnetic pulses delivered significantly improved remission rates. "These findings suggest that this new method of treatment may be particularly useful for these late life onset depressions and that even greater response rates might be achieved by utilizing more pulses of magnetic stimulation," Robinson says. The findings of this study were published in the March 2008 issue of the Archives of General Psychiatry.
The study participants had clinical or imaging evidence indicating lack of blood flow in the brain, and had failed to respond to standard treatments for depression. They were given either 12,000 or 18,000 pulses of rTMS or a sham (inactive) treatment over a two-week period. Neither the patient nor the examiner knew if the treatment was actual rTMS or sham, thus removing any possible bias. Improvement of depression was documented by scores on the Hamilton Depression Scale. The next step in this research is to determine precisely how many magnetic stimulations will achieve the maximum response among patients with vascular depression.

Recognizing the dangers of anti-depressant drugs

According to the FDA several recent scientific publications suggest the possibility of an increased risk of suicidal behavior for people who are being treated with antidepressant medications. This concern lead the FDA to mandate black box warning labels on all antidepressant drugs disclosing the increased risks of suicidal thinking and behavior, known as suicidality. It has now very important to begin recognizing the dangers of anti-depressant drugs.
The purpose of SSRI drugs is to prevent serotonin from being reabsorbed. Serotonin, also known as the “happy drug”, is thought to be contrived of chemicals that our body creates to keep our spirits up. One of the major problems with the use of SSRI drugs is that they can result in serotonin syndrome. This syndrome is caused by over stimulation of the neurons associated with serotonin, which can lead to changes in mental status, restlessness, abnormal body movement, tremors, high fevers, and agitation which may lead to suicide.
SSRI drugs have gone through tedious testing under the care of the Food and Drug Administration (FDA); however, the testing of new drugs is not done by the FDA, it is actually the pharmaceutical company that supports, funds, and carries out the drugs testing. The FDA relies on the pharmaceutical company's validity of research, which then results in an approval by the FDA.
Recognizing the dangers of anti-depressant drugs can be important for those taking such medications. Some side effects can include, nausea, constipation or diarrhea, heart palpitations, loss of appetite, loss or gain of weight, memory impairment, blurred vision, headaches, confusion, burning and tingling in extremities, muscle twitching, dry mouth, dizzy, chills, fatigue, mood swings, anxiety, sexual dysfunction, impulsive behaviors, suicidal thoughts and completed suicide.
There is much debate on the placebo effect and antidepressants. Through a Freedom of Information Act request, two psychologists obtained 47 studies used by the FDA for approval of the six antidepressants prescribed most widely. Overall, antidepressant pills worked only 18% better than placebos.
It is important that people considering a medication approach to treating symptoms of depression to do research before deciding to take a certain medication and recognizing the dangers of anti-depressant drugs. Patients should have a list of questions to ask their doctors before agreeing to medications. More and more people are recognizing alternative treatments for mild to moderate depression can be helpful and do not carry high risk factors or side effects.
SSRI’s can be good for some people. Many have reported “gaining their lives back again” after being on SSRI’s such as Celexa, Lexapro, Paxil, Prozac and Zoloft. What is important to remember is people considering a medical approach to their depression should pay attention to the dangers of anti-depressant drugs.

Studying Antidepressant Use Among Children, Adolescents With Mental Illness

Are antidepressants effective as treatments for mentally ill children and adolescents? Are they harmful? These questions have been the topic of immense public debate and are of considerable public health importance.
To learn more about the role of antidepressants in the treatment of children and adolescents living with mental illnesses, the Child and Adolescent Psychiatry Trials Network (CAPTN) is launching the first independently funded large-scale safety registry to track antidepressant use among youth.
The goal of the Antidepressant Safety in Kids (ASK) study is to determine factors that may help doctors better understand the risks and benefits associated with using antidepressant medications as part of a young person’s treatment plan. It will seek to answer, "Which treatment is most effective for which child?"
"It is of considerable public health importance that we address the long-term safety and effectiveness of medications used in the care of mentally ill youth. This work marks an important step toward understanding the usefulness of antidepressant medications in children and adolescents," said John March, M.D., chief of child and adolescent psychiatry at Duke University and lead investigator on CAPTN. "My hope is to repeat the success of networks established for other common illnesses, such as heart disease and cancer, to determine the effect of psychotropic medications on patient outcomes."
Funded through a grant from the National Institute of Mental Health to the Duke Clinical Research Institute in cooperation with the American Academy of Child and Adolescent Psychiatry (AACAP), CAPTN is an innovative practical clinical trials network of 200 practicing child and adolescent psychiatrists throughout the United States and Canada.
The first study to be conducted under the CAPTN umbrella is ASK, a prospective longitudinal cohort study of 2,420 children and adolescents with a depressive disorder, anxiety disorder, obsessive-compulsive disorder or eating disorder. The study participants will be prescribed either a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). While these two classes of medications are widely used among adults and prescribed to approximately two to three percent of American children, questions have arisen about potential adverse events, especially suicidal events, associated with use of these medications. Through ASK, information will be collected about the safety, tolerability, effectiveness and potential benefits of these medications.