We work to improve the quality of life for those affected by schizophrenia and psychosis through education, support programs, influencing public policy, and encouraging research.
Showing posts with label antipsychotic medication. Show all posts
Showing posts with label antipsychotic medication. Show all posts
Sanford-Burnham study suggests that many antipsychotics affect metabolism because they activate the TGFbeta pathway -- a finding that could lead to safer therapeutics for bipolar disorder and schizophrenia patients
LA JOLLA, Calif. -- In 2008, roughly 14.3 million Americans were taking antipsychotics — typically prescribed for bipolar disorder, schizophrenia, or a number of other behavioral disorders — making them among the most prescribed drugs in the U.S. Almost all of these medications are known to cause the metabolic side effects of obesity and diabetes, leaving patients with a difficult choice between improving their mental health and damaging their physical health. In a paper published January 31 in the journal Molecular Psychiatry, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) reveal how antipsychotic drugs interfere with normal metabolism by activating a protein called SMAD3, an important part of the transforming growth factor beta (TGFbeta) pathway.
The TGFbeta pathway is a cellular mechanism that regulates many biological processes, including cell growth, inflammation, and insulin signaling. In this study, all antipsychotics that cause metabolic side effects activated SMAD3, while antipsychotics free from these side effects did not. What's more, SMAD3 activation by antipsychotics was completely independent from their neurological effects, raising the possibility that antipsychotics could be designed that retain beneficial therapeutic effects in the brain, but lack the negative metabolic side effects.
"We now believe that many antipsychotics cause obesity and diabetes because they trigger the TGFbeta pathway. Of all the drugs we tested, the only two that didn't activate the pathway were the ones that are known not to cause metabolic side effects," said Fred Levine, M.D., Ph.D. [pictured], director of the Sanford Children's Health Research Center at Sanford-Burnham and senior author of the study.
In a previous study aimed at developing new insights into diabetes, Dr. Levine and his team used Sanford-Burnham's high-throughput screening capabilities to search a collection of known drugs for those that alter the body's ability to generate insulin, the pancreatic hormone that helps regulate glucose. That's when they first noticed that many antipsychotics alter the activity of the insulin gene. In this current study, the researchers set out to connect the dots between antipsychotics and insulin. In doing so, experiments in laboratory cell-lines showed that antipsychotics known to cause metabolic side effects also activated the TGFbeta pathway—a mechanism that controls many cellular functions, including the production of insulin—while the drugs without these side effects did not.
Wondering whether their initial laboratory observations were relevant to the human experience, the researchers reanalyzed previously published gene expression patterns in brain tissue from schizophrenic patients treated with antipsychotics. What they found supported their earlier findings—TGFbeta signaling was activated only in those patients receiving antipsychotic treatment. Looking further, they found that the extent to which each antipsychotic drug activated the TGFbeta pathway in human brains correlated very closely with the extent to which those same drugs activated SMAD3 and affected the insulin promoter in their cell culture experiments.
The TGFbeta pathway also plays an important role in metabolic disease in people who don't take antipsychotic medications. "It's known that people who have elevated TGFbeta levels are more prone to diabetes. So having a dysregulated TGFbeta pathway—whether caused by antipsychotics or through some other mechanism—is clearly a very bad thing," said Dr. Levine. "The fact that antipsychotics activate this pathway should be a big concern to pharmaceutical companies. We hope this new information will lead to the development of improved drugs."
###
This study was funded by a gift from Mr. T. Denny Sanford to the Sanford Children's Health Research Center at Sanford-Burnham. Co-authors include Thomas Cohen, Sanford-Burnham and University of California, San Diego; S. Sundaresh, NextBio; and Fred Levine, Sanford-Burnham.
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham is a highly innovative organization, currently ranking second nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded, according to government statistics.
Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), Santa Barbara, and Orlando (Lake Nona). For more information, please visit our website (http://www.sanfordburnham.org) or blog (http://beaker.sanfordburnham.org). You can also receive updates by following us on Facebook and Twitter.
Contact
Heather Buschman, Ph.D.
hbuschman@sanfordburnham.org
858-795-5343
Sanford-Burnham Medical Research Institute
Karen Ellet [pictured] says she still misses Howard Hyde’s amazing voice.
“I miss his voice, his beautiful singing voice," the Dartmouth woman said Thursday.
Ellet, who was Hyde’s common- law wife, said she has been dealing with her grief since he died on Nov. 22, 2007, after a violent conflict with jail guards at the Central Nova Scotia Correctional Facility in Dartmouth.
But she is taking comfort in the recommendations resulting from the provincial inquiry into his death.
If the suggestions outlined in a report released Wednesday are adopted, they will make a huge difference in the way mentally ill people in crisis are dealt with, Ellet said.
“I am very pleased. She is a very compassionate judge," she said of Anne Derrick, the provincial court judge who helmed the 11-month fatality inquiry.
She said Hyde would be pleased with Derrick’s report, too.
“He would be ecstatic about it," Ellet said. “He would like to see (the recommendations) implemented, so the (report) is not sitting on a library shelf."
In her report, Derrick rejected a medical examiner’s conclusion that Hyde died of excited delirium and found instead that the struggle with the jail guards played a role in his death.
Hyde, a 45-year-old musician who was diagnosed with schizophrenia in his 20s, was having a psychotic episode at the jail when he was forced to lie on his stomach with his hands behind his back. The restraint technique may have interfered with his ability to breathe, Derrick found.
“He did not die because he was mentally ill," she wrote in her report.
Ellet said she still has difficulty thinking of the emotional and physical pain that Hyde endured in the last 30 hours of his life.
On the night of Nov. 21, 2007, Ellet called a crisis hotline to complain that Hyde had assaulted her while in a psychotic state.
Police arrested Hyde, but not before Ellet told them her husband had not been taking his medication and needed psychiatric help.
“Howard didn’t understand why he was in jail," she said. “He couldn’t comprehend his surroundings."
Ellet said she has been keeping a low profile due to her grief, but she believes it is important for her to speak up about the changes she thinks Hyde would have wanted to see in the justice system and in society at large.
“I believe he would want to have a professional such as a mental health provider to be with people who have a mental illness when they are in crisis, to speak on behalf of them," she said.
Ellet said Hyde would want all professionals to be issued handbooks so they could learn more about the signs and symptoms of mental illness and how to handle somebody who is having a psychotic episode. “Howard would want more housing available (for mentally ill people)," she said. “Howard found it horrific to know that people with mental illness are living in shelters and on the streets. It really upset him. He wished he could have done something but he didn’t know what to do."
Ellet said Hyde also would have wanted more research into the development of psychiatric drugs.
“Not all medications agree with each particular person," she said. “There are so many sideeffects."
More mental health funding and clubhouses, support groups and associations in support of the mentally ill would also be on Hyde’s list, Ellet said.
“I believe there is a large amount of fundraising that can make miracles happen to help (prevent) people with mental challenges from living on the streets," she said.
“Mental illness is no different from somebody walking around with diabetes."
Some of Derrick’s recommendations concern stun guns — she said they should not be used on people in a state of agitation due to a psychological disturbance, and changes should be made in the training for how to use them.
The judge also recommended that crisis intervention training be provided to all correctional officers at the Dartmouth jail and that several aspects of training in general be improved for jail guards in the province and for front-line police officers and doctors.
Ellet said it is poignant that the report on Hyde’s death came out on the 30th anniversary of the murder of John Lennon.
Hyde, who sang and played the saxophone, was also an extraordinary musician, she said.
“Howard had the musical ability to play anything," she said. “He had the most astounding voice you can imagine."
Also like Lennon, Hyde despised war. “He just wanted peace in the world," Ellet said.
Reviewed by John M. Grohol, Psy.D., on November 1, 2010
The U.S. Food and Drug Administration has approved Latuda (lurasidone HCl) tablets for the treatment of adults with schizophrenia.
“Schizophrenia can be a devastating illness requiring lifelong treatment,” said Thomas Laughren, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research.
“Some patients do not respond well to certain types of drug therapy, so it is important to have multiple treatment options available.”
Latuda is included in the atypical antipsychotic class of drugs. All atypical antipsychotics contain a boxed warning alerting prescribers to an increased risk of death associated with off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis.
No drug in this class is approved to treat patients with dementia-related psychosis.
Four six-week controlled studies of adults with schizophrenia demonstrated the effectiveness and safety of Latuda. In the trials, patients treated with Latuda had fewer symptoms of schizophrenia than those taking an inactive pill (placebo).
The most common adverse reactions reported by those in clinical trials were drowsiness, feelings of restlessness and the urge to move (akathisia), nausea, movement abnormalities such as tremors, slow movement, or muscle stiffness (Parkinsonism), and agitation.
Pictured left to right are Dr. Gary Hasey, Department of Psychiatry and Behavioural Neurosciences; Professor James Reilly and Ph.D. student Ahmad Khodayari‑Rostamabad, Department of Electrical and Computer Engineering; Prof. Hubert de Bruin, McMaster School of Biomedical Engineering. Missing: Dr. Duncan MacCrimmon, Department of Psychiatry and Behavioural Neurosciences.
A commonplace electroencephalography (EEG) test may hold the key to predicting whether a person will respond to certain prescribed drugs, particularly those related to psychiatric conditions.
In a study to be published by Clinical Neurophysiology, and now posted online, engineering and health sciences researchers at McMaster University applied machine learning to EEG patterns and successfully predicted how patients with schizophrenia would respond to clozapine therapy.
Clozapine is recognized as an effective treatment for chronic medication-resistant schizophrenia but can produce serious side effects such as seizures, cardiac arrhythmias or bone marrow suppression. Some patients can develop blood problems that are life-threatening. Weekly to monthly blood sampling is required.
"Some people can suffer terrible side effects from clozapine," said Dr. Gary Hasey, associate professor at McMaster and director of the Transcranial Magnetic Stimulation laboratory at St. Joseph's Healthcare Mood Disorders Clinic in Hamilton. "The logistic difficulties for the patient and treatment team are also substantial. A method to reliably determine, before the onset of therapy, whether a patient will or will not respond to clozapine would greatly assist the clinician in determining whether the risks and logistic complexity of clozapine are outweighed by the potential benefits."
To conduct the study, EEGs were taken from 23 patients diagnosed with medication-resistant schizophrenia before they began taking clozapine. Twelve were men and 11 were women, all of middle age. The brainwave patterns and response to the clozapine therapy of these patients were used to "train" a computer algorithm to predict whether or not a specific patient will respond to the drug. The prediction accuracy was approximately 89 per cent. This algorithm showed similar predictive accuracy when it was further tested in a new group of 14 additional patients treated with clozapine.
This innovative work grows out of the close collaborative relationship between members of the Department of Electrical and Computer Engineering (Prof. James Reilly, Ph.D. student Ahmad Khodayari-Rostamabad), the School of Biomedical Engineering (Prof. Hubert de Bruin), and the Department of Psychiatry and Behavioural Neurosciences (Drs. Gary Hasey and Duncan MacCrimmon).
"The computational power available today supports new machine learning methodologies that can help doctors better diagnose and treat illness and disease," said Prof. Reilly. "Large amounts of data can be processed very quickly to identify patterns or predict outcomes. We're looking forward to applying the findings to other areas."
EEG records the brain's electrical activity close to the scalp. Traditionally, it has been used to monitor for epilepsy, and to diagnose coma, encephalopathies, and brain death. EEG is still often used as a first-line method to diagnose tumors, stroke and other focal brain disorders.
"EEG is an inexpensive, non-invasive technique widely available in smaller hospitals and in community laboratories," explains Dr. MacCrimmon. "Also, EEG readings take only 20 to 30 minutes of a patient's time, with no preparation required, so pose minimal inconvenience."
Funding for the research was provided in part by The Magstim Company Ltd., a developer and manufacturer of medical and research devices for the neurological and surgical fields. The company is based in Wales, U.K.
The researchers now plan to test their findings on a larger sample group. They have successfully demonstrated the application of machine learning methods for analyzing EEG signals to predict the response to various treatments available for patients with other psychiatric conditions, specifically major depression. They have also demonstrated the effectiveness of machine learning methods as a diagnostic tool for distinguishing various forms of psychiatric illness. It may also be possible to incorporate a range of other clinical and laboratory data such as personality inventory scores, personal and demographic information and treatment history to improve performance.
.jpg)