Scientists have discovered how the toxoplasmosis parasite may trigger the development of schizophrenia and other bipolar disorders.

The team from the University of Leeds’ Faculty of Biological Sciences has shown that the parasite may play a role in the development of these disorders by affecting the production of dopamine - the chemical that relays messages in the brain controlling aspects of movement, cognition and behaviour.

Toxoplasmosis, which is transmitted via cat faeces (found on unwashed vegetables) and raw or undercooked infected meat, is relatively common, with 10-20% of the UK population and 22% of the US population estimated to carry the parasite as cysts. Most people with the parasite are healthy, but for those who are immune-suppressed - and particularly for pregnant women - there are significant health risks that can occasionally be fatal.

Dr Glenn McConkey, lead researcher on the project, says: “Toxoplasmosis changes some of the chemical messages in the brain, and these changes can have an enormous effect on behaviour. Studies have shown there is a direct statistical link between incidences of schizophrenia and toxoplasmosis infection and our study is the first step in discovering why there is this link.”

The parasite infects the brain by forming a cyst within its cells and produces an enzyme called tyrosine hydroxylase, which is needed to make dopamine. Dopamine’s role in mood, sociability, attention, motivation and sleep patterns are well documented and schizophrenia has long been associated with dopamine, which is the target of all schizophrenia drugs on the market.

The team has recently received $250,000 (£160,000) to progress its research from the US-based Stanley Medical Research Institute, which focuses on mental health conditions and has a particular emphasis on bipolar illnesses.

Dr McConkey says: “It’s highly unlikely that we will find one definitive trigger for schizophrenia as there are many factors involved, but our studies will provide a clue to how toxoplasmosis infection - which is more common than you might think can impact on the development of the condition in some individuals.

“In addition, the ability of the parasite to make dopamine implies a potential link with other neurological conditions such as Parkinson’s Disease, Tourette’s syndrome and attention deficit disorders, says Dr McConkey. “We’d like to extend our research to look at this possibility more closely.”

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Cephalon, Inc. (Nasdaq: CEPH) announced positive results from a phase two clinical trial of NUVIGIL(R) (armodafinil) Tablets [C-IV] as adjunctive therapy for treating major depressive disorder in adults with bipolar I disorder. An estimated two million American adults are affected by bipolar I disorder, which is characterized by fluctuations between extreme highs (manic) and lows (depressed) in mood. People with bipolar disorders cycle between periods of manic or depressive mood and typically spend more time in the depressed phase of the illness.

The eight-week, double-blind, placebo-controlled study evaluated the efficacy and safety of NUVIGIL (150 mg/day) as an adjunctive therapy to mood stabilizers in 257 patients with bipolar I disorder, who experienced a major depressive episode that was not completely managed by their other treatments. Patients in the study taking NUVIGIL as adjunctive therapy showed improvement of depressive symptoms (p=0.042) as measured on the primary endpoint - the 30-Item Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C30) scale. The IDS-C30 scale is an instrument used to evaluate depressive episodes and associated symptoms. The results of this study will be presented at an upcoming medical meeting.

“We are encouraged that the results of this study point toward the potential utility of NUVIGIL in managing the depressive episodes in bipolar I disorder,” said Dr. Lesley Russell, Executive Vice President and Chief Medical Officer at Cephalon. “We now plan to conduct phase three trials to further evaluate the efficacy and safety of NUVIGIL in this patient population.”

NUVIGIL was generally well-tolerated in the study. The incidence of mania, hypomania, depression and suicidal ideation were comparable between the NUVIGIL and placebo groups. There were two serious adverse events of mania in the placebo group but none in the NUVIGIL group. Other adverse events that occurred more frequently in the NUVIGIL versus the placebo group included restlessness and anxiety.

Cephalon is preparing to launch NUVIGIL, the longer-lasting isomer of modafinil, in the third quarter of 2009. NUVIGIL is indicated to improve wakefulness in patients with excessive sleepiness associated with treated obstructive sleep apnea (OSA), shift work sleep disorder, also known as shift work disorder (SWD), and narcolepsy. NUVIGIL is not approved for the treatment of bipolar disorders, depression or their associated symptoms.

The U.S. Food and Drug Administration-approved prescribing information for NUVIGIL, including a bolded warning, is available at http://www.NUVIGIL.com.

About Cephalon, Inc.

Founded in 1987, Cephalon, Inc. is an international biopharmaceutical company dedicated to the discovery, development and commercialization of many unique products in four core therapeutic areas: central nervous system, inflammatory diseases, pain and oncology. A member of the Fortune 1000 and the S&P 500 Index, Cephalon currently employs approximately 3,000 people in the United States and Europe. U.S. sites include the company’s headquarters in Frazer, Pennsylvania, and offices, laboratories or manufacturing facilities in West Chester, Pennsylvania, Salt Lake City, Utah, and suburban Minneapolis, Minnesota.

Cephalon has a growing presence in Europe, the Middle East and Africa. The Cephalon European headquarters and pre-clinical development center are located in Maisons-Alfort, France, just outside of Paris. Key business units are located in England, Ireland, France, Germany, Italy, Spain, the Netherlands for the Benelux countries, and Poland for Eastern and Central European countries. Cephalon Europe markets more than 30 products in four areas: central nervous system, pain, primary care and oncology.

The company’s proprietary products in the United States include: AMRIX(R) (cyclobenzaprine hydrochloride extended-release capsules), TREANDA(R) (bendamustine hydrochloride) for Injection, FENTORA(R) (fentanyl buccal tablet) [C-II], PROVIGIL(R) (modafinil) Tablets [C-IV], TRISENOX(R) (arsenic trioxide) injection, GABITRIL(R) (tiagabine hydrochloride), NUVIGIL and ACTIQ(R) (oral transmucosal fentanyl citrate) (C-II).

In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Cephalon’s current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, development of potential pharmaceutical products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, sales and earnings guidance, and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as “anticipate,” “estimate,” “expect,” “project,” “intend,” “plan,” “believe” or other words and terms of similar meaning. Cephalon’s performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, regulatory and political conditions affecting the biotechnology and pharmaceutical industries as well as more specific risks and uncertainties facing Cephalon such as those set forth in its reports on Form 8-K, 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Cephalon does not intend to update publicly any forward-looking statement, except as required by law. The Private Securities Litigation Reform Act of 1995 permits this discussion.

Cephalon, Inc.
http://www.cephalon.com

• Mood Dysfunction Improved In Gene Knockout Mice

Researchers at MIT’s Picower Institute for Learning and Memory have found that inhibiting a key brain enzyme in mice reversed schizophrenia-like symptoms. The finding, reported in the March 20 issue of Cell, identified how a particular gene controls this brain enzyme. Better understanding of the relationship could lead to new drug treatments for schizophrenia, the severe brain disorder that affects about 1 percent of the population and is characterized by hallucinations, delusions, poor social and emotional functioning and disorganized thoughts.

The Picower research focused on a gene known as DISC1 (short for “disrupted in schizophrenia 1″), which was first identified in the 1990s by researchers studying the genetic makeup of a large Scottish family with mental and behavioral disorders. DISC1 has since been shown to help brain neuronal cells migrate to their correct positions and to help new neurons grow in the developing brain, but its role was not well understood.

Now, Li-Huei Tsai, the Picower Professor of Neuroscience in MIT’s Department of Brain and Cognitive Sciences, and colleagues have shown for the first time that DISC1 directly inhibits the activity of a brain enzyme called glycogen synthase kinase 3 beta, also known as GSK3B.

Lithium chloride, the mood-stabilizing drug often prescribed for schizophrenia and bipolar disorder, also acts on GSK3B.

“This work for the first time provides a detailed explanation of how DISC1 functions normally in our brains,” said Tsai, a Howard Hughes Medical Institute investigator and director of the neurobiology program of the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT.

“With this new knowledge of the DISC1-GSK3B interaction, one of the goals is to develop new drugs targeting schizophrenia, providing some hope that this devastating disease will be treated more effectively in the near future,” she said.

Growing new neurons

Working with mice, Tsai and colleagues found that DISC1 regulates the growth of neural stem cells in both developing and adult brains. “During brain development, a fine-tuned mechanism regulates when neural stem cells divide and replenish their own population and when they turn into newborn neurons that will mature and grow appropriate connections with other neurons,” Tsai said.

Tsai and colleagues found that halting expression of the DISC1 gene in neural stem cells causes them to stop dividing and prematurely turn into newborn neurons.

Eliminating DISC1 in adult mouse neural stem cells caused similar defects and produced behavioral changes such as hyperactivity, a symptom of schizophrenia in mice models of the disease. “Giving a chemical inhibitor of GSK3B to these mice completely reversed their abnormal behavior,” Tsai said.

DISC1 works by directly inhibiting the activity of GSK3B, a target of the drug lithium. “It seems that DISC1 regulates the balance between neural stem cell self-renewal and turning into neurons, which impacts overall brain circuitry and can lead to compromised cognition and behavioral abnormalities,” Tsai said. “Understanding the normal function of DISC1 in the brain could lead to new information on how schizophrenia arises due to genetic predisposition and environmental factors.”

In addition to Tsai, co-authors are Picower Institute postdoctoral fellow Yingwei Mao; MIT Brain and Cognitive Sciences graduate student Xuecai Ge, Picower Institute postdoctoral associate Christopher L. Frank; Broad Institute researchers Jon M. Madison, Erin M. Berry, Takahiro Soda and Karun K. Singh; and colleagues at Massachusetts General Hospital, the Harvard-MIT Division of Health Sciences and Technology and the University of Washington School of Medicine.

This work was supported by the National Institutes of Health, the Stanley Center, the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the Human Frontier Science Program.

Written by Deborah Halber, Picower Institute

Source
MIT

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• Long-Term Tolerability And Safety Data Of Abilify(R) In Combination Treatment For Patients With Bipolar I Disorder
• Depressive, social anxiety symptoms severe among anxiety disordered patients

Impax Laboratories, Inc. (NASDAQ: IPXL) confirmed that the U.S. Food and Drug Administration (FDA) has granted final approval of the Company’s Abbreviated New Drug Application (ANDA) for generic version of Depakote® (divalproex ER) 250mg Extended-release Tablets. The Company also received tentative approval on the 500mg tablets and expects to receive final approval on August 3, 2009, upon expiration of the 180-day exclusivity period. Abbott Laboratories markets Depakote® ER for the treatment of epilepsy and bipolar disorders.

The Company expects to launch both the 250mg and 500mg tablets on August 3, 2009, through Global Pharmaceuticals, Impax’s generic division.

According to Wolters Kluwer Health, U.S. sales of Depakote® ER 250mg and 500mg tablets were approximately $115 million and $796 million, respectively, for the 12 months ended March 2009.

Source
Impax Laboratories, Inc.

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