Neuroplasticity Studies Give Hope for Treatment Advances
Neuroplasticity studies are offering both new insight into causes of psychiatric disorders and the potential for novel therapies.
Findings from neuroplasticity research may enable clinicians to provide faster, more effective treatment for bipolar disorder (BPD) and other chronic psychiatric illnesses, with fewer adverse effects than current treatments do. This research also suggests new strategies to correct underlying vulnerabilities that prompt recurrences of these disorders.
Studies conducted in the past decade illuminate normal functioning of nerve-cell signaling pathways that allow the brain to adapt to its ever-changing environment. They also highlight negative consequences for overall health of breakdowns in this process.
A dozen reviews exploring recent advances in brain plasticity in psychiatric disorders appear in the January Neuropsychopharmacology Reviews, the journal's inaugural annual review issue.
In the search to clarify biological underpinnings of mood disorders, the new focus on brain plasticity is a major departure from the study of absolute changes in neurochemicals such as monoamines and neuropeptides—the prime focus of research in the field for the past 40 years—according to a report on neuroplasticity in BPD by Husseini Manji, M.D., director of the mood and anxiety disorders research program at the National Institute of Mental Health (NIMH), and colleagues.
Robert Schloesser, a predoctoral fellow, and Jian Huang, Ph.D., working with Manji in the NIMH Laboratory of Molecular Pathophysiology, are co-first authors of this paper.
Mood disorders “can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters,” the researchers said.
The “here and now” symptoms of BPD, such as profound mood swings, racing thoughts, and frenetic energy, are thought to stem from faulty information processing along nerve-cell signaling pathways known as cellular plasticity cascades, they said.
Many hormones implicated in the pathophysiology of BPD and other mood disorders, including gonadal steroids, thyroid hormones, and glucocorticoids, act on cellular plasticity cascades.
Long-lasting abnormalities in these pathways likely cause brain-cell loss and atrophy of both neurons and glia, the researchers added. Since these pathways regulate diverse physiologic functions, persistent abnormalities also may trigger many of the medical comorbidities associated with BPD, such as cardiovascular disease, diabetes, obesity, and thyroid disease.
While some existing medications act on these pathways, current treatment for BPD leaves much to be desired, Manji said. “We can get people out of an acute manic crisis,” he noted, “but two years later, perhaps only 40 percent have returned to their previous level of functioning. After several episodes, people often function quite poorly.”
Pilot studies suggest plasticity-enhancing medications may bring more precise and speedier relief for acute mania than present therapies and may reduce the frequency and severity of extreme mood cycling.
Today's most effective antidepressant medications increase intrasynaptic levels of serotonin and/or norepinephrine in the brain, but take days to weeks to exert their clinical antidepressant effects. This time lag, Manji said, suggests a cascade of downstream events produces their therapeutic benefits.
Lithium remains the most effective therapy for the disorder. Taken consistently, it helps stabilize mood and reverses some of the deterioration shown in neuroimaging studies. It increases the volume of gray matter, for example.
Lithium's adverse effects have prompted an ongoing search for a replacement with similar efficacy but fewer disadvantages. Scientists have found several direct targets of lithium in the brain, including the enzyme protein kinase C, thought to be overactive in the manic phase of BPD.
The only medication other than lithium approved for human use that crosses the blood-brain barrier and blocks protein kinase C is tamoxifen, the most widely used hormonal therapy for breast cancer.
Carlos Zarate Jr., M.D., chief of experimental therapeutics in NIMH's mood and anxiety disorders research program, working with Manji and others, assessed tamoxifen's effects in BPD.
The researchers randomly assigned 16 adults with BPD who were experiencing an acute manic episode to receive either tamoxifen or a placebo for three weeks. In five of the eight who received tamoxifen, but only one of the eight who received the placebo, symptoms of mania subsided significantly within five days. This improvement obtained with tamoxifen was sustained for the rest of the study, the researchers reported in the September 2007 Bipolar Disorders.
Tamoxifen is not ready for prime time, Zarate said. Its long-term use would pose an increased risk of endometrial cancer. This and a few other small studies suggest, however, that protein kinase C inhibitors hold promise for treating acute episodes of mania and warrant larger, controlled trials.
In other reports in the forthcoming Neuropsychopharmacology Reviews, Gregory Quirk, Ph.D., and Devin Mueller, Ph.D., of the Department of Psychiatry at the University of Puerto Rico School of Medicine, describe efforts to develop novel pharmacological treatments targeting cellular plasticity cascades to reduce exaggerated fear responses in anxiety disorders and erase traumatic memories.
Judith Rapoport, M.D., chief of NIMH's Child Psychiatry Branch, and Nitin Gogtay, M.D., an NIMH staff physician, discussed longitudinal, noninvasive, brain-imaging studies showing evidence of brain shrinkage in children with schizophrenia and children with attention-deficit/hyperactivity disorder, two conditions that the researchers say may be, in part, disorders of brain plasticity.
The articles on neuroplasticity in Neuropsychopharmacology Reviews can be accessed at<www.nature.com/nppr/index.html>. An NIMH publication on BPD in children is posted at<www.nimh.nih.gov/about/director/updates/2007/nimh-perspective-on-diagnosing-and-treating-bipolar-disorder-in-children.shtml>.▪
