Psychiatr News January 18, 2008
Volume 43, Number 2, page 28
© 2008 American Psychiatric Association
Neuroplasticity Studies Give Hope for Treatment Advances
Lynne Lamberg
Advances are occuring rapidly in knowledge about brain plasticity and
its role in mental illness. Researchers hope their findings will eventually
lead to new treatment options for bipolar and other psychiatric
disorders.
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>.
Related Article:
-
Neuroimaging Highlights Need for Early BPD Treatment
Psychiatr News 2008 43: 30.
[Full Text]
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