“There is nothing good to be said for it except that it gives you the experience of how it must be to be old, to be old and sick, to be dying; to be slow of mind; to be lacking in grace, polish, and coordination; to be ugly; to have no belief in the possibilities of life, the pleasures of sex, the exquisiteness of music, or the ability to make yourself and others laugh.”

Kay Redfield Jamison, An Unquiet Mind

Depression is not the same as ordinary sadness. At certain points in life, we all feel pain, but individuals suffering from depression experience something quite different — an incapacitating sense of loss and meaninglessness. “Loss in all of its manifestations is the touchstone of depression,” writes William Styron in his memoir Darkness Visible. “One dreads the loss of all things, all people close and dear.” Other depressive symptoms include disturbed sleeping and eating patterns, feelings of guilt or worthlessness, lack of enjoyment in activities that were once pleasurable, difficulty concentrating, and a preoccupation with death.

Clinical depression can be difficult to define precisely. Some sufferers describe it as a black despair, a black wave, or as Styron writes, “a toxic and unnameable tide.” Physicians of the ancient world associated it with black bile. These days, psychiatrists and scientists typically describe depression in terms of observable symptoms. According to the American Psychological Association, a person may be diagnosed with major depression (also called unipolar disorder) if he or she exhibits at least five depressive symptoms and impairment in daily function during a two-week period.

The Brain’s Role In Depression
There are effective drugs to treat depression, and these drugs provide insight into the biological basis of the illness. The first antidepressant drugs were discovered almost by accident. In the 1950s, doctors observed that some hypertension patients exhibited depressive symptoms after being treated with a newly isolated plant derivative called reserpine. Around the same time, doctors noticed that depressed patients sometimes demonstrated elevated moods after treatment with a tuberculosis drug. It turns out that reserpine depletes certain neurotransmitters in the brain, while the tuberculosis drug helps to sustain them.

Neurotransmitters act as chemical messengers in the brain’s communication system. They are molecules that travel from a source neuron to destination neuron, where they affect changes in the destination neuron. Two special kinds of molecules on the surface of the destination neuron help to regulate the movement of neurotransmitters: autoreceptors send signals to the source neuron indicating when to stop releasing the neurotransmitter, and transporters return certain amounts of the neurotransmitter back to the source neuron (a process called reuptake).

In individuals with depression, the movement of certain neurotransmitters is not regulated properly. In other words, these neurotransmitters – norepinephrine, serotonin, and dopamine – do not move from one neuron to the next in appropriate amounts. The first generation of antidepressant drugs, which appeared on pharmacy shelves in the 1950s, was developed to regulate all three of these neurotransmitters. The second generation of drugs, which became available shortly thereafter, regulates two of them, norepinephrine and serotonin.

The newest generation of antidepressant drugs acts only on serotonin. Specifically, these new drugs work by preventing transporters on the destination neuron from returning serotonin to the source neuron. Selective serotonin reuptake inhibitors (SSRIs), as they are called, first became available in the late 1980s and are now widely prescribed by psychiatrists under the commercial names Luvox, Paxil, Prozac, and Zoloft. While all three generations of antidepressant drugs are effective, SSRIs tend to produce the fewest side effects. Unfortunately, even SSRIs can take days or weeks to produce benefits – which can seem like eternity to the suffering patient.

The hormonal system is also implicated in the biological basis of depression. Hormones are chemicals that travel through the bloodstream to various targets in the body, where they regulate functions such as growth, metabolism, and sexual development. The hormonal system that regulates the body’s response to stress by heightening alertness – often called the “fight or flight” response – appears to be chronically over-active in depressed individuals. While the exact relationship between neuronal and hormonal activity in depression is unclear, it does appear that antidepressant drugs alter the secretion of certain stress-related hormones.

Types of Depression
Depressive symptoms manifest themselves differently in each person. The course of depression in a person’s life – the onset, frequency, duration, and severity of depressive episodes over time – can illuminate the nature of the illness and help psychiatrists make appropriate diagnoses.

Some individuals cycle through periods of depression and mania, a condition called manic-depressive illness (or bipolar disorder). During a manic episode, the individual may experience racing thoughts, become excessively talkative, exhibit inflated self-esteem, and engage in pleasurable but ultimately damaging activities, such as shopping sprees. In her memoir An Unquiet Mind, Kay Redfield Jamison describes a manic episode in which she scurried up and down the aisles of a pharmacy in Los Angeles, and suddenly decided that she must purchase twelve snakebite kits. “God had chosen me,” she writes, “and apparently only me, to alert the world to the wild proliferation of killer snakes in the Promised Land.” Manic cycles might arise from the brain’s overproduction of norepinephrine or serotonin.

Individuals with atypical depression may occasionally show brightening of mood in response to positive events, but can also crash and burn in the face of even the smallest obstacles. They are particularly sensitive to romantic rejection, and their depression has a chronic, rather than episodic, nature. People with atypical depression may oversleep well into the daytime hours, they may overeat, and their mood is likely to worsen as the day wears on into evening.

Despite its identifiable traits, we don’t know exactly how depression arises or what form it may take in different individuals. In her memoir Prozac Nation, Elizabeth Wurtzel describes the onset of her depression around age twelve. Her father exhibited some depressive symptoms, and her parents divorced early, but these don’t seem to be sufficient explanations for the pain she experiences. “Here was this thing called depression,” she writes, “that was not definable in any sort of concrete way (was it bigger than a breadbox? smaller than an armoire? animal, vegetable, or mineral?).”

Who is Likely to Suffer from Depression?
In the United States, the National Institute of Mental Health estimates that 19 million people over the age of 18 experience depression each year. Women are at a much higher risk for major depression than men. Although the reasons for this are unclear, some scientists speculate that hormonal factors are involved, particularly since the gender difference exists primarily after adolescence but before old age. The societal stress endured by women – the multiple roles they play at home and work, as well as their vulnerability to violence and abuse – may also be a factor. Kay Redfield Jamison, describing her alternations between depression and mania, writes: “Depression, somehow, is much more in line with society’s notion of what women are all about.”

Depression also tends to run in families, which means that children of a depressed parent sometimes get “two hits” — they may inherit genes for depression, and they may also grow up in a strained household. Scientists have not yet discovered which genes are responsible for depression, and it is possible that a predisposition to the illness involves multiple genes.

Depression can also break your heart – literally. Several studies have established links between depression and heart disease. Researchers in Montreal, for example, found that heart patients who were depressed were four times as likely to die in the next six months as those who were not depressed. And depressed individuals are at risk for suicide, a possibility that should be treated seriously by anyone who knows a person suffering from depression.

An Illness Of Mind And Body
Depression highlights many of the complex relationships between the mind and the body. While it is considered a mental illness, many individuals describe it as a physical sensation. “I’m in so much pain,” writes Elizabeth Wurtzel in Prozac Nation, “not just in my head but all over, all over, like a bad flu, but one that’s definitely emotional even though it’s all coming out physical.”

Depression raises questions about how events in our lives trigger chemical responses in the body. Researchers working with animal models of depression have found that traumatic changes in a monkey’s social environment can alter norepinephrine levels in the monkey’s brain. Premature separation from the mother can also cause monkeys to exhibit elevated levels of “fight or flight” hormones. In humans, too, depressive symptoms may have some roots in a difficult childhood, or may be triggered by traumatic events, such as the death of a loved one.

But some depressed adults remember happy childhoods, and triggers can come in many guises. William Styron, for example, describes how his decision to stop drinking alcohol precipitated the onset of his depression at age sixty. Some people cannot even point to a particular moment in their lives when depression began.

Despite what we are learning about the biological basis of depression, healing does not take place with drugs alone. Psychotherapy is usually an important part of the recovery process. Therapy can help patients deal with the cognitive and emotional distortions brought about by depression. It can also provide a supportive context in which patients bid farewell to their depressive self and adjust to the effects of antidepressants.

There is light at the end of the tunnel. Over 80 percent of people with depression respond positively to antidepressant drugs, psychotherapy, or both. New drugs are under development, and controlled studies are underway to test the efficacy of the homeopathic remedy St. John’s Wort. Scientists, psychiatrists, and sufferers themselves are all working to create an open discussion about depression and its impact. The more we understand about depression as an illness, the better prepared we are to relieve the pain that it inflicts on the mind and body.