Higher Stress Disorders In Women May Have Biological Basis

There may be a biological reason why depression and other stress-related psychiatric disorders are more common among women compared to men. Studying stress signaling systems in animal brains, neuroscience researchers found that females are more sensitive to low levels of an important stress hormone and less able to adapt to high levels than males.


"This is the first evidence for sex differences in how neurotransmitter receptors traffic signals," said study leader Rita J. Valentino, Ph.D., a behavioral neuroscientist at The Children's Hospital of Philadelphia. "Although more research is certainly necessary to determine whether this translates to humans, this may help to explain why women are twice as vulnerable as men to stress-related disorders."


The research appears online today in Molecular Psychiatry. The study's first author is Debra A. Bangasser, Ph.D., a fellow in Valentino's laboratory.



It has long been recognized that women have a higher incidence of depression, post-traumatic stress disorder, and other anxiety disorders, said Valentino, but underlying biological mechanisms for that difference have been unknown. Her research focuses on corticotropin-releasing factor (CRF), a hormone that organizes stress responses in mammals.


Analyzing the brains of rats that responded to a swim stress test, Valentino's team found that in female rats, neurons had receptors for CRF that bound more tightly to cell signaling proteins than in male rats, and thus were more responsive to CRF. Furthermore, after exposure to stress, male rats had an adaptive response, called internalization, in their brain cells. Their cells reduced the number of CRF receptors, and became less responsive to the hormone. In female rats this adaptation did not occur because a protein important for this internalization did not bind to the CRF receptor.


"This is an animal study, and we cannot say that the biological mechanism is the same in people," said Valentino, adding that other mechanisms play a role in human stress responses, including the actions of other hormones. However, she added, "researchers already know that CRF regulation is disrupted in stress-related psychiatric disorders, so this research may be relevant to the underlying human biology."


Furthermore, said Valentino, much of the previous research on stress disorders in animal models used only male rodents, so important sex differences may have gone undetected. "Pharmacology researchers investigating CRF antagonists as drug treatments for depression may need to take into account gender differences at the molecular level," she said.


The National Institutes of Health provided funding support for this study. Co-authors with Valentino and Bangasser were Andre Curtis, Ph.D., Thelma T. Bethea, Ioannis Parastatidis, M.D., and Harry Ischiropoulos, Ph.D., all of The Children's Hospital of Philadelphia; and Elisabeth J. Van Bockstaele, Ph.D., of the Farber Institute for Neurosciences of Thomas Jefferson University.


"Sex differences in corticotrophin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology," Molecular Biology, published online June 15, 2010. dx.doi/10.1038/MP.2010.66


Source

Children's Hospital of Philadelphia

Potential adverse effects of SSRIs and other anti depressants on newborns

Health Canada is advising Canadians that newborns may be adversely affected when pregnant women take Selective Serotonin Re-uptake Inhibitors (SSRIs) and other newer anti-depressants during the third trimester of pregnancy. This advisory is intended to increase awareness among mothers and physicians of the possible symptoms that may occur in the newborn, so that symptoms can be recognized and addressed quickly.


This advisory applies to the following anti-depressants: bupropion (whether used for depression or for smoking cessation), citalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine.


International and Canadian reports reveal that some newborns whose mothers took these medications during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding. Reported symptoms include: feeding and/or breathing difficulties, seizures, muscle rigidity, jitteriness and constant crying. In most cases, the newer anti-depressant was taken during the third trimester of pregnancy. These symptoms are consistent with either a direct adverse effect of the anti-depressant on the baby, or possibly a discontinuation syndrome caused by sudden withdrawal from the drug.


When treating depression in pregnant women, physicians and patients should carefully consider the potential risks and benefits of the various treatment options for both the mother and the unborn baby. To date, there is little evidence-based information on how best to treat depression during pregnancy. However, physicians may consider slowly decreasing the dose of these medications in the third trimester.


If a woman is pregnant and is taking an SSRI, or other newer anti-depressant, she should discuss with the risks and benefits of the various treatment options with her health care professional. It is very important that patients do NOT stop taking these medications without first consulting with their doctor.


The frequency of symptoms may vary with each drug. In the case of two of the newer anti-depressants - bupropion and mirtazapine - discontinuation problems appear to be less than with the other drugs. In the case of mirtazapine, there are only two reports. Health Canada is issuing this advisory to encompass all newer anti-depressants in order to alert Canadians to the potential risk. Health Canada has also worked with the manufacturers of these medications to update their labelling with new precaution information.


Any suspected adverse reactions can be reported directly to the product manufacturer or to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP) Marketed Health Products Directorate

HEALTH CANADA

Address Locator: 0701C

OTTAWA, Ontario, K1A 0K9

Tel: (613) 957-0337 or Fax: (613) 957-0335


To report an Adverse Reaction, consumers and health professionals may call toll free:

Tel: 866 234-2345

Fax: 866 678-6789


hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adr_guideline_e.html


The Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.html

hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adr_guideline_e.html


Media Inquiries:

Jirina Vlk

Health Canada

(613) 957-2988

Public Inquiries:

(613) 957-2991

Brain stimulation treats resistant depression

Electrical deep brain stimulation can dramatically alleviate depression that is resistant to other treatments,
researchers have found in an initial study on six patients. The finding is important, they said, because up to 20 percent of
patients with depression fail to respond to standard treatments--requiring combinations of antidepressant drugs,
psychotherapy, and electroconvulsive treatment (ECT) that still may fail. The number of resistant depression patients can be
large, since depression is the leading source of disability in adults under age 50 in North America.


The 6 month study led by Helen Mayberg of Emory University School of Medicine and colleagues showed that the patients
reported immediate improvements in mood when the electrical stimulation of a few volts was applied to the implanted
electrodes. These effects persisted in four of the patients for the full 6 months, with three patients achieving remission or
near remission of the depression. No psychological side effects were reported, and other adverse effects were limited to
minor infections around the implant site, which were treatable with antibiotics, wrote the researchers.


The researchers concluded that, although the study was limited in scope and length, deep brain stimulation "may represent an
effective, novel intervention for severely disabled patients with treatment-resistant depression."


The six patients who participated in the study showed severe depression according to the Hamilton Depression Rating Scale.
They had all failed to respond to at least four different treatments, including drugs, psychotherapy, and ECT.


The researchers implanted the array of electrodes in a region called the "subgenual cingulate region," which their earlier
studies had indicated to be overactive in treatment-resistant depression.


Precisely calibrated stimulation of a few volts produced immediate effects, the researchers wrote. "All patients
spontaneously reported acute effects including 'sudden calmness or lightness,' 'disappearance of the void,' sense of
heightened awareness, increased interest, 'connectedness,' and sudden brightening of the room, including a description of the
sharpening of visual details and intensification of colors in response to electrical stimulation," wrote the researchers.
These effects were reversed when stimulation was turned off and returned when it was resumed.


"Unexpectedly, with application of stimulation for progressively longer periods (from 1 to 3 hr), there was an increasing and
correspondingly longer carry-over of the beneficial behavioral effects beyond cessation of the stimulation," reported the
researchers.


During the initial weeks of stimulation, "Patients and their families described renewed interest and pleasure in social and
family activities, decreased apathy and anhedonia, as well as an improved ability to plan, initiate, and complete tasks that
were reported as impossible to attempt prior to surgery."















Analysis of brain activity using positron emission tomography revealed that the deep brain stimulation corrected abnormal
hyperactivity in the subgenual cingulate region, which was correlated with abnormally decreased activity in the prefrontal
cortex of the brain.


Psychological testing showed that the surgery did not reduce cognitive function in the patients. In fact, patients showed
significant improvement in hand-eye coordination, verbal fluency, and judgment of risk.


Over a 6 month period of chronic stimulation, four of the patients continued to show significant antidepressant response,
with three showing remission or near remission of illness, reported the researchers.


Helen S. Mayberg, Andres M. Lozano, Valerie Voon, Heather E. McNeely, David Seminowicz, Clement Hamani, Jason M. Schwalb, and
Sidney H. Kennedy: "Deep Brain Stimulation for Treatment-Resistant Depression"


The researchers included Helen S. Mayberg of the Rotman Research Institute at Baycrest Centre, University of Toronto, and
Emory University School of Medicine; Andres M. Lozano, Clement Hamani, and Jason M. Schwalb from the Toronto Western Hospital
Research Institute, University Health Network at University of Toronto; Valerie Voon and Sidney H. Kennedy of the University
Health Network at University of Toronto; Heather E. McNeely of Center for Addiction and Mental Health at University of
Toronto; and David Seminowicz of the Rotman Research Institute at Baycrest Centre and the Institute of Medical Science at
University of Toronto. This study was supported by a distinguished Investigator Award to H.S.M. from the National Alliance
for Research in Schizophrenia and Depression (NARSAD).


Publishing in Neuron, Volume 45, Number 5, March 3, 2005, pages 651-660. neuron


Contact: Heidi Hardman

hhardmancell

1-617-397-2879

Cell Press

cell

Exposure To Family Violence Especially Harmful To Previously Abused Children

Millions of American children are exposed to violence in their homes each year, putting them at risk for a variety of emotional and behavioral problems. According to a new study in the September/October 2008 issue of the journal Child Development, children who are maltreated tend to have a lot of re-exposure to family violence, and this re-exposure often leads to increased psychological problems.



Researchers at the University of Pennsylvania, University of California, Irvine, and West Chester University found that the types of violence that abused children were subsequently re-exposed to led to specific types of psychological problems. Specifically, previously abused children who witnessed family violence had more symptoms of depression and anxiety, while previously abused children who were subjected to harsh physical discipline were more aggressive and broke rules more frequently.



"Our study has implications for mental health treatment and policy: Clinicians and service providers should be especially concerned about the substantial number of maltreatment victims who are re-exposed to family violence, because these children are highly vulnerable to ongoing emotional and behavioral problems," according to Andrea Kohn Maikovich, a Ph.D. candidate at the University of Pennsylvania and the study's lead author.



"Understanding more about how violence affects youth can help us develop more cost-effective and targeted interventions for our nation's young victims of violence," she added. "Because victims of abuse and neglect are at increased risk of witnessing and experiencing other forms of family violence, intervention efforts must focus not only on protecting children from re-victimization as it is defined legally, but work to decrease even non-abusive forms of physical discipline such as corporal punishment and the amount of adult domestic violence children witness in their homes."



In the study, family violence was defined as partner-on-partner abuse, including yelling, throwing an object, hitting, beating up, pointing or using a knife or gun, and dealing drugs, as well as adult-on-child abuse, including the above examples and spanking. Harsh physical discipline was defined as anything from an adult spanking a child to an adult choking a child.



The researchers studied a racially diverse group of 2,925 children ages 5 to 16 years. All of the children had been reported to Child Protective Services as suspected victims of abuse (for neglect as well as physical, sexual, and emotional abuse). Three times over a three-year period, the children's caregivers reported how much physical discipline they used with the children, and the children reported how much violence they saw in their homes. Caregivers also reported on the children's emotional and behavioral problems.



It can be difficult to determine whether a child's emotional and behavioral problems are the result of experiencing violence in the home or are caused by the other stressful events that many victims of family violence experience. The researchers used a type of statistical testing that allowed them to examine whether witnessing home violence and experiencing harsh physical discipline were associated with children's emotional and behavioral problems above and beyond the effects of other factors that predict childhood mental illness and are strongly tied to violence, including poverty and caregivers' mental health problems. They also took into consideration each child's age and gender, as well as normal expected changes in childhood mental health over time.







The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.



Summarized from Child Development, Vol. 79, Issue 5, Effects of Family Violence on Psychopathology Symptoms in Children Previously Exposed to Maltreatment by Maikovich, AK, Jaffee, SR (University of Pennsylvania), Odgers, CL (University of California, Irvine), and Gallop, R (West Chester University). Copyright 2008 The Society for Research in Child Development, Inc. All rights reserved.

FDA Approves Viibryd To Treat Major Depressive Disorder

The U.S. Food and Drug Administration approved Viibryd tablets (vilazodone hydrochloride) to treat major depressive disorder in adults.


Major depressive disorder, also called major depression, is characterized by symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Episodes of major depression often recur throughout a person's lifetime, although some may experience only a single occurrence.


Signs and symptoms of major depression include: depressed mood, loss of interest in usual activities, significant change in weight or appetite, insomnia or excessive sleeping (hypersomnia), restlessness/pacing (psychomotor agitation), increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicide attempts or thoughts of suicide. All people with major depression do not experience the same symptoms.


"Major depressive disorder is disabling and prevents a person from functioning normally," said Thomas Laughren, M.D., director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Medications affect everyone differently, so it is important to have a variety of treatment options available to patients who suffer from depression."


The most frequent adverse reactions reported by patients taking Viibryd in clinical trials included diarrhea, nausea, vomiting, and insomnia.


The drug will be available in 10, 20 and 40 milligram tablets.


Viibryd and all other antidepressant drugs have a boxed warning and a patient medication guide describing the increased risk of suicidal thinking and behavior in children, adolescents, and young adults ages 18 to 24 during initial treatment.


The warning also says data did not show this increased risk in adults older than 24 and that patients ages 65 and older who take antidepressants have a decreased risk of suicidal thinking and behavior. The warning says depression and other serious psychiatric disorders themselves are the most important causes of suicide and that close monitoring of patients starting these medications is necessary.


Viibryd is manufactured by PGxHealth, New Haven, Conn.

Targacept Announces Plans To Develop Enantiomer Of Mecamylamine As Augmentation Therapy For Depression

Targacept, Inc. (NASDAQ: TRGT), a clinical-stage biopharmaceutical company developing a new class of drugs known as NNR Therapeutics (TM), announced plans to advance TC-5214, one of two enantiomers of mecamylamine hydrochloride, into clinical development as an augmentation therapy for patients who are inadequate responders to first-line antidepressant treatments. Targacept expects to initiate a Phase 1 trial of TC-5214 in the first quarter of 2008 and to initiate Phase 2 development soon thereafter. The company has no current plans to conduct further clinical development of mecamylamine.


Mecamylamine hydrochloride is a racemic compound comprised of two mirror image halves known as the S+ and R- enantiomers. TC-5214 is the S+ enantiomer of mecamylamine. In a Phase 2 trial in patients who did not respond adequately to first-line treatment with citalopram hydrobromide that Targacept completed in 2006, patients whose citalopram regimen was augmented with mecamylamine showed greater improvement on symptoms of depression and irritability than patients who received citalopram and a placebo. Citalopram hydrobromide is a commonly prescribed treatment for depression from the drug class selective serotonin reuptake inhibitors that is marketed as Celexa® in the United States.


Targacept recently presented research findings comparing the activity of TC-5214, mecamylamine and the R- enantiomer of mecamylamine at the 20th European College of Neuropsychopharmacology held in Vienna, Austria. The results presented illustrate the superior potency of TC-5214 relative to mecamylamine at specific NNR subtypes believed to have therapeutic application for depression, as well as a favorable preclinical efficacy profile. In light of the Phase 2 results with mecamylamine described above, these findings suggest the compelling potential of TC-5214 as an augmentation treatment for major depression.


"Major depression is a serious medical illness affecting 15 million American adults, and the current treatment options simply are not adequate for many people," said Ranga Krishnan, M.D., Chair of the Department of Psychiatry at the Duke University Medical Center and an internationally recognized expert in depression treatments. "The results from Targacept's Phase II efficacy trial of mecamylamine as an augmentation therapy to citalopram helped establish the NNR mechanism as a potential new treatment paradigm for depression," said Dr. Krishnan. "The profile of TC-5214 as a more potent NNR modulator than racemic mecamylamine bodes well for its potential to help address the unmet need."


Targacept's poster of preclinical research findings of TC-5214 is available on the company's home page at targacept.















About Targacept


Targacept is a clinical-stage biopharmaceutical company that discovers and develops NNR Therapeutics (TM), a new class of drugs for the treatment of central nervous system diseases and disorders. Its product candidates selectively modulate neuronal nicotinic receptors that serve as key regulators of the nervous system to promote therapeutic effects and limit adverse side effects. Targacept has product candidates in development for Alzheimer's disease and cognitive deficits in schizophrenia, pain, and depression and anxiety disorders, as well as multiple preclinical programs. Targacept also has strategic alliances with AstraZeneca and GlaxoSmithKline. Additional information about Targacept is available at targacept.


Forward-Looking Statements


Any statements in this press release about strategies, prospects, plans, expectations or objectives for Targacept, Inc., including, without limitation, statements regarding the progress, timing or scope of the research and development of TC-5214, mecamylamine hydrochloride or any of our other product candidates or related regulatory filings or clinical trials, our future operations, financial position, revenues or costs, and all other statements that are not purely historical in nature, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "may," "will," "could," "would," "should," "expect," "intend," "plan," "anticipate," "believe," "estimate," "predict," "project," "potential," "promise," "continue," "ongoing" and similar expressions are intended to identify forward-looking statements. Actual results may differ materially from those expressed or implied by forward-looking statements as a result of various important factors, including our critical accounting policies and risks and uncertainties relating to: AstraZeneca's right in the future to terminate the preclinical research collaboration that we and AstraZeneca are currently conducting prior to the end of the planned four-year term; the results of clinical trials and non-clinical studies and assessments with respect to our current and future product candidates in development; the conduct of such trials, studies and assessments, including the performance of third parties that we engage to execute them and difficulties or delays in the completion of patient enrollment or data analysis; the timing and success of submission, acceptance and approval of regulatory filings; our ability to obtain substantial additional funding and our ability to establish additional strategic collaborations. These and other risks and uncertainties are described in greater detail under the heading "Risk Factors" in our most recent Annual Report on Form 10-K and in other filings that we make with the Securities and Exchange Commission. As a result of the risks and uncertainties, the results or events indicated by the forward-looking statements may not occur. We caution you not to place undue reliance on any forward-looking statement.


In addition, any forward-looking statements in this press release represent our views only as of the date of this release and should not be relied upon as representing our views as of any subsequent date. We anticipate that subsequent events and developments may cause our views to change. Although we may elect to update these forward-looking statements publicly at some point in the future, whether as a result of new information, future events or otherwise, we specifically disclaim any obligation to do so, except as required by applicable law. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make.


NNR Therapeutics(TM) is a trademark of Targacept, Inc. Other service marks, trademarks and trade names appearing in this press release are the property of their respective owners.




View drug information on Celexa.

Being Depressed And Hostile Increases The Mortality Risk

This study conducted on a sample of 20,625 employees of the French national gas and electricity companies demonstrates that being depressed and hostile increases the mortality risk.


Depressive mood is associated with mortality. Because personality has been found to be associated with depression and mortality as well, a group of French investigators aim to test whether depressive mood could predict mortality when adjusting for several measures of personality. 20,625 employees of the French national gas and electricity companies gave consent to enter in the GAZEL cohort in 1989. Questionnaires were mailed in 1993 to assess depressive mood, type A behavior pattern, hostility, and the six personality types proposed by Grossarth-Maticek and Eysenck. Vital status and date of death were obtained annually for all participants. The association between psychological variables and mortality was measured by the Relative Index of Inequality (RII) computed through Cox regression. 14,356 members of the GAZEL cohort (10,916 men, mean age: 49 years; 3,965 women, mean age: 46 years) completed the depressive mood scale and at least one personality scale. During a mean follow-up of 14.8 years, 687 participants had died. Depressive mood predicted mortality, even after adjustment for age, sex, education level, body mass index, alcohol consumption, and smoking [RII (95% CI) = 1.56 (1.16 - 2.11)]. However, this association was dramatically reduced (RII reduction: 78.9%) after further adjustment for cognitive hostility (i.e. hostile thoughts) [RII (95% CI) = 1.12 (0.80 - 1.57)]. Cognitive hostility was the only personality measure remaining associated with mortality after adjustment for depressive mood [RII (95% CI) = 1.97 (1.39 - 2.77)]. Cognitive hostility may either confound or mediate the association between depressive mood and mortality.