E
DITORIAL
Structural Plasticity: Cause, Result, or Correlate of
Depression
The articles in this issue of Biological Psychiatry are derived from oral presentations at a conference, “Depres-sion in the 21st Century: New Insight into Drug Develop-ment and Neurobiology,” held February 2–22, 2000 in Dana Point, California. The speakers represented a range of clinical practitioners, pathologists, and preclinical in-vestigators, with strong focus on the neurobiology of mood disorders, as well as a few basic scientists like myself who had a strong interest in the field but little experience with directly relevant models. My comments here reflect a view of biological psychiatry from the perspective of a generalist observing a fast moving field, integrating basic observations in neurobiology with clini-cally defined problems.
Biological Psychiatryhas emerged in parallel with, and as a result of, strong evidence that mood disorders have neurochemical consequences, in addition to the hypothesis that neurochemical alterations are causally related to mood disorders. The appreciation for the neurochemical basis of psychiatric disorders has led to a global hypothesis that a biochemical imbalance of neurotransmitter systems can cause disease. In addition, this hypothesis has led to effective strategies for pharmacologic intervention. Recent advances in molecular biology have led to the investiga-tion of the cellular and molecular mechanism underlying the observed neurochemical imbalance.
More recently, evidence has accumulated supporting the persistence of “structural plasticity” in the adult brain. The plasticity is reflected both in the birth of new cells in the adult brain and in the death of genetically healthy cells in response to the individual’s interaction with the environ-ment. Of converging relevance to mood disorder are the reports that the limbic structures (particularly the hip-pocampus and, very specifically, the dentate gyrus) con-tain proliferating populations of cells that can give rise to granular cell neurons throughout life in all species. Impor-tantly, the rate of cell birth or cell genesis, as well as survival and neural differentiation, is regulated by experi-ence. Growing evidence supports the view that experimen-tal paradigms that are designed to simulate stress result in some combination of a decrease in cell proliferation, cell differentiation, or survival. A combination of these obser-vations has led to the suggestion that mood disorders may be caused by, or result in, structural changes in the brain. It is this hypothesis that the majority of the articles in this issue ofBiological Psychiatryaddress.
The reviews here are timely and represent the rapid pace
at which modern biology is moving. Three articles provide the foundation and context within which to consider structural changes, being relevant to affective disorders. McEwen (2000) outlines the importance of considering stress and stress hormones in relationship to psychiatric disorders and, in particular, emphasizes how glucocorti-coids may interact with other neurotransmitter systems to amplify structural changes in the brain, particularly in the hippocampus. Sapolsky (2000) specifically addresses the mechanisms that may be responsible for the neuronal cell death that can occur with major depression and makes a strong case that the elevated levels of glucocorticoids that occur during stress may play an important contributing role in the process of cell death. Gould et al (2000) focus on the ongoing neurogenesis that occurs in the adult dentate gyrus of the hippocampus and review some of the external factors that appear to regulate the production and survival of these neurons. Given the potential importance of the hippocampus in affective disorders, the forms of structural plasticity that are summarized in these three articles are likely very important, and several of the other reviews in this issue build on these initial observations. Specifically, Duman et al (2000) present a plausible scenario wherein major depression and other affective disorders could result in loss of neuroplasticity. They argue through review of emerging data that loss of neural plasticity and synaptic interaction could directly contribute to a loss of neurotrophic action and thus cell survival and synaptic efficacy, a truly vicious cycle. Duman et al compellingly and thoroughly summarize the intracellular signaling cascades that may be responsible for these actions, drawing from preclinical and clinical data, much from their own results. Manji et al (2000) present an interesting set of data that take as a starting point the clear mood-stabilizing effects of lithium and valproate. The link between structural changes and these drugs comes from the recent observations that lithium has a robust effect on the expression of Bcl-2, an antiapoptotic protein, as well as neurotrophic activity, by influencing intracellular sig-naling. These findings provide for clear hypotheses to test for the direct action of the mood stabilizers on structural maintenance and repair. Kaufman et al (2000) take the specific example of child abuse and the subsequent ele-vated rates of major depression and other psychiatric disorders in adulthood to summarize the more recent evidence for mechanisms that could account for long-term changes in the brain due to early experience. Evidence is
© 2000 Society of Biological Psychiatry 0006-3223/00/$20.00
presented for short changes in several components of the hypothalamic–pituitary–adrenal axis, the monaminergic systems, and the g-aminobutyric acid system as being
potential causes of long structural changes due to early experience. Identification of these systems suggests clear targets for intervention to facilitate recovery from early stress.
Several reviews summarize the recent evidence for structural changes in patients with affective disorders using standard pathologic methods, as well as newly developed imaging techniques. Importantly, Sheline (2000) summarizes her important results showing that with high-resolution three-dimensional magnetic reso-nance imaging detectable changes are reported in several areas in association with early-onset major depression, with the most consistent changes occurring in the volume of the hippocampus. Though at present the nature of the volume loss is not known, this is critical informa-tion. Corroboration of these findings was presented by Rajkowska (2000), who showed that, in postmortem stud-ies, neuronal and glial histopathology related to major depression and bipolar disorder in both the prefrontal cortex and the hippocampal gyrus. The prefrontal cortex changes detected in postmortem tissue are further corrob-orated by Drevets (2000) with neuroimaging studies using cerebral blood flow that reveal persistent physiologic abnormalities in the orbital and medial prefrontal cortex in patients with mood disorders. New developments in neu-roimaging tracers have made it possible to ask very specific questions about the function of specific neuro-transmitter systems. In particular, Fujita et al (2000) summarize the recent findings with the new 5-HT2Aand
5-HT1Areceptor imaging tracers to study serotonin
neu-rotransmission in depressive disorders. Although the re-sults are not fully consistent at present, the variability likely reflects the heterogeneity in what are now consid-ered more homogeneous disorders. The use of imaging techniques to reveal heterogeneity is dramatically demon-strated in the article by Mayberg et al (2000), in which they examine the differences in brain glucose metabolism using 18fluorodeoxyglucose positron emission
tomogra-phy in hospitalized unipolar depressed patients treated with fluoxetine. They report clear and interesting differ-ences between patients who respond to fluoxetine and those who do not, which appear to be associated with a failure of adaptive neural changes in the nonresponsive group, once again revealing perhaps a physiologic basis for heterogeneity.
Clearly, this is an exciting field of study, and the
evidence supporting structural changes in major depres-sion is likely to have significant impact on diagnosis, treatment, and therapy. A clearer understanding of the cellular and molecular mechanisms underlying structural plasticity will be essential for the further rapid and rational development in this field. What seems to be happening is that the clear hypothesis of the importance of structural changes in mood disorders is forcing the development of new methods, particularly in imaging and cell and molec-ular biology, to test the validity of this hypothesis.
Fred H. Gage
Salk Institute for Biological Studies Laboratory of Genetics
10010 North Torrey Pines Road La Jolla CA 92037
References
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714 BIOL PSYCHIATRY Editorial
