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Medical Updates
Neuroplasticity, Early Intervention, and a Personalized Medicine Approach

Neuroplasticity refers to the brain's innate capacity to adapt to environmental demands. This adaptation can be as simple as learning a new skill or as complex as recovering brain function after injury. The brain responds to these challenges by becoming more efficient--by strengthening synaptic connections between neurons or by creating new neurons in the hippocampal region of the brain, a process known as neurogenesis. Recent research indicates that antidepressants may act by promoting neuroplasticity and neurogenesis. This is accomplished by the release of growth factors such as "brain-derived neurotrophic factor" (BDNF), which stimulate the production of new neurons and the formation of synaptic connections.

Deficient neuroplasticity may play a role early in the course of schizophrenia. Several studies have found that blood levels of the growth factor, BDNF, are low in people who develop the illness. The activity of BDNF in the brain can be estimated by analysis of a person's BDNF genotype or by measuring the level of BDNF expression in lymphocytes (blood cells). In two studies these approaches have strongly linked BDNF deficiency to a loss of brain volume in early-stage schizophrenia, which in turn has been associated with a decline in functioning and with memory deficits.

Recently investigators have found that activities that stimulate neuroplasticity and neurogenesis may have a therapeutic role in schizophrenia. For example, physical exercise (30 minutes on a stationary bicycle daily) increased hippocampal brain volume and improved memory in healthy subjects and in people with schizophrenia. Similarly, cognitive remediation (computerized memory exercises) combined with social skills group therapy protected against brain volume loss and improved memory early in the course of schizophrenia. These findings suggest that we might be able to identify individuals with low levels of BDNF activity and intervene early to prevent progression of the illness. Treatment with an antidepressant combined with psychosocial interventions is a particularly promising approach to restore neuroplasticity and promote neurogenesis early in the course of schizophrenia.

While at Harvard, I received a grant from the National Institute of Mental Health (NIMH) to evaluate the potential benefit of antidepressant treatment as an early intervention in schizophrenia and am now in the process of moving this project to Bellevue Hospital. Surprisingly, this has not been studied before despite the fact that depression is quite common in first episode psychosis and is associated with demoralization, relapse and increased risk for suicide. After a thorough evaluation and stabilization with optimal treatment for their condition, we invite individuals to participate in a year-long trial of an antidepressant or inactive placebo while we carefully monitor their response to treatment and perform brain scans at regular intervals. It is our hope that by use of "biomarkers" including the BDNF genotype, and other measures of BDNF activity, we will be able to identify those individuals who benefit from early intervention with an antidepressant. This approach is an example of "personalized medicine" in which treatments are individualized according to a person's unique biology.

In another example of personalized medicine, my colleague Josh Roffman and I found in several studies of people with schizophrenia that low intake of the vitamin folic acid, combined with a genetic vulnerability that reduces their ability to absorb and activate folic acid is associated with negative symptoms (apathy and loss of emotional expressiveness). In a small "pilot trial" and more recently in a larger study conducted at several centers we found that folate supplementation improves negative symptoms but only in those individuals with the genetic vulnerability.

Although still at an early stage, the translation of recent discoveries in neuroscience into an individualized, early intervention approach raises the hope that we will be able to improve the long-term trajectory of psychiatric illness and possibly prevent development of psychiatric illness in some vulnerable individuals.

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