While sadness touches all of our lives at different times, depression can have enormous depth and staying power. Being depressed has nothing to do with personal weakness; it’s about neural pathways, chemistry, and more.
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Features on Depression
Living Forward With Depression
by Harvard Medical School
It's often said that depression results from a chemical imbalance, but that figure of speech doesn't capture how complex the disease is. Depression has many causes, including genetic vulnerability and other influences such as life events, illnesses, and medications.
Every part of your body, including your brain, is controlled by genes. Genes make proteins that are involved in biological processes. Throughout life, different genes turn on and off, so that — in the best case — they make the right proteins at the right time. But if the genes get it wrong, they can alter your biology in a way that results in your mood becoming unstable. In a vulnerable person, any stress (a fight with your spouse, a missed deadline at work, or a medical illness, for example) can then push this system off balance.
To be sure, chemicals are involved in this process, but it is not a simple matter of one chemical being too low and another too high. Rather, many chemicals are involved, working both inside and outside nerve cells. There are millions, even billions, of chemical reactions that make up the dynamic system that is responsible for your mood, perceptions, and how you experience life. With this level of complexity, you can see how two people might have similar symptoms of depression, but the problem on the inside, and therefore what treatments will work best, may be entirely different.
The fact that depression and bipolar disorder run in families has long been clear, but experts now have a developing picture of how much of that tendency comes from nature and how much reflects nurture. Studies of twins and adopted children, plus a wealth of research from the Human Genome Project and the Human Genetics Initiative at the National Institute of Mental Health, have begun to answer some important questions.
The clearest genetic link is to bipolar disorder. Most experts believe it affects 1% of the general population, although some preliminary evidence suggests it could be even more common. Half of those with bipolar disorder have a relative with a similar pattern of mood fluctuations. Studies of identical twins, who share a genetic blueprint, show that if one twin has bipolar disorder, the other has a 60%–80% chance of developing it, too. These numbers don't apply to fraternal twins who, like other biological siblings, share only about half of their genes. If one fraternal twin has bipolar disorder, the other has a 20% chance of developing it.
The genetic components of other mood disorders are far harder to pin down. A person who has a first-degree relative who suffered major depression has a 1.5%–3% higher-than-normal risk of experiencing the condition as well. But researchers have found it quite difficult to sort out the actual influence of genes versus environmental factors.
Thus far, experts say genes alone are not responsible for causing mood disorders. Rather, these illnesses probably result when genes make a person vulnerable; then the illness is triggered by environmental factors like early losses or long-term stress.
Research indicates that a person's genes also affect how well he or she responds to different treatments. Although we do not yet have genetic tests to help us choose the best treatment, such tests may not be too far off (see "On the horizon").
Popular lore has it that emotions reside in the heart. Science, though, tracks the seat of your emotions to the brain. While researchers believe that brain chemicals and neural pathways have a major impact on depression, their understanding of the neurological underpinnings of mood is incomplete. The outer edges of the puzzle appear to be in place, but scientists are working to fill huge gaps in knowledge.
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Areas of the brain affected by depression
Depression affects several areas of the brain that play a role not just in mood, but also in memory and other mental and physical functions. The cerebral cortex coordinates functions like speech, movement, memory, and learning. The thalamus receives and relays sensory information. The hippocampus processes long-term memories, while the amygdala oversees emotionally charged memories.
Advances in technology permit a much closer look at the working brain than was possible in the past. Increasingly sophisticated forms of brain imaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), enable scientists to study the brain while it's at work (see "Advances in brain imaging"). This has led to a better understanding of which areas of the brain help regulate mood and other functions, such as memory, that may be affected by depression (see Figure 1). Researchers have learned the following:
Not all that long ago, the brain could be viewed only during an autopsy or neurosurgery. Fortunately, newer technology offers a variety of noninvasive ways to study the living, working brain.
Magnetic resonance imaging (MRI), for example, generates a colorful, three-dimensional computer image that accurately depicts structures in the brain. A variant of this brain scan, called functional MRI (fMRI), tracks swift, small metabolic changes that take place when a region of the brain responds during various tasks. For example, fMRI can show the expansion of blood vessels and changes in temperature that typically occur in the brain when a person exercises.
Other types of brain scans, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), also track brain activity. PET can zero in on the metabolism of blood sugar, which is an indicator of brain activity. PET and SPECT can map the brain in other ways as well — for example, by measuring the distribution and density of neurotransmitter receptors in certain areas.
Another method, called quantitative electroencephalography, takes things a step further. As with a conventional electroencephalogram (EEG), electrodes placed on the scalp measure electrical activity. But during a quantitative EEG, researchers also calculate values that correlate with activity in specific regions of the brain, allowing scientists to map the brain's structure and activity. For example, this technology can be used to see what parts of the brain respond when a patient takes a drug.
Brain imaging enables investigators to research:
One fMRI study published in the Journal of Neuroscience found that the hippocampi of 24 women who had a history of depression were 9%–13% smaller than those of women who did not. The more bouts of depression a woman had, the smaller the hippocampus. Other brain-scan research has found that depressed people generally have less activity in the prefrontal cortex, a region of the brain vital to judgment and planning.
Ultimately, these sophisticated methods may reveal how nerve pathways work and interact, helping define the roles of specific neurotransmitters in mood disorders. By showing how the brain responds to medications and other forms of therapy, new imaging techniques might help improve treatment.
If you trained a high-powered microscope on a slice of brain tissue, you might be able to see a loosely braided network of neurons (nerve cells) that send and receive messages. While every cell in the body has the capacity to send and receive signals, neurons are specially designed for this function. Each neuron has a cell body containing the structures that any cell needs to thrive. Stretching out from the cell body are short, branchlike fibers called dendrites and one longer, more prominent fiber called the axon.
A combination of electrical and chemical signals allows communication within and between neurons. When a neuron becomes activated, it passes an electrical signal from the cell body down the axon to its end (known as the axon terminal), where chemical messengers called neurotransmitters are stored. The signal releases certain neurotransmitters into the space between that neuron and the dendrite of a neighboring neuron. That space is called a synapse. As the concentration of a neurotransmitter rises in the synapse, neurotransmitter molecules begin to bind with receptors embedded in the membranes of the two neurons (see Figure 2).
How neurons communicate
The release of a neurotransmitter from one neuron can activate or inhibit a second neuron. If the signal is activating, or excitatory, the message continues to pass farther along that particular neural pathway. If it is inhibitory, the signal will be suppressed. The neurotransmitter also affects the neuron that released it. Once the first neuron has released a certain amount of the chemical, a feedback mechanism (controlled by that neuron's receptors) instructs the neuron to stop pumping out the neurotransmitter and start bringing it back into the cell. This process is called reabsorption or reuptake. Enzymes break down the remaining neurotransmitter into smaller molecules.
When the system falters. Brain cells usually produce levels of neurotransmitters that keep senses, learning, movements, and moods perking along. But in some people who are severely depressed or manic, the complex systems that accomplish this go awry. For example, receptors may be oversensitive or insensitive to a specific neurotransmitter, causing their response to its release to be excessive or inadequate. Or a message might be weakened if the originating cell pumps out too little of a neurotransmitter or if an overly efficient reuptake mops up too much before the molecules have the chance to bind to the receptors on other neurons. Any of these system faults could significantly affect mood.
Kinds of neurotransmitters. Scientists have identified many different neurotransmitters. Here is a description of a few believed to play a role in depression:
Many people feel sad when summer wanes, but some actually develop depression with the season's change. Known as seasonal affective disorder (SAD), this form of depression affects about 1%–2% of the population, particularly women and young people. Symptoms are similar to general depression and include lethargy, loss of interest in once-pleasurable activities, irritability, inability to concentrate, and a change in sleeping patterns, appetite, or both.
SAD seems to be triggered by more limited exposure to daylight; typically it comes on during the fall or winter months and subsides in the spring. While experts don't fully understand the cause of SAD, some speculate that the hormone melatonin, which helps regulate your body's sleep-wake cycle (circadian rhythm), plays a role. The brain secretes melatonin at night, so longer periods of darkness in the winter months may spur greater production of this hormone. Researchers also believe that the same neurotransmitters implicated in other forms of depression are involved in SAD.
To combat SAD, doctors suggest exercise, particularly outdoor activities during daylight hours. Exposing yourself to bright artificial light may also help. Light therapy, also called phototherapy, usually involves sitting close to a special light source that is far more intense than normal indoor light for 30 minutes every morning. The light must enter through your eyes to be effective; skin exposure has not been proven to work. Some people feel better after only one light treatment, but most people require at least a few days of treatment, and some need several weeks. You can buy boxes that emit the proper light intensity (10,000 lux) with a minimal amount of ultraviolet light without a prescription, but it is best to work with a professional who can monitor your response.
There are few side effects to light therapy, but you should be aware of the following potential problems:
Just as neurotransmitters help ferry signals along nerve pathways, other complex chemicals called hormones carry messages to organs or groups of cells throughout the body. These chemicals trigger or regulate certain activities, such as the release of an egg from a woman's ovary and the delicate control of blood sugar levels.
The hypothalamus in your brain, the pituitary gland below your brain, and the adrenal glands atop your kidneys form a trio known as the hypothalamic-pituitary-adrenal (HPA) axis. Together these structures govern a multitude of hormonal activities in the body and may play a role in depression as well.
The hypothalamus secretes corticotropin-releasing hormone (CRH), a hormone vital to rousing your body when a physical or emotional threat looms. This hormone follows a pathway to your pituitary gland, where it stimulates the secretion of adrenocorticotropic hormone (ACTH), which pulses into your bloodstream. When ACTH reaches your adrenal glands, it triggers the release of cortisol. The boost in this hormone prompts a cascade of reactions in your body that can help you respond quickly to a threat.
Stress hormones race through your bloodstream, preparing you to fight or flee. Your heart beats faster — up to five times as quickly as normal — and your blood pressure rises. Your breath quickens as your body takes in extra oxygen. Sharpened senses, such as sight and hearing, make you more alert. This release of stress hormones is often called the stress response.
Normally, a feedback loop allows the body to turn off these defenses when the threat passes. In some cases, though, the floodgates never close properly, and cortisol levels rise too often or simply stay high. This can contribute to problems such as high blood pressure, immune suppression, asthma, and possibly depression.
Studies have shown that people who are depressed or have dysthymia typically have increased levels of CRH. Antidepressants and electroconvulsive therapy are both known to reduce these high CRH levels (see "Medications used for depression and bipolar disorder" and "Electroconvulsive therapy"). As CRH levels return to normal, depressive symptoms recede.
CRH is also distributed through the cerebral cortex, part of the amygdala, and the brainstem. When you face severe stress, this hormone is thought to play a major role in coordinating your hormonal defenses, thoughts and behaviors, emotional reactions, and involuntary responses. The neural pathways that carry the effects of CRH beyond the HPA axis reach other regions of the brain as well, and they link with neurons that release serotonin and norepinephrine. Disturbances in hormonal systems, therefore, may well affect neurotransmitters and vice versa. Research suggests that trauma during childhood can negatively affect the functioning of CRH and the HPA axis throughout life.
Physical factors such as genes, hormones, and brain function aren't the only contributors to depression; life events also play a role. Profound early losses, such as the death of a parent or the withdrawal of a loved one's affection, may resonate throughout life, eventually expressing themselves as depression. When an individual is unaware of the wellspring of his or her illness, he or she can't easily move past the depression. Moreover, unless the person gains a conscious understanding of the source of the condition, later losses or disappointments may trigger its return.
The British psychiatrist John Bowlby focused on early losses in a number of landmark studies of monkeys. When he separated young monkeys from their mothers, the monkeys passed through predictable stages of a separation response. Their furious outbursts trailed off into despair, followed by apathetic detachment. Inwardly, the levels of their stress hormones rose. Later investigators extended this research. One study found that the stress response — specifically the CRH system and HPA axis — got stuck in overdrive in adult rodents that had been separated from their mothers too early in life. This held true whether or not the rats were purposely put under stress. Some research suggests that having an overactive HPA axis may lay the groundwork for depression (see "Hormones and the HPA axis").
Interestingly, antidepressants and electroconvulsive therapy relieve the symptoms of animals distressed by such separations.
Early losses are not the only life events indelibly etched on the psyche. A small but intriguing study in the Journal of the American Medical Association showed that women who were abused physically or sexually as children had more extreme stress responses than women who had not been abused. The women had higher levels of the stress hormones ACTH and cortisol, and their hearts beat faster when they performed stressful tasks, such as working out mathematical equations or speaking in front of an audience. This hypersensitivity to stress occurred whether or not the women were suffering from major depression at the time.
Many researchers believe that early trauma causes subtle changes in brain function that account for symptoms of depression and anxiety. The key brain regions involved in the stress response may be altered at the chemical or cellular level. Changes might include fluctuations in the concentration of neurotransmitters or damage to nerve cells. However, further investigation is needed to clarify the relationship between the brain, psychological trauma, and depression.
Ever taken on so many commitments at work or home that you can't possibly fulfill the promises you've made? Or maybe you've recently suffered a financial setback? Or perhaps you've had a painful disagreement with your spouse or teenager? All of these situations — and plenty of others, minor or momentous — are commonly recognized sources of stress. Even positive events, such as buying a house or getting married, can be stressful.
Any stressor can trigger a host of responses in hormonal and neurological systems. Yet the same stressor can induce different reactions in different people. You may thrive on making split-second decisions at work, but the same situation might send a friend's heartbeat skyrocketing. Your friend, in turn, might be unfazed by a social situation that would bother you considerably. Or one of you might just be far more sensitive to life's stresses. Over time, it might take less and less stress to provoke a mood shift. This process may reflect incremental changes that occur in the brain over time. Eventually, the changes might build to a depression or usher in a relapse.
How you react to stress is probably defined by your genes. Research reported in 2003 found that one gene that influences how your body uses serotonin comes in two forms, called the long and short forms. The researchers found that people with the short form are more likely to become depressed when under stress than those with the long form. More studies are needed to confirm this finding and figure out how to use it in treating stress-related depression.
While your body is designed to deal with many sources of stress, some varieties may put you at greater risk for depression or anxiety. Research from the National Institute of Mental Health has found that long-term or severe stresses have far-reaching effects. For example, investigators studying a fairly small group of women who had survived physical or sexual abuse in childhood noted that they were more likely to have overly sensitive and longer-lasting reactions to stressful experiences (see "The role of trauma," above). And some animal studies have found that traumas early in life, such as separation from a mother, can wreak long-lasting biological changes (see "Early losses, life events, and temperament").
In addition, how resilient you are in the face of difficult life events, such as a job loss or divorce, may depend partly on your temperament and view of the world. Temperament — for example, how excitable you are or whether you tend to withdraw from or engage in social situations — certainly helps dictate behavior. According to cognitive therapists, so, too, do unacknowledged assumptions about the workings of the world that you develop early on and automatically fall back on when loss, disappointment, or rejection occurs. Yet while temperament or world view may have a hand in depression, neither is unchangeable. Therapy and medications can shift thoughts and attitudes that have developed over time.
It's quite common for someone to appear depressed after the death of a loved one. We often use the word grief to describe this feeling. A distinction can be made between grief that becomes depression and grief that slowly ebbs. Your grief may initially be so deep that it interferes with every aspect of your life. But usually, a steady improvement occurs over two to six months. Many people find it helpful to join a bereavement group or talk with a counselor or therapist as they come to terms with their loss. Consider seeking help if your distress leaves you unable to function for more than two months or if you feel overwhelmed or suicidal at any time.
Sometimes, symptoms of depression or mania are a side effect of certain drugs, such as steroids or blood pressure medication. Be sure to tell your doctor or therapist what medications you take and when your symptoms began. A professional can help sort out whether a new medication, a change in dosage, or interactions with other drugs or substances might be affecting your mood.
The table below lists drugs that may affect mood. However, keep in mind the following:
Antimicrobials, antibiotics, antifungals, and antivirals
acyclovir (Zovirax); alpha-interferons; cycloserine (Seromycin); ethambutol (Myambutol); levofloxacin (Levaquin); metronidazole (Flagyl); streptomycin; sulfonamides (AVC, Sultrin, Trysul); tetracycline
Heart and blood pressure drugs
beta blockers such as propranolol (Inderal), metoprolol (Lopressor, Toprol XL), atenolol (Tenormin); calcium-channel blockers such as verapamil (Calan, Isoptin, Verelan) and nifedipine (Adalat CC, Procardia XL); digoxin (Digitek, Lanoxicaps, Lanoxin); disopyramide (Norpace); methyldopa (Aldomet)
Hormones
anabolic steroids; danazol (Danocrine); glucocorticoids such as prednisone and ACTH; estrogens (e.g., Premarin, Prempro); oral contraceptives (birth control pills)
Tranquilizers, insomnia aids, and sedatives
barbiturates such as phenobarbital (Solfoton) and secobarbital (Seconal); benzodiazepines such as diazepam (Valium) and clonazepam (Klonopin)
Miscellaneous
acetazolamide (Diamox); antacids such as cimetidine (Tagamet) and ranitidine (Zantac); antiseizure drugs; baclofen (Lioresal); cancer drugs such as asparaginase (Elspar); cyclosporine (Neoral, Sandimmune); disulfiram (Antabuse); isotretinoin (Accutane); levodopa or L-dopa (Larodopa); metoclopramide (Octamide, Reglan); narcotic pain medications (e.g., codeine, Percodan, Demerol, morphine); withdrawal from cocaine or amphetamines
Certain medical problems are linked to lasting, significant mood disturbances — either the sadness or loss of pleasure typical of depression or the elation or hyperirritability seen in mania. In fact, medical illnesses or medications may be at the root of up to 10%–15% of all depressions.
Among the best-known culprits are two thyroid hormone imbalances. An excess of thyroid hormone (hyperthyroidism) can trigger manic symptoms. Hyperthyroidism occurs in about two and a half million Americans. Hypothyroidism, a condition in which your body produces too little thyroid hormone, often leads to exhaustion and depression. This imbalance affects more than nine million Americans.
Heart disease has also been linked to depression, with up to half of heart attack survivors reporting feeling blue and many having significant depression. Depression can spell trouble for heart patients: It's been linked with slower recovery, future cardiovascular trouble, and a higher risk of dying within about six months. Although doctors have hesitated to give heart patients older depression medications called tricyclic antidepressants (TCAs) because of their impact on heart rhythms, newer drugs such as selective serotonin reuptake inhibitors (SSRIs) seem safe for people with heart conditions.
The following medical conditions have also been associated with mood disorders:
When considering the connection between health problems and depression, an important question to address is which came first, the medical condition or the mood changes. There is no doubt that the stress of having certain illnesses can trigger depression. In other cases, depression precedes the medical illness and may even contribute to it. To find out whether the mood changes occurred on their own or as a result of the medical illness, a doctor carefully considers a person's medical history and the results of a physical exam.
If depression or mania springs from an underlying medical problem, the mood changes should disappear after the medical condition is treated. If you have hypothyroidism, for example, lethargy and depression often lift once treatment regulates the level of thyroid hormone in your blood. In many cases, however, the depression is an independent problem, which means that in order to be successful, treatment must address depression directly.
Used with permission of StayWell.Terms of UseMedical Disclaimer
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