Thursday, November 25, 2010

From Cognition to Genomics: Progress in Schizophrenia Research

Thomas Insel
NIMH


This week’s issue of Nature has a special section dedicated to research progress on schizophrenia.i There have been few such issues dedicated to any medical disorder, so this is a landmark for schizophrenia research, a follow-up perhaps to an editorial in Nature at the beginning of this year predicting a “decade for psychiatric disorders”.ii But beyond the mere fact that schizophrenia has been singled out for this distinction, the contents document remarkable progress on a disorder that has been such a conundrum for the past century.

For one thing, schizophrenia can now be described as a brain disorder or, more precisely, as a disorder of brain circuits. With neuroimaging, several of the major nodes in the circuit have been identified, especially within the prefrontal cortex. A major advance has been linking changes in circuit function to cognition and behavior. As a result, we are increasingly focusing on the cognitive deficits of schizophrenia as the core problem, preceding and perhaps leading to the more obvious positive symptoms of hallucinations and delusions.

Another area of unambiguous progress has been genomics. Five years ago the field was frustrated by the lack of replicated findings. With the creation of international consortia sharing data from thousands of patients, we can now see several of the major risk genes. They are not the usual suspects, such as genes involved in dopamine or serotonin neurotransmission. Common variants in genes from the MHC complex, which is important for immune self-recognition, a gene for a transcription factor called TCF4, and several genes that encode synaptic proteins have all been found to confer increased risk. The list is probably not complete as together these explain only a fraction of the genetic risk for the disorder. Many rare variants have also been described in the past year, adding to the known major structural lesions like DISC1 and the 22q11 deletion. These rare events may explain only a small fraction of cases, but as with hypertension and cancer, even rare mutations that cause disease can yield important clues to the pathophysiology underlying more common forms of disease.

From genomics have come clues to the importance of reconceptualizing schizophrenia as a neurodevelopmental disorder. Many of the genetic factors are involved with neurodevelopment; hardly surprising as thousands of genes must be expressed in a carefully choreographed sequence to develop a healthy brain. What is unexpected is that many of the genetic variations associated with schizophrenia appear to disrupt fragments of proteins expressed only in fetal development. And experimental reductions of DISC1 transiently during fetal development in mice have profound effects on physiology and behavior, emerging only in early adulthood. These kinds of observations, along with reports of prenatal and perinatal environmental factors that increase risk for schizophrenia, point to a model of schizophrenia that begins early in life, with subtle cognitive effects through much of development, and emergence of psychosis as a late stage in early adulthood.

If psychosis is a late stage of schizophrenia, analogous to myocardial infarction in coronary artery disease, then we need to develop biomarkers for early detection and treatments that can preempt psychosis. This is where the next decade of research could lead. If the core deficits are cognitive, the “biomarker” for detection might be a working memory task or some assessment of executive function. And the treatments to preempt psychosis might not resemble anti-psychotic medications. Instead of medication, imagine brain training to rewire the circuitry just as we use exercise to reduce cardiac risk. Continuing the coronary artery disease analogy, drugs such as marijuana might be, for someone at risk for psychosis, analogous to the high lipid diet for someone at risk for coronary disease: something that needs to be avoided.

Over the past half-century, we have learned to diagnose coronary artery disease well before a heart attack using tests of cardiovascular risk factors and function. We have averted millions of cardiac deaths through preventive measures such as diet, exercise, and medications for those at risk. For the past century, schizophrenia has been defined by psychosis and we have made too little progress for too many people challenged by this disorder. This issue of Nature marks new hope that we can develop a preemptive approach to schizophrenia, as done for cardiac disease.

There have been many apparent breakthroughs for schizophrenia over the past several decades, followed by non-replication or findings suggesting lack of treatment effectiveness. Finally, we are making real progress on many fronts, from cognition to genomics. As the articles in Nature note, we still have a long way to go. But this is an important moment to recognize – the “decade for psychiatric disorders” has begun.

Source link: http://www.nimh.nih.gov/about/director/2010/from-cognition-to-genomics-progress-in-schizophrenia-research.shtml

Sunday, November 14, 2010

Spotlight on Postpartum Depression

Thomas Insel
National Institute of Mental Health (NIMH)

The postpartum period is a time of major adjustment for new parents. Biological changes in mothers that occur after childbirth are often accompanied by significant changes in family roles and responsibilities as well. Generally, postpartum depression (PPD) is thought to be associated with the drastic changes in hormone levels that occur during and just after pregnancy. Couple that with the daunting challenges associated with caring for a newborn, and the estimated 7 to 13 percent prevalence rate i becomes less surprising. And likely, that number is on the low side because like many mental disorders, PPD is generally under-recognized and under-treated. Recently, disorders during the postpartum period have also been described in new fathers. ii

Congress has taken note of the seriousness of PPD as well. The Affordable Care Act of 2010 specifically mentions the need “to continue activities on postpartum [conditions]…including research to expand the understanding of the causes of, and treatments for, postpartum conditions." iii

Consistent with Congressional interest, NIMH recently convened a workshop to encourage innovative research in PPD and other mood disorders that emerge during and after pregnancy. Participants discussed ways to optimize the use of currently available treatments based on a better understanding of individual differences among women. Studies of these individual differences, based on biomarkers, personal history or clinical features, will pave the path to personalized medicine. Meeting participants also discussed how to align new PPD research approaches with broader NIMH priority areas. These include research on comparative effectiveness, cost effectiveness, and global mental health.

The current recommended treatments for women with PPD generally follow the course for any type of major depressive disorder (MDD) and include medication and psychotherapy. We now know that pregnancy is not protective against mental health disorders, and stopping antidepressants during pregnancy may lead to relapse. iv In addition, a mother’s depression can have physical effects on the fetus. But questions remain about how antidepressants affect a growing fetus or nursing baby. v Many pregnant or postpartum women choose not to take these medications. And although psychotherapy has been shown to be effective, getting access to evidence-based treatment can be difficult. So the need for alternatives, better treatments, and better delivery of services is great.

What new treatments are on the horizon? In preliminary trials, 17-beta estradiol, a form of estrogen, was shown to have a relatively rapid antidepressant effect in women with PPD, faster than typical antidepressant medications like SSRIs, which can take up to 8 weeks to start working. And unlike antidepressants, evidence suggests that the increased levels of estrogen associated with the treatment are not detected in breast milk, and therefore presumably do not pass to the nursing newborn. vi

Another NIMH study is modeling the effects of the normal hormonal changes in pregnancy and the postpartum period in non-pregnant women with a history of PPD, and comparing their progress with healthy volunteers. The study is testing whether hormonal events during the postpartum period trigger mood changes in women with PPD. It will serve as a source of information about both the biology of PPD and the factors that could put a woman at risk for developing it. Both of these studies provide evidence that the change in estrogen levels during the postpartum period may be a primary hormonal trigger for PPD.

Other studies are looking at the pathophysiology of PPD by identifying changes in the pregnant and postpartum brain that may help us better understand the neurochemical vulnerability to this disorder. vii In particular, neurosteroids, some of which are the products of progesterone, have long been suspected as mediators of anxiety and recently have been implicated in PPD. In animal studies, the normal massive increase in neurosteroids during pregnancy and precipitous decline at childbirth is usually compensated by a change in GABA receptors in the cortex of the brain. Mice without this compensatory GABA receptor change manifest many of the features of postpartum depression, including profound deficits in maternal care.

We know that women with a history of depression are at higher risk for PPD. What can we do to prevent it? Prevention is still a “work in progress." For example, current NIMH-funded research is investigating cognitive therapy and exercise programs to prevent PPD in pregnant women who are at high risk for PPD. NIMH is also funding studies to improve screening for PPD, web-based interventions and treatment models that use home visits.

These studies are a good start. But we still have a long way to go in treating and preventing PPD, and understanding its long-term impact on families.

Source link: http://www.nimh.nih.gov/about/director/2010/spotlight-on-postpartum-depression.shtml

Saturday, October 30, 2010

In children, hallucinations are not always a sign of psychosis

Current Psychiatry
Vol. 9, No. 10 / October 2010

Although hallucinations frequently are considered synonymous with psychotic disorders, in children this rare. Neurobiologic studies (fMRI) of adults show activation of Broca’s area (left inferior frontal gyrus) seconds before patients perceive auditory verbal hallucinations, which suggests that auditory hallucinations may be misidentified self-talk.a,b According to Piaget,c children age <7 may have difficulty distinguishing between events occurring while dreaming and awake. He further theorized that nonpathologic hallucinations could become pathologic when combined with trauma such as abuse. Straussd suggested that psychosis might lie on a continuum with normal phenomenon. In a case series, Wilking and Paulie described how developmental difficulties, deprivation, sociocultural conditions, and family relationships could contribute to impaired reality testing. Imaginary friends or companions are common among all children. Children who have imaginary friends are more likely to report hearing “voices.”f Imaginary friends: * appear, function, and disappear at the wish of the child * pose no threat and often are a source of comfort * often can be described in detail * are not ego-dystonic Also, children with imaginary friends will not show evidence of a thought disorder.

Full text: http://www.currentpsychiatry.com/article_pages.asp?aid=8973

Brain Molecule May Offer Key to Erasing Fearful Memories

by Jon Hamilton

Scientists have discovered a molecule in the brain that may help erase the fearful memories that afflict people with post-traumatic stress disorder.

The substance, described in an online edition of the journal Science, was found in mice. But it's part of a memory system that seems to work the same way in people.

Roger Clem and Richard Huganir of the Johns Hopkins University School of Medicine made the discovery while studying mice conditioned to associate a particular sound with an electric shock.

"If they hear the tone the next day, or even weeks later, the mouse will freeze" because it will bring up the fearful memory of the shock, Huganir tells Shots.

Clem and Huganir wanted to understand how that fearful memory is created.

So they studied the brains of mice that had just gone through fear conditioning. And they noticed that an unusual protein appeared in the amygdala, a part of the brain involved in emotions.

That molecule remained for only a few days and appeared to strengthen the brain circuit responsible for maintaining the fearful memory.

But when the researchers eliminated the protein during this period, mice lost their fearful memory. Forever.

The trick was to eliminate the protein soon after a fearful incident, Huganir says.

"Maybe this is a window of time when behavioral therapy would work much better," Huganir says, adding that it may also be possible to eliminate the protein with drugs.

And he says research on people suggests that it may be possible to create a new window for treatment by having people deliberately recall a fearful memory.

Researchers from New York University found that when people did that, there was a 6-hour window in which the original memory could be altered permanently through behavioral techniques.

Experiments in rodents suggest that's because the molecule involved in fear memories appears once again in the amygdala, Huganir says.

If so, he says, it may be possible to eliminate a person's unwanted memory during the critical period by giving a drug that interferes with the fear molecule.

Source link: http://www.npr.org/blogs/health/2010/10/29/130913234/brain-molecule-may-offer-key-to-erasing-fearful-memories-treating-ptsd?ft=1&f=1007

Thursday, October 28, 2010

Reversal of Depressed Behaviors in Mice by p11 Gene Therapy in the Nucleus Accumbens

Sci Transl Med 20 October 2010:  Vol. 2, Issue 54, p. 54ra76
ABSTRACT

The etiology of major depression remains unknown, but dysfunction of serotonergic signaling has long been implicated in the pathophysiology of this disorder. p11 is an S100 family member recently identified as a serotonin 1B [5-hydroxytryptamine 1B (5-HT1B)] and serotonin 4 (5-HT4) receptor–binding protein. Mutant mice in which p11 is deleted show depression-like behaviors, suggesting that p11 may be a mediator of affective disorder pathophysiology. Using somatic gene transfer, we have now identified the nucleus accumbens as a key site of p11 action. Reduction of p11 with adeno-associated virus (AAV)–mediated RNA interference in the nucleus accumbens, but not in the anterior cingulate, of normal adult mice resulted in depression-like behaviors nearly identical to those seen in p11 knockout mice. Restoration of p11 expression specifically in the nucleus accumbens of p11 knockout mice normalized depression-like behaviors. Human nucleus accumbens tissue shows a significant reduction of p11 protein in depressed patients when compared to matched healthy controls. These results suggest that p11 loss in rodent and human nucleus accumbens may contribute to the pathophysiology of depression. Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.

Source link: http://stm.sciencemag.org/content/2/54/54ra76.abstract

Full Text: http://stm.sciencemag.org/content/2/54/54ra76.full

Tuesday, October 26, 2010

Nature Neuroscience: November 2010, Volume 13 No 11 pp1299-1440

Meridia (sibutramine): Market Withdrawal Due to Risk of Serious Cardiovascular Events

FDA U.S. Food and Drug Administration

AUDIENCE: Primary Care, Consumers

ISSUE: Abbott Laboratories and FDA notified healthcare professionals and patients about the voluntary withdrawal of Meridia (sibutramine), an obesity drug, from the U.S. market because of clinical trial data indicating an increased risk of heart attack and stroke.

BACKGROUND: Meridia was approved November 1997 for weight loss and maintenance of weight loss in obese people, as well as in certain overweight people with other risks for heart disease. The approval was based on clinical data showing that more people receiving sibutramine lost at least 5 percent of their body weight than people on placebo who relied on diet and exercise alone. FDA has now requested market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT). SCOUT is part of a postmarket requirement to look at cardiovascular safety of sibutramine after the European approval of the drug. The trial demonstrated a 16 percent increase in the risk of serious heart events, including non-fatal heart attack, non-fatal stroke, the need to be resuscitated once the heart stopped, and death, in a group of patients given sibutramine compared with another given placebo. There was a small difference in weight loss between the placebo group and the group that received sibutramine.

RECOMMENDATION: Physicians are advised to stop prescribing Meridia to their patients, and patients should stop taking this medication. Patients should talk to their health care provider about alternative weight loss and weight loss maintenance programs.

Source link: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm228830.htm