Researchers at the University of Illinois at Chicago are the first to use brain imaging to examine the effects of emotion on working memory function in children with pediatric bipolar disorder or attention deficit hyperactivity disorder.
The study is published in the October issue of the Journal of the American Academy of Child & Adolescent Psychiatry.
PBD and ADHD are very severe developmental disorders that share behavioral characteristics such as impulsivity, irritability and attention problems.
Using functional magnetic resonance imaging, researchers at UIC examined the brain activity of children as they performed a working memory task while viewing faces with different emotions, such as angry, happy or neutral expressions.
The children, ages 10 to 18, were asked to remember the faces and to press a button in the MR-scanner if they saw the same face that was presented two trials earlier. The study involved 23 non-medicated children with bipolar disorder, 14 non-medicated children with ADHD and 19 healthy controls.
"It's a simple yet elegant working memory test that tells us a lot about how their brain remembers stimuli like faces or objects," said Alessandra Passarotti, assistant professor of psychiatry at UIC and lead author of the study. "We also added in an emotional component -- because both disorders show emotional deficits -- to study how their working memory is affected by emotional challenge."
The researchers found that while both disorders show dysfunction in the prefrontal cortex relative to healthy controls, the ADHD group had the most severe dysfunction in this important region. The prefrontal cortex controls behavior, such as impulsivity, and executive function, as well as complex cognitive processes such as working memory, attention and language.
From a treatment, learning and intervention perspective, the next step for researchers and clinicians is to figure out how to help patients use their prefrontal cortex, Passarotti said.
The researchers also found that while the ADHD group had greater dysfunction in working memory circuits in the brain, the bipolar group had more deficits in regions of the brain involved in emotion-processing and regulation.
Now that researchers are starting to differentiate between the two disorders at a brain network level, rather than just at a behavioral level, the long-term goal is to develop diagnostic tests based on neurological and behavioral markers of illness that can be used in a clinical setting. Currently patients are diagnosed using clinical measures, questionnaires, behavior scales and interviews with parents.
It is difficult for physicians to differentiate between the two disorders behaviorally, which may lead to an incorrect diagnosis and wrong medications, a worsening of symptoms, and greater frustration for children and parents, said Passarotti, a researcher in UIC's Institute for Juvenile Research.
She said that while researchers still do not understand all of the neurological deficits that characterize ADHD and PBD profiles, they know that drug treatment that works for ADHD does not work for bipolar disorder.
"In fact, if you give a stimulant to a child with bipolar disorder, they become more manic, and this makes their illness even worse, whereas if you give the mood-regulation medicine commonly prescribed for PBD to a child with ADHD, they still show a lot of attention deficits and do not show any improvement," Passarotti said.
"Our hope is that by better differentiating between these two severe developmental illnesses, we can help develop more accurate diagnoses and more targeted treatments for PBD and ADHD."
Co-authors of the study are Dr. Mani Pavuluri, the Berger-Colbeth Term Chair in Child Psychiatry and director of the Pediatric Brain Research and Intervention Center at UIC, and John Sweeney, professor of psychiatry, neurology and psychology and director of the Center for Cognitive Medicine at UIC.
Source: University of Illinois at Chicago.
Sunday, 17 October 2010
Alexza Pharmaceuticals Receives Complete Response Letter For AZ-004 (Staccato® Loxapine) NDA
Alexza Pharmaceuticals, Inc. (Nasdaq: ALXA) announced that it has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA or Agency) regarding its New Drug Application (NDA) for AZ-004 (Staccato® loxapine), submitted as Adusuve™ Staccato® (loxapine) inhalation aerosol, 5 mg and 10 mg. A CRL is issued by FDA's Center for Drug Evaluation and Research indicating that the NDA review cycle is complete and the application is not ready for approval in its present form. AZ-004 is being developed for the rapid treatment of agitation in schizophrenia or bipolar disorder patients.
In the CRL, the FDA stated that their primary clinical safety concern was related to data from the three Phase 1 pulmonary safety studies with AZ-004. This concern was primarily based on observed, dose-related post-dose decreases in forced expiratory volume in one second, or FEV1, a standard measure of lung function, in healthy subjects and in subjects with COPD and asthma. The agency also noted that decreases in FEV1 were recorded in subjects who were administered device-only, placebo versions of AZ-004. Alexza intends to meet with the FDA in the near future to discuss steps to address this FDA concern. As Alexza has previously reported, there were no serious or severe respiratory adverse events in these trials or reported in the two Phase 3 clinical trials of AZ-004. All respiratory symptoms that developed after treatment in the Phase 1 subjects with COPD and asthma were either self-limiting or readily managed with an inhaled bronchodilator.
The CRL also raised issues relating to the suitability of the stability studies undertaken by Alexza and certain other items relating to the agency's recently completed pre-approval manufacturing inspection. Because AZ-004 incorporates a novel delivery system, the CRL also included input from FDA's Center for Devices and Radiological Health (CDRH). CDRH requested a human factors study and related analysis to validate that the product can be used effectively in the proposed clinical setting. CDRH also requested further bench testing of the product under an additional "worst-case" manufacturing scenario.
"We are reviewing the Complete Response Letter and plan to meet with the FDA as soon as possible to discuss the Agency's pulmonary safety concern. Alexza shares the agency's deep interest in patient safety, and believes the pulmonary data is supportive of the safety of AZ-004. We look forward to discussing the appropriate way to address this issue," said Thomas B. King, Alexza President and CEO. "We are also undertaking steps to address the other items raised in the CRL. We appreciate the FDA's review of the first NDA for our novel Staccato technology, and we expect to work closely with FDA to resolve the issues raised in the Complete Response Letter. Alexza continues to believe in the safety and efficacy of AZ-004 based on the comprehensive clinical development program we have conducted."
Psychiatric Drug Facts - Do You Know The Long Term Effects Of Psychiatric Drugs? Free Info Kit - CCHR.org
Safe Harbor Statement
This press release includes forward-looking statements regarding the development and safety of the Company's product candidates and technologies. Any statement describing the Company's expectations or beliefs is a forward-looking statement, as defined in the Private Securities Litigation Reform Act of 1995, and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of developing and commercializing drugs. The Company's forward-looking statements also involve assumptions that, if they prove incorrect, would cause its results to differ materially from those expressed or implied by such forward-looking statements. These and other risks concerning Alexza's business are described in additional detail in the Company's Annual Report on Form 10-K for the year ended December 31, 2009, and the Company's other Periodic and Current Reports filed with the Securities and Exchange Commission including the risks under the headings: "Regulatory authorities may not approve our product candidates even if they meet safety and efficacy endpoints in clinical trials.", "We have a history of net losses. We expect to continue to incur substantial and increasing net losses for the foreseeable future, and we may never achieve or maintain profitability.", "We will need substantial additional capital in the future. If additional capital is not available, we will have to delay, reduce or cease operations.", and "Unless our preclinical studies demonstrate the safety of our product candidates, we will not be able to commercialize our product candidates.". Forward-looking statements contained in this announcement are made as of this date, and we undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Source: Alexza Pharmaceuticals, Inc
In the CRL, the FDA stated that their primary clinical safety concern was related to data from the three Phase 1 pulmonary safety studies with AZ-004. This concern was primarily based on observed, dose-related post-dose decreases in forced expiratory volume in one second, or FEV1, a standard measure of lung function, in healthy subjects and in subjects with COPD and asthma. The agency also noted that decreases in FEV1 were recorded in subjects who were administered device-only, placebo versions of AZ-004. Alexza intends to meet with the FDA in the near future to discuss steps to address this FDA concern. As Alexza has previously reported, there were no serious or severe respiratory adverse events in these trials or reported in the two Phase 3 clinical trials of AZ-004. All respiratory symptoms that developed after treatment in the Phase 1 subjects with COPD and asthma were either self-limiting or readily managed with an inhaled bronchodilator.
The CRL also raised issues relating to the suitability of the stability studies undertaken by Alexza and certain other items relating to the agency's recently completed pre-approval manufacturing inspection. Because AZ-004 incorporates a novel delivery system, the CRL also included input from FDA's Center for Devices and Radiological Health (CDRH). CDRH requested a human factors study and related analysis to validate that the product can be used effectively in the proposed clinical setting. CDRH also requested further bench testing of the product under an additional "worst-case" manufacturing scenario.
"We are reviewing the Complete Response Letter and plan to meet with the FDA as soon as possible to discuss the Agency's pulmonary safety concern. Alexza shares the agency's deep interest in patient safety, and believes the pulmonary data is supportive of the safety of AZ-004. We look forward to discussing the appropriate way to address this issue," said Thomas B. King, Alexza President and CEO. "We are also undertaking steps to address the other items raised in the CRL. We appreciate the FDA's review of the first NDA for our novel Staccato technology, and we expect to work closely with FDA to resolve the issues raised in the Complete Response Letter. Alexza continues to believe in the safety and efficacy of AZ-004 based on the comprehensive clinical development program we have conducted."
Psychiatric Drug Facts - Do You Know The Long Term Effects Of Psychiatric Drugs? Free Info Kit - CCHR.org
Safe Harbor Statement
This press release includes forward-looking statements regarding the development and safety of the Company's product candidates and technologies. Any statement describing the Company's expectations or beliefs is a forward-looking statement, as defined in the Private Securities Litigation Reform Act of 1995, and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of developing and commercializing drugs. The Company's forward-looking statements also involve assumptions that, if they prove incorrect, would cause its results to differ materially from those expressed or implied by such forward-looking statements. These and other risks concerning Alexza's business are described in additional detail in the Company's Annual Report on Form 10-K for the year ended December 31, 2009, and the Company's other Periodic and Current Reports filed with the Securities and Exchange Commission including the risks under the headings: "Regulatory authorities may not approve our product candidates even if they meet safety and efficacy endpoints in clinical trials.", "We have a history of net losses. We expect to continue to incur substantial and increasing net losses for the foreseeable future, and we may never achieve or maintain profitability.", "We will need substantial additional capital in the future. If additional capital is not available, we will have to delay, reduce or cease operations.", and "Unless our preclinical studies demonstrate the safety of our product candidates, we will not be able to commercialize our product candidates.". Forward-looking statements contained in this announcement are made as of this date, and we undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Source: Alexza Pharmaceuticals, Inc
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