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Causes
CBS CARES: What causes depression?
DR. KAHN: The cause of depression is thought by most scientists often to be an interaction between life stress and inborn genetic aspects of brain chemistry. We also know that terrible loss or trauma early in life can sometimes cause the brain to develop abnormally, leading to depression later in life.
CBS CARES: Would you say the causes of depression are mostly genetic, societal or environmental?
DR. ROOSE: It appears that in most cases there is a combination of factors at work. Genetic vulnerability is often quite important, but genetics actually operate by creating a vulnerability that is expressed if other social or environmental triggers occur. In a unique and fascinating study, the genetic vulnerability to depression was determined in a group of New Zealand women who were followed over 20 years. In women who were genetically vulnerable, depression was expressed when environmental stress, such as abuse, occurred. However, if a woman was not genetically vulnerable to depression, even in the face of an environmental stress, depression did not develop. The interaction between genes and environments not only explains vulnerability to depression, but also illuminates the phenomenon of resilience, that is, when people seem to emerge intact despite seemingly horrific experiences.
CBS CARES: The heroic hotel manager Paul Rusesabagina, about whom the movie "Hotel Rwanda" was made, was interviewed recently and was asked why, despite having witnessed mass genocide--including relatives of his--he still frequently gives a "hotel manager smile" (a diplomatic, but not heartfelt smile). He answered, "I don't want to show my depression." By contrast, the Canadian General who commanded UN forces in Rwanda during the genocide, but was precluded by the UN from using force to stop the killings, had a subsequent breakdown and seems very expressive about his feelings and depression. Can we learn anything psychologically from how differently these two men have dealt with tragedy and related depression?
DR. KAHN: People are wired in many different ways; innumerable factors contribute to resilience under extraordinary duress. Acts of heroism often require a degree of denial, at least during the crisis. The factors that enable some to mask their feelings and continue to function are not well understood, but undoubtedly are a mixture of genetics, early life experiences, acquired personality traits, etc. To speculate, the Rwandan may have witnessed so much deprivation up to that point in his life that he felt able to suppress emotions at one more tragedy, and was satisfied by saving some of the people, while the Canadian, perhaps raised in a safer environment and with a strong sense of horror at any loss of life, was unable to hold it all in. In addition, for all we know, the Canadian may have had a family history of depression or anxiety leading to a lower biological threshold to becoming traumatized. In a way, accounting for these differences is like asking why some people get heart attacks in their 40's while others stay well into old age: genetics, environment, and habits we learn all feed into the answer.
CBS CARES: Is depression essentially physical?
DR. KAHN: There is often a strong physical component. Most depressed people have changes in sleep and appetite, reflecting abnormal activity in regions of the brain that control these basic biological functions. Nutrition and alertness can suffer. Depressed people show unusual patterns in the daily levels of many hormones, particularly hormones related to the cortisol system involved in regulating stress, energy, and even immunity. Menstrual abnormalities may occur in women. In another sense, asking if the psychological feelings that are central to depression are essentially physical is asking the mind-body question: Is the mind physical, as a product of the organ we call the brain?
CBS CARES: How does the brain chemistry factor into this?
DR. KAHN: The basis for all these physical changes is the chemistry of the brain, where neurotransmitters such as serotonin are known to function abnormally. Research has shown changes in the sensitivity of various brain cells to serotonin and other chemicals, as well as in the pathways by which nerve cells are connected to each other. How these chemical events are translated into the conscious, psychological experience of depression or even just consciousness is one of the great unsolved riddles of science and philosophy.
CBS CARES: Is there a difference between the structural function of depressed people's brains vs. those who are not depressed?
DR. SILBERSWEIG: Magnetic resonance imaging (MRI) and positron emission tomography (PET) have identified changes in the structure and function of specific regions of the brain in patients suffering with depression, versus non-depressed people. While more work needs to be done to determine the nature and specificity of these changes, a number of convergent findings in core frontal and temporal lobe brain regions affecting emotion, thought and behavior have been noted.
CBS CARES: How does depression affect someone's physical health and well-being?
DR. MUSKIN: Depression may have a negative effect on the immune system, may increase the risk of developing cardiovascular disease, and may influence the risk of developing diabetes. Patients with depression often do not comply with diets, and may have difficulty in adhering to the medical plan to treat their diabetes. Untreated depression has been shown to dramatically increase the risk of dying after a heart attack. For this reason, patients who have heart attacks and are depressed should speak to their cardiologists. Cardiologists should assess depression as part of the follow up when patients are discharged from the hospital.
CBS CARES: Why is there a relationship between depression and heart disease?
DR. GLASSMAN: There are numerous reasons why this relationship might exist. Depressed patients often have what psychologists refer to as poor health behaviors. They are more likely to smoke and less likely to exercise. Their platelets seem to be stickier than those of patients who are not depressed. This is the opposite of what aspirin does and it likely increases the risk of vascular disease. There are also autonomic nervous system differences that tend to make heart disease more dangerous.
CBS CARES: How long does this increased risk of death due to depression continue, and can treating depression reduce the risk?
DR. MUSKIN: The risk continues for the next several years. As for treatment, some antidepressants may have an anticoagulant effect, that is, they make our platelets less sticky. This may be beneficial in preventing another heart attack. Even if this turns out not to be the major mechanism, treating the depression will enable patients to enjoy their lives more fully, adhere to medical regimens, find it easier to maintain healthy diets, and be less likely to engage in unhealthy habits.
CBS CARES: How do childhood relationships and experiences affect the likelihood of being depressed in adult life?
DR. WEISSMAN: There's some very interesting data here. In the Freudian days, depression was all about early childhood, and then I think we lost sight of that with the spectacular introduction of medication. But now we're coming around to seeing the importance of the gene/environment interaction. There are some data that show that children who have been abused or who have had very difficult relationships at home are more vulnerable to depression, particularly if they carry the genetic vulnerability. This is what makes psychotherapy very important, because you can't intervene in genes but you can help the person cope with their environment.
CBS CARES: Will a child's perception of his or her parents' marriage and of family life affect his or her susceptibility to depression in adult life?
DR. SHAFFER: There is a statistical relationship between family disruption (i.e., disagreements, separations, and divorce) and later depression. The relationship is stronger in families who experience economic difficulties after the separation or divorce and in which the divorce or separation was preceded by violence within the family. One reason why being brought up in an unhappy family or experiencing family disruption and then going on to be depressed in later life might occur is that depression tends to run in families, and depression in one parent or spouse often leads to significant marital difficulties. In such a case, the child both inherits a predisposition towards depression and experiences a host of negative experiences resulting from the unhappiness between both parents. These can include parental preoccupation, so that the parents show reduced sensitivity towards their child, because they are too preoccupied with their marital concerns. Sometimes, the reverse takes place, and an unhappily married parent becomes too preoccupied with and too close to their child, who might then lose the ability to master problems themselves or start to feel responsible for the happiness and well-being of their parents. Last but not least, unhappy marriages are more likely to spawn physical and sexual abuse, which can have lasting consequences.
CBS CARES: Can good parenting and a happy environment counteract someone's predisposition to depression?
DR. WEISSMAN: Yes.
CBS CARES: As the child matures and becomes an adult, will he or she still have the genetic predisposition to depression?
DR. WEISSMAN: Yes, genes don't go away.
CBS CARES: Could a loving, reinforcing childhood cause brain chemistry to change and make a person a happier adult?
DR. WEISSMAN: That's all in the area of speculation, but it's not inconceivable. We learn at a very young age how to respond to situations and our responses are biological responses that are manifested in our behavior.
CBS CARES: Is there a connection between anger and depression?
DR. KAHN: Freud first posed the connection between anger turned inwards and the onset of depression in his classic paper, "Mourning and Melancholia." While many depressed people are self-critical, it is a stretch to say that they are basically angry at the outside world and just happen to be turning it in on themselves. Self-criticism is a symptom of depression, and we often see it alleviated by effective treatment. Another approach is to look at the chemistry of aggression and depression. In both conditions, low activity of the neurotransmitter serotonin appears to play an important role. Some depressed people, in fact, can be quite aggressive, either showing irritability towards others, or in the worst case, violently harming themselves in suicide attempts. Researchers suggest that low serotonin activity may be the culprit when suicide involves violent means.
CBS CARES: Are extroverted people happier?
DR. KAHN: Extroversion can certainly be a sign of happiness, but can also be a sign of needing to please other people in order to avoid inner feelings of depression, so it depends.
CBS CARES: Are married people generally more or less depressed than single people?
DR. KAHN: Unhappily married people have more risk of depression than single people; a happy marriage is protective.
CBS CARES: Are people with kids generally less or more depressed than those without kids?
DR. KAHN: There has been little research into being childless and being depressed, but the evidence so far suggests it is not a direct relationship. People who have chosen not to have children, often because of commitment to a career, may be quite satisfied with their choice. Of course, if someone very much wants kids, but has not had them… that could be a cause of depression in their specific case.
CBS CARES: Since the reality of life involves aging, illness and ultimate mortality, is some degree of denial or rationalization necessary to achieve happiness or at least to avoid depression?
DR. KAHN: Outside of religion, in which an affirmative meaning may be given to death, degrees of denial and rationalization are mature responses to the alternative view that illness and death void life. It can be argued that living in the present requires us sometimes to embrace denial and put aside active fear of illness and death that would otherwise paralyze our ability to enjoy life. The other side of the coin is that excessive denial can prevent seeking out appropriate help or care, when it can make a meaningful difference in quality of life to the individual. Healthy denial enables one to do what has to be done; it doesn't prevent one from taking action.
CBS CARES: Is there actually a "midlife crisis" and, if so, is depression often part of it?
DR. KAHN: Psychologists and psychiatrists have often commented on the crises experienced in each transitional phase of life: separation and individuation in the young child, adolescent rebellion, self-sufficiency and self-definition in the 20's and 30's with establishment of one's own career and family, and so forth through the elder years. Mid-life brings with it intimations of one's own mortality, yet can also be the period of greatest fulfillment of one's capacities. It has its own psychological perils, but no more so than earlier periods in life. Depressive illness, in fact, is generally a condition that has its onset in the teens and 20's, rather than appearing for the first time in mid-life.
CBS CARES: We've read that low testosterone in addition to creating other potential health problems such as osteoporosis and impotence can cause depression. Should depressed middle-aged and older male patients be tested for low testosterone?
DR. GLASSMAN: Depressed men, regardless of age, should not routinely be tested for testosterone. Testosterone always decreases with age and low testosterone can produce some or all of the symptoms of depression. The drug carries certain very real risks in older males including increasing the malignancy of prostate cancer. It should not be used without solid evidence that it can be beneficial and that does not exist for the treatment of depression. In cases where other symptoms suggest a deficiency testing should be done.
CBS CARES: Does loss of estrogen in women cause depression?
DR. WEISSMAN: That has been the belief, but what's interesting is that the rates of depression do not go up in menopause. The first onset of depression in women is usually before menopause and it's uncommon to have a first onset of depression at menopause. Women who become depressed at menopause are usually having a recurrence of an illness that began a long time ago.
CBS CARES: Do the rates of depression increase during peri-menopause (the years just before menopause)?
DR. WEISSMAN: There is some suggestion of a little blip in the rate at peri-menopause, but that's not very firm.
CBS CARES: How do mood and anxiety disorders increase the risks of dementia?
DR. MUSKIN: It is not clear why mood and anxiety disorders predict dementia. One strong possibility is that an underlying biological mechanism connects the disorders. Depression, for some people, may be an early sign of dementia. Anxiety may be the result of cognitive impairments that are very mild at first. That is to say, the subtle biological changes that result in the depressive or anxiety disorders, eventually disrupt the function of the brain and result in dementia. For most of the dementias, the vast majority of which are Alzheimer Dementia, symptoms appear many years after the biological processes have begun. It is possible that the disorders are related by chance, i.e., that the genes responsible for the disorders happen to sit relatively close to each other on chromosomes. Thus people who have depression or anxiety, which will show up earlier in life than does dementia, are also likely to get dementia.
CBS CARES: So, treating the depression and/or anxiety may help delay or prevent dementia later in life?
DR. MUSKIN: Yes. Treating the depression and/or anxiety may help to prevent dementia later in life. In the same way that we know that people who remain active physically and mentally are less likely to develop dementia, people who have untreated depression and/or anxiety disorders are less likely to challenge themselves mentally and engage in regular physical exercise.
CBS CARES: Can treating depression in older people actually reverse loss of memory or mental functioning?
DR. MUSKIN: If the individual has what is referred to as "pseudodementia" in the depression, that person's memory will definitely improve with treatment. Depression causes a loss of function in many areas, which will all improve with treatment. Treatment would not reverse the loss of function that accompanies Alzheimer Dementia, but the person would perform in a better way after treatment for the depression.
CBS CARES: Is depression more prevalent at lower socioeconomic levels?
DR. KAHN: Lower socioeconomic status, especially in childhood, has been linked to higher rates of depression. However, this may be in part mediated by such factors as broken families or substance abuse, rather than just the experience of being poor, as suggested in studies of immigrant families who avoid depression by staying closely knit.
CBS CARES: Do the rates of depression vary among different ethnic groups?
DR. WEISSMAN: Different ethnic and racial groups may have different genetic susceptibilities to depression. We don't know this yet, but it's certainly conceivable.
There are some consistent findings. For example, the rates of depression are consistently lower in Mainland China and Taiwan. The Chinese have the lowest rate. The Japanese are next, and Koreans have the higher rate, but still lower than any of the European countries or the Americas. Now, we don't know whether that is a result of the cultural expression of the disorder, although these studies were done in these communities by people in the community.
James Jackson, who is a very distinguished African-American scientist, has just completed a national study in the US showing that African-Americans have slightly lower rates of depression than white Americans. I think Jackson believes that the lower rate of depression is due to the fact that African-Americans have such difficult lives that they don't develop depression, but they do develop serious chronic illnesses like diabetes and hypertension. These chronic illnesses many be due to life stress or they may be due to engaging in risky behaviors due to life stress such as smoking, over eating etc.
CBS CARES: Do infectious diseases cause depression?
DR. FALLON: A variety of infections have been associated with depression and other psychiatric disorders. The first microbe to focus our attention in this area was "Treponema pallidum"-the spirochete that causes syphilis. Today, the spirochete that is most likely to be a cause of depression is "Borrelia burgdorferi," the agent of Lyme disease. Patients with Lyme disease, for example, may become atypically irritable, agitated, or tearful at the least provocation. In addition, they may experience mood swings that may be misdiagnosed as a bipolar disorder. Viruses, such as HIV & Herpes Simplex, are also well recognized as agents of unusual neuropsychiatric and depressive states. In these cases, identification and treatment of the underlying infectious cause is clearly critical to improving the patient's neuropsychiatric disorder.
CBS CARES: Are there indirect effects of infection that can cause depression?
DR. FALLON: What person, when hit with the flu, has not experienced amotivation, debilitating fatigue, reduced sex drive, irritability, and anorexia? These are depression-like symptoms that are a common concomitant of infection. A series of studies over the last decade have demonstrated that immune activation as a consequence of bacterial or viral infections can induce symptoms of depression in both humans and animals. This is thought to be due to the direct effect of pro-inflammatory cytokines, as these produce depression-like symptoms in humans and animals. Also of interest is that when patients are being treated with cytokines (such as interferons) for diseases such as hepatitis C, they will often experience an array of significant depressive symptoms, including tearfulness, reduced sexual drive, sleep disturbance, anorexia, and psychomotor retardation. Therefore, it is clear that infections themselves can cause mood disorders indirectly through the stimulation of the immune cascade.
CBS CARES: You just said that pro inflammatory cytokines produce depression. Why then do potent anti-inflammatories such as prednisone often cause depression at higher doses or with chronic use?
DR. FALLON: Your question is a good one. It would stand to reason that if substances that induce inflammation can cause depression then substances that reduce inflammation should result in less depression. Or to be more precise, if an increase in pro-inflammatory cytokines can induce depression through enzymatic pathways that deplete the supply of peripheral and central serotonin (a neurotransmitter essential to the maintenance of a non-depressed state), then a reduction in pro-inflammatory cytokines as a result of prednisone should result in an enhanced availability of tryptophan and its metabolite serotonin and therefore a less depressed state. In fact, if you look at the research studies on the acute effect of prednisone on medically ill subjects, one finds that those patients who are depressed become less depressed and that the primary effect in most subjects is euphoric rather than depressive. This would be consistent with the above hypothesis.
However, your question also asked why the chronic use of prednisone appears to trigger depression - a common clinical observation that has been supported in one recent study. Corticosteroids like prednisone have diverse physiologic effects, primarily influencing the hypothalamic-pituitary-adrenal axis (disorders of which are known to cause depression), but also influencing astrocyte physiology, central neurotransmitter or neurohormone levels, modulation of serotonin receptor binding density, and possibly, after prolonged exposure, neuronal atrophy (particularly in the hippocampus, an area rich in serotonin receptors). The chronic mood lowering effect of prednisone may be related to these long-term physiologic effects.
CBS CARES: Given that most states of depression are not due to an underlying infection, could you tell us what clues tip you off that infection may be the cause in specific patients?
DR. FALLON: In our training as doctors, we learn that the patient's history will tell us most of what we need to know. If a person develops depression completely out of the blue without recent stressors or a family history suggestive of a congenital predisposition, then one has to consider that there may be an underlying infectiousmedical cause. The list for the medical differential diagnosis of depression is long, but would include exploration of neurological (e.g., multiple sclerosis), multisystemic (e.g, systemic lupus), infectious (e.g., Lyme disease, HIV), endocrine (e.g., thyroid), hematologic (vitamin B12 deficiency, anemia), malignant (e.g., pancreatic cancer), traumatic (e.g., subdural hematoma), and cardiovascular (e.g., reduced cardiac output) causes.
If a person reports a recent history of flu-like symptoms, such as unrelenting fatigue, coughing, sore throat, fever, enlarged lymph nodes, or diarrhea, then this would increase the likelihood of an infectious cause. If a person has symptoms that would be atypical for depression alone (e.g. arthralgias or radicular pains), multisystemic medical etiologies need to be considered. Further, if a person's depression is not responding to the treatments that commonly are effective, one should re-examine the possibility of an undetected medical illness. In our part of the country, where Lyme disease is so endemic, symptoms such as arthralgias, myalgias, unusual rashes, tick bite, shooting pains, numbness and tingling, cognitive problems, intense headaches, and/or severe fatigue would all be signs suggestive of the diagnosis of Lyme disease. While laboratory tests are helpful, the clinical history most often points to the cause.
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