Some types of depression run in families, indicating that a biological vulnerability to depression can be inherited. This seems to be the case, especially with bipolar disorder. Families in which members of each generation develop bipolar disorder have been studied.
The investigators found that those with the illness have a somewhat different genetic makeup than those who do not become ill. However, the reverse is not true. That is, not everybody with the genetic makeup that causes vulnerability to bipolar disorder will develop the illness. Apparently, additional factors, possibly a stressful environment, are involved in its onset and protective factors are involved in its prevention.

Major depression also seems to occur in generation after generation in some families, although not as strongly as in bipolar I or II. Indeed, major depression can also occur in people who have no family history of depression.

An external event often seems to initiate an episode of depression. Thus, a serious loss, chronic illness, difficult relationship, financial problem, or any unwelcome change in life patterns can trigger a depressive episode. Very often, a combination of genetic, psychological, and environmental factors is involved in the onset of a depressive disorder. Stressors that contribute to the development of depression sometimes affect some groups more than others. For example, minority groups who more often feel impacted by discrimination are disproportionately represented. Socioeconomically disadvantaged groups have higher rates of depression compared to their advantaged counterparts. Immigrants to the United States may be more vulnerable to developing depression, particularly when isolated by language.

Regardless of ethnicity, men appear to be particularly sensitive to the depressive effects of unemployment, divorce, low socioeconomic status, and having few good ways to cope with stress. Women who have been the victim of physical, emotional, or sexual abuse, either as a child or perpetrated by a romantic partner are vulnerable to developing a depressive disorder as well. Men who engage in sex with other men seem to be particularly vulnerable to depression when they have no domestic partner, do not identify themselves as homosexual, or have been the victim of multiple episodes of antigay violence. However, it seems that men and women have similar risk factors for depression for the most part.

Nothing in the universe is as complex and fascinating as the human brain. The 100-plus chemicals that circulate in the brain are known as neurochemicals or neurotransmitters. Much of our research and knowledge, however, has focused on four of these neurochemical systems: norepinephrine, serotonin, dopamine, and acetylcholine. In the new millennium, after new discoveries are made, it is possible that these four neurochemicals will be viewed as the "black bile, yellow bile, phlegm, and blood" of the 20th century.

Different neuropsychiatric illnesses seem to be associated with an overabundance or a lack of some of these neurochemicals in certain parts of the brain. For example, a lack of dopamine at the base of the brain causes Parkinson's disease. Alzheimer's dementia seems to be related to lower acetylcholine levels in the brain. The addictive disorders are under the influence of the neurochemical dopamine. That is to say, drugs and alcohol work by releasing dopamine in the brain. The dopamine causes euphoria, which is a pleasant sensation. Repeated use of drugs or alcohol, however, desensitizes the dopamine system, which means that the system gets used to the drugs and alcohol. Therefore, a person needs more drugs or alcohol to achieve the same high feeling. Thus, the addicted person takes more substance but feels less and less high and increasingly depressed.

Certain medications used for a variety of medical conditions are more likely than others to cause depression as a side effect. Specifically, some medications that are used to treat high blood pressure, cancer, seizures, extreme pain, and to achieve contraception can result in depression. Even some psychiatric medications like some sleep aids and medications to treat alcoholism and anxiety can contribute to the development of depression.

Many mental-health conditions or developmental disabilities are associated with depression as well. Individuals with anxiety, attention deficit hyperactivity disorder (ADHD), substance abuse, and developmental disabilities may be more vulnerable to developing depression.

The different types of schizophrenia are associated with an imbalance of dopamine (too much) and serotonin (poorly regulated) in certain areas of the brain. Finally, the depressive disorders appear to be associated with altered brain serotonin and norepinephrine systems. Both of these neurochemicals may be lower in depressed people. Please note that depression is "associated with" instead of "caused by" abnormalities of these neurochemicals because we really don't know whether low levels of neurochemicals in the brain cause depression or whether depression causes low levels of neurochemicals in the brain.

What we do know is certain medications that alter the levels of norepinephrine or serotonin can alleviate the symptoms of depression. Some medicines that affect both of these neurochemical systems appear to perform even better or faster. Other medications that treat depression primarily affect the other neurochemical systems. The most powerful treatment for depression, electroconvulsive therapy (ECT), is certainly not specific to any particular neurotransmitter system. Rather, ECT, by causing a seizure, produces a generalized brain activity that probably releases massive amounts of all of the neurochemicals.

Women are twice as likely to become depressed as men. However, scientists do not know the reason for this difference. Psychological factors also contribute to a person's vulnerability to depression. Thus, persistent deprivation in infancy, physical or sexual abuse, clusters of certain personality traits, and inadequate ways of coping (maladaptive coping mechanisms) all can increase the frequency and severity of depressive disorders, with or without inherited vulnerability.

The effect of maternal-fetal stress on depression is currently an exciting area of research. It seems that maternal stress during pregnancy can increase the chance that the child will be prone to depression as an adult, particularly if there is a genetic vulnerability. It is thought that the mother's circulating stress hormones can influence the development of the fetus' brain during pregnancy. This altered fetal brain development occurs in ways that predispose the child to the risk of depression as an adult. Further research is still necessary to clarify how this happens. Again, this situation shows the complex interaction between genetic vulnerability and environmental stress, in this case, the stress of the mother on the fetus.