| By the year 2020, The World Health Organization (WHO) estimates depression
will be the number-two cause of "lost years of healthy life" worldwide
-- second only to ischemic heart disease.(1) Currently, an estimated 340
million people suffer from depression worldwide -- approximately 17 million
Americans. Of those, less than half are properly diagnosed.(2)
Depression is a chronic disorder with high levels of social and occupational impairment. With symptoms ranging from low moods and irritability to thoughts of suicide, depression can have a devastating effect on not only the lives of the sufferers, but also those of their families and friends. Disease symptoms can be so disabling that they impact all social and work activities, disrupting the day-to-day lives of patients and those surrounding them. In fact, due in large part to the extensive loss in productivity, the economic cost of depression is estimated at more than $44 billion per year in the United States alone. Depression costs lives as well — for those who have been hospitalized with depression, an estimated 15 percent will commit suicide.(3) According to the U.S. Centers for Disease Control and Prevention (CDC), suicide is the ninth leading cause of death in the United States, claiming 30,862 lives in 1996. Because of the number of cases where cause of death is difficult to determine, many investigators feel even this number is a gross underestimation of suicides.(4) Who Suffers from Depression? Research has been, and continues to be, conducted on the mechanisms behind depression, involving a complex mix of emotional and biological factors. There is not one clear answer for all depressed patients. Although depression can affect anyone of any gender, age, ethnicity and social class, women experience depression at roughly twice the rate of men.(5) One-third of the population will have at least a mild episode of depression during their lifetime(6) and about 15 percent of the general public will suffer from major depressive disorder sometime in their life. Unfortunately, the disorder will be accurately diagnosed and treated in only one in three.(7) Major life events, such as important losses or stressful circumstances, can trigger depression. However, some people may be genetically predisposed to developing the disease.(8) Those most at risk of developing depression are young adults, women (especially after giving birth), people who have a family history of depression, people with a physical illness (especially a chronic disease) and alcoholics.(9) The disease is also highly prevalent in the elderly, and often misdiagnosed, unrecognized or masked by underlying ailments or cognitive deficits.(10) Symptoms of Depression According to the American Psychiatric Association (APA), psychological symptoms of depression can include: Physical symptoms can include:
Despite the overwhelming statistics surrounding the disease, only about one in ten people suffering from depression receive adequate treatment.(12) This is due to a number of both patient- and physician-based reasons. Patients are often reluctant to visit a mental healthcare specialist due to the stigma attached to mental illness. Other patient-based reasons include their failure to recognize the symptoms, their underestimation of the severity of depression and a lack of adequate insurance reimbursement.(13) Physician-based reasons often stem from the amount of time psychiatric disorders take to diagnose and treat, which is more time than is usually needed for many other medical conditions. Prescribing insufficient antidepressant medications for inadequate time periods, poor insurance coverage and fear of offending the patient also contribute to the problem.(14) Diagnosis can be difficult for the healthcare provider. Patients may describe a variety of symptoms — insomnia, lack of energy, loss of appetite, anxiety — which could be due to any one of a number of medical or non-medical reasons. Patients may also focus on physical symptoms, which can mislead the healthcare provider. Depressed patients often hide their feelings, especially their negative thoughts, due to shame or embarrassment. Many people who are suffering from depression do not even seek medical attention. They may not want to admit that they need help or they may not think their symptoms are serious enough to visit a professional. In some cases, they may simply not have the energy and motivation to make, or follow through with, an appointment. Sadly, of those depressed people who do consult their doctor, only half will be diagnosed correctly on the first visit.(15) When a patient does present with a particular combination of symptoms,
a diagnosis of "major depressive disorder," or MDD, can be made. This term
describes the syndrome, not the severity of the disease, which can be mild,
moderate or severe.(16) Criteria for a diagnosis of major depressive episode
include five or more of the following symptoms present nearly every day
during the same two-week period; at least one of the symptoms must be either
1) a depressed mood or 2) a loss of interest or pleasure. Other symptoms
are as follows:
The presence of major depression and other depressive disorders is often an indication of a need for drug treatment.(18) Medication is usually prescribed in conjunction with counseling, psychotherapy or cognitive treatments, all of which help the patient to manage undesirable behavior patterns.(19) In more than 80 percent of cases, depression can be effectively treated.(20) As the disease has been linked to abnormal levels of neurotransmitters (biochemicals that are released by brain cells) such as norepinephrine and serotonin, treatment of the disease aims to correct these imbalances. In recent years, research has been primarily focused on serotonin. However, scientists have indicated that serotonin is not the only neurotransmitter involved in clinical depression. New research is looking at the role that norepinephrine plays in this disease, and new treatments targeting this neurotransmitter may provide patients with an alternative to current serotonin-focused therapies. Researchers believe that of those who are treated with antidepressants, 20-25 percent will experience full remission of depression, 30-45 percent will partially respond to medication, 25-35 percent will not respond and 10-25 percent will not be helped due to lack of tolerability of the medications.(21) Successful treatment, however, depends on a range of factors, including the choice of drug, its dosage, duration of treatment, individual patient response and patient compliance. An estimated 50 percent of failed treatment is because patients stop taking their medication too soon. Reasons patients give up treatment prematurely include the fear of relying on the drug too much or becoming addicted, unacceptable side effects and feeling better (leading them to believe that continuing treatment is unnecessary).(22) The Antidepressants Tricyclic antidepressants (TCAs) block both norepinephrine and serotonin reuptake. They are effective antidepressants, but they also affect many other receptor systems, which may cause a wide range of side effects, as well as toxicity in overdose.(23) Side effects may include dry mouth and constipation. Selective serotonin reuptake inhibitors (SSRIs) have minimal efficacy advantages over TCAs, and may even be less effective in some cases of severe depression. However, they are less toxic in overdose. Although side effects for SSRIs are generally fewer in number, they are often less acceptable to patients (e.g., nausea, headache and sexual dysfunction). Serotonin and norepinephrine reuptake inhibitors (SNRIs) were, in theory, designed to combine the actions of both neurotransmitters. In practice, however, SNRIs' primary effect is on serotonin unless taken in higher doses (with a concurrent risk and range of side effects). At standard doses, side effects are similar to those seen with SSRIs. Norepinephrine and specific serotonin antidepressants (NaSSAs) do not work by inhibiting neurotransmitter reuptake, but the net effect is increasing brain levels of norepinephrine and serotonin. Commonly reported side effects include drowsiness, excess sedation, weight gain and dry mouth. Researchers are currently exploring a new class of antidepressants, selective norepinephrine reuptake inhibitors (NRIs), which block the reuptake of norepinephrine suggesting that they may be effective antidepressants. Side effects can include dizziness, insomnia, dry mouth, urinary retention, sweating and headache. Every individual is at risk for depression at some point in his or her
lifetime. With increasing prevalence of depression-related disabilities
and deaths, ongoing education is critical in alleviating many of the misunderstandings
surrounding this serious and chronic disease.
-------------------------------------------------------------------------------- 1. World Health Organization 2. DataMonitor, U.S. Treatment Algorithms: Improving Outcomes in Depression. Data on file with P&U Market Research (+ 20 million) and National Mental Health Association (NMHA) (17 million) 3. Thompson C et al, "Effective management of Depression Today: Report from an InteractiveWorkshop," International Clinical Psychopharmacology, 1996, 11, Suppl 1, 45-50 [Note: updated statistic from Dave Keck] 4. Center for Disease Control, 1996 5. National Institute of Mental Health, 1996 6. Paykel ES & Priest RG, "Recognition and Management of Depression in General Practice: A Consensus Statement," British Medical Journal, 1992, 305, 1198-1202 7. NIH web page 8. Ogilvie AD et al, "Polymorphism in Serotonin Transporter Gene Associated with Susceptibilityto Major Depression," Lancet, 1996, 347, 731-3 9. "Paykel ES & Priest RG, Recognition and Management of Depression in General Practice: A Consensus Statement," British Medical Journal, 1992, 305, 1198-1202 10. MA Jenike, "Neuropsychiatric Assessment and Treatment of Geriatric Depression," PsychiatricTimes, 1995, Vol. XII, Issue 5 11. APA, Diagnostic Criteria from DSM-IV, 1994, 161-2 12. NDMDA web page 13. NDMDA web page 14. NDMDA web page 15. Paykel ES & Priest RG, "Recognition and Management of Depression in General Practice: A Consensus Statement," British Medical Journal, 1992, 305,1198-1202. 16. Lepine J-P et al, "Depression in the Community: The First Pan-European Study DEPRES(Depression Research in European Society)," International Clinical Psychopharmacology, 1997, 12,19-29 17. Diagnostic Criteria from DSM-IV, American Psychiatric Association, 1994, 161-2 18. Lader M, Current Trends in Drugs for Depression, Update, 1996, 52, 149-153 19. Paykel ES & Priest RG, "Recognition and Management of Depression in General Practice: A Consensus Statement," British Medical Journal, 1992, 305, 1198-1202. 20. NDMDA web page 21. Nemeroff, CB, "Problems with Currently Available Antidepressants," APA Presentation, May1999 22. Paykel ES & Priest RG, "Recognition and Management of Depression in General Practice: A Consensus Statement," British Medical Journal, 1992, 305, 1198-1202 23. Lader M, Current Trends in Drugs for Depression, Update, 1996, 52,
149-153
Depression Resources The Neurobiology of Depression
by Charles B. Nemeroff ...........
The Norepinephrine Link Serotonin Connections Hormonal Abnormalities Support for a Model
SIDEBARS:
Contributions from Imaging
ILLUSTRATIONS:
Serotonin in Action Hormonal System
FURTHER READING
RELATED LINKS
He [a psychiatrist] asked me if I was suicidal, and I reluctantly told him yes. I did not particularize--since there seemed no need to--did not tell him that in truth many of the artifacts of my house had become potential devices for my own destruction: the attic rafters (and an outside maple or two) a means to hang myself, the garage a place to inhale carbon monoxide, the bathtub a vessel to receive the flow from my opened arteries. The kitchen knives in their drawers had but one purpose for me. Death by heart attack seemed particularly inviting, absolving me as it would of active responsibility, and I had toyed with the idea of self-induced pneumonia--a long frigid, shirt-sleeved hike through the rainy woods. Nor had I overlooked an ostensible accident, á la Randall Jarrell, by walking in front of a truck on the highway nearby.... Such hideous fantasies, which cause well people to shudder, are to the deeply depressed mind what lascivious daydreams are to persons of robust sexuality. As this passage demonstrates, clinical depression is quite different
from the blues everyone feels at one time or another and even from the
grief of bereavement. It is more debilitating and dangerous, and the overwhelming
sadness combines with a number of other symptoms. In addition to becoming
preoccupied with suicide, many people are plagued by guilt and a sense
of worthlessness. They often have difficulty thinking clearly, remembering,
or taking pleasure in anything. They may feel anxious and sapped of energy
and have trouble eating and sleeping or may, instead, want to eat and sleep
excessively.
At the moment, those of us teasing out the neurobiology of depression somewhat resemble blind searchers feeling different parts of a large, mysterious creature and trying to figure out how their deductions fit together. In fact, it may turn out that not all of our findings will intersect: biochemical abnormalities that are prominent in some depressives may differ from those predominant in others. Still, the extraordinary accumulation of discoveries is fueling optimism that the major biological determinants of depression can be understood in detail and that those insights will open the way to improved methods of diagnosing, treating and preventing the condition. Pressing Goals One subgoal is to distinguish features that vary among depressed individuals. For instance, perhaps decreased activity of a specific neurotransmitter (a molecule that carries a signal between nerve cells) is central in some people, but in others, overactivity of a hormonal system is more influential (hormones circulate in the blood and can act far from the site of their secretion). A related goal is to identify simple biological markers able to indicate which profile fits a given patient; those markers could consist of, say, elevated or reduced levels of selected molecules in the blood or changes in some easily visualizable areas of the brain. After testing a depressed patient for these markers, a psychiatrist could, in theory, prescribe a medication tailored to that individual's specific biological anomaly, much as a general practitioner can run a quick strep test for a patient complaining of a sore throat and then prescribe an appropriate antibiotic if the test is positive. Today psychiatrists have to choose antidepressant medications by intuition and trial and error, a situation that can put suicidal patients in jeopardy for weeks or months until the right compound is selected. (Often psychotherapy is needed as well, but it usually is not sufficient by itself, especially if the depression is fairly severe.) Improving treatment is critically important. Although today's antidepressants have fewer side effects than those of old and can be extremely helpful in many cases, depression continues to exact a huge toll in suffering, lost lives and reduced productivity. The prevalence is surprisingly great. It is estimated, for example, that 5 to 12 percent of men and 10 to 20 percent of women in the U.S. will suffer from a major depressive episode at some time in their life. Roughly half of these individuals will become depressed more than once, and up to 10 percent (about 1.0 to 1.5 percent of Americans) will experience manic phases in addition to depressive ones, a condition known as manic-depressive illness or bipolar disorder. Mania is marked by a decreased need for sleep, rapid speech, delusions of grandeur, hyperactivity and a propensity to engage in such potentially self-destructive activities as promiscuous sex, spending sprees or reckless driving. Beyond the pain and disability depression brings, it is a potential killer. As many as 15 percent of those who suffer from depression or bipolar disorder commit suicide each year. In 1996 the Centers for Disease Control and Prevention listed suicide as the ninth leading cause of death in the U.S. (slightly behind infection with the AIDS virus), taking the lives of 30,862 people. Most investigators, however, believe this number is a gross underestimate. Many people who kill themselves do so in a way that allows another diagnosis to be listed on the death certificate, so that families can receive insurance benefits or avoid embarrassment. Further, some fraction of automobile accidents unquestionably are concealed suicides. The financial drain is enormous as well. In 1992 the estimated costs of depression totaled $43 billion, mostly from reduced or lost worker productivity. Accumulating findings indicate that severe depression also heightens the risk of dying after a heart attack or stroke. And it often reduces the quality of life for cancer patients and might reduce survival time. Genetic Findings Geneticists have provided some of the oldest proof of a biological component to depression in many people. Depression and manic-depression frequently run in families. Thus, close blood relatives (children, siblings and parents) of patients with severe depressive or bipolar disorder are much more likely to suffer from those or related conditions than are members of the general population. Studies of identical twins (who are genetically indistinguishable) and fraternal twins (whose genes generally are no more alike than those of other pairs of siblings) also support an inherited component. The finding of illness in both members of a pair is much higher for manic-depression in identical twins than in fraternal ones and is somewhat elevated for depression alone. In the past 20 years, genetic researchers have expended great effort trying to identify the genes at fault. So far, though, those genes have evaded discovery, perhaps because a predisposition to depression involves several genes, each of which makes only a small, hard-to-detect contribution. Preliminary reports from a study of an Amish population with an extensive history of manic-depression once raised the possibility that chromosome 11 held one or more genes producing vulnerability to bipolar disorder, but the finding did not hold up. A gene somewhere on the X chromosome could play a role in some cases of that condition, but the connection is not evident in most people who have been studied. Most recently, various regions of chromosome 18 and a site on chromosome 21 have been suggested to participate in vulnerability to bipolar illness, but these findings await replication. As geneticists continue their searches, other investigators are concentrating
on neurochemical aspects. Much of that work focuses on neurotransmitters.
In particular, many cases of depression apparently stem at least in part
from disturbances in brain circuits that convey signals through certain
neurotransmitters of the monoamine class. These biochemicals, all derivatives
of amino acids, include serotonin, norepinephrine and dopamine; of these,
only evidence relating to norepinephrine and serotonin is abundant.
AREAS OF THE BRAIN
The Norepinephrine Link But which monoamines were most important in depression? In the 1960s Joseph J. Schildkraut of Harvard University cast his vote with norepinephrine in the now classic "catecholamine" hypothesis of mood disorders. He proposed that depression stems from a deficiency of norepinephrine (which is also classified as a catecholamine) in certain brain circuits and that mania arises from an overabundance of the substance. The theory has since been refined, acknowledging, for instance, that decreases or elevations in norepinephrine do not alter moods in everyone. Nevertheless, the proposed link between norepinephrine depletion and depression has gained much experimental support. These circuits originate in the brain stem, primarily in the pigmented locus coeruleus, and project to many areas of the brain, including to the limbic system--a group of cortical and subcortical areas that play a significant part in regulating emotions. To understand the recent evidence relating to norepinephrine and other monoamines, it helps to know how those neurotransmitters work. The points of contact between two neurons, or nerve cells, are termed synapses. Monoamines, like all neurotransmitters, travel from one neuron (the presynaptic cell) across a small gap (the synaptic cleft) and attach to receptor molecules on the surface of the second neuron (the postsynaptic cell). Such binding elicits intracellular changes that stimulate or inhibit firing of the postsynaptic cell. The effect of the neurotransmitter depends greatly on the nature and concentration of its receptors on the postsynaptic cells. Serotonin receptors, for instance, come in 13 or more subtypes that can vary in their sensitivity to serotonin and in the effects they produce. The strength of signaling can also be influenced by the amount of neurotransmitter released and by how long it remains in the synaptic cleft--properties influenced by at least two kinds of molecules on the surface of the releasing cell: autoreceptors and transporters. When an autoreceptor becomes bound by neurotransmitter molecules in the synapse, the receptors signal the cell to reduce its firing rate and thus its release of the transmitter. The transporters physically pump neurotransmitter molecules from the synaptic cleft back into presynaptic cells, a process termed reuptake. Monoamine oxidase inside cells can affect synaptic neurotransmitter levels as well, by degrading monoamines and so reducing the amounts of those molecules available for release. Among the findings linking impoverished synaptic norepinephrine levels to depression is the discovery in many studies that indirect markers of norepinephrine levels in the brain--levels of its metabolites, or by-products, in more accessible material (urine and cerebrospinal fluid)--are often low in depressed individuals. In addition, postmortem studies have revealed increased densities of certain norepinephrine receptors in the cortex of depressed suicide victims. Observers unfamiliar with receptor display might assume that elevated
numbers of receptors were a sign of more contact between norepinephrine
and its receptors and more signal transmission. But this pattern of receptor
"up-regulation" is actually one that scientists would expect if norepinephrine
concentrations in synapses were abnormally low. When transmitter molecules
become unusually scarce in synapses, postsynaptic cells often expand receptor
numbers in a compensatory attempt to pick up whatever signals are available.
SERATONIN IN ACTION
Serotonin Connections The data connecting norepinephrine to depression are solid and still growing. Yet research into serotonin has taken center stage in the 1990s, thanks to the therapeutic success of Prozac and related antidepressants that manipulate serotonin levels. Serious investigations into serotonin's role in mood disorders, however, have been going on for almost 30 years, ever since Arthur J. Prange, Jr., of the University of North Carolina at Chapel Hill, Alec Coppen of the Medical Research Council in England and their co-workers put forward the so-called permissive hypothesis. This view held that synaptic depletion of serotonin was another cause of depression, one that worked by promoting, or "permitting," a fall in norepinephrine levels. Defects in serotonin-using circuits could certainly dampen norepinephrine signaling. Serotonin-producing neurons project from the raphe nuclei in the brain stem to neurons in diverse regions of the central nervous system, including those that secrete or control the release of norepinephrine. Serotonin depletion might contribute to depression by affecting other kinds of neurons as well; serotonin-producing cells extend into many brain regions thought to participate in depressive symptoms--including the amygdala (an area involved in emotions), the hypothalamus (involved in appetite, libido and sleep) and cortical areas that participate in cognition and other higher processes. Among the findings supporting a link between low synaptic serotonin levels and depression is that cerebrospinal fluid in depressed, and especially in suicidal, patients contains reduced amounts of a major serotonin by-product (signifying reduced levels of serotonin in the brain itself). In addition, levels of a surface molecule unique to serotonin-releasing cells in the brain are lower in depressed patients than in healthy subjects, implying that the numbers of serotonergic cells are reduced. Moreover, the density of at least one form of serotonin receptor--type 2--is greater in postmortem brain tissue of depressed patients; as was true in studies of norepinephrine receptors, this up-regulation is suggestive of a compensatory response to too little serotonin in the synaptic cleft. Further evidence comes from the remarkable therapeutic effectiveness of drugs that block presynaptic reuptake transporters from drawing serotonin out of the synaptic cleft. Tricyclic antidepressants (so-named because they contain three rings of chemical groups) joined monoamine oxidase inhibitors on pharmacy shelves in the late 1950s, although their mechanism of action was not known at the time. Eventually, though, they were found to produce many effects in the brain, including a decrease in serotonin reuptake and a consequent rise in serotonin levels in synapses. Investigators suspected that this last effect accounted for their antidepressant action, but confirmation awaited the introduction in the late 1980s of Prozac and then other drugs (Paxil, Zoloft and Luvox) able to block serotonin reuptake transporters without affecting other brain monoamines. These selective serotonin reuptake inhibitors (SSRIs) have now revolutionized the treatment of depression, because they are highly effective and produce much milder side effects than older drugs do. Today even newer antidepressants, such as Effexor, block reuptake of both serotonin and norepinephrine. Studies of serotonin have also offered new clues to why depressed individuals are more susceptible to heart attack and stroke. Activation and clumping of blood platelets (cell-like structures in blood) contribute to the formation of thrombi that can clog blood vessels and shut off blood flow to the heart and brain, thus damaging those organs. Work in my laboratory and elsewhere has shown that platelets of depressed people are particularly sensitive to activation signals, including, it seems, to those issued by serotonin, which amplifies platelet reactivity to other, stronger chemical stimuli. Further, the platelets of depressed patients bear reduced numbers of serotonin reuptake transporters. In other words, compared with the platelets of healthy people, those in depressed individuals probably are less able to soak up serotonin from their environment and thus to reduce their exposure to platelet-activation signals. Disturbed functioning of serotonin or norepinephrine circuits, or both, contributes to depression in many people, but compelling work can equally claim that depression often involves dysregulation of brain circuits that control the activities of certain hormones. Indeed, hormonal alterations in depressed patients have long been evident. Hormonal Abnormalities The hypothalamus of the brain lies at the top of the hierarchy regulating hormone secretion. It manufactures and releases peptides (small chains of amino acids) that act on the pituitary, at the base of the brain, stimulating or inhibiting the pituitary's release of various hormones into the blood. These hormones--among them growth hormone, thyroid-stimulating hormone and adrenocorticotropic hormone (ACTH)--control the release of other hormones from target glands. In addition to functioning outside the nervous system, the hormones released in response to pituitary hormones feed back to the pituitary and hypothalamus. There they deliver inhibitory signals that keep hormone manufacture from becoming excessive. Depressed patients have repeatedly been demonstrated to show a blunted
response to a number of substances that normally stimulate the release
of growth hormone. They also display aberrant responses to the hypothalamic
substance that normally induces secretion of thyroid-stimulating hormone
from the pituitary. In addition, a common cause of nonresponse to antidepressants
is the presence of previously undiagnosed thyroid insufficiency.
HORMONAL SYSTEM
As long ago as the late 1960s and early 1970s, several research groups reported increased activity in the HPA axis in unmedicated depressed patients, as evinced by raised levels of cortisol in urine, blood and cerebrospinal fluid, as well as by other measures. Hundreds, perhaps even thousands, of subsequent studies have confirmed that substantial numbers of depressed patients--particularly those most severely affected--display HPA-axis hyperactivity. Indeed, the finding is surely the most replicated one in all of biological psychiatry. Deeper investigation of the phenomenon has now revealed alterations at each level of the HPA axis in depressed patients. For instance, both the adrenal gland and the pituitary are enlarged, and the adrenal gland hypersecretes cortisol. But many researchers, including my colleagues and me at Emory University, have become persuaded that aberrations in CRF-producing neurons of the hypothalamus and elsewhere bear most of the responsibility for HPA-axis hyperactivity and the emergence of depressive symptoms. Notably, study after study has shown CRF concentrations in cerebrospinal fluid to be elevated in depressed patients, compared with control subjects or individuals with other psychiatric disorders. This magnification of CRF levels is reduced by treatment with antidepressants and by effective electroconvulsive therapy. Further, postmortem brain tissue studies have revealed a marked exaggeration both in the number of CRF-producing neurons in the hypothalamus and in the expression of the CRF gene (resulting in elevated CRF synthesis) in depressed patients as compared with controls. Moreover, delivery of CRF to the brains of laboratory animals produces behavioral effects that are cardinal features of depression in humans, namely, insomnia, decreased appetite, decreased libido and anxiety. Neurobiologists do not yet know exactly how the genetic, monoamine and hormonal findings piece together, if indeed they always do. The discoveries nonetheless suggest a partial scenario for how people who endure traumatic childhoods become depressed later in life. I call this hypothesis the stress-diathesis model of mood disorders, in recognition of the interaction between experience (stress) and inborn predisposition (diathesis). The observation that depression runs in families means that certain genetic traits in the affected families somehow lower the threshold for depression. Conceivably, the genetic features directly or indirectly diminish monoamine levels in synapses or increase reactivity of the HPA axis to stress. The genetically determined threshold is not necessarily low enough to induce depression in the absence of serious stress but may then be pushed still lower by early, adverse life experiences. My colleagues and I propose that early abuse or neglect not only activates the stress response but induces persistently increased activity in CRF-containing neurons, which are known to be stress responsive and to be overactive in depressed people. If the hyperactivity in the neurons of children persisted through adulthood, these supersensitive cells would react vigorously even to mild stressors. This effect in people already innately predisposed to depression could then produce both the neuroendocrine and behavioral responses characteristic of the disorder. Support for a Model To test the stress-diathesis hypothesis, we have conducted a series of experiments in which neonatal rats were neglected. We removed them from their mothers for brief periods on about 10 of their first 21 days of life, before allowing them to grow up (after weaning) in a standard rat colony. As adults, these maternally deprived rats showed clear signs of changes in CRF-containing neurons, all in the direction observed in depressed patients--such as rises in stress-induced ACTH secretion and elevations of CRF concentrations in several areas of the brain. Levels of corticosterone (the rat's cortisol) also rose. These findings suggested that a permanent increase in CRF gene expression and thus in CRF production occurred in the maternally deprived rats, an effect now confirmed by Paul M. Plotsky, one of my co-workers at Emory. We have also found an increase in CRF-receptor density in certain brain regions of maternally deprived rats. Receptor amplification commonly reflects an attempt to compensate for a decrease in the substance that acts on the receptor. In this case, though, the rise in receptor density evidently occurs not as a balance to decreased CRF but in spite of an increase--the worst of all possibilities. Permanently elevated receptor concentrations would tend to magnify the action of CRF, thereby forever enhancing the depression-inducing effects of CRF and stress. In an exciting preliminary finding, Plotsky has observed that treatment with one of the selective serotonin reuptake inhibitors (Paxil) returns CRF levels to normal, compensates for any gain in receptor sensitivity or number (as indicated by normal corticosterone production lower down in the axis) and normalizes behavior (for instance, the rats become less fearful). We do not know exactly how inhibition of serotonin reuptake would lead to normalization of the HPA axis. Even so, the finding implies that serotonin reuptake inhibitors might be particularly helpful in depressed patients with a history of childhood trauma. Plotsky further reports that all the HPA-axis and CRF abnormalities returned when treatment stopped, a hint that pharmaceutical therapy in analogous human patients might have to be continued indefinitely to block recurrences of depression. Studies of Bonnet macaque monkeys, which as primates more closely resemble humans, yielded similar results. Newborns and their mothers encountered three foraging conditions for three months after the babies' birth: a plentiful, a scarce and a variable food supply. The variable situation (in which food was available unpredictably) evoked considerable anxiety in monkey mothers, who became so anxious and preoccupied that they basically ignored their offspring. As our model predicts, the neonates in the variable-foraging condition were less active, withdrew from interactions with other monkeys and froze in novel situations. In adulthood, they also exhibited marked elevations in CRF concentrations in spinal fluid. The rat and monkey data raise profound clinical and public health questions. In the U.S. alone in 1995, more than three million children were reportedly abused or neglected, and at least a million of those reports were verified. If the effects in human beings resemble those of the animals, the findings imply that abuse or neglect may produce permanent changes in the developing brain--changes that chronically boost the output of, and responsiveness to, CRF, and therefore increase the victims' lifelong vulnerability to depression. If that conclusion is correct, investigators will be eager to determine whether noninvasive techniques able to assess the activity of CRF-producing neurons or the number of CRF receptors could identify abused individuals at risk for later depression. In addition, they will want to evaluate whether antidepressants or other interventions, such as psychotherapy, could help prevent depression in children who are shown to be especially susceptible. Researchers will also need to find out whether depressed adults with a history of abuse need to take antidepressants in perpetuity and whether existing drugs or psychotherapy can restore normal activity in CRF-producing neurons in humans. The stress-diathesis model does not account for all cases of depression; not everyone who is depressed has been neglected or abused in childhood. But individuals who have both a family history of the condition and a traumatic childhood seem to be unusually prone to the condition. People who have no genetic predisposition to depression (as indicated by no family history of the disorder) could conceivably be relatively protected from serious depression even if they have a bad childhood or severe trauma later in life. Conversely, some people who have a strong inherited vulnerability will find themselves battling depression even when their childhoods and later life are free of trauma. More work on the neurobiology of depression is clearly indicated, but the advances achieved so far are already being translated into ideas for new medications. Several pharmaceutical houses are developing blockers of CRF receptors to test the antidepressant value of such agents. Another promising class of drugs activates specific serotonin receptors; such agents can potentially exert powerful antidepressive effects without stimulating serotonin receptors on neurons that play no part in depression. More therapies based on new understandings of the biology of mood disorders
are sure to follow as well. As research into the neurobiological underpinnings
progresses, treatment should become ever more effective and less likely
to produce unwanted side effects.
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THE ROLE OF SEROTONIN IN THE PATHOPHYSIOLOGY OF DEPRESSION: FOCUS ON THE SEROTONIN TRANSPORTER. Michael J. Owens and Charles B. Nemeroff in Clinical Chemistry, Vol. 40, No. 2, pages 288-295; February 1994. BIOLOGY OF MOOD DISORDERS. K. I. Nathan, D. L. Musselman, A. F. Schatzberg and C. B. Nemeroff in Textbook of Psychopharmacology. Edited by A. F. Schatzberg and C. B. Nemeroff. APA Press, Washington, D.C., 1995. THE CORTICOTROPIN-RELEASING FACTOR (CRF) HYPOTHESIS OF DEPRESSION: NEW
FINDINGS AND NEW DIRECTIONS. C. B. Nemeroff in Molecular Psychiatry, Vol.
1, No. 4, pages 336-342; September 1996.
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