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

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