What causes depression?

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Stressful life events

At some point, nearly everyone encounters stressful life events: the death of a loved one, the loss of a job, an illness, or a relationship spiraling downward. Some must cope with the early loss of a parent, violence, or sexual abuse. While not everyone who faces these stresses develops a mood disorder — in fact, most do not — stress plays an important role in depression.

As the previous section explained, your genetic makeup influences how sensitive you are to stressful life events. When genetics, biology, and stressful life situations come together, depression can result.

Stress has its own physiological consequences. It triggers a chain of chemical reactions and responses in the body. If the stress is short-lived, the body usually returns to normal. But when stress is chronic or the system gets stuck in overdrive, changes in the body and brain can be long-lasting.

How stress affects the body

Stress can be defined as an automatic physical response to any stimulus that requires you to adjust to change. Every real or perceived threat to your body triggers a cascade of stress hormones that produces physiological changes. We all know the sensations: your heart pounds, muscles tense, breathing quickens, and beads of sweat appear. This is known as the stress response.

The stress response starts with a signal from the part of your brain known as the hypothalamus. The hypothalamus joins the pituitary gland and the adrenal glands to form a trio known as the hypothalamic-pituitary-adrenal (HPA) axis, which governs a multitude of hormonal activities in the body and may play a role in depression as well.

When a physical or emotional threat looms, the hypothalamus secretes corticotropin-releasing hormone (CRH), which has the job of rousing your body. Hormones are complex chemicals that carry messages to organs or groups of cells throughout the body and trigger certain responses. CRH 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 prompts the release of cortisol.

The boost in cortisol readies your body 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.

CRH also affects the cerebral cortex, part of the amygdala, and the brainstem. It is thought to play a major role in coordinating your thoughts and behaviors, emotional reactions, and involuntary responses. Working along a variety of neural pathways, it influences the concentration of neurotransmitters throughout the brain. Disturbances in hormonal systems, therefore, may well affect neurotransmitters, and vice versa.

Normally, a feedback loop allows the body to turn off "fight-or-flight" 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. As CRH levels return to normal, depressive symptoms recede. Research also suggests that trauma during childhood can negatively affect the functioning of CRH and the HPA axis throughout life.

Early losses and trauma

Certain events can have lasting physical, as well as emotional, consequences. Researchers have found that early losses and emotional trauma may leave individuals more vulnerable to depression later in life.

Childhood losses. 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. Meanwhile, the levels of their stress hormones rose. Later investigators extended this research. One study found that 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. Interestingly, antidepressants and electroconvulsive therapy relieve the symptoms of animals distressed by such separations.

The role of trauma. Traumas may also be 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.

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.

Seasonal affective disorder: When winter brings the blues

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% to 2% of the population, particularly women and young people.

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. 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.

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:

  • Mild anxiety, jitteriness, headaches, early awakening, or eyestrain can occur.
  • There is evidence that light therapy can trigger a manic episode in people who are vulnerable.
  • While there is no proof that light therapy can aggravate an eye problem, you should still discuss any eye disease with your doctor before starting light therapy. Likewise, since rashes can result, let your doctor know about any skin conditions.
  • Some drugs or herbs (for example, St. John's wort) can make you sensitive to light.
  • If light therapy isn't helpful, antidepressants may offer relief.

Medical problems

Certain medical problems are linked to lasting, significant mood disturbances. In fact, medical illnesses or medications may be at the root of up to 10% to 15% of all depressions.

Among the best-known culprits are two thyroid hormone imbalances. An excess of thyroid hormone (hyperthyroidism) can trigger manic symptoms. On the other hand, hypothyroidism, a condition in which your body produces too little thyroid hormone, often leads to exhaustion and depression.

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 because of their impact on heart rhythms, selective serotonin reuptake inhibitors seem safe for people with heart conditions.

The following medical conditions have also been associated with mood disorders:

  • degenerative neurological conditions, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease
  • stroke
  • some nutritional deficiencies, such as a lack of vitamin B12
  • other endocrine disorders, such as problems with the parathyroid or adrenal glands that cause them to produce too little or too much of particular hormones
  • certain immune system diseases, such as lupus
  • some viruses and other infections, such as mononucleosis, hepatitis, and HIV
  • cancer
  • erectile dysfunction in men.

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.

An out-of-sync body clock may underlie SAD and other mood disorders

Research into one form of depression — seasonal affective disorder (SAD) — has uncovered another potential factor in mood disorders: an internal body clock that has gone awry.

Experts don't fully understand the cause of SAD, but a leading theory has been that the hormone melatonin 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. Some researchers believe light therapy has been helpful in treating SAD because exposure to light artificially lengthens daytime and decreases melatonin production.

But another theory has emerged: that SAD stems, at least partly, from an out-of-sync body clock. The researchers who propose this idea suggest that light therapy works because it resets the body's internal clock.

Each of us has a biological clock that regulates the circadian (meaning "about a day") rhythm of sleeping and waking. This internal clock — which is located in a small bundle of brain cells called the suprachiasmatic nucleus and gradually becomes established during the first months of life — controls the daily ups and downs of biological patterns, including body temperature, blood pressure, and the release of hormones. Although the clock is largely self-regulating, it responds to several cues to keep it set properly, including light and melatonin production.

When researchers expose people to light at intervals that are at odds with the outside world, this resets the subjects' biological clocks to match the new light input. Likewise, melatonin affects the body clock. It's produced in a predictable daily rhythm by the pineal gland, with levels climbing after dark and ebbing after dawn. Scientists believe this daily light-sensitive pattern helps keep the sleep/wake cycle on track.

Not keeping proper time

In 2006, a group of researchers presented findings that support the theory that SAD symptoms may stem from a body clock that isn't keeping time properly. They suggested that these rhythms can be thrown off by the late dawn and early dusk of winter.

The researchers tracked sleep patterns and depressive symptoms in 68 SAD patients. By examining healthy subjects, the researchers determined that circadian rhythms are synchronized when melatonin is secreted roughly six hours before the midpoint of sleep. In about 70% of the individuals with SAD, the interval was shorter than six hours, meaning they produced melatonin late, perhaps because of the later winter dawn. About 30% of the study's participants had the opposite problem: the interval between melatonin production and the midpoint of sleep was longer than the ideal six hours.

The SAD patients were split randomly into three groups: two that received low doses of melatonin (one group in the morning and the other in afternoon) and one that received a placebo. In this way, the circadian clock in some individuals was reset properly, and in others it remained out of sync.

Researchers found that depressive symptoms lifted when the cycles were synchronized. Taking melatonin at the correct time of day — afternoon for people with a late rhythm and morning for those with an early rhythm — more than doubled their improvement in depression scores, compared with taking the hormone at the wrong time or taking a placebo.

This study casts doubt on the theory that light therapy is beneficial because it reduces melatonin levels. If that were the case, the participants receiving melatonin shouldn't have shown improvement, but many did. Still, the debate is not over. Researchers still have much to learn about how light exposure and melatonin secretion interact with the brain's mood-regulating function.

Beyond SAD

A case is being made that circadian rhythms influence other mood disorders as well. Studies have uncovered out-of-sync circadian rhythms among people with bipolar disorder, schizophrenia, borderline personality disorder, or night eating disorder.

Figure 3: Getting back in sync

Getting back in sync

Medications

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.

Table 1 lists drugs that may affect mood. However, keep in mind the following:

  • Researchers disagree about whether a few of these drugs — such as birth control pills or propranolol — affect mood enough to be a significant factor.
  • Most people who take the medications listed will not experience mood changes, although having a family or personal history of depression may make you more vulnerable to such a change.
  • Some of the drugs cause symptoms like malaise (a general feeling of being ill or uncomfortable) or appetite loss that may be mistaken for depression.
  • Even if you are taking one of these drugs, your depression may spring from other sources.

Table 1: Medications that may cause depression

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 adrenocorticotropic hormone; 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

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