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.

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.

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.

Depression may also be iatrogenic (the result of healthcare), such as drug induced depression. Therapies associated with depression include interferon therapy, beta-blockers, Isotretinoin, contraceptives, cardiac agents, anticonvulsants, antimigraine drugs, antipsychotics, and hormonal agents such as gonadotropin-releasing hormone agonist.

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.

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.

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.

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.

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.

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%.

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.

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.

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.

About 8% of children and adolescents suffer from depression. Research suggests that the prevalence of young depression sufferers in Western cultures ranges from 1.9% to 3.4% among primary school children and 3.2% to 8.9% among adolescents. Studies have also found that among children diagnosed with a depressive episode, there is a 70% rate of recurrence within five years. Furthermore, 50% of children with depression will have a recurrence at least once during their adulthood. While there is no gender difference in depression rates up until age 15, after that age the rate among women doubles compared to men. However, in terms of recurrence rates and symptom severity, there is no gender difference. In an attempt to explain these findings, one theory asserts that pre-adolescent women, on average, have more risk factors for depression than men. These risk factors then combine with the typical stresses and challenges of adolescent development to trigger the onset of depression.

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.

"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."

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.

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.

High rates of major depressive disorder occur in heavy drinkers and those with alcoholism. Controversy has previously surrounded whether those who abused alcohol and developed depression were self-medicating their pre-existing depression. But recent research has concluded that, while this may be true in some cases, alcohol misuse directly causes the development of depression in a significant number of heavy drinkers. Participants studied were also assessed during stressful events in their lives and measured on a "Feeling Bad Scale." Likewise, they were also assessed on their affiliation with " deviant " peers, unemployment, and their partner’s substance use and criminal offending. High rates of suicide also occur in those who have alcohol-related problems. It is usually possible to differentiate between alcohol-related depression and depression that is not related to alcohol intake by taking a careful history of the patient. Depression and other mental health problems associated with alcohol misuse may be due to distortion of brain chemistry, as they tend to improve on their own after a period of abstinence.

Schizoaffective disorder is estimated to occur in 0.5 to 0.8 percent of people at some point in their life. It is more common in women than men; however, this is because of the high concentration of women in the depressive subcategory, whereas the bipolar subtype has a more or less even gender distribution.

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.

In general, atypical depression tends to cause greater functional impairment than other forms of depression. Atypical depression is a chronic syndrome that tends to begin earlier in life than other forms of depression—usually beginning in the teenage years. Similarly, patients with atypical depression are more likely to suffer from personality disorders and anxiety disorders such as borderline personality disorder, avoidant personality disorder, generalized anxiety disorder, obsessive-compulsive disorder, and bipolar disorder.

Recent research suggests that young people are more likely to suffer from hypersomnia while older people are more likely to suffer from polyphagia.

Medication response differs between chronic atypical depression and acute melancholic depression. Some studies suggest that the older class of antidepressants, monoamine oxidase inhibitors (MAOIs), may be more effective at treating atypical depression. While the more modern SSRIs and SNRIs are usually quite effective in this illness, the tricyclic antidepressants typically are not. The wakefulness-promoting agent modafinil has shown considerable effect in combating atypical depression, maintaining this effect even after discontinuation of treatment. Antidepressant response can often be enhanced with supplemental medications, such as buspirone, bupropion, or aripiprazole. Psychotherapy, whether alone or in combination with medication, is also an effective treatment.

Cases of depression in which the patient also displays psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of depressive episodes. Finally, patients with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.

A clear causal connection between drug use and psychotic spectrum disorders, including schizoaffective disorder, has been difficult to prove. In the specific case of marijuana or cannabis, however, evidence supports a link between earlier onset of psychotic illness and cannabis use. The more often cannabis is used, particularly in early adolescence, the more likely a person is to develop a psychotic illness, with frequent use being correlated with double the risk of psychosis and schizoaffective disorder. A 2009 Yale review stated that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. While cannabis use is accepted as a contributory cause of schizoaffective disorder by many, it remains controversial, since not all young people who use cannabis later develop psychosis, but those who do use cannabis have an increased odds ratio of about 3.

There is evidence that the two major component cannabinoids in cannabis have different effects: tetrahydrocannabinol (THC), which causes a "high," may increase propensity to psychosis; while cannabidiol (CBD), which doesn't cause a "high" and may have neuroprotective effects—that is, reduce psychosis and have mood stabilizing effects.

About half of those with schizoaffective disorder use drugs or alcohol excessively. There is evidence that alcohol abuse via a kindling mechanism can occasionally cause the development of a chronic substance induced psychotic disorder, i.e. schizoaffective disorder. There is little evidence to suggest that psychotic individuals choose specific drugs to self-medicate; there is some support for the hypothesis that they use drugs to cope with unpleasant states such as depression, anxiety, boredom and loneliness.

Amphetamine, cocaine, and to a lesser extent alcohol, can result in psychosis that presents clinically like psychosis in schizoaffective disorder. It is well understood that methamphetamine and cocaine use can result in methamphetamine or cocaine-induced psychosis that may persist even when users remain abstinent. Alcohol-induced psychosis can also persist during abstinence, though it appears to do so at a lower rate, than when it is being abused.

Although it is not generally believed to be a cause of the illness, people with schizoaffective disorder use nicotine at much greater rates than the general population.