The cause of major depressive disorder is unknown. The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression. The diathesis–stress model specifies that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. The preexisting vulnerability can be either genetic, implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood.

Childhood abuse, either physical, sexual or psychological are all risk factors for depression, among other psychiatric issues that co-occur such as anxiety and drug abuse. Childhood trauma also correlates with severity of depression, lack of response to treatment and length of illness. However, some are more susceptible to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.

Endogenous depression occurs as the results of an internal stressor—commonly cognitive or biological—and not an external factor. Potential risk factors include these cognitive or biological factors. Patients with endogenous depression often are more likely to have a positive family history of disorders and fewer psychosocial and environmental factors that cause their symptoms. A family history of depression and perceived poor intimate relationships are internal risk factors associated with this type of depression. It is important to know these risk factors in order to take steps to recognize and help prevent this illness.

This type of depression often occurs due to biological reasons. Since symptoms are due to an internal phenomena, prevalence rates tend to be higher in older adults and more prevalent among women. Although endogenous depression has been associated with increased age, there has been few attempts to evaluate this fully. More research is needed to indicate factual prevalence rates on this type of depression in society.

Several studies have shown that the risk of suicide is higher in patients who suffer from Bipolar II than those who suffer from Bipolar I, and especially higher than patients who suffer from major depressive disorder.

In results of a summary of several lifetime study experiments, it was found that 24% of Bipolar II patients experienced suicidal ideation or suicide attempts compared to 17% in Bipolar I patients and 12% in major depressive patients. Bipolar disorders, in general, are the third leading cause of death in 15- to 24-year-olds. Bipolar II patients were also found to employ more lethal means and have more complete suicides overall.

Bipolar II patients have several risk factors that increase their risk of suicide. The illness is very recurrent and results in severe disabilities, interpersonal relationship problems, barriers to academic, financial, and vocational goals, and a loss of social standing in their community, all of which increase the likelihood of suicide. Mixed symptoms and rapid-cycling, both very common in Bipolar II, are also associated with an increased risk of suicide. The tendency for Bipolar II to be misdiagnosed and treated ineffectively, or not at all in some cases, leads to an increased risk.

As a result of the high suicide risk for this group, reducing the risk and preventing attempts remains a main part of the treatment; a combination of self-monitoring, close supervision by a therapist, and faithful adherence to their medication regimen will help to reduce the risk and prevent the likelihood of a completed suicide.

Depressed mood can be the result of a number of infectious diseases, nutritional deficiencies, neurological conditions and physiological problems, including hypoandrogenism (in men), Addison's disease, Cushing's syndrome, hypothyroidism, Lyme disease, multiple sclerosis, Parkinson's disease, chronic pain, stroke, diabetes, and cancer.

While the causes of PPD are not understood, a number of factors have been suggested to increase the risk:

- Prenatal depression or anxiety

- A personal or family history of depression

- Moderate to severe premenstrual symptoms

- Maternity blues

- Birth-related psychological trauma

- Birth-related physical trauma

- Previous stillbirth or miscarriage

- Formula-feeding rather than breast-feeding

- Cigarette smoking

- Low self-esteem

- Childcare or life stress

- Low social support

- Poor marital relationship or single marital status

- Low socioeconomic status

- Infant temperament problems/colic

- Unplanned/unwanted pregnancy

- Elevated prolactin levels

- Oxytocin depletion

Of these risk factors, formula-feeding, a history of depression, and cigarette smoking have been shown to have additive effects.

These above factors are known to correlate with PPD. This correlation does not mean these factors are causal. Rather, they might both be caused by some third factor. Contrastingly, some factors almost certainly attribute to the cause of postpartum depression, such as lack of social support.

Not surprisingly, women with fewer resources indicate a higher level of postpartum depression and stress than those women with more resources, such as financial. Rates of PPD have been shown to decrease as income increases. Women with fewer resources may be more likely to have an unintended or unwanted pregnancy, increasing risk of PPD. Women with fewer resources may also include single mothers of low income. Single mothers of low income may have more limited access to resources while transitioning into motherhood.

Studies have also shown a correlation between a mother's race and postpartum depression. African American mothers have been shown to have the highest risk of PPD at 25%, while Asian mothers had the lowest at 11.5%, after controlling for social factors such as age, income, education, marital status, and baby's health. The PPD rates for First Nations, Caucasian and Hispanic women fell in between.

Sexual orientation has also been studied as a risk factor for PPD. In a 2007 study conducted by Ross and colleagues, lesbian and bisexual mothers were tested for PPD and then compared with a heterosexual sample group. It was found that lesbian and bisexual biological mothers had significantly higher Edinburgh Postnatal Depression Scale scores than did the heterosexual women in the sample. These higher rates of PPD in lesbian/bisexual mothers may reflect less social support, particularly from their families of origin and additional stress due to homophobic discrimination in society.

A correlation between postpartum thyroiditis and postpartum depression has been proposed but remains controversial. There may also be a link between postpartum depression and anti-thyroid antibodies.

Studies have shown that those who fall into minorities due to either their gender identity or sexual orientation (such as those that identify as LGBT), are more prone to depression.

The 5-HTTLPR, or serotonin transporter promoter gene's short allele has been associated with increased risk of depression. However, since the 1990s results have been inconsistent, with three recent reviews finding an effect and two finding none. Other genes that have been linked to a GxE interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis.

Estimates of the numbers of people suffering from major depressive episodes and Major Depressive Disorder (MDD) vary significantly. In their lifetime, 10% to 25% of women, and 5% to 12% of men will suffer a major depressive episode. Fewer people, between 5% and 9% of women and between 2% and 3% of men, will have MDD, or full-blown depression. The greatest differences in numbers of men and women diagnosed are found in the United States and Europe. The peak period of development is between the ages of 25 and 44 years. Onset of major depressive episodes or MDD often occurs to people in their mid-20s, and less often to those over 65. Prepubescent girls and boys are affected equally. The symptoms of depression are the same in both children and adolescents though there is evidence that their expression within an individual may change as he or she ages.

In a National Institute of Mental Health study, researchers found that more than 40 percent of people with post-traumatic stress disorder suffered from depression 4 months after the traumatic event they experienced.

Cultural factors can influence the symptoms displayed by a person experiencing a major depressive episode. The values of a specific culture may also influence which symptoms are more concerning to the person or and their friends and family. It is essential that a trained professional knows not to dismiss specific symptoms as merely being the "norm" of a culture.

Women who have recently given birth may be at increased risk for having a major depressive episode. This is referred to as postpartum depression and is a different health condition than the baby blues, a low mood that resolves within 10 days after delivery.

Like their adult counterparts, children and adolescent depression sufferers are at an increased risk of attempting or committing suicide. Suicide is the third leading cause of death among 15-19 year olds. Adolescent males may be at an even higher risk of suicidal behavior if they also present with a conduct disorder. In the 1990s, the National Institute of Mental Health (NIMH) found that up to 7% of adolescents who develop major depressive disorder may commit suicide as young adults. Such statistics demonstrate the importance of interventions by family and friends, as well as the importance of early diagnosis and treatment by medical staff, to prevent suicide among depressed or at-risk youth.

According to research by RM Carney et al., any history of child depression influences the occurrence of adolescent cardiac risk factors, even if individuals no longer suffer from depression. They are much more likely to develop heart disease as adults.

Major Depression is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities.Nearly 5 million of the 31 million Americans who are 65 years or older are clinically depressed, and 1 million have major depression. Approximately 3 percent of healthy elderly persons living in the community have major depression. Recurrence may be as high as 40 percent. Suicide rates are nearly twice as high in depressed patients as in the general population. Major depression is more common in medically ill patients who are older than 70 years and hospitalized or institutionalized. Severe or chronic diseases associated with high rates of depression include stroke (30 to 60 percent), coronary heart disease (8 to 44 percent), cancer (1 to 40 percent), Parkinson's disease (40 percent), Alzheimer's disease (20 to 40 percent), and dementia (17 to 31 percent).

Minor depression is a clinically significant depressive disorder that does not fulfill the duration criterion or the number of symptoms necessary for the diagnosis of major depression. Minor depression, which is more common than major depression in elderly patients, may follow a major depressive episode. It also can be a reaction to routine stressors in older populations. Fifteen to 50 percent of patients with minor depression develop major depression within two years.

Comorbid conditions are extremely common in individuals with BP-II. In fact, individuals are twice as likely to present a comorbid disorder than not. These include anxiety, eating, personality (cluster B), and substance use disorders. For bipolar II disorder, the most conservative estimate of lifetime prevalence of alcohol or other drug abuse disorders is 20%. In patients with comorbid substance abuse disorder and BP-II, episodes have a longer duration and treatment compliance decreases. Preliminary studies suggest that comorbid substance abuse is also linked to increased risk of suicidality.

A 2013 Cochrane review found evidence that psychosocial or psychological intervention after childbirth helped reduce the risk of postnatal depression. These interventions included home visits, telephone-based peer support, and interpersonal psychotherapy. Support is an important aspect of prevention, as depressed mothers commonly state that their feelings of depression were brought on by "lack of support" and "feeling isolated."

In couples, according to a systematic review and meta-analysis of 2015, emotional closeness and global support by the partner protect against both perinatal depression and anxiety. Further factors such as communication between the couple and relationship satisfaction have a protective effect against anxiety alone.

A major part of prevention is being informed about the risk factors. The medical community can play a key role in identifying and treating postpartum depression. Women should be screened by their physician to determine their risk for acquiring postpartum depression. Also, proper exercise and nutrition appear to play a role in preventing postpartum depression and depressed mood in general.

There are no known biological causes that apply consistently to all cases of dysthymia, which suggests diverse origin of the disorder. However, there are some indications that there is a genetic predisposition to dysthymia: "The rate of depression in the families of people with dysthymia is as high as fifty percent for the early-onset form of the disorder". Other factors linked with dysthymia include stress, social isolation, and lack of social support.

In a study using identical and fraternal twins, results indicated that there is a stronger likelihood of identical twins both having depression than fraternal twins. This provides support for the idea that dysthymia is in part caused by heredity.

According to a substantial amount of epidemiology studies conducted, women are twice as likely to develop certain mood disorders, such as major depression. Although there is an equal number of men and women diagnosed with bipolar II disorder, women have a slightly higher frequency of the disorder.

In 2011, mood disorders were the most common reason for hospitalization among children aged 1–17 years in the United States, with approximately 112,000 stays. Mood disorders were top principal diagnosis for Medicaid super-utilizers in the United States in 2012. Further, a study of 18 States found that mood disorders accounted for the highest number of hospital readmissions among Medicaid patients and the uninsured, with 41,600 Medicaid patients and 12,200 uninsured patients being readmitted within 30 days of their index stay—a readmission rate of 19.8 per 100 admissions and 12.7 per 100 admissions, respectively. In 2012, mood and other behavioral health disorders were the most common diagnoses for Medicaid-covered and uninsured hospital stays in the United States (6.1% of Medicaid stays and 5.2% of uninsured stays).

A study conducted in 1988 to 1994 amongst young American adults involved a selection of demographic and health characteristics. A population-based sample of 8,602 men and women ages 17–39 years participated. Lifetime prevalence were estimated based on six mood measures:

1. major depressive episode (MDE) 8.6%,

2. major depressive disorder with severity (MDE-s) 7.7%,

3. dysthymia 6.2%,

4. MDE-s with dysthymia 3.4%,

5. any bipolar disorder 1.6%, and

6. any mood disorder 11.5%.

Major depressive episodes may show comorbidity (association) with other physical and mental health problems. About 20-25% of individuals with a chronic general medical condition will develop major depression. Common comorbid disorders include: eating disorders, substance-related disorders, panic disorder, and obsessive-compulsive disorder. Up to 25% of people who experience a major depressive episode have a pre-existing dysthymic disorder.

Some persons who have a fatal illness or are at the end of their life may experience depression, although this is not universal.

Bipolar disorder can cause suicidal ideation that leads to suicidal attempts. Individuals whose bipolar disorder begins with a depressive or mixed affective episode seem to have a poorer prognosis and an increased risk of suicide. One out of two people with bipolar disorder attempt suicide at least once during their lifetime and many attempts are successfully completed. The annual average suicide rate is 0.4 percent, which is 10–20 times that of the general population. The standardized mortality ratio from suicide in bipolar disorder is between 18 and 25. The lifetime risk of suicide has been estimated to be as high as 20 percent in those with bipolar disorder.

"At least three-quarters of patients with dysthymia also have a chronic physical illness or another psychiatric disorder such as one of the anxiety disorders, cyclothymia, drug addiction, or alcoholism". Common co-occurring conditions include major depression (up to 75%), anxiety disorders (up to 50%), personality disorders (up to 40%), somatoform disorders (up to 45%) and substance abuse (up to 50%). People with dysthymia have a higher-than-average chance of developing major depression. A 10-year follow-up study found that 95% of dysthymia patients had an episode of major depression. When an intense episode of depression occurs on top of dysthymia, the state is called "double depression."

Some patients who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression. Endocrine disorders like hypothyroidism, Cushing's disease, and Addison's disease are among the most commonly identified as contributing to depression. Others include diabetes, coronary artery disease, cancer, HIV, and Parkinson's disease.

Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.

A lifelong condition with periods of partial or full recovery in between recurrent episodes of relapse, bipolar disorder is considered to be a major health problem worldwide because of the increased rates of disability and premature mortality. It is also associated with co-occurring psychiatric and medical problems and high rates of initial under- or misdiagnosis, causing a delay in appropriate treatment interventions and contributing to poorer prognoses. After a diagnosis is made, it remains difficult to achieve complete remission of all symptoms with the currently available psychiatric medications and symptoms often become progressively more severe over time.

Compliance with medications is one of the most significant factors that can decrease the rate and severity of relapse and have a positive impact on overall prognosis. However, the types of medications used in treating BD commonly cause side effects and more than 75% of individuals with BD inconsistently take their medications for various reasons.

Of the various types of the disorder, rapid cycling (four or more episodes in one year) is associated with the worst prognosis due to higher rates of self-harm and suicide. Individuals diagnosed with bipolar who have a family history of bipolar disorder are at a greater risk for more frequent manic/hypomanic episodes. Early onset and psychotic features are also associated with worse outcomes, as well as subtypes that are nonresponsive to lithium.

Early recognition and intervention also improve prognosis as the symptoms in earlier stages are less severe and more responsive to treatment. Onset after adolescence is connected to better prognoses for both genders, and being male is a protective factor against higher levels of depression. For women, better social functioning prior to developing bipolar disorder and being a parent are protective towards suicide attempts.

Meta-analyses show that high scores on the personality domain neuroticism is a strong predictor for the development of mood disorders. A number of authors have also suggested that mood disorders are an evolutionary adaptation. A low or depressed mood can increase an individual's ability to cope with situations in which the effort to pursue a major goal could result in danger, loss, or wasted effort. In such situations, low motivation may give an advantage by inhibiting certain actions. This theory helps to explain why negative life incidents precede depression in around 80 percent of cases, and why they so often strike people during their peak reproductive years. These characteristics would be difficult to understand if depression were a dysfunction.

A depressed mood is a predictable response to certain types of life occurrences, such as loss of status, divorce, or death of a child or spouse. These are events that signal a loss of reproductive ability or potential, or that did so in humans' ancestral environment. A depressed mood can be seen as an adaptive response, in the sense that it causes an individual to turn away from the earlier (and reproductively unsuccessful) modes of behavior.

A depressed mood is common during illnesses, such as influenza. It has been argued that this is an evolved mechanism that assists the individual in recovering by limiting his/her physical activity. The occurrence of low-level depression during the winter months, or seasonal affective disorder, may have been adaptive in the past, by limiting physical activity at times when food was scarce. It is argued that humans have retained the instinct to experience low mood during the winter months, even if the availability of food is no longer determined by the weather.

Much of what we know about the genetic influence of clinical depression is based upon research that has been done with identical twins. Identical twins both have exactly the same genetic code. It has been found that when one identical twin becomes depressed the other will also develop clinical depression approximately 76% of the time. When identical twins are raised apart from each other, they will both become depressed about 67% of the time. Because both twins become depressed at such a high rate, the implication is that there is a strong genetic influence. If it happened that when one twin becomes clinically depressed the other always develops depression, then clinical depression would likely be entirely genetic.

Bipolar disorder is also considered a mood disorder. In the case of bipolar disorder several causes have been considered as possible, please see the wikipedia page Bipolar disorder for more details on the most common attributed causes. Recently, apart of the recent knowledge, it is hypothesized and there is evidence that bipolar disorder might be caused by mitochondrial dysfunction or mitochondrial disease.

The exact changes in brain chemistry and function that cause either late life or earlier-onset depression are unknown. It is known, however, that brain changes can be triggered by the stresses of certain life events such as illness, childbirth, death of a loved one, life transitions (such as retirement), interpersonal conflicts, or social isolation. Risk factors for depression in elderly persons include a history of depression, chronic medical illness, female sex, being single or divorced, brain disease, alcohol abuse, use of certain medications, and stressful life events.

For women taking psychiatric medication, the decision as to whether continue during pregnancy and whether to take them while breast feeding is difficult in any case; there is no data to guide this decision with respect to preventing postpartum psychosis. There is no data to guide a decision as to whether women at high risk for postpartum psychosis should take antipsychotic medicine to prevent it. For women at risk of postpartum psychosis, informing medical care-givers, and monitoring by a psychiatrist during pregnancy, in the perinatal period, and for a few weeks following delivery, is recommended.

For women with known bipolar disorder, taking medication during pregnancy roughly halves the risk of a severe postpartum episode, as does starting to take medication immediately after the birth.

Various factors have been found to be more associated with a diagnosis of AD than other axis I disorders, including:

- younger age

- more identified psychosocial and environmental problems

- increased suicidal behaviour, more likely to be rated as improved by the time of discharge from mental healthcare

- less frequent previous psychiatric history

- shorter length of treatment

Those exposed to repeated trauma are at greater risk, even if that trauma is in the distant past. Age can be a factor due to young children having fewer coping resources; children are also less likely to assess the consequences of a potential stressor.

A stressor is generally an event of a serious, unusual nature that an individual or group of individuals experience. The stressors that cause adjustment disorders may be grossly traumatic or relatively minor, like loss of a girlfriend/boyfriend, a poor report card, or moving to a new neighborhood. It is thought that the more chronic or recurrent the stressor, the more likely it is to produce a disorder. The objective nature of the stressor is of secondary importance. Stressors' most crucial link to their pathogenic potential is their perception by the patient as stressful. The presence of a causal stressor is essential before a diagnosis of adjustment disorder can be made.

There are certain stressors that are more common in different age groups:

Adulthood:

- Marital conflict

- Financial conflict

- Health issues with Oneself/Partner or Dependent children

- Personal tragedy (Death/personal loss)

- Loss of job or unstable employment conditions (e.g. Corporate takeover/redundancy)

Adolescence and childhood:

- Family conflict/parental separation

- School problems/changing schools

- Sexuality issues

- Death/illness/trauma in the family

In a study conducted from 1990 to 1994 on 89 psychiatric outpatient adolescents, 25% had attempted suicide in which 37.5% had misused alcohol, 87.5% displayed aggressive behaviour, 12.5% had learning difficulties, and 87.5% had anxiety symptoms.