To reduce symptoms of mental illness and retrain the brain
Larry H. Bernstein, MD, FCAP, Curator
Leaders in Pharmaceutical Intelligence
Series E. 2; 5.11
Researchers have found that by specifically targeting a central signaling pathway in the brain, they can improve the innate behavioral response to stress in mice. Stress-induced behaviors in rodents reflect many of the symptoms that affect people suffering from major depression and other clinical conditions associated with stress. The findings, published July 20th online in the journalNature Neuroscience, suggest a new strategy for treating depression and other stress-associated disorders.
The study was led by James A. Bibb, Ph.D., at The University of Texas Southwestern Medical Center, who received NARSAD Young Investigator grants in 2000 and 2003, and lead authorFlorian Plattner, Ph.D. The scientific team also included Paul Greengard, Ph.D., a member of BBRF’s Scientific Council and a 1992, 2002, and 2008 Distinguished Investigator; Eric J. Nestler, M.D., Ph.D., a Scientific Council Member and a 1996 Distinguished Investigator; 2006 Young Investigator Kanehiro Hayashi, Ph.D.; 2007 Young Investigator Eunice Y. Yuen, Ph.D.; 1999 and 2004 Young Investigator Zhen Yan, Ph.D.; and 1999 Independent Investigator and 2006 Distinguished Investigator Angus C. Nairn, Ph.D.
The team’s findings are a result of a detailed investigation into a “signaling cascade,” called the cAMP/PKA pathway, which regulates a wide range of processes in the central nervous system. Disruption of the pathway has been linked with several mental disorders, including depression. Some existing antidepressant medications are known to boost cAMP signaling, but better understanding how this signaling network works could help researchers develop treatments that are more effective or cause fewer side effects.
Two new small-molecule compounds tested in mice can alleviate some symptoms of schizophrenia-like behaviors, including movement abnormalities, social avoidance, and cognitive performance. As reported in the July 1st issue of Neuropsychopharmacology, these research results may point the way toward new kinds of medications that treat specific aspects ofschizophrenia behaviors.
Current antipsychotic drugs used to treat the disorder target the dopamine D2 receptor, an important communication port for some neurons in the brain. These drugs are used primarily to treat schizophrenia “positive” symptoms such as delusions and hallucinations. They are less effective in treating “negative” symptoms such as a lack of pleasure in everyday life, or concentration and memory problems (“cognitive symptoms”), according to Duke University Medical Center scientists William C. Wetsel, Ph.D., a 1998 NARSAD Independent Investigator grantee, and Marc G. Caron, Ph.D., a Foundation Scientific Council member and 2005 NARSAD Distinguished Investigator grantee.
Current antipsychotic drugs were developed to bind to and block one specific type of communication pathway through dopamine D2 receptors, but the receptors are involved in more than one type of signaling pathway. Dr. Wetsel and colleagues decided to look for drug candidates that would block other pathways related to the dopamine D2 receptor, in the hope that this might reveal novel ways to treat a wider variety of schizophrenia symptoms.
They tested two dopamine D2 receptor-targeting compounds called UNC9975 and UNC9994 (developed by Jian Jin, Ph.D., of the University of North Carolina) that influence the beta-arrestin communication pathway, a different pathway than the one typically affected by antipsychotic drugs. The researchers showed that the compounds could normalize schizophrenia-like symptoms in mice by reducing their hyperactive movements, improving their memory for novel stimuli, and making them more social around other mice, among other improvements.
The new compounds also produced a much lower level of catalepsy—the rigid muscle, “trance-like” state that is sometimes a side effect of schizophrenic treatment—than traditional antipsychotic drugs such as haloperidol. Targeting different pathways connected to the dopamine D2 receptors, the researchers say, may increase the possibilities for treating people with schizophrenia in more individualized, fine-tuned ways that match their exact symptoms and vulnerabilities to side effects.
Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice
Su M Park1, Meng Chen1, Claire M Schmerberg1, Russell S Dulman1, Ramona M Rodriguiz1,2, Marc G Caron3, Jian Jin4 and William C Wetsel1,2,3,5
Neuropsychopharmacology 2015; http://dx.doi.org:/10.1038/npp.2015.196
Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. Whereas all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit Gi/o-mediated adenylyl cyclase, a recent study has shown that many APDs affect not only Gi/o– but they can also influence β-arrestin- (βArr)-mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated Gi/o protein signaling, but are simultaneously partial agonists for D2R/βArr interactions. The purpose of this study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia-like behaviors in phencyclidine-treated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available.
The estrogen-related drug raloxifene can improve attention and memory in men and women with schizophrenia, according to a new study published in the journal Molecular Psychiatry.
University of New South Wales researcher Cynthia S. Weickert, Ph.D., a 1999 and 2001 NARSAD Young Investigator and 2004 Independent Investigator grantee, and her colleagues say their raloxifene findings could help improve some cognitive problems related to schizophrenia that have been the most difficult to treat with drugs. Dr. Weickert’s research team included NARSAD Young Investigator grantees Rhoshel K. Lenroot, M.D., (2003), and Ans Vercammen, Ph.D., (2010), along with Independent Investigator grantee Jayashri Kulkarni, Ph.D., (2000), and her husband and first author Tom Weickert, Ph.D.
A growing body of evidence suggests that estrogen plays a beneficial role in the brain, supporting growth and protecting neurons from damage. From work supported by her NARSAD Young Investigator awards, Dr. Weickert and her colleagues found that brain estrogen receptors are altered in some people with schizophrenia, blunting their ability to respond to estrogen’s beneficial effects. Raloxifene stimulates estrogen receptors and can help overcome a blunted estrogen response. Raloxifene is probably best known as a treatment for osteoporosis in women, where it mimics estrogen’s beneficial action in bones. The drug also stimulates estrogen receptors in the brain and may guard against memory loss in aging, making it potentially useful for cognitive problems in schizophrenia patients.
The research team examined the drug’s effect in 98 people diagnosed with schizophrenia or schizoaffective disorder (which combines symptoms of schizophrenia and depression). All of the patients received a daily dose of raloxifene along with their usual antipsychotic medications in one phase of the clinical trial and a placebo in another phase.
After the first six-week period, patients taking raloxifene had improved scores on memory and attention, compared to those taking placebo. When considering all the people in the study during both phases, raloxifene treatment significantly improved attention and thought processing speed. Raloxifene didn’t reduce the severity of schizophrenia symptoms more than the placebo did, but both groups showed less symptoms overall during the study, and none of the patients had severe side effects from the treatment.
Dr. Weickert and colleagues did detect some signs that the positive impact of raloxifene lasted more than one month after the treatment stopped. Although the researchers do not know the exact reasons for the lasting effects, they note that stimulating estrogen receptors might protect neurons, reduce inflammation, and increase connections between nerve cells in the brain over a longer time frame than drugs working on other neurotransmitter receptors. In light of their findings, they suggest future studies should replicate these results in a larger group of schizophrenia patients and also determine how long the cognitive benefits of a six-week treatment with raloxifene may last.
An injectable antipsychotic medication whose effects last for three months has successfully delayed the return of schizophrenia symptoms, researchers have found. Taking the drug in this form may help people with schizophrenia who struggle to stay on treatment by enabling them to take medication less frequently.
The research team, which included Adam J. Savitz, M.D., Ph.D., recipient of a NARSAD Young Investigator Grant in 2001, examined use of the long-acting antipsychotic medication paliperidone palmitate (Invega) in treating symptoms of schizophrenia such as hallucinations, delusions, and strong feelings of suspicion. The research was published online March 29th inJAMA Psychiatry.
When a person with schizophrenia cannot maintain a daily medication schedule, the drug level in his or her body can dip too low to combat symptoms, leading to relapse (return of symptoms) and an increased risk of being hospitalized. This study aimed to determine whether a dosage that would only have to be taken once every three months, rather than every day, would effectively hold off symptoms. After starting with a once-monthly dosage, patients took a three-month dosage to maintain symptom prevention and then were given randomly either placebo or the same three-month dosage every 12 weeks to see whether the medication’s positive effects would persist. (A placebo is a look-alike with inactive ingredients.)
Significantly fewer people who got the second three-month dosage experienced symptom relapse during the experimental phase of the study, compared to those taking a placebo. During this phase, the placebo group also reported more severe symptoms, while the paliperidone palmitate group’s symptoms remained constant.
The two groups also showed different patterns of side effects. The more serious side effects occurred in the placebo group: anxiety and return of other symptoms of schizophrenia. The paliperidone palmitate group more frequently experienced headaches, weight gain, common colds, as well as so-called extrapyramidal symptoms, which involve disruptions to movement.
This study did not include people with a history of substance dependence, major active medical problems, or other serious mental disorders. More research is needed to know whether less frequent dosage of long-acting injectable medication like paliperidone palmitate can help prevent relapse in these groups.
Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia – A Randomized Clinical Trial
Joris Berwaerts, MD1; Yanning Liu, MS2; Srihari Gopal, MD, MHS1; Isaac Nuamah, PhD1; Haiyan Xu, PhD1; Adam Savitz, MD, PhD1; Danielle Coppola, MD1; Alain Schotte, PhD3; Bart Remmerie, Chem Eng3; Nataliya Maruta, MD, PhD4; David W. Hough, MD1
JAMA Psychiatry. 2015; 72(8):830-839. http://dx.doi.org:/10.1001/jamapsychiatry.2015.0241.
Design, Setting, and Participants This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase.
Interventions Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase.
Main Outcomes and Measures Time from randomization to the first relapse event (time to relapse) in the DB phase.
Results In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%).
Conclusions and Relevance Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations.
Trial Registration clinicaltrials.gov Identifier:NCT01529515
Tracking Down the Causes of Alzheimer’s
University of Basel
http://www.biosciencetechnology.com/news/2015/09/tracking-down-causes-alzheimers?et_cid=4792750&et_rid=535648082&location=top
Researchers from the University of Basel were able to show that memory function (image shows the hippocampus highlighted) depends on calcium-regulating genes. (Source: MCN University of Basel
http://www.biosciencetechnology.com/sites/biosciencetechnology.com/files/bt1509_basel_brain.jpg
Genes are not only important for regular memory performance, but also for the development of Alzheimer’s disease. Researchers at the University of Basel now identified a specific group of genes that plays a central role in both processes. This group of molecules controls the concentration of calcium ions inside the cell. Their results appear in the current issue of the journal JAMA Psychiatry.
Intact memory capacity is crucial for everyday life. This fact becomes apparent once a memory disorder has developed. Alzheimer’s disease is the most common cause of age-associated memory disorders. Due to increasing life expectancy, the disease is on the rise in Switzerland and worldwide. Unfortunately, there is no effective treatment to cure or even slow down Alzheimer’s yet. Thus, understanding the origins of this neurodegenerative disorder is key to the development of much needed treatments.
Scientists have known for some years now, that genes do not only play a crucial role in normal memory performance, but also in the development of Alzheimer’s. However, it was so far unclear if specific genes are involved in both these processes.
Researchers at the transfaculty research platform at the Psychiatric University Clinics Basel and the Faculty of Psychology at the University of Basel were now able to show in a large scale study that a specific group of genes controls several processes that are central for regular brain functions as well as for the development of Alzheimer. First author Dr. Angela Heck collected and analyzed data of over 57,000 participants for this study.
Calcium is crucial
The study identified genes responsible for the concentration of calcium ions in the cell as central players of physiological and disease processes in the brain. Calcium genes stand in mutual relationship with memory performance of young and older healthy adults as well as with the function of the hippocampus, a brain region that is central to intact memory. Furthermore, calcium genes correlate with the risk for Alzheimer disease. The results contribute to the understanding of the complex processes that lead to memory disorders, such as Alzheimer’s.
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