Depressive disorders are characterized by sadness severe enough or persistent enough to interfere with function and often by decreased interest or pleasure in activities. The exact cause is unknown but probably involves heredity, changes in neurotransmitter levels, altered neuroendocrine function, and psychosocial factors. Diagnosis is based on history. Treatment usually consists of drugs, psychotherapy, or both, and sometimes electroconvulsive therapy or rapid transcranial magnetic stimulation (rTMS).

The term depression is often used to refer to any of several depressive disorders. Some are classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by specific symptoms:

• Major depressive disorder (often called major depression)
• Persistent depressive disorder (dysthymia)
• Other specified or unspecified depressive disorders

Others are classified by Etiology:

• Premenstrual dysphoric disorder
• Depressive disorder due to another medical condition
• Substance/medication-induced depressive disorder

Depressive disorders occur at any age but typically develop during the mid-teens, 20s, or 30s (see also Depressive Disorders in Children and Adolescents). In primary care settings, as many as 30% of patients report depressive symptoms, but < 10% have major depression.

* Demoralization and grief

The term depression is often used to describe the low or discouraged mood that results from disappointments (eg, financial calamity, natural disaster, serious illness) or losses (eg, death of a loved one). However, better terms for such moods are demoralization and grief.

The negative feelings of demoralization and grief, unlike those of depression, do the following:

• Occur in waves that tend to be tied to thoughts or reminders of the inciting event.
• Resolve when circumstances or events improve.
• May be interspersed with periods of positive emotion and humor.
• Are not accompanied by pervasive feelings of worthlessness and self-loathing.

The low mood usually lasts days rather than weeks or months, and suicidal thoughts and prolonged loss of function are much less likely.

However, events and stressors that cause demoralization and grief can also precipitate a major depressive episode, particularly in vulnerable people (eg, those with a history or family history of major depression). In a small but substantial number of patients, grief may become persistent and disabling. This condition is termed prolonged grief disorder and may require specifically targeted treatment.

 

• Etiology of Depressive Disorders

The exact cause of depressive disorders is unknown, but genetic and environmental factors contribute.

Heredity accounts for about half of the Etiology (less so in late-onset depression). Thus, depression is more common among 1st-degree relatives of depressed patients, and concordance between identical twins is high. Also, genetic factors probably influence the development of depressive responses to adverse events.

Other theories focus on changes in neurotransmitter levels, including abnormal regulation of cholinergic, catecholaminergic (noradrenergic or dopaminergic), glutamatergic, and serotonergic (5-hydroxytryptamine) neurotransmission (1). Neuroendocrine dysregulation may be a factor, with particular emphasis on 3 axes: hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, and hypothalamic-pituitary-growth hormone.

Psychosocial factors also seem to be involved. Major life stresses, especially separations and losses, commonly precede episodes of major depression; however, such events do not usually cause lasting, severe depression except in people predisposed to a mood disorder.

People who have had an episode of major depression are at higher risk of subsequent episodes. People who are less resilient and/or who have anxious tendencies may be more likely to develop a depressive disorder. Such people often do not develop the social skills to adjust to life pressures. The presence of other mental disorders increases the risk for major depressive disorder.

Women are at higher risk, but no theory explains why. Possible factors include the following:

• Greater exposure to or heightened response to daily stresses
• Higher levels of monoamine oxidase (the enzyme that degrades neurotransmitters considered important for mood)
• Higher rates of thyroid dysfunction
• Endocrine changes that occur with menstruation and at menopause

In peripartum-onset depression, symptoms develop during pregnancy or within 4 weeks after delivery (postpartum depression); endocrine changes have been implicated, but the specific cause is unknown.

In seasonal affective disorder, symptoms develop in a seasonal pattern, typically during autumn or winter; the disorder tends to occur in climates with long or severe winters.

Depressive symptoms or disorders may accompany various physical disorders, including thyroid disorders, adrenal gland disorders, benign and malignant brain tumors, stroke, AIDS, Parkinson's disease, and multiple sclerosis (see Table Some Causes of Symptoms of Depression and Mania).

Certain drugs, such as corticosteroids, beta-blockers, interferon, and reserpine, can also result in depressive disorders. Abuse of some recreational drugs (eg, alcohol, amphetamines) can lead to or accompany depression. Toxic effects or withdrawal of drugs may cause transient depressive symptoms.

 

 

• Symptoms and Signs of Depressive Disorders

Depression causes cognitive, psychomotor, and other types of dysfunction (eg, poor concentration, fatigue, loss of sexual desire, loss of interest or pleasure in nearly all activities that were previously enjoyed, and sleep disturbances), as well as a depressed mood. People with depressive disorder frequently have thoughts of suicide and may attempt suicide. Other mental symptoms or disorders (eg, anxiety and panic attacks) commonly coexist, sometimes complicating diagnosis and treatment.

Patients with all forms of depression are more likely to abuse alcohol or other recreational drugs in an attempt to self-treat sleep disturbances or anxiety symptoms; however, depression is a less common cause of alcoholic use disorder and other substance use disorders than was once thought. Patients are also more likely to become heavy smokers and neglect their health, increasing the risk of the development or progression of other disorders (eg, chronic obstructive pulmonary disease [COPD]).

Depression may reduce protective immune responses. Depression increases the risk of cardiovascular disorders, myocardial infarctions (MIs), and stroke, perhaps because in depression, cytokines and factors that increase blood clotting are elevated and heart rate variability is decreased—all potential risk factors for cardiovascular disorders.

Major depression (unipolar disorder)

Patients may appear miserable, with tearful eyes, furrowed brows, down-turned corners of the mouth, slumped posture, poor eye contact, lack of facial expression, little body movement, and speech changes (eg, soft voice, lack of prosody, use of monosyllabic words). Appearance may be confused with Parkinson's disease. In some patients, their depressed mood is so deep that tears dry up; they report that they are unable to experience usual emotions and feel that the world has become colorless and lifeless.

Nutrition may be severely impaired, requiring immediate intervention.

Some depressed patients neglect personal hygiene or even their children, other loved ones, or pets.

For diagnosis of major depression, ≥ 5 of the following must have been present nearly every day during the same 2-week period, and one of them must be depressed mood or loss of interest or pleasure:

• Depressed mood most of the day
• Markedly diminished interest or pleasure in all or almost all activities for most of the day
• Significant (> 5%) weight gain or loss or decreased or increased appetite.
• Insomnia (often sleep-maintenance insomnia) or hypersomnia.
• Psychomotor agitation or retardation observed by others (not self-reported)
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt
• Diminished ability to think or concentrate or indecisiveness.
• Recurrent thoughts of death or suicide, a suicide attempt, or a specific plan for committing suicide

 

Persistent depressive disorder

Depressive symptoms that persist for ≥ 2 years without remission are classified as persistent depressive disorder (PDD), a category that consolidates disorders formerly termed chronic major depressive disorder and dysthymic disorder.

Symptoms typically begin insidiously during adolescence and may persist for many years or decades. The number of symptoms often fluctuates above and below the threshold for a major depressive episode.

Affected patients may be habitually gloomy, pessimistic, humorless, passive, lethargic, introverted, hypercritical of self and others, and complaining. Patients with PDD are also more likely to have underlying anxiety disorders, substance use disorders, or personality (ie, borderline personality) disorders.

For diagnosis of persistent depressive disorder, patients must have had a depressed mood for most of the day for more days than not for ≥ 2 years plus ≥ 2 of the following:

• Poor appetite or overeating
• Insomnia or hypersomnia
• Low energy or fatigue
• Low self-esteem
• Poor concentration or difficulty making decisions.
• Feelings of hopelessness

 

• Premenstrual Dysphoric Disorder

The premenstrual dysphoric disorder involves mood and anxiety symptoms that are related to the menstrual cycle, with onset during the premenstrual phase and a symptom-free interval after menstruation. Symptoms must be present during most menstrual cycles during the past year.

Manifestations are similar to those of premenstrual syndrome but are more severe, causing clinically significant distress and/or marked impairment of social or occupational functioning. The disorder may begin any time after menarche; it may worsen as menopause approaches but ceases after menopause. Prevalence is estimated at 2 to 6% of menstruating women in a given 12-month interval.

For diagnosis of premenstrual dysphoric disorder, patients must have ≥ 5 symptoms during the week before menstruation. Symptoms must begin to remit within a few days after the onset of menses and become minimal or absent in the week after menstruation. Symptoms must include ≥ 1 of the following:

• Marked mood swings (eg, suddenly feeling sad or tearful)
• Marked irritability or anger or increased interpersonal conflicts.
• Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts.
• Marked anxiety, tension, or an on-edge feeling.

In addition, ≥ 1 of the following must be present:

• Decreased interest in usual activities
• Difficulty concentrating
• Low energy or fatigue
• Marked change in appetite, overeating, or specific food cravings.
• Hypersomnia or insomnia
• Feeling overwhelmed or out of control
• Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a feeling of being bloated, and weight gain

 

• Prolonged Grief Disorder

Prolonged grief is persistent sadness following the loss of a loved one. It is distinct from depression in that sadness relates to the specific loss rather than the more general feelings of failure associated with depression. In contrast to normal grief, this condition may be highly disabling and require therapy specifically designed for prolonged grief disorder.

Prolonged grief is considered present when the grief response (typified by persistent longing or yearning and/or preoccupation with the deceased) lasts a year or longer and is persistent, pervasive, and exceeding cultural norms. It also must be accompanied by ≥ 3 of the following for the last month to a degree that causes distress or disability:

• Disbelief
• Intense emotional pain
• The feeling of identity confusion
• Avoidance of reminders of the loss
• Feelings of numbness
• Intense loneliness
• Feelings of meaninglessness
• Difficulty engaging in the ongoing life

Some useful screening tools include the Inventory of Complicated Grief and the Brief Grief Questionnaire.

• Other Depressive Disorder
• Clusters of symptoms with characteristics of a depressive disorder that do not meet the full criteria for other depressive disorders but that cause clinically significant distress or impairment of functioning are classified as other depressive (specified or unspecified) disorders.
• Included are recurrent periods of dysphoria with ≥ 4 other depressive symptoms that last < 2 weeks in people who have never met criteria for another mood disorder (eg, recurrent brief depression) and depressive periods that last longer but that include insufficient symptoms for diagnosis of another depressive disorder.

 

• Specific

Major depression and persistent depressive disorder may include one or more specifiers that describe additional manifestations during a depressive episode:

• Anxious distress: Patients feel tense and unusually restless; they have difficulty concentrating because they worry or fear that something awful may happen, or they feel that they may lose control of themselves.
• Mixed features: Patients also have ≥ 3 manic or hypomanic symptoms (eg, elevated mood, grandiosity, greater talkativeness than usual, flight of ideas, decreased sleep). Patients who have this type of depression are at increased risk of developing bipolar disorder.
• Melancholic: Patients have lost pleasure in nearly all activities or do not respond to usually pleasurable stimuli. They may be despondent, feel excessive or inappropriate guilt, or have early morning awakenings, marked psychomotor retardation or agitation, and significant anorexia or weight loss.
• Atypical: Patients' mood temporarily brightens in response to positive events (eg, a visit from children). They also have ≥ 2 of the following: overreaction to perceived criticism or rejection, feelings of leaden paralysis (a heavy or weighted-down feeling, usually in the extremities), weight gain or increased appetite, and hypersomnia.
• Psychotic: Patients have delusions and/or hallucinations. Delusions often involve having committed unpardonable sins or crimes, harboring incurable or shameful disorders, or being persecuted. Hallucinations may be auditory (eg, hearing accusatory or condemning voices) or visual. If only voices are described, careful consideration should be given to whether the voices represent true hallucinations.
• Catatonic: Patients have severe psychomotor retardation, engage in excessive purposeless activity, and/or withdraw; some patients grimace and mimic speech (echolalia) or movement (echopraxia).
• Peripartum onset: Onset is during pregnancy or in the 4 weeks after delivery. Psychotic features may be present; infanticide is often associated with psychotic episodes involving command hallucinations to kill the infant or delusions that the infant is possessed.
• Seasonal pattern: Episodes occur at a particular time of year, most often in fall or winter.

 

 

• Diagnosis of Depressive Disorders
• Clinical criteria (DSM-5)
• Complete blood count (CBC), electrolytes, and thyroid-stimulating hormone (TSH), vitamin B12, and folate levels to rule out physical disorders that can cause depression.

Diagnosis of depressive disorders is based on the identification of the symptoms and signs and the clinical criteria described above. Specific closed-ended questions help determine whether patients have the symptoms required by DSM-5 criteria for diagnosis of major depression. To help differentiate depressive disorders from ordinary mood variations, there must be significant distress or impairment in social, occupational, or other important areas of functioning.

Severity is determined by the degree of pain and disability (physical, social, occupational) and by the duration of symptoms. A physician should gently but directly ask patients about any thoughts and plans to harm themselves or others, any previous threats of and/or suicide attempts, and other risk factors. Psychosis and catatonia indicate severe depression. Melancholic features indicate severe or moderate depression. Coexisting physical conditions, substance use disorders, and anxiety disorders may add to the severity.

Differential diagnosis

Depressive disorders must be distinguished from demoralization and grief. Other mental disorders (eg, anxiety disorders) can mimic or obscure the diagnosis of depression. Sometimes more than one disorder is present. Major depression (unipolar disorder) must be distinguished from bipolar disorder.

In older patients, depression can manifest as dementia of depression (formerly called pseudodementia), which causes many of the symptoms and signs of dementia such as psychomotor retardation and decreased concentration. However, early dementia may cause depression. In general, when the diagnosis is uncertain, treatment of a depressive disorder should be tried.

Differentiating chronic depressive disorders, such as dysthymia, from substance use disorders may be difficult, particularly because they can coexist and may contribute to each other.

Physical disorders must also be excluded as a cause of depressive symptoms. Hypothyroidism often causes symptoms of depression and is common, particularly among older patients. Parkinson's disease, in particular, may manifest with symptoms that mimic depression (eg, loss of energy, lack of expression, paucity of movement). A thorough neurologic examination is needed to exclude this disorder.

Screening

Several brief questionnaires are available for screening for depression. They help elicit some depressive symptoms but cannot be used alone for diagnosis. However, many of these tools are useful in identifying at-risk people who need more detailed evaluation. Some of the more widely used screening tools include the Patient Health Questionnaire-9 (PHQ-9) and the Beck Depression Inventory (BDI).

Testing

No laboratory findings are pathognomonic for depressive disorders. However, laboratory testing is necessary to exclude physical conditions that can cause depression (see Table Some Causes of Depression). Tests include complete blood count, thyroid-stimulating hormone levels, routine electrolytes, vitamin B12, and folate levels, and, in older men, testosterone levels. Testing for illicit drug use is sometimes appropriate.

• Treatment of Depressive Disorders
• Support
• Psychotherapy
• Drugs

 

(See also Drug Treatment of Depression.)

Symptoms may remit spontaneously, particularly when they are mild or of short duration. Mild depression may be treated with general support and psychotherapy. Moderate to severe depression is treated with drugs, psychotherapy, or both, and sometimes electroconvulsive therapy. Some patients require a combination of drugs. Improvement may not be apparent until after 1 to 4 weeks of drug treatment.

Depression, especially in patients who have had > 1 episode, is likely to recur; therefore, severe cases often warrant long-term maintenance drug therapy.

Most people with depression are treated as outpatients. Patients with significant suicidal ideation, particularly when family support is lacking, require hospitalization, as do those with psychotic symptoms or physical debilitation.

In patients with substance use disorders, depressive symptoms often resolve within a few months of stopping substance use. Antidepressant treatment is much less likely to be effective while substance use continues.

If a physical disorder or drug toxicity could be the cause, treatment is directed first at the underlying disorder. However, if the diagnosis is in doubt or if symptoms are disabling or include suicidal ideation or hopelessness, a therapeutic trial with an antidepressant or a mood-stabilizing drug may help.

Prolonged grief disorder may benefit from psychotherapy specifically tailored to this disorder.

Initial support

Until definite improvement begins, a physician may need to see patients weekly or biweekly to provide support and education and to monitor progress. Telephone calls may supplement office visits.

Patients and loved ones may be worried or embarrassed about the idea of having a mental disorder. The physician can help by explaining that depression is a serious medical disorder caused by biological disturbances and requires specific treatment and that the prognosis with treatment is good. Patients and loved ones should be reassured that depression does not reflect a character flaw (eg, laziness, weakness). Telling patients that the path to recovery often fluctuates helps them put feelings of hopelessness in perspective and improves adherence.

Encouraging patients to gradually increase simple activities (eg, taking walks, exercising regularly) and social interactions must be balanced with acknowledging their desire to avoid activities. The physician can suggest that patients avoid self-blame and explain that dark thoughts are part of the disorder and will go away.

·Psychotherapy

Numerous controlled trials have shown that psychotherapy, particularly cognitive-behavioral therapy, and interpersonal therapy, is effective in patients with major depressive disorder, both to treat acute symptoms and to decrease the likelihood of relapse. Patients with mild depression tend to have better outcomes than those with more severe depression, but the magnitude of improvement is greater in those with more severe depression.

·Drug therapy for depression

Several drug classes and drugs can be used to treat depression:

• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin modulators (5-HT₂ blockers)
• Serotonin-norepinephrine reuptake inhibitors
• Norepinephrine-dopamine reuptake inhibitor
• Heterocyclic antidepressants
• Monoamine oxidase inhibitors (MAOIs)
• Melatonergic antidepressant
• Ketamine-like drugs

 

The choice of drug may be guided by past response to a specific antidepressant. Otherwise, SSRIs are often the initial drugs of choice. Although the different SSRIs are equally effective for typical cases, certain properties of the drugs make them more or less appropriate for certain patients (see table Antidepressants).

Electroconvulsive therapy (ECT)

ECT involves the electrical induction of a seizure under controlled conditions. Its mechanism of action is uncertain, but the production of seizure activity appears to be integral to its antidepressant effects. Modern ECT, delivered under heavy sedation/general anesthesia, is typically well tolerated but confusion and memory impairment may occur acutely. Much of this improves and is resolved within 6 months following a course of ECT, but retrograde amnesia may persist for the long term. This is particularly so for memories from the several months preceding ECT. Patients with baseline cognitive deficits, those receiving bilateral treatments, older patients, and patients receiving lithium are at higher risk for memory impairment and confusion.

The following are often treated with ECT if drugs are ineffective:

• Severe suicidal depression
• Depression with agitation or psychomotor retardation
• Delusional depression
• Depression during pregnancy

Patients who have stopped eating may need ECT to prevent death. ECT is particularly effective for psychotic depression.

Response to 6 to 10 ECT treatments is usually dramatic and may be lifesaving. Relapse after ECT is common, and drug therapy is often maintained after ECT is stopped.

Phototherapy

Phototherapy is best known for its effects on seasonal depression but appears to be equally effective for nonseasonal depression.

Treatment can be provided at home with a special light unit that provides 2500 to 10,000 lux at a distance of 30 to 60 cm that patients look at for 30 to 60 minutes/day (longer with a less intense light source).

In patients who go to sleep late at night and rise late in the morning, phototherapy is most effective in the morning, sometimes supplemented with 5 to 10 minutes of exposure between 3 PM and 7 PM. For patients who go to sleep and rise early, phototherapy is most effective between 3 PM and 7 PM.

Other therapies

Psychostimulants (eg, dextroamphetamine, methylphenidate) are sometimes used, often with antidepressants. Several controlled trials support their use in depressive disorders (1).

Medicinal herbs are used by some patients. St. John’s wort may be effective for mild depression, although data are contradictory. St. John’s wort may interact with other antidepressants and other drugs. Some placebo-controlled studies of omega-3 supplementation, used as augmentation or as monotherapy, have suggested that eicosapentaenoic acid 1 to 2 g once a day has useful antidepressant effects.

Vagus nerve stimulation involves intermittently stimulating the vagus nerve via an implanted pulse generator. It may be useful for depression refractory to other treatments but usually takes 3 to 6 months to be effective.

The use of repetitive transcranial magnetic stimulation (rTMS) for the acute treatment of major depressive disorder has substantial support from controlled trials. Low-frequency rTMS may be applied to the right dorsolateral prefrontal cortex (DLPC), and high-frequency rTMS can be applied to the left DLPC. The most common adverse effects are headaches and scalp discomfort; both occur more often when high-frequency rather than low-frequency rTMS is used.

Deep brain stimulation using implanted electrodes that target the subgenual cingulate or the anterior ventral internal capsule/ventral striatum has had promising results in uncontrolled case series (2). Controlled trials are underway.

Support groups (eg, the Depression and Bipolar Support Alliance [DBSA] ) can help patients by providing a forum to share their common experiences and feelings.

 

• Key Points
• Depression is a common disorder that involves depressed mood and/or near-complete loss of interest or pleasure in activities that were previously enjoyed; somatic (eg, weight change, sleep disturbance) and cognitive manifestations (eg, difficulty concentrating) are common.
• Depression may markedly impair the ability to function at work and to interact socially; the risk of suicide is significant.
• Sometimes depressive symptoms are caused by physical disorders (eg, thyroid or adrenal gland disorders, benign or malignant brain tumors, stroke, AIDS, Parkinson's disease, multiple sclerosis) or the use of certain drugs (eg, corticosteroids, some beta-blockers, interferon, some recreational drugs).
• Diagnosis is based on clinical criteria; physical disorders must be ruled out by clinical evaluation and selected testing (eg, CBC; electrolyte, TSH, B12, and folate levels).
• Treatment involves psychotherapy and usually drugs; SSRIs are usually tried first, and if they are ineffective, other drugs that affect serotonin, norepinephrine, and/or dopamine may be tried.