FDA Approves Once-Monthly Paliperidone Palmitate Injection for Treating Schizophrenia

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By: Yael Waknine

August 5, 2009 — The US Food and Drug Administration (FDA) has approved a long-acting, once-monthly formulation
of paliperidone palmitate injection (Invega Sustenna, Janssen, a division of Ortho-McNeil-Janssen Pharmaceuticals,
Inc) for the acute and maintenance treatment of schizophrenia in adults.

Although schizophrenic symptoms and the risk for relapse can be managed in most patients with continuous, long-term antipsychotic therapy, some 80% of patients relapse within 5 years of diagnosis. The risk for relapse increases as a result of therapeutic noncompliance, which is a common occurrence in patients receiving oral antipsychotics.

“Inconsistent compliance with medications is arguably one of the single greatest impediments to managing the
symptoms of schizophrenia and delaying the time to relapse,” said Henry A. Nasrallah, MD, in a company news
release. “The approval of once-monthly Invega Sustenna will provide healthcare professionals with a treatment option
that is, at the same time, a definitive monitoring tool for uninterrupted medication compliance, which may help optimize clinical outcomes in schizophrenia.”

Dr. Nasrallah is a clinical investigator who worked on the Invega Sustenna clinical trials and a professor of psychiatry
and neuroscience and director of the Schizophrenia Research Program at the University of Cincinnati College of
Medicine, Ohio.

The clinical trial program consisted of 4 acute symptom control studies and 1 longer-term maintenance study. The 4
studies (n = 1695) demonstrated that extended-release paliperidone injection was significantly more effective than
placebo for improving Positive and Negative Syndrome Scale (PANSS) total scores in schizophrenic patients.

PANSS is a multi-item inventory that measures positive symptoms, negative symptoms, disorganized thoughts,
uncontrolled hostility/excitement, and anxiety/depression.

Results of the longer-term maintenance study (n = 410) revealed that extended-release paliperidone injection
significantly delayed the time to first relapse (P < .0001), with fewer patients experiencing a relapse relative to placebo
(10% vs 34%). Patients receiving placebo had a 3.6-fold higher rate of relapse compared with extended-release
paliperidone palmitate. This study was stopped early because maintenance of efficacy was demonstrated.

Adverse events most commonly reported in paliperidone-treated patients (incidence ≥ 5% and occurring twice as often vs placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.

Treatment with extended-release paliperidone palmitate should be initiated with a dose of 234 mg on treatment day 1
and then 156 mg 1 week later, with both injections administered in the deltoid muscle. The recommended monthly
maintenance dose is 117 mg; some patients may benefit from lower or higher maintenance doses within the
recommended range of 39 to 234 mg based on individual tolerability and/or efficacy. Monthly maintenance doses can
be administered in either the deltoid or gluteal muscle.

Yael Waknine is a freelance writer for Medscape.

FDA Panel Gives the Nod to New Antipsychotic Drug

By: Fran Lowry

August 3, 2009 — The US Food and Drug Administration’s (FDA’s) Psychopharmacologic Drugs Advisory Committee
has endorsed claims of efficacy and safety for the atypical antipsychotic drug asenapine (Saphris, Schering-Plough) for
the acute treatment of adults with schizophrenia and mania/mixed episodes of bipolar 1 disorder.

The drug is administered as a sublingual tablet and should provide a useful alternative for those patients who are
unable to swallow pills, Andrew Winokur, MD, PhD, from the University of Connecticut School of Medicine, Farmington, and a member of the expert panel, said.

The 14-member panel gave asenapine, a 5HT 2D2 antagonist, a relatively easy ride, as it voted unanimously in favor
of the drug’s efficacy and safety in the treatment of adults with mania and bipolar disorder. Only 2 panel members said
they were not convinced of asenapine’s safety and efficacy in the acute treatment of adult schizophrenia because 1 of
the 3 studies presented by the sponsor was negative for the new antipsychotic. In all, the manufacturer presented
efficacy data on more than 3000 patients and safety data — which extended more than 2 years in some cases — on
more than 4500 patients with schizophrenia or mania bipolar disorder.

Thomas P. Laughren, MD, director of the FDA’s division of psychiatry products, told the panel at the outset of the
hearing that although the FDA had not yet reached a final conclusion about the sponsor’s new drug application for
asenapine, “I can say that in general, we are in agreement with the sponsor that they have shown that the drug is
effective for these 2 claimed indications and that the safety profile for asenapine qualitatively looks very much like what we’ve seen for other atypical antipsychotics and in our view is acceptable.”

Panel members by and large agreed.

“I thought the safety was acceptable for an agent used for schizophrenia and it offered a variety of different side
effects, many of which were better than other agents in the class,” said Robert L. Hendren, DO, from the University of
California, San Francisco. “For bipolar and mania, it showed good efficacy and a novel, or interesting, safety profile that
would allow a greater range of possibilities for someone prescribing medications for people in this category.”

Ruth S. Day, PhD, from Duke University, Durham, North Carolina, said she thought the safety profile was comparable
with other drugs in the class, “but also a little bit better in some respects.”

The sole patient representative on the panel, Musa J. Mayer, MS, from New York City, said that to have a drug
available that does not cause significant weight gain “is really an important part of the armamentarium” in the treatment of mania and bipolar disorder.

However, she was less impressed with the efficacy and safety data in regard to schizophrenia. As 1 of the 2 naysayers,
Ms. Mayer told the hearing committee: “I believe that we get the kinds of drugs that we ask for and are willing to accept
and I think that if we demand more efficacy, we will find ourselves with better drugs. I’ve seen this work in cancer
treatment and I think it’s important to keep the standards high regardless of the difficulties of the research.”

Her remark prompted Gail W. Griffith, a writer and activist from Washington, DC, and the consumer representative on
the panel, to remark, “I sense that there is a concern that we aren’t setting the bar high enough with respect to this
class of drugs, or maybe all psychotropic drugs, and I suspect that these drugs are more maligned as a class of drugs,
as are the illnesses.”

The panel agreed that it is important for patients with these illnesses to have a variety of therapeutic options. Richard
P. Malone, MD, professor of psychiatry at Drexel University College of Medicine in Philadelphia, Pennsylvania, and
acting chair of the advisory committee, said asenapine “looks like a viable treatment option. Individual patients will have their individual responses both for efficacy and for safety, and asenapine will give them an opportunity for another option.”

Dr. Laughren also emphasized the importance of more treatment choices for patients with these disorders. “At the
present time, there are a number of other medications available for treating these conditions, but as you also know, it is important to have treatment options because not every patient responds to the available treatments, either because
they do not work or because they do not tolerate the drug, and so asenapine, if approved, would represent another
treatment option.”

Fran Lowry is a freelance writer for Medscape.

Neuroimaging Provides Clearer Picture of Brain Dysfunction in Schizophrenia

By: Megan Rauscher

NEW YORK (Reuters Health) Aug 04 – In schizophrenic patients, there are regions within the prefrontal cortex that are
hypoactive and others that are hyperactive, functional neuroimaging data show.

“The hyperactive areas may be compensating for the hypoactive areas,” Dr. Michael J. Minzenberg, of the department
of psychiatry, University of California, Davis School of Medicine, Sacramento, noted in an email to Reuters Health.

To better understand prefrontal cortex dysfunction in schizophrenia, Dr. Minzenberg and colleagues performed a
quantitative meta-analysis of 41 peer-reviewed studies that investigated executive function in schizophrenic patients
and healthy controls using functional magnetic resonance imaging.

They report, in the Archives of General Psychiatry for August, that healthy adults and schizophrenic patients activate a qualitatively similar neural network during executive task performance, “consistent with the engagement of a general purpose cognitive control network.” Predominant areas of activation include the dorsolateral prefrontal cortex,
ventrolateral prefrontal cortex, and anterior cingulate cortex and the thalamus.

However, patients with schizophrenia also show reduced activation in the left dorsolateral prefrontal cortex,
rostral/dorsal anterior cingulate cortex, left thalamus and inferior/posterior cortical areas, whereas increased activity
was seen in other prefrontal cortex areas.

“The present results taken together strongly argue against a simple hypofrontality versus hyperfrontality account of the altered function of the frontal cortex in schizophrenia,” the researchers write.

“The main clinical implications,” Dr. Minzenberg added, “are that there might be relatively few pathological processes
that may give rise to the diversity of PFC dysfunction in schizophrenia, and that the cognitive control network that we
propose may serve as a major, overarching treatment target.”

Arch Gen Psychiatry 2009;66:811-822.

Upcoming Events

Webcast: The Social Services System: Supporting Treatment and Recovery for Individuals and Families

August 5, 2009

This Center for Substance Abuse Treatment webcast will examine ways in which social services effectively deliver assistance – via foster care, housing, job training, medical care, and veteran support, for example – to the children and families of people with substance use disorders. The webcast will also offer tips on how to improve cooperation with other sectors of society.


National Conference on Health Communication, Marketing, and Media 2009

August 11-13, 2009, Atlanta, Georgia

SAMHSA is joining with the Centers for Disease Control and Prevention to sponsor the 2009 National Conference on Health Communication, Marketing, and Media. SAMHSA’s goal for co-sponsoring the conference is to increase the visibility and presence of mental health and substance abuse service delivery organizations, providers, and advocates, and to leverage the new media environment to address the needs of people with or at risk for substance use and mental disorders.


National Alcohol and Drug Addiction Recovery Month (Recovery Month)

September 2009

The Recovery Month observance highlights the societal benefits of substance abuse treatment, lauds the contributions of treatment providers and promotes the message that recovery from substance abuse in all its forms is possible. The observance also encourages citizens to take action to help expand and improve the availability of effective substance abuse treatment for those in need.


Toolkit now available: http://www.recoverymonth.gov/Recovery-Month-Kit.aspx

New Spanish-Language Consumer Guides

New Spanish-Language Consumer Guides Compare Treatments for Depression, and Other Conditions

Spanish speakers who want to know how soon they can expect to feel better when taking an antidepressant, can get this and other treatment information through new Spanish-language consumer guides released by the Agency for Healthcare Research and Quality (AHRQ).



This issue of The Dialogue, Volume 5, Issue 4, 2009, summarizes the information presented and discussed at the All-Hazards Disaster Behavioral Health: Optimizing Psychological Health and Resiliency in Difficult Economic Times conference. This 3-day conference brought together disaster mental health and substance abuse coordinators, researchers, and other professionals from across the country to discuss how to maximize resources, build resilience, and manage stress in difficult economic times.

Disability.gov Offers Social Media Tools, Upgrades to Complement Information from 22 Federal Agencies on Disability-Related Programs and Services

In conjunction with the 19th anniversary of the Americans with Disabilities Act, the U.S. Department of Labor has re-named and re-launched DisabilityInfo.gov as Disability.gov. The site offers comprehensive information about programs and services to better serve more than 50 million Americans with disabilities, their family members, veterans, employers, educators, caregivers and anyone interested in disability-related information.


Schizophrenia (Easy-to-Read)

This easy-to-read booklet on schizophrenia explains what it is, when it starts and how to get help.


NIH and VA Announce $7 Million Partnership for Substance Abuse Research among Military Personnel, Veterans and their Families: Research Will Focus on War Efforts in Iraq and Afghanistan

Two federal departments have joined forces to create a first-time collaborative funding project to support research on substance abuse and associated problems among U.S. military personnel, veterans and their families. The National Institute on Drug Abuse, in partnership with two other NIH Institutes — the National Institute on Alcohol Abuse and Alcoholism, and the National Cancer Institute  — are jointly collaborating with the Department of Veterans Affairs (VA), on a seven million dollar funding opportunity announcement for research in this area. The funding opportunity announcement will focus on the causes, screening and identification, prevention and treatment of substance use and abuse — including alcohol, tobacco and other drugs — and associated problems, including post-traumatic stress disorder.

Press Release: http://www.nih.gov/news/health/jul2009/nida-30.htm

NIH Launches The Human Connectome Project to Unravel The Brain’s Connections

The National Institutes of Health Blueprint for Neuroscience Research is launching a $30 million project that will use cutting-edge brain imaging technologies to map the circuitry of the healthy adult human brain. By systematically collecting brain imaging data from hundreds of subjects, the Human Connectome Project (HCP) will yield insight into how brain connections underlie brain function, and will open up new lines of inquiry for human neuroscience.  Investigators have been invited to submit detailed proposals to carry out the HCP, which will be funded at up to $6 million per year for five years. The HCP is the first of three Blueprint Grand Challenges, projects that address major
questions and issues in neuroscience research.
Press Release: http://www.nimh.nih.gov/science-news/2009/nih-launches-the-human-connectome-project-to-unravel-the-brains-connections.shtml