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.

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.

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.

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%.

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.

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.

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.

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.

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.

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.

"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."

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.

The exact cause of cyclothymia is unknown. It is known that major depression, bipolar disorder, and cyclothymia often occur together within families. There may be a genetic component to cyclothymia: In one study, it was found that an individual is 2–3 times more likely to have the disorder if an identical twin is affected.

It is also believed that a person suffering with PTSD may experience similar shifts in mood based on how many flashbacks they've been dealing with.

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.

Winter depression is a common slump in the mood of some inhabitants of most of the Nordic countries. It was first described by the 6th century Goth scholar Jordanes in his "Getica" wherein he described the inhabitants of Scandza (Scandinavia). Iceland, however, seems to be an exception. A study of more than 2000 people there found the prevalence of seasonal affective disorder and seasonal changes in anxiety and depression to be unexpectedly "low" in both sexes. The study's authors suggested that propensity for SAD may differ due to some genetic factor within the Icelandic population. A study of Canadians of wholly Icelandic descent also showed low levels of SAD. It has more recently been suggested that this may be attributed to the large amount of fish traditionally eaten by Icelandic people, in 2007 about 90 kilograms per person per year as opposed to about 24 kg in the US and Canada, rather than to genetic predisposition; a similar anomaly is noted in Japan, where annual fish consumption in recent years averages about 60 kg per capita. Fish are high in vitamin D. Fish also contain docosahexaenoic acid (DHA), which help with a variety of neurological dysfunctions.

In many species, activity is diminished during the winter months in response to the reduction in available food, the reduction of sunlight (especially for diurnal animals) and the difficulties of surviving in cold weather. Hibernation is an extreme example, but even species that do not hibernate often exhibit changes in behavior during the winter. Presumably, food was scarce during most of human prehistory, and a tendency toward low mood during the winter months would have been adaptive by reducing the need for calorie intake. The preponderance of women with SAD suggests that the response may also somehow regulate reproduction.

Various proximate causes have been proposed. One possibility is that SAD is related to a lack of serotonin, and serotonin polymorphisms could play a role in SAD, although this has been disputed. Mice incapable of turning serotonin into N-acetylserotonin (by serotonin N-acetyltransferase) appear to express "depression-like" behavior, and antidepressants such as fluoxetine increase the amount of the enzyme serotonin N-acetyltransferase, resulting in an antidepressant-like effect. Another theory is that the cause may be related to melatonin which is produced in dim light and darkness by the pineal gland, since there are direct connections, via the retinohypothalamic tract and the suprachiasmatic nucleus, between the retina and the pineal gland. Melatonin secretion is controlled by the endogenous circadian clock, but can also be suppressed by bright light.

One study looked at whether some people could be predisposed to SAD based on personality traits. Correlations between certain personality traits, higher levels of neuroticism, agreeableness, openness, and an avoidance-oriented coping style, appeared to be common in those with SAD.

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.

Women with a history of bipolar disorder, schizophrenia, prior episode of postpartum psychosis, or a family history of postpartum psychosis are at high risk; about 25-50% of women in this group will have postpartum psychosis. around 37% of women with bipolar disorder have a severe postpartum episode. Women with a prior episode of postpartum psychosis have about a 30% risk of having another episode in the next pregnancy. For a woman with no history of mental illness who has a close relative (a mother or sister) who had postpartum psychosis, the risk is about 3%. There may be a genetic component; while mutations in chromosome 16 and in specific genes involved in serotoninergic, hormonal, and inflammatory pathways have been identified, none had been confirmed as of 2014.

Family history of affective psychosis, prenatal depression, and autoimmune thyroid dysfunction also increase the risk of postpartum psychosis.

About half of women who experience postpartum psychosis had no risk factors. Many other potential factors like pregnancy and delivery complications, caesarean section, sex of the baby, length of pregnancy, changes in psychiatric medication, and psychosocial factors have been researched and no clear association has been found; the only clear risk factor identified as of 2014 was that postpartum psychosis happens more often to women giving birth for the first time, than to women having second or subsequent deliveries, but the reason for that was not known. There may be a role for hormonal changes that occur following delivery, in combination with other factors; there may be a role changes in the immune system as well.

Atypical depression, or depression with atypical features as it has been known in the DSM IV, is depression that shares many of the typical symptoms of the psychiatric syndromes major depression or dysthymia but is characterized by improved mood in response to positive events. In contrast, people with melancholic depression generally do not experience an improved mood in response to normally pleasurable events. Atypical depression also features significant weight gain or an increased appetite, hypersomnia, a heavy sensation in the limbs and interpersonal rejection sensitivity that results in significant social or occupational impairment.

Despite its name, "atypical" depression does not mean it is uncommon or unusual. The reason for its name is twofold: (1) it was identified with its "unique" symptoms subsequent to the identification of melancholic depression and (2) its responses to the two different classes of antidepressants that were available at the time were different from melancholic depression (i.e., MAOIs had clinically significant benefits for atypical depression, while tricyclics did not).

Atypical depression is two to three times more common in women than in men. Individuals with atypical features tend to report an earlier age of onset (e.g. while in high school) of their depressive episodes, which also tend to be more chronic and only have partial remission between episodes. Younger individuals may be more likely to have atypical features, whereas older individuals may more often have episodes with melancholic features. Atypical depression has high comorbidity of anxiety disorders, carries more risk of suicidal behavior, and has distinct personality psychopathology and biological traits.

Atypical depression is more common in individuals with bipolar I, bipolar II, cyclothymia and seasonal affective disorder. Depressive episodes in bipolar disorder tend to have atypical features, as does depression with seasonal patterns.

Another theory is that there may be shared risk factors that can lead to both substance abuse and mental illness. Mueser hypothesizes that these may include factors such as social isolation, poverty, lack of structured daily activity, lack of adult role responsibility, living in areas with high drug availability, and association with people who already misuse drugs.

Other evidence suggests that traumatic life events, such as sexual abuse, are associated with the development of psychiatric problems and substance abuse.

The use of lithium and quetiapine (Seroquel) have both shown to be particularly valuable, though several other medications of the anticonvulsants and atypical antipsychotics classes may also be helpful.

- Lithium – Lithium has been shown to help stabilize the mood of patients suffering from cyclothymia and as well as bipolar disorders. It also aids in the prevention of acute suicidal and manic episodes. Dosage must be carefully monitored as lithium has a plethora of side effects.

- Atypical antipsychotics – (e.g., quetiapine (Seroquel), also olanzapine (Zyprexa), and risperidone (Risperdal).

- Anticonvulsants – (e.g., valproic acid, lamotrigine (Lamictal), and valproate semisodium (Depakote)).

- Electroconvulsive therapy – Through a systematic review done by Versiani, Cheriaux, and Landeira-Fernandez, it was determined that the efficacy and safety of ECT in patients with bipolar disorder had been poorly investigated and the evidence had methodological limitations.

The alleviation of dysphoria theory suggests that people with severe mental illness commonly have a negative self-image, which makes them vulnerable to using psychoactive substances to alleviate these feelings. Despite the existence of a wide range of dysphoric feelings (anxiety, depression, boredom, and loneliness), the literature on self-reported reasons for use seems to lend support for the experience of these feelings being the primary motivator for drug and alcohol misuse.

MD is supposed to be a common clinical phenomenon. According to some authors, masked depression is as frequent as overt depression. Although masked depression can be found at any age, it has been observed more commonly after mid-life.

Making the diagnosis and the management of MD in clinical practice are complicated by the fact that he who has got MD is unaware of his mental illness.

Patients with MD are reluctant to associate their physical symptoms with an affective disorder and refuse mental health care. As a rule, these patients attribute their disturbances to physical illness, seek medical care for them, and report only somatic complaints to their physicians, with the consequence that many of such depressions are not recognized or are misdiagnosed and mistreated Estimates of depressed patients who are correctly identified and treated range from 5% to 60%. Recent data show that about 10% of people who consult a physician for any reason originally suffer from affective disorders disguised by physical symptoms.